autacoids (local hormones) (local hormones) pharmacology by: dr. marwa shaalan pharm-d pharm-d 1
TRANSCRIPT
AUTACOIDS AUTACOIDS (LOCAL HORMONES) (LOCAL HORMONES) PHARMACOLOGY
BY Dr Marwa ShaalanBY Dr Marwa Shaalan PHARM-D PHARM-D
1
bullendogenous compounds bullplay an important role
in the physiological and
pathological processesbull have very short t12
bull have local action
AutacoidsAutacoids
2
a) Histaminea) Histamine 1 Monoamines1 Monoamines1 Monoamines1 Monoamines
The synthesis and breakdown of histamine 3
bullHistamine is presented in high concentration in the skin and in the mucous layer of the lung and GIT as an autacoid
bullAt cellular level it is found largely in mast cells and basophiles
bullNon-mast-cell histamine occurs as a neurotransmitter in CNS
4
In mast cells and basophiles histamineis located in intracellular granulestogether with heparin
distributionHistamine
5
Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions)
The secretory process is initiated by a raise in intracellular Ca2+Histamine is released from mast Cells
6
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
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- Slide 64
- ANY QUESTIONS
-
bullendogenous compounds bullplay an important role
in the physiological and
pathological processesbull have very short t12
bull have local action
AutacoidsAutacoids
2
a) Histaminea) Histamine 1 Monoamines1 Monoamines1 Monoamines1 Monoamines
The synthesis and breakdown of histamine 3
bullHistamine is presented in high concentration in the skin and in the mucous layer of the lung and GIT as an autacoid
bullAt cellular level it is found largely in mast cells and basophiles
bullNon-mast-cell histamine occurs as a neurotransmitter in CNS
4
In mast cells and basophiles histamineis located in intracellular granulestogether with heparin
distributionHistamine
5
Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions)
The secretory process is initiated by a raise in intracellular Ca2+Histamine is released from mast Cells
6
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
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- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
a) Histaminea) Histamine 1 Monoamines1 Monoamines1 Monoamines1 Monoamines
The synthesis and breakdown of histamine 3
bullHistamine is presented in high concentration in the skin and in the mucous layer of the lung and GIT as an autacoid
bullAt cellular level it is found largely in mast cells and basophiles
bullNon-mast-cell histamine occurs as a neurotransmitter in CNS
4
In mast cells and basophiles histamineis located in intracellular granulestogether with heparin
distributionHistamine
5
Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions)
The secretory process is initiated by a raise in intracellular Ca2+Histamine is released from mast Cells
6
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
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- Slide 17
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- Slide 20
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- Slide 23
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- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
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- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
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- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullHistamine is presented in high concentration in the skin and in the mucous layer of the lung and GIT as an autacoid
bullAt cellular level it is found largely in mast cells and basophiles
bullNon-mast-cell histamine occurs as a neurotransmitter in CNS
4
In mast cells and basophiles histamineis located in intracellular granulestogether with heparin
distributionHistamine
5
Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions)
The secretory process is initiated by a raise in intracellular Ca2+Histamine is released from mast Cells
6
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
In mast cells and basophiles histamineis located in intracellular granulestogether with heparin
distributionHistamine
5
Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions)
The secretory process is initiated by a raise in intracellular Ca2+Histamine is released from mast Cells
6
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 31
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- Slide 33
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- Slide 35
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- Slide 38
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- Slide 40
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- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions)
The secretory process is initiated by a raise in intracellular Ca2+Histamine is released from mast Cells
6
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
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- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
7 7
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
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- Slide 44
- Slide 45
- Slide 46
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- Slide 49
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- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Histamine Releasers1- drugs (mainly alkaloids atropine morphine reserpinetubocurarine in high doses)bullrelease histamine can cause bronchoconstriction hypotension itching and skin rash and other unwanted effects
8
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 42
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- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Folia UrticaeNaja naja (Leaves of Nettle)9
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
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- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Spoilt (putrid) fish contains histidine
10
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullcontains potent allergens can be potentially dangerousbullremains allergenic despite cooking
FISH
11
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Physiological antagonists
adrenaline salbutamol and others----inhibit histamine secretion and produce bronchodilation(antiasthmatic effect) 12
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullHistamine Receptors H1 H2 H3 H4 and H5
bullHistaminersquos receptors are G-protein coupled
13
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
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- Slide 5
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- Slide 41
- Slide 42
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- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
1-Stimulation of H1-receptorsPharmacological actions1-Contraction of smooth muscles (bronchi uterus and GIT)2- CVS- Vasodilatation of BV- Increased capillary permeability (oedema)-Tachycardia Cardiac stimulation --
3-Dilatation of cerebral vessels ( headache histamine cephalgia) 4-Exocrine glands stimulates gastric secretion -Stimulation of sensory nerve endings (pain amp itching) 5-Skin Triple response SkinA-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings) 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma
1048708
14
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
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- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
H1-receptors(H1-blockers)
ANTIHISTAMINIC
15
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
H1-blockersbullUsed in treatment of urticaria and hay feverbullSome of them (Mepyramine promethazine) have antiemetic effect too
16
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
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- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Didimetindene
Embramine
Chlorpyramine
PPromethazineromethazine
Cyproheptadine
(H1amp5-HT2)
1st generation H1-blockers (with sedative and Atropine-LIKE effects)
Clemastine (weak sedation) 17
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 46
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- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Hydroxyzine
is an H1-blocker with anxiolytic antiemeticantimuscarinic and spasmolyticeffects It is effective in pruritus and urticaria
18
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
AstemizoleCetirizine
Fexofenadine
LoratadineTerfenadine
prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia
2nd generation H1-blockers (without sedative and M-cholinolytic effects
19
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 13
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- Slide 19
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- Slide 23
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- Slide 25
- Slide 26
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- Slide 28
- Slide 29
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- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
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- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
H1-blockers from 33helliprdhelliphelliprdhellip generation
bullDesloratadine (Aeriusreg ndash film-tab 5 mg t12 27 h)bullLevocitirizine
20
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 26
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- Slide 33
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- Slide 35
- Slide 36
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- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
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- Slide 45
- Slide 46
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- Slide 49
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- Slide 51
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- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullcardiac stimulationbullstimulation of gastric acid secretion
Activation of H2-receptors
21
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 19
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- Slide 22
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- Slide 25
- Slide 26
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- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
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- Slide 44
- Slide 45
- Slide 46
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- Slide 49
- Slide 50
- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullCimetidine ( hellip)bullFamotidine bullNizatidinebullRanitidine bullRoxatidine
Antagonist of H2-receptors(H2-blockers) ndash for the treatmentof peptic ulcer
22
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
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- Slide 22
- Slide 23
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- Slide 26
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- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Cromoglycate ndash per inh (Cromolyn ndash USAN)Ketotifen (po)Nedocromil ndash per inh
Mast cell stabilizers bullThey prevent degranulation and release of histamine and other autacoids from mast cells bull They also inhibit leukocyte activation and chemotaxis
Indications prophylactic treatment of asthma
23
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
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- Slide 49
- Slide 50
- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
b) Serotoninb) Serotonin (5-Hydroxytryptamine (5-Hydroxytryptamine 5-HT)5-HT)
Indol derivative
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
24
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
25
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Structures rich in 5-HT
bull GIT (chromaffin cells and enteric neurons)bull plateletsbull CNS
26
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
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- Slide 23
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- Slide 31
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- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Important actions of 5-HTbullincreased GI motility bullincreased platelet aggregationbullincreased microvascular permeabilitybullstimulation of nociceptive nerve endings
bullcontrol of appetite sleep mood hallucinations stereotyped behavior pain perception and vomiting
27
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Clinical conditions in which5-HT plays a role include
bull migrainebull mood disorders (depressive illnesses)bull anxietybull vomitingbull carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
28
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
29
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
5-HT1-receptors
bull5-HT1A 5-HT1F
bullAll subtypes occur in CNS and cause neural inhibitionbullAct by inhibiting adenylate cyclase
30
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Buspironebullanxiolytic agent bullpartial agonist of the 5-HT1A-receptorsbullused in anxiety
31
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
5-HT1D-receptors are found in some blood vessels (a carotis externa et interna meningeal vessels) They produce vasoconstriction pathophysiology of migraine
32
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Pathogenesis of migraine and drug treatment
Rang et al Pharmacologyndash 5st Ed (2003)
Rang et al Pharmacologyndash 5st Ed (2003)
33
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
The agonist of 5-HT1D-receptors
are highly effective but expensivein acute attacks of migraine
bullNaratriptanbullRizatriptanbullSumatriptanbullZolmitriptan
34
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 13
- Slide 14
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- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
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- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
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- Slide 38
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- Slide 41
- Slide 42
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- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
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- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Activation of5-HT2-receptorsbullin CNS produces excitementbullin blood vessels - contraction and platelet aggregation bullact through phospholipase C inositol phosphate pathway 35
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 13
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- Slide 17
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- Slide 26
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- Slide 33
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- Slide 35
- Slide 36
- Slide 37
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- Slide 40
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- Slide 46
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- Slide 49
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- Slide 51
- Slide 52
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- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Antagonists of 5-HT2-receptors are used
bullfor prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen
bullas a peripheral vasodilator- Naftidrofuryl (Dusodrilreg)
36
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
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- Slide 26
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- Slide 28
- Slide 29
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- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
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- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Adverse effectsof methysergidebullretroperitoneal fibrosisbullrenal failure
37
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
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- Slide 22
- Slide 23
- Slide 24
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- Slide 27
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- Slide 30
- Slide 31
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- Slide 33
- Slide 34
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- Slide 36
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- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors) reuptake inhibitors) FluvoxamineFluvoxamine Citalopram FluoxetineCitalopram FluoxetineParoxetineParoxetineSertraline Sertraline are used inare used inhumans humans to treatto treatbullchronic anxietychronic anxietybullDepression Depression bulimiabulimia 38
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
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- Slide 48
- Slide 49
- Slide 50
- Slide 51
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- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
5-HT3-receptorsbullLocated in enteric neurons and in CNSbullAct by stimulating adenylate cyclasebullEffects are excitatory causing GI motility and vomiting
39
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 16
- Slide 17
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- Slide 36
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- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
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- Slide 49
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- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT3-receptors are verypowerful antiemetics
40
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
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- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
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- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Agonists of 5-HT4-receptors
bullTegaserod (Zelmacreg) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion Indication colon irritable syndrome 41
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms) 2 EICOSANOIDS2 EICOSANOIDS(20 carbon atoms) (20 carbon atoms)
bullprostanoids
prostaglandins (PGs)
thromboxanes (Txs)
bullleucotrienes (LTs)
bulllipoxins
(eic
osi =
20)
42
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
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- Slide 31
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- Slide 33
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- Slide 39
- Slide 40
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- Slide 42
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- Slide 44
- Slide 45
- Slide 46
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- Slide 49
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- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullThe eicоsanoids are important mediators of inflammation and allergy
bullThe main source of eicosanoids is arachidonic acid It is a 20-carbon unsaturated fatty acid
43
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Phospholipase APhospholipase A22PhospholipidsPhospholipids
Arachidonic acidArachidonic acid
5-lipoxygenase5-lipoxygenase
LeucotrienesLeucotrienes
Cyclooxygenase (CoxCyclooxygenase (Cox))
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
15-lipoxygenase15-lipoxygenase
LipoxinsLipoxins
Inflammatory stimulusInflammatory stimulus
44
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
PGI2 (prostacyclin) is located
predominantly in vascular endothelium Main effects
bullvasodilatationbullinhibition of platelet aggregation
TxA2 is found in the platelets
Main effectsbullplatelet aggregationbullvasoconstriction
PROSTANOIDS (PGs amp Txs)PROSTANOIDS (PGs amp Txs)
45
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
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- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
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- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
PGEPGE11
bullalprostadil (prodrug ndash used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis) bullmisoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs) bullgemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy 46
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
PGEPGE22 causesbullcontraction of pregnant uterusbullinhibition of gastric acid secretionbullcontraction of GI smooth muscles
PGFPGF22αα ndash main effectsbullcontraction of bronchibullcontraction of myometrium
47
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
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- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
PGFPGF22αα (dinoprost)(dinoprost)
PGEPGE22 (dinoprostone)(dinoprostone)
areare given forgiven forbullinduction of labourinduction of labourbulltermination of pregnancytermination of pregnancy
PGEPGE11 (gemeprost)(gemeprost)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
Dorlandrsquos IllustratedDorlandrsquos IllustratedMedical DictionaryMedical Dictionary
(2003 2004)(2003 2004)
48
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum COX exists in3 isoformsbullCOX-1COX-1 (constitutive) acts in physiological conditionsbullCOX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulusbullCOX-3COX-3 (in brain) 49
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
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- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
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- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
50
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
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- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
This has relevance for the mechanism of action of NSAIDs Most of theminhibit mainly COX-1and can cause peptic ulcerGI bleeding bronchial asthma and nephrotoxicity
51
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
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- Slide 24
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- Slide 26
- Slide 27
- Slide 28
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- Slide 31
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
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- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Arachidonic acidArachidonic acid
Cyclooxygenase (Cox)Cyclooxygenase (Cox)
EndoperoxidesEndoperoxides
PGsPGs TxATxA22
(())
AspirinAspirin
Thromboxane AThromboxane A22 synthase synthase (()) 100 mg24 h100 mg24 h
gt1 g24 hgt1 g24 h
52
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
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- Slide 31
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
COX-2COX-2inhibitorsinhibitors bull Selective (coxibs)Selective (coxibs)bull PreferentialPreferential
SelectiveSelectiveCOX-3COX-3
inhibitorsinhibitorsbullAntipyreticAntipyretic analgesicsanalgesics
NonselectiveNonselectiveCOX-1COX-2COX-1COX-2
inhibitorsinhibitors
ILILregregILILregreg
NSAIDsNSAIDs
COX INHIBITORSCOX INHIBITORS
53
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
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- Slide 20
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- Slide 40
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- Slide 42
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- Slide 49
- Slide 50
- Slide 51
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- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Coxibs are selective COX-2 inhibitors They exertanti-inflammatory analgesic and antipyretic actionwith low ulcerogenic potentialSIDE EFFECTS Coxibs can causeinfertility They have prothrombotic cardiovascularrisk
PfizerPfizer$23 $23 billionsbillionspenaltypenalty
54
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
Arachidonic acidArachidonic acid
5-Lipoxygenase5-Lipoxygenase
Leukotrienes (LTs)Leukotrienes (LTs)
LTCLTC44--receptorreceptor
LTDLTD44--receptorreceptor
LTELTE44--receptorreceptor
Montelukast ZafirlukastMontelukast Zafirlukast(-)(-)(-)(-)
55
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
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- ANY QUESTIONS
-
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
3 Platelet activating 3 Platelet activating factor (PAF)factor (PAF)
bullPLAPLA22 releases PAF in inflammation releases PAF in inflammationbullPAF causes vasodilatation PAF causes vasodilatation increases vascular permeabilityincreases vascular permeability activates platelet aggregationactivates platelet aggregation
56
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
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- Slide 2
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- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
4 PeptidesA-Endothelins ET-1 ET-2 RT-3
57
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
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- Slide 64
- ANY QUESTIONS
-
B-Kinins B-Kinins (kallikrein (kallikrein bradykininbradykinin
Cholecystokinin Cholecystokinin (CCK)(CCK) ndash ndash neuripeptide involved in pathogenesisneuripeptide involved in pathogenesisof panic reactionsof panic reactions
58
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
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- Slide 63
- Slide 64
- ANY QUESTIONS
-
soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors Cytokines are involvedreceptors Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponseresponse
55 Cytokines ndash Cytokines ndash
59
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
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- Slide 5
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- Slide 64
- ANY QUESTIONS
-
Cytokines act together (ldquoas a teamrdquo) onendothelium leucocytesmastocytes fibroblasts stem cellsand osteoclastsCytokines control their proliferationdifferentiation andor activation byreceptor mechanism
60
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
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- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
IL-1IL-1 participates in the pathogenesisof rheumatoid arthritisGlucocorticosteroids andglucosamine depress the synthesisof ILndash1IL-2IL-2 used iv in renalcarcinoma but has ADRsIL-11IL-11 stimulates thrombocytopoesis
INTERLEUKINES (ILs)
61
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
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- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
IL-18bullUpregulated INF productionbullEnhenced NK cell cytotoxicityIL-23bullAnti-viral activitybullStimulates T-cell macrophage andbullNK cell activitybullDirect anti-tumor effectsbullUsed therapeuticaly in viral and autoimmune conditions 62
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
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- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullInterferon alpha-2bInterferon alpha-2b (Introncopy) - in chronic hepatitis B and C
- lymphomas melanomas etc
bullInterferon beta-1bInterferon beta-1b (Betaferoncopy) sc in multiple sclerosisbullInterferon gammaInterferon gamma ndash in the regulation of the immune system
INTERFERONS (INFs)
63
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
- Slide 3
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- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
- ANY QUESTIONS
-
bullColony-stimulating factorsColony-stimulating factors - Filgrastim Molgramustim- Filgrastim Molgramustim Lenograstim Lenograstim
bullTNF-alpha (alfa)TNF-alpha (alfa)bullTNF-betaTNF-betabullVEGFVEGFbullPDGFPDGFbullTGF etcTGF etc 64
ANY QUESTIONS
THANK YOU
65
- Slide 1
- Slide 2
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- Slide 64
- ANY QUESTIONS
-
ANY QUESTIONS
THANK YOU
65
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- ANY QUESTIONS
-