Download - Pharmacology of Eicosanoid
EICOSANOIDSEICOSANOIDSProstaglandins Thromboxanes Leukotrienes
EicosaniodsEicosaniods• Derived from 20-crabon polyunsaturated fatty
acids• Short half-lives (10 secs – 5 mins) so that
functions are usually limited to actions on nearby cells.
• Bind to specific cell surface G-protein coupled receptors, and generally increase cAMP levels. May also bind to nuclear receptors and alter gene transcription.
Major Classes of EicosanoidsMajor Classes of Eicosanoids
• Prostaglandins• Thromboxanes• Prostacyclins• Leukotrienes• HETES
• Induction of inflammation• Mediation of pain signals• Induction of fever• Smooth muscle contraction (including uterus)• Smooth muscle relaxation• Protection of stomach lining• Simulation of platelet aggregation• Inhibition of platelet aggregation• Sodium and water retention
Effects of EicosaniodsEffects of Eicosaniods
Precursors of EicosanoidsPrecursors of Eicosanoids
• Arachidonic acid (ω6)• Eicosatrienoic acid (-linolenic acid, ω6)• Eicosapentaenoic Acid (ω3)
Dietary Linoleic Acid (C18: ∆9,12) (from plant oils)
Elongase
Desaturase
Arachidonic Acid (C20: ∆5, 8, 11, 14)
Membrane Phospholipids
Phosphatidyl choline
Arachidonic acid
Phospholipase A2 Ca++
Phosphatidylinositol bisphosphate
Phospholipase C
1,2 Diacylglycerol
Arachidonic acid Monoacylglycerol
DAG lipase
Arachidonic acid
MAG lipase
Arachidonic acid release from membrane Arachidonic acid release from membrane lipidslipids
Stimulus
Prostaglandins – Structural FeaturesProstaglandins – Structural Features
PGA, PGD, PGE, PGF, PGG, PGH, PGIDepending on the functional groups present at X
and YPGF 1, 2 or 3
Depending on the number of double bonds present in the linear hydrocarbon chain
CYCLO-OXYGENASE CYCLO-OXYGENASE PATHWAY PATHWAY
PG and TX synthesisPG and TX synthesis
2GSH
2GSSG
PGD2PGD synthase
PGF2a
PGE 9-keto reductase
PGE2PGE synthase
PGI2PGI synthase
TXA2TXA synthase
In 1930s human semen was found to contract isolated uterine and other smooth muscle strips and to cause fall in BP in animals so named as prostaglandins (assuming derived from prostate)
ProstaglandinsProstaglandins
Blood vessels: PGE2-vasodilatation, decrease blood pressurePGF2-Vasodilatation, larger veins contract, little effect on Blood pressurePGI2-Vasodiatation (marked and widespread) lead to rapid decrease in blood pressureVasocontriction – TXA2
Functions of ProstaglandinsFunctions of Prostaglandins
Heart- PGE2-Weak inotropic, reflex cardiac stimulationPGF2-Weak inotropicPlatelets- Antiaggregatory effect of PGI2Aggregation and release reaction by TXA2Uterus- Contraction , relaxes nongravid human uterus by PGE2Contraction of uterus by PGF2alpha
Functions of ProstaglandinsFunctions of Prostaglandins
Bronchi- PGE2/PGI2-Dilatation, inhibit histamine releaseBronchoconstriction by PGF2, TXA2Stomach- Decrease acid secretion, increase mucus production by PGE2, Decrease acid secretion and mucosal vasodilatation by PGI2Intestine- Contracts longitudinal and relaxes circular muscle, Increase peristalsis/cl-/water secretion
Functions of ProstaglandinsFunctions of Prostaglandins
Intestine- spasmogenic , ↑fluid & electrolyte secretion by PGF2, Inhibit toxin induced fluid secretion- PGI2Weak spasmogenic-TXA2Kidney-Natriuresis, ↓cl- reabsorption, inhibit ADH action, Vasodilatation, renin release-PGE2/PGI2Vasoconstriction by TXA2
Functions of ProstaglandinsFunctions of Prostaglandins
CNS- Pyrogenic, variety of effect on I.C.V injection- sedation, rigidity, behavioral changes, ↑body temperature, fever- PGE2TXA2- not pyrogenicRelease of NA- depending on the PG and species, release of NA and inhibition of NA both are observed Afferent nerves- PGE2/PGI2-sensitize nerve ending to pain inducing chemical/ mechanical stimuli, irritate mucosa membrane and produce long lasting pain
Functions of ProstaglandinsFunctions of Prostaglandins
Endocrine system- PGE2-Release of ant pituitary hormones, steroids, insulin, TSH like actionRelease of gonadotropins and prolactin, luteolysis (in animals)-PGF2Metabolism- Antilipolytic, insulin like action, mobilization of bone calcium – PGE2
Functions of ProstaglandinsFunctions of Prostaglandins
LipoxygenaseLipoxygenase pathway pathway
Straight chain lipoxygenase products of arachidonic acid are produced by more limited no of cells
LTB4- NeutrophilsLTC4/LTD4- Macrophages
LTs are pathophysiologically as important as PGs
Some Functions of ProstaglandinsSome Functions of Prostaglandins
CVS and Blood- LTC4/LTD4 injected i.v evoke a brief rise in BP, followed by more prolonged fall
Note : fall in BP is not due to vasodilatation nor relaxation of Blood vessel it is may be due to
coronary constriction induced ,↓cardiac output, ↓circulation volume, ↑vascular permeability
LTB4- chemotactic , migration of neutrophils
Some Functions of ProstaglandinsSome Functions of Prostaglandins
Smooth muscle- LTC4 and D4- potent constrictors of bronchi and G.I.T, ↑ mucus secretions
Afferent nerves- Like PGE2/I2 the LTB4 also sensitizes afferents carrying pain impulses- ↑pain and ↑inflammation
• Leukotrienes are a hundred times more potent than histamine
• Histamine provided a rapid response to an allergen
• In the later stages leukotrienes are principally responsible for inflammation, smooth muscle constriction, constriction of the airways and mucous secretion form mucosal epithelium
Leukotrienes and allergiesLeukotrienes and allergies
1. Abortion2. Induction/ augmentation of labour3. Cervical priming (ripening)4. Postpartum haemorrhage (PPH)- carboprost 5. Peptic ulcer- Misoprostol6. Glaucoma- latanoprost, travoprost, bimatoprost7. Maintain patency of ductus arteriosus- Alprostadil8. Avoid platelet damage-Epoprostenol9. Peripheral vascular disease- rest pain, healing of
ischemic10.Impotency- Alprostadil
USES of EicosanoidsUSES of Eicosanoids
All prostanoid receptors are G-protein coupled receptors which can be functionally categorized
1. ‘excitatory’ or ‘contractile’ 2. ‘inhibitory’ or ‘relaxant’
•The contractile group (EP1, FP, TP) couple primarily with Gq protein and generate IP3-DAG. •The relaxant group (DP1, EP2, EP4 and IP) couple with Gs protein—activate c AMP
PROSTANOID RECEPTORS
Receptor Subtypes Action Location Nature
DP DP1 and DP2 PGD2/PGE2
Blood vessels Relaxant receptor
EP EP1 EP2 EP3 EP4
PGE2 Smooth muscle, intestinal mucosa, adipose tissue
Contractile EP1Relaxant EP2/4Inhibitory EP3
FP Nil PGF2alpha Genital tract Contractile receptor
TP Nil TXA2 PGH2
Platelet (aggregatory), CVS, Immune cell
Contractile receptor
IP Nil PGI2 PGE2
Heart , lungs, kidney, platelet (anti)
Relaxant receptore
PROSTANOID RECEPTORS
Anti inflammatory Drugs inhibit Anti inflammatory Drugs inhibit Eicosanoid SynthesisEicosanoid Synthesis
LeukotrienesProstaglandins, thromboxanes
NSAIDs
Cyclo-oxyg
enase Lipoxygenase
Membrane lipids
Arachidonic Acid
Steroids
Phospholipase A2
Mechanism of ActionMechanism of Action
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