2
* Basic & clinical pharmacology-Katzung* Examination It boardreview I pharmacology ....
-;
Katzung ,* Lippincott illustrated review
Pharmacology
REFERENCES·.,~
Dr.Zheen A. Mutabchi
Autonomic NervousSystem DRUGS
CANS)
UNIVERSITY OF SULAIMANICOLLEGE OF PHARMACYDEPARTMENT OF PHARMACOLOGY
4
3
Objectives- Divisions of Nervous System._.Functions & Importance of the differentparts of ANS & SNS.
- Neurotransmitters in the ANS (synthesis,storage, release, effects, & deactivation) .
- Studying cholinergic agonists &antagonists I adrenergic agonists &antagonists I & their clinicalapplications.
6
AutonomiC NS vs. Somatic NS
The ANS differs from the SNS in thefollowing areas:
• Effectors.-Efferent pathways.• Neurotransmitter.
Parasympathetic 5Sympathetic
These neuronsbring informationfrom the peripheryto the eNS .(input)
e. g. sensorynerves
Afferent division
Somatic
I
They carry signals away from thebrain and spinal cord to the peripheraltissues.(output) e.g. motor nerves
Efferent division
Central Nervous System Peripheral Nervous SystemI .. ......I .\. , ~
Brain Spinal cord
Nervous SystemI . .
8
Motor (Efferent) Pathways• Axons in the Somatic NS have
A single, myelinated axon extending fromthe eNS to the effector.
, • Axons in the Autonomic NS havetwo-neuron chain
The preganglionic (first) neuron extends toganglion.The postganglionic (second) neuron extendsfrom ganglion to an effector organ.
7
Effectors• The effectors of the
SNSare:skeletal muscles.
• The effectors of theANSare:Cardiac muscles,smooth muscles,adipocytes,
&glands.
10
9
• All somatic motor neurons release:Acetylcholine (ACh) ,
• ANS neurons release:. Norepinephrine (Sympathetic division)Acetylcholine (Sympathetic and
.Parasympathetic divisions)
, Neurotransmit,ter Effects
-The two divisions counterbalance eachother's activity .
...Most organs receive both sympathetic& parasympathetic innervations.
- SOME organ receive only sympatheticinnervations like:
SWEAT GLANDSPLEEN
MOST BLOOD VESSELS
11
• Sympathetic mobilizes body during extreme
situations "fig ht-or-flight".
• Parasympathetic performs maintenance activities"Housekeeping" or " Rest &. Digest".
ParasympatheticSympathetic
Two divisionsDivisions of the ANS.
14
• Shunts blood away from the skin andviscera to the skeletal muscles, brain, andheart.
• Inhibits peristalsis in the GIT.• Inhibits contraction of the bladder andrectum.
13
• Stimulates heart beat ..,. Raises blood pressure.• Dilates the pupils.• Dilates the trachea and bronchi.• Stimulates the conversion of liverglycogen into glucose.
Sympathetic. Effects
16
• Slowing down of the heart beat,• Lowering of blood pressure.• Constriction of the pupils.• Increased blood flow to the skin andviscera.
• Peristalsis of the GI tract.
Parasympathetic .Effects
18
• Rest & digest.
• Preganglionic Fibers ernergefrom brain and sacral. 1973;52-54
• Long preganglionic fibers;short postganglionic,Limited to head, neck, 8r.trunk.
• Ganglia found in visceral.effectors
• Minimal preganglionicbranching
• All cholinergic fibers use(Ach), rapidly destroyedlocally.
athetic
• Extensive preganglionicbranching
• All preganglionicfibers useACh, MOSTpostganglionicuse NE.NE is more stable &diffuses for wider action.
• Fight or flight.
• Preganglionic Fibers arisefrom thoracolumbar.Is. T128r. Ll- Ls.
• Short ••.•preganglionicfibers; long •••••••••••••••postganglionic ,WideDistribution.
• Ganglia near spinal cord.
Sympathetic
19
Ul'inary'bladdi'
R0:
1...1',•. inte_ineSmal•.intestine.4drenat.glandandkldne,'
.E,e~acri.IJ'lII•.gllnd.and naS8[muooa.$ubmandlbu1ti'and.lublingual.•glands..Parotid glandLung .
NormetancphrilW
CH30 HO HHO'n '~-~-NH"~- I I ~
H H
COMT· ,...
3-Methoxy - 4-hydroxymandclicacid(VnniIlylmandeHc acid)
CH=o-'p. . yH nHO V '\ C -- C -- OH
- IH
COMT
Metanepnrtne
CH=O-.30 ... . yH fHO 7 '\ .. C-C-NHCH~
- I I "H H
23
VMWIar s)'Stem
Norepmephrine
HO OH H
HO ~ , .~--~:-NH2
H H
MAO
3,4-Dihydmxymandelic acid
MAO
Bpi nephrtne
HO ·OH H
HO (' i - f -NHCH;1.
H H
.Adre:t'llllineOH..... I
HO('r.... CH-CHcNH-CHa
HOV·
Dopamine
DOPA
Tyrosine
synthesis, storage, release, &deactivation of N E
NANCTransmission• Neurotransmitters rather thanAch ,NE, and Dopamine may be.stored in nerve vesicles with thepreviously mentioned ones oralone like: ATP, Substance P,. Enkiphalines, Neurotensin .• They are acting as a modulatorof neurotransmitter release.. . 25
28
Examination & board review by Katzung:chapter 6, page 52, 9th edition.
See:
Question ..?••••
•Complex organ control: theEYEas an example.
30
Sites of Ach release1.Ganglia. All Sympathetic &
Parasympathetic ganglia.2. Post ganglionic parasympathetic
nerve endings.3. Sweat Gland.4.Somatic nerve endings supplying
Skeletal Muscles.5. Adrenal medulla.6. eNS.
29
- Cholinoceptor activating- Cholinesterase inhibitors
Cholinergic Drugs
32
AGetyk;hgfine~ •
DiliGd;..aciin'QctUJ~~nergicdruS
.Presynaptic V~L<:~EiiIS,contaniing aeel:yBcJ'tOIine
31
CHOLINERGIC AGONIST DRUGSI
Direct~cting Indirect lacting1 I ·1 • I .
• • •Muscarinic Nicotinic : : :.. . .1 Edrophonium ~ ~
Alkaloids Choline ester Carbamate ~Pilocarpine Ach,Methacholine, :MlISCCIine carbachol, ' organOPhosPha~esArecoline bethanicol
2
REFERENCES ...* Basic& dinical pharmacologyKatzung* Examination &. board review
pharmacology --Katzung* Lippincott illustrated review
Pharmacology
1
Dr.ZheenA. Mutabchi
Drugs affectingAutonomic Nervous
..SystemCANS)
UNIVERSITY OF SULAIMANICOLLEGEOF PHARMACYDEPARTMENT OF PHARMACOLOGY& TOXICOLOGY
4
Sites of Ach release1.Ganglia. All Sympathetic &
Parasympathetic ganglia.2. Post ganglionic parasympathetic, nerve endings.
3. Sweat Gland.4. Somatic nerve endings supplying
Skeletal Muscles.5. Adrenal medulla.6. eNS.
3
- Cholinoceptor activating- Cholinesterase inhibitors
Cholinergic Drugs
6
•AG8tYfd1glin&~
Oire:cl-aclil.ngcholinergic dn.JS
Presynaptic ve(~.dcles.mntaining aosi;yk;holine
5
tOrganophosphates
.Ach, Methacholine,. carbachol,bethanicol
Choline ester
• • •• • •• • •.. : :Edrophonium ~ ~
T :..Carbamate ~
•••
INicotinic
IMuscarinic
1
Indirect lacting· I .
D•· .t J t·. Ifec ac IngI
CHOLINERGIC AGONIST DRUGSI
IAlkaloiijPilocarpine·MuscarineArecolineLobeline
14
Eyes .
R.T.S .
Blood vessels .... parasympathetic innervations ..??!G.1. T .
Heart ... vagal stimulation
Tissue & Organ effects
13
on, H3C-.c -0 ~;CH2-cH2-~ -'CH3Ace Ichollne . CH:l; I
Quaternary ammonium compound.Has both muscarinic & nicotinic activity.Has NO therapeutic application
rapid inactivationlack of specificity
H31
ACETYLCHOLINE
DIRECT ACTING DRUGS
16
* S/E .
Bethanechol* similar to Ach. quaternary ammonium. compound.. .* Not hydrolyzed by AChE.* Has STRONG MUSCARINIC but nonicotinic activity.
c, * Mainly acts on smooth muscle of bladder&GIT.
'* Therapeutic value in Post partum &postoperative atonic bladder .
+Ilmcreased b400d,' flCPA"for incr_s~ngheet dfss4patlon
IBronchllal sec:.-etiondecreasedBrol"lchodillatfon
Bronchllal secretionBrol"lchocol"IstrJction
REJlStiessne_frrimbilmtyHall!UclrnatlonsAntfpftridnsonfaneffectAntietnetfe, effect:IRaba'"AV oondUotion t r-'-----
18
• Glaucoma.
Pll~1f1W1lJW• Contraction of the ciliary muscles& MIOSIS. IPu~1wlda
, • Tertiary amine structure.• Stable to hydrolysis by AChE.
Pilocarpine• Natural alkaloid.
17
Glaucoma.
DOA is tonq 1 hr.
Similar to bethanicol in its resistance to AchE.
Similar to Ach in its affinity to M,N Receptors.
CARBACHOL
20
II,'.ml'"m~'~~'~~t!~~~!~~l~,~d/...~~eJJ~~I_m'awJ,'~I'D~m~~m&lili'I, .~~i
ra; 111~~fJhltll(illlm " fl~j~ni~~, ~.r~~m~~I.·:.;g]]l~,,
19
Adverse. reactions.. ftlxldtl Iellflm itllB ttl~lnlmil_mDn'\V1lIl •_ ,Dl;_~f__ ~!_titio~I_~_m alipi.sntdt Il1Id acnYil1, J , >' ,
u ,i '. 'maet)" IfiQ ' 'Hallen. :accUl1·.Jol- .I ..'""'"..V,. .",,>' . ..~
I~. '.J ' ill ~ ~.. 1Il,~;]inl~ou~131~,~bl
22
CLASSIFICATIONDURATION OF ACTION-- Very short actingedrophonium-- intermediate -long actingcarbamates( carbaryl, propoxure,aldicarb)
-- very long- actingorganophosphates( malathion,parathion, sumithion, sarin , &tabun),
21
CLASSIFICATIONCHEMICAL STRUCTURE:-- Esters of carbamic acid:
carbamates neostigmine-- Esters of phosphoric acid:
phosphates organophosphates-- R-OH:
. Edrophonium
INDIRECT ACTING CHOLINERGICAGONISTS
24
•Acafylcht)lina"__~;
lDire,d..,actingcholinergic drug
, Presynaptic \fesicleHSmntaining aosl¥lcholine
.Acstylcoolinesterass
23
-- Irreversible: organophosphates(parathion, malathion, echothiophate,nerve gases [tabun, sarin, soman];diazinon, dyflos). '
--Reversible: Physostigmine,neostigmine,pyridostigmine, rivastigmine,donepezil, edrophonium, ambinonium.
CLASSIFICATIONREVERSIBILITY .
26
There are two major types ofcholinesterases
.acetylcholinesterase (AChE) alsoknown as true, specific I and are foundmai.nlyat(cholinergic neuroeffector junction)
pseudocholinesterase (pseudo-ChE)(liver, skin, plasma)
PreSYnipticvesi~,~oonmining acetylchol'ine
IndnGt"adingcholnergic
drug bound toacetylchoUnMtems~
(S9; nut box)
27
• There are two main forms ofcholinesterase both enzymes belong to thefamily of serine hydrolases:-acetylcholinesterase (AChE), which ismainly membrane bound, relativelyspecific for ACh and responsible forrapid ACh hydrolysis at cholinergic
..synapses.- butyrylcholinesterase (BuChE) orpseudocholinesterase, which is relatlvelvnon-selective and occurs in plasma andmany tissues.
30
o1.1
-C-O-H
, .~Ph'J4':R.''; •• DiI'Je
Physostigmine
REVERSIBLE ANTICHOLINESTERASES
29
Clinical applications of indirect actingcholinomimetics
32
··HaG
NEOSTIGMINE
REVERSIBLE ANTICHOLINESTERASES·
31
sU1
Uses-GLUCOMA-OVERDOSES of ATROPINE ,TCA.-Intestinal & bowel atony.-ACCOMMODATIVE ESOTROPIAADVERSE· EFFECTS
34I.V. in diagnosis of Myasthenia Gravis
USES
. EDROPHONIUM
33
Antidote for Tubocurarine
Urinary Retention & paralytic ileus
...Myasthenia Gravis direct stimulation Nmindirect effect on AchE
USES
The drug is well absorbed after oraladministration and absorption is unaffectedby food. It is highly bound (96%) to plasmaproteins. It is metabolized in the liver toseveral metabolites, some of which arepharmacologically active; metabolites and
- some unchanged drug are excreted mainlyin urlne,Adverse effects include nausea, vomiting,diarrhea, bradycardia, and possibleaggravation of asthma, peptic ulcerdisease, and chronic obstructive pulmonarydisease. Jaw tremor 38
37
• is used to treat mild to moderateAlzheimer's disease. In long term studies,donepezHdelayed the progression of thedisease for up to 55 weeks. Donepezilincreases acetylcholine in the brain byinhibiting its metabolism.
DONEPEZIL