Agents Show LOVE 💛 AND HATE For Cholinergic Receptors Either Directly Or Indirectly ( CHOLINERGIC AGONIST)

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Neurotransmitter:

Chemical signals involved in communication b/w nerve cells, and b/w 

nerve cells & effector cells e.g Norepinephrine, Epinephrine, Acetylcholine, Dopamine, 

Serotonin, Histamine, GABA 

Hormone :

Released from endocrine cells, into blood stream, travel throughout the body 

Local mediators:

cells secrete the chemicals act locally in their immediate environment 

e.g Histamine, Prostaglandins 

Second Messenger:

produced in response to neurotransmitter


binding to receptors, translate the extracellular signal into response

e.g cAMP, IP3, DAG Botulinum 

Toxin: 

blocked release of Ach from vesicles into Synaptic cleft

Spider Venom causes release of Ach from vesicles 

AcetylCholineEsterases: degrade Ach in the synaptic cleft by hydrolyzing 

Ca2+ : 

Elevated level of calcium causes fusion of vesicles & release of Ach in synaptic 

cleft 

Muscarinic Receptors: 

G-protein coupled receptors---Bind with Ach & Muscarine 

M1,M2,M3,M4,M5-----only M1,M2,M3 functionally active 

Gq coupled : M1=found in Gatric ,Parietal cells

Gq activate Phspholipase C--- yield DAG &IP3---causes in Ca++, hyperpolarization or contraction 

Gi-coupled: M2=Heart, Smooth Muscles , Gi Ï´ Adenylyl cyclase--- in K+, 

Hyperpolarization 

M3=Blood vessels, Bladder, Exocrine, Smooth muscles 

Nicotinic Receptors:

 Nn, Nm ----ligand-gated ion receptors 

Darifenacin: M3 anatagonist : used for overactive Bladder 

AcetylCholine actions: decrease in Heart rate & cardiac output

-ve chronotropic 

decrease in B.P…vasodilation…relaxation of smooth muscles by production of 

NO(EDRF)….hyperpolarization…relaxation of smooth muscle

Increase secretions..increase motility..Bronchoconstriction…increased urine expulsion

Miosis =constriction of ciliary muscle 

Bethanechol = not hydrolyzed by AchEsterase….lack nicotinic activity…used to treat Neurogenic atony & megacolon, atonic bladder 

S.E= Diarrhea, Bronchospasm, 

Crabachol:

muscarinic+ nicotinic action…Quaternary amine..cause miosis & spasm of 

accommodation 

T.USES= rarely used in glaucoma 

Pilocarpine:

Ester of Ach…tertiary amine…can penetrate CNS…M3 receptors 

T.USES= Secretagogue used in Sjogren‟s syndrome & xerostomia…..DOC in glaucoma 

S.E=diaphoresis(increased sweating) , salivation

Indirect-Acting Cholinergic Agonist/AcetylCholinEsterase

Inhibitor/Reversible

AchE is an enzyme that cleaves Ach…they reversibly inhibit AchE..increase intracellular

response…

Endrophoium: 

Quaternary amine..short duration of action 10-20min…

T.E= for diagnosis of Myasthenia Gravis..Antidote for Tubocurarine..

Myasthenia Gravis= Autoimmune disease. 

Antibody destroy Nicotine receptor at NMJ..Few receptors for Ach.. Muscle weakness

Physostigmine:

nitrogenous carbamic acid…tertiary amine..Increase intestinal & bladder motility…decrease intraocular pressure..

T.E=reverse CNS &cardiac effects of Antidepressents…Reverse CNS effects of Atropine

Neostigmine = Long acting 2-4hour...quaternary nitrogen…effect on skeletal muscle

>physostigmine

T.E=treatment of Myasthenia gravis..antidote for tubocurarine..

Pyridostigmine & Ambenonium=DOC in chronic management of Myasthenia

Gravis

Tacrine,Donepzil, Rivastigmine, Galantamine= first-line treatment in Alzheimer

disease.. only Tacrine hepatotoxic…Galantamine cause GIT distress

Indirect-Acting CholinEsterase Agonists/Irreversible(AnticholinEsterase)

Echothiophate:

covalently bind via Phosphate group…to –OH of serine at the active site of AchE….enzyme permanently inactive..

Aging = Phosphorylated enzyme slowly release one of its alkyl group

T.E=used in the chronic open angle glaucoma…not first line agent..long duration 1 week

S.E= risk for cataracts

Parathion 

used as insecticides

Reactivation of AchEsterase

Paralidoxime:

chemical reactivator of AchE…unable to penetrate CNS..cannot break bond of Echothiophate…it is weak reactivator


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