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