CHOLINERGIC TRANSMISSION A Precursor Choline B Enzyme Synthesizing
CHOLINERGIC TRANSMISSION A: - Precursor - Choline B : - Enzyme. Synthesizing - Choline Acetylase Degrading - Acetycholine Esterase (TRUE) - Butyrylcholine Esterase(PSEUDO) C : - 300, 000 vesicles Quantum - 0. 1 to 0. 3 mv - 1 mepp/sec
CHOLINERGIC TRANSMISSION (CONTD. ) RECEPTORS N - Ligand gated ion channels Nn & Nm M - Through G- protein signalling systems M 1 – Stomach Glands - Release of hist. - Secretion of acid M 2 – (i) Myocardium - ↓ generation of impulses –SA - ↓ conduction of impulse – AV - ↓ contractility –Atria & Ventricle
CHOLINERGIC TRANSMISSION (CONTD. ) (ii) Pre-synaptic ↓ Ach from cholinergic neurons ↓ NA Postgang. sym. Neurones M 3 - Smooth muscle – Contraction - Exocrine glands – ↑ secretion - Vascular Endothelium – ↑ NO secretion
CLASSIFICATION CHOLINE ESTERS - Acetylcholine - Methacholine - Carbachol - Bethanechol - Cevimeline NATURAL ALKALOID - Muscarine - Pilocarpine - Arecoline - Nicotine
ANTI- CHOLINESTERASES A) Reversible - Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmine Donepezil
ANTI- CHOLINESTERASES(contd. ) B) Irreversible - Parathion (agricultural insecticides) - Malathion - Diazinon (Household) - Propoxur - Tabun - Sarin (Chemical warfare) - Soman
PHARMACOLOGICAL ACTIONS 1) CVS (M 2) a) Heart : ↓ G/C /C in Myocardium (PR ↑ – AV) b) Blood Vessel(M 3) Dilatation – ↓ BP → Reflex tachycardia innervation is only on face to neck 2) Exocrine glands (M 3) Sweating > Salivation > Lacrimation = TBT secretion >> Gastric secretion
PHARMACOLOGICAL ACTIONS(contd. ) 3) Smooth Muscle a) G. I. – ↑ Tone & Peristalsis b) Urinary System – ↑ Tone , Voiding c) Bronchi – ↑ Tone (Bronchial Asthma) 4) Eye- Cont. of circular mus. of iris →Miosis. - Cont. of ciliary mus. → thickening of lens
PHARMACOLOGICAL ACTIONS(contd. ) 5) Skeletal muscles (NM) Twitching & fasciculation 6) Autonomic ganglia(Nn) Both Ad & Ch- unpredictable 7) CNS (M+N) Rapid destruction + min. entry →unpredictable response. 8) Stomach (M 1) – ↑ acid+ Pepsin
USES OF CHOLINE ESTERS 1) Cardiac – PSVT – Methacholine 2) Intestinal – Paralytic ileus , Megacolon (carbachol / bethanechol) 3) Urinary - Retention of urine (carbachol /bethanechol) 4) Lacrimal Secretion & Sialogogue – Cevimeline
CHOLINOMIMETIC ALKALOIDS Pilocarpine : - As eye drops – Miosis - Ch. simple glaucoma – Drops Vs. Ocusert - To prevent and break adhesions between iris / lens and iris / cornea Muscarine, Arecoline and Nicotine
CHOLINESTERASE INHIBITORS Reversible Physostigmine (Eserine) : -Natural , lipid soluble compound -Rapidly absorbed and crosses BBB – CNS effects -Poisoning with Atropine , Phenothiazines & Tricyclic Antidepressants
CHOLINESTERASE INHIBITORS(contd. ) Neostigmine – -Synthetic, much less lipid soluble -Does not cross BBB – No central effects - ACh action on NMJ – Myasthenia gravis - If intolerable M effects – Atropine -Steroids – ↓ production of Nm antibodies -Thymectomy • Also in paralytic ileus & bladder atony.
CHOLINESTERASE INHIBITORS (contd. ) Pyridostigmine - Less potent , Long duration Edrophonium - Very short duration - To identify between “Myasthenic” and “Cholinergic” crisis Rivastigmine Newer agents, AD, Long acting, Donepezil Well tolerated
OTHER USES : - a) Cobra bite –venom b) Decurarisation after G. A c) Curare & other poisonings d) Edrophonium (PSVT)
Ch. E INHIBITORS – IRREVERSIBLE High efficacy ------ Toxicity (cross BBB) High lipid soluble – Rapid absorption from all routes Poisoning occurrence - Accidental , suicidal, homicidal
Muscarinic Effects - Inhalation / ingestion/ vapours (Eye) Miosis , lacrimation - ↑ secretion – Dehydration - Fall in BP – Reflex Tachycardia - ↑ dose –VMC at medulla (Bradycardia) - ↑ contraction of smooth muscle - Ataxia, convulsion , coma , death due to Respiratory Failure
TREATMENT • Change clothes. Wash skin , eyes. Gastric lavage. • Fresh air, Patent airway, PPR, Hydration • Maintenance of BP- vasopressor agent • CONVULSION – Diazepam i. v Atropine Enzyme Reactivator – Oximes DAM, Pralidoxime, Obidoxime
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