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 - 1mepp/sec

CHOLINERGIC TRANSMISSION (CONTD.) RECEPTORS N - Ligand gated ion channels Nn & Nm M - Through G- protein signalling systems M1 – Stomach Glands - Release of hist. - Secretion of acid M2 – (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 M3 - 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 CVS (M2) a) Heart :- ↓ G/C /C in Myocardium (PR ↑ – AV) b) Blood Vessel(M3) Dilatation – ↓ BP → Reflex tachycardia innervation is only on face to neck 2) Exocrine glands (M3) 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 (M1) – ↑ 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

b) Decurarisation after G.A c) Curare & other poisonings OTHER USES :- a) Cobra bite –venom b) Decurarisation after G.A c) Curare & other poisonings d) Edrophonium (PSVT)

ChE 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