Pawitra Pulbutr M.Sc. In Pharm (Pharmacology) Cholinomimetic agents: Cholinoceptor activating and Cholinesterase inhibitors Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

Objectives นิสิตมีความรู้ความเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร์ การใช้ประโยชน์ทางคลินิก อาการไม่พึงประสงค์ ข้อควรระวังการใช้ยาของยาที่ออกฤทธิ์กระตุ้นระบบประสาทพาราซิมพาเทติกและยาที่ออกฤทธิ์ยับยั้งเอนไซม์โคลินเอสเตอร์เรส

Cholinomimetic agents Parasympathomimetic = Action like Parasympathetic nervous system stimulation Alkaloid … “Muscarine” Stimulate effector organ receptor Muscarinic receptor Alkaloid … “Nicotine” Stimulate autonomic ganglia & neuromuscular junction (NMJ) Nicotinic receptor ACh >>> Stimulate both muscarinic & nicotinic receptor

Cholinoceptor Receptor of ACh and other cholinoceptor activating agents Muscarinic receptor GPCR Effector organ … heart, exocrine gland, presynaptic nerve, endothelial cell (no nerve innervation) Effector organ which is innervated by cholinergic sympathetic nerve CNS Nicotinic receptor Ion channel linked receptor Autonomic ganglia (both sym & parasym), Neuromuscular junction (NMJ) [skeletal muscle; somatic nerve innervation]

Mode of action of cholinomimetic drugs Direct acting agents Cholinoceptor activating drugs [Agonist] Directly bind to cholinoceptor Indirect acting agents Cholinesterase inhibiting agents [AChE Inhibitors] Anti-cholinesterase Inhibit ACh hydrolysis Increase endogenous ACh

Basic pharmacology of direct acting cholinoceptor stimulants Choline ester Ester of acetic acid: Acetylcholine (ACh), Methacholine Ester of carbamic acid: Carbachol, Bethanechol Alkaloids Muscarine, Nicotine Derivative: Pilocarpine, Lobeline, Oxotremorine

Organ system effects Direct effect … Parasympathetic stimulation – like effect Organ Responses Eye Sphincter muscle of iris Ciliary muscle Contraction (miosis) Contraction for near vision Heart Sinoatrial node Atria Atrioventricular node Ventricles Decrease in rate (negative chronotropic) Decrease in contractile strength (negative inotropic) Decrease in refractory period Decrease in conduction velocity (negative dromotropy) Increase in refractory period Small decrease in contractile strength

Blood vessels Arteries Veins Dilation (via EDRF) Constriction (high dose direct effect) Lung Bronchial muscle Bronchial gland Contraction (bronchoconstriction) Stimulation Gastrointestinal tract Motility Sphincter Secretion Increase Relaxation

Urinary bladder Detrusor Trigone and sphincter Contraction Relaxation Glands Sweat, salivary, lacrimal, nasopharyngeal Secretion

Peripheral nervous system Autonomic ganglia >>> Nicotinic receptor Nicotine High affinity to neuronal nicotinic RC Affect both sym & parasym ganglia CVS … Sympathetic … Hypertension GI, Urinary sys … Parasympathetic … nausea, vomiting, diarrhea, voiding Can cause “depolarizing blockade”

Neuromuscular junction (NMJ) Nicotinic receptor Immediate depolarization of motor end plate Increase Na+/K+ permeability Disorganized fasciculation >>> Strong contraction of muscle Depolarization blockade ….Muscle weakness (Flaccid paralysis)

Basic Pharmacology of AChE inhibitors Acetylcholinesterase enzyme (AChE) Hydrolysis of ACh MW ~320,000 Mostly found at cholinergic synapse AChE inhibitors Bind at active site … Inhibit AChE action Increase endogenous ACh Reversible Simple alcohol Carbamic acid ester Irreversible Organophosphates

Carbamate Organophosphate Irreversible Dealkylation

Clinical Pharmacology Glaucoma Accommodative Estropia Postoperative atony, Neurogenic bladder, Postpartum NMJ disease (Myasthenis gravis) Antimuscarinic drug intoxication Alzheimer’s disease Supraventricular tachyarrhythmia

Toxicity & ADRs Direct acting muscarinic stimulant n/v, diarrhea, salivation, sweating, cutaneous vasodilation, bronchoconstriction Inhibited by Atropine Direct acting nicotinic stimulant Central stimulant action … convulsion, coma, respiratory depression Skeletal muscle end plate depolarization … muscle weakness, respiratory paralysis (Not response to AChE inhibitor) Hypertension, cardiac arrhythmia Symptomatic treatment … Atropine, Anti-convulsant Long term effect of nicotine from cigarette smoke Vascular disease Sudden coronary death Peptic ulcer recurrence

Toxicity & ADRs AChE inhibitors esp. Insecticide Acute toxic effect ~ Direct cholinomimetics Emergency treatment of insecticide intoxication Miosis, salivation, sweating, bronchoconstriction, vomiting, diarrhea, CNS effect, depolarizing NM blockade Maintain vital sign Decontamination Atropine … control muscarinic excess Pralidoxime … AChE regerator Chronic exposure … Demyelination of neuron … Neuropathy

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