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Cholinomimetic agents: Cholinoceptor activating and Cholinesterase inhibitors

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

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Cholinomimetic agents: Cholinoceptor activating and Cholinesterase inhibitors

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

  2. Objectives • นิสิตมีความรู้ความเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร์ การใช้ประโยชน์ทางคลินิก อาการไม่พึงประสงค์ ข้อควรระวังการใช้ยาของยาที่ออกฤทธิ์กระตุ้นระบบประสาทพาราซิมพาเทติกและยาที่ออกฤทธิ์ยับยั้งเอนไซม์โคลินเอสเตอร์เรส

  3. 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

  4. 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] • CNS

  5. 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

  6. 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

  7. Organ system effects • Direct effect … Parasympathetic stimulation – like effect

  8. 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”

  9. 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)

  10. 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

  11. Carbamate Organophosphate Irreversible Dealkylation

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

  13. 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

  14. 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

  15. Q & A

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