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Anticholinesterases

Anticholinesterases. 1. Reversible anticholinesterases 2. Irreversible anticholinesterases. Reversible anticholinesterases. anionic site esteratic site Acetylcholinesterase is the mechanism of terminating ACh effects. Action of acetylcholinesterase.

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Anticholinesterases

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  1. Anticholinesterases 1. Reversible anticholinesterases 2. Irreversible anticholinesterases

  2. Reversible anticholinesterases • anionic site esteratic site • Acetylcholinesterase is the mechanism of terminating ACh effects

  3. Action of acetylcholinesterase

  4. Acetylcholinese:structure for interaction with substrate

  5. Reversible anticholinesterases Neostigmine 新斯的明 Neostigmine 新斯的明

  6. Reversible anticholinesterases • 1. Pharmacological effects • binding to AChE, but slowly hydrolysis • inhibiting AChE activity • Properties of Effects • stronger effect on skeletal muscles • AChE (-), ACh release, stimulating NM receptor • effective on GI tract and urinary bladder • more polar and can not enter CNS • relatively ineffective on CVS, glands, eye

  7. Effect of neostigmine on AChE

  8. Action of neostigmine on acetylcholinesterase

  9. Reversible anticholinesterases • 2. Clinical uses • (1) Myasthenia gravis（重症肌无力）:symptomatic treatment, overdose: cholinergic crisis • (2) Paralytic ileus and bladder（手术后肠道及膀胱麻痹）: post operative abdominal distension and urinary retention • (3) Antidote for nondepolarizing skeletal muscle relaxants poisoning（解除非除极化型肌松药中毒） • (4) Paroxysmal superventricular tachycardia（阵发性室上性心动过速）

  10. Reversible anticholinesterases • 3. Adverse effects • （1）Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic) • （2）Contraindications： • mechanical ileus（机械性肠梗阻） • urinary obstruction（尿路阻塞） • bronchial asthma（支气管哮喘） • poisoning of depolarizing skeletal muscle relaxants • （除极化型肌松药中毒）

  11. Reversible anticholinesterases • Other reversible anticholinesterases • Pyridostigmine (吡斯的明): myasthenia gravis, paralytic ileus and bladder • Physostigmine (毒扁豆碱): glaucoma • Edrophonium chloride (依酚氯铵)：myasthenia gravis • Galantarmine (加兰他敏)：myasthenia gravis

  12. Reversible anticholinesterases • Anticholinesterases improving memory • Tacrine (他克林)：improving memory / hepatic toxicity • Donepezil (多奈哌齐) and rivastigmine (利凡斯的明): • improving menory;used in mild/moderate Alzheimer patients • Huperzine (哈伯因，石杉碱甲)：myasthenia gravis, improving memory

  13. Irreversible anticholinesterasesand cholinesterase reactivators • 1. Organophosphates（有机磷酸酯类） • (1) Toxicology • Irreversible binding to esteric site of AChE by covalent attachment－phosphorylatedAChE－aging • ACh accumulated in the synaptic sites, and caused toxic effects

  14. Irreversibly binding to esteric site of AChE by covalent attachment－phosphorylated AChE

  15. Irreversible anticholinesterasesand cholinesterase reactivators • (2) Toxic symptoms • Acute intoxication • Muscarinic symptomseye, exocrine glands, respiration, GI tract, urinary tract, CVS • Nicotinic symptoms NN: elevation of BP, increase of HR;NM: tremor of skeletal muscles • Central symptomsexcitation, convulsion; depression (advanced phase)

  16. Irreversible anticholinesterasesand cholinesterase reactivators • Chronic intoxication • usually occupational poisoning • plasma ChE activity ↓ • weakness, restlessness, anxiety, tremor, miosis, ……

  17. Irreversible anticholinesterasesand cholinesterase reactivators • (3) Detoxication • Elimination of poison; Supportive therapy • Antidotes • Atropine－antagonizing muscarinic effects; early, larger dose, and repeated use • Cholinesterase reactivators－reactivation of phosphorylated AChE; moderate-severe patients, early use, combined with atropine

  18. Irreversible anticholinesterasesand cholinesterase reactivators • 2. Cholinesterase reactivators Pyraloxime methoiodide 碘解磷定, PAM oxime group Conjugated with organo-phosphates Recognizing and binding to AChE

  19. Irreversible anticholinesterasesand cholinesterase reactivators • (1) Pharmacological effects • a. Recognizing and binding to AChE, conjugating with organophosphate by oxime group (肟基) • b. Conjugation with free organophasphates • c. Rapid reactivation of AChE of neuromuscular junctions

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  21. Irreversible anticholinesterasesand cholinesterase reactivators • (2) Clinical uses • a. Moderate-severe patients • b.Early use, ineffective for aged phosphorylated AChE • c. More effective on tremor • d.Combination with larger dose of atropine

  22. Irreversible anticholinesterasesand cholinesterase reactivators • (3) Adverse effects • a. Central reactions: i.v. > 500 mg/min • b. Iodine toxic effects • c. overdose: inhibiting AChE

  23. Irreversible anticholinesterasesand cholinesterase reactivators • Other Cholinesterase Reactivators • Pralidoxime chloride (氯解磷定): • saver than PAM • Obidoxime chloride (双复磷): • two active oxime groups; • central active; • overdose: inhibiting AChE

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