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Cholinesterase inhibitors

Cholinesterase inhibitors. R1 이영석. Cholinergic agonist. Direct acting acetylcholine, methacholine, bethanechol, carbachol Indirect acting (reversible) neostigmine, edrophonium pyridostigmine, physostigmine Indirect acting (irreversible)

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Cholinesterase inhibitors

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  1. Cholinesterase inhibitors R1 이영석

  2. Cholinergic agonist • Direct acting acetylcholine, methacholine, bethanechol, carbachol • Indirect acting (reversible) neostigmine, edrophonium pyridostigmine, physostigmine • Indirect acting (irreversible) organophosphate (pesticides)

  3. Cholinergic pharmacology

  4. Acetycholine • Entire parasympathetic nervous system (parasympathetic ganglions & effector cells) • Parts of the sympathetic nervous system (sympathetic ganglions, adrenal medulla, sweat gl) • Some neurons in the CNS • Somatic nerves innervating skeletal m.

  5. Cholinergic receptors • Nicotinic receptor -> autonomic ganglia & skeletal m -> blocked by neuromuscular blockers • Affinity muscarine < acetylcholine < nicotine

  6. Cholinergic receptors • Muscarinic receptor -> end-organ effector cells in bronchial smooth m, salivary gl, SA node -> blocked by anticholinergic drugs • Affinity muscarine > acetylcholine > nicotine

  7. Cholinergic receptors

  8. Mechanism of action • Normal neuromuscular transmission -> Ach. binding to nicotinic cholinergic receptor on motor end plate • Nondepolarizing muscle relaxantsact by competing with Ach.

  9. Mechanism of action • Primary clinical use -> reverse nondepolarizing muscle blockade • Reversal of blockade-spontaneous reversal-pharmacological reversal by specific reversal agent • Nondepolarizing agent 와 경쟁할 수 있는 acetylcholine의 양을 간접적으로 증가시킴 -> normal neuromuscular transmission

  10. Mechanism of action • In excessive doses, cholineseterase inhibitors paradoxically potentiate a nondepolarizing NM blockade • Prolong the depolarization blockade of succinylcholine

  11. Mechanism of action • nicotinic  Acetylcholine  muscarinic • Reversing neuromuscular blockade-> maximize nicotinic transmission-> minimize muscarinic side effects

  12. Parasympathetic nervous system

  13. Anticholinergics 을 사용함으로써 cholinesterase inhibitor의 side effect를 최소화 할 수 있다 - atropine - glycopyrroate - scopolamine Clinical pharmacology

  14. Clinical pharmacology • Dosage requirements는 neuromuscular block의 정도에 따라 다름. • Block의 정도는 pph.nerve stimulation에 대한 반응에 따라 추정 • Reversal이 시도되기 전에 spontaneous recovery의 증거가 있어야 함(the 1st twitch of the TOF)

  15. Clinical pharmacology • Full reversal에 요구되는 시간-cholinesterase inhibitor의 종류와 용량-길항될 muscle relaxant의 종류-reversal전의 blockade의 정도 • edrophonium 은 neostigmine 보다 빨리 반응 neostigmine은 large dose 시에 더빨리 반응 • Intermediate-acting m. relaxants > long-acting m. relaxants • Shallow block > deep block

  16. Clinical pharmacology • Reversal agent ->nondepolarizing m. relaxant를 투여한 경우 routinely administration • pph. nerve stimulation-monitoring the progress and confirm the adequacy of reversal • Suggested end points of recovery-anesthesized pt.: sustained tetanus for 5s in response to a 100Hz stimulus-awake pt.: sustained head lift

  17. Specific cholinesterase inhibitors

  18. Neostigmine Neostigmine • Physical structure -Lipid insoluble, BBB통과 못함

  19. Neostigmine • Dosage and packaging-0.04-0.08 mg/kg (up to 5mg in adult)-10mL of a 1mg/mL • Clinical consideration-Effect apparent in 5-10 min peak at 10 min last more than 1h-Pediatric and elderly patients 는 more sensitive, rapid onset -> small dose사용

  20. Neostigmine -glycopyrrolate와 병용 (0.2mg per 1mg of neostigmine) -placenta 를 통과하여 fetal bradycardia 유발 가능하므로 임산부에서는 atropine 선택 -intrathecal anesthesia시 보조약제로 사용 (50-100 ug) -> prolongation of sensory and motor blockade -Side effect nausea, vomiting, incontinence, delayed recovery room discharge, atropine-resistant bradycardia (higher dose, 200ug)

  21. Pyridostigmine Pyridostigmine • Physical structure -Lipid insoluble, BBB통과 못함

  22. Pyridostigmine • Dosage and packaging-0.4mg/kg (total 20mg in adults) -solution of 5mg/mL • Clinical consideration-onset of action slower (10-15 min) duration longer (>2h) vs neostigmine -glycopyrrolate (0.05mg per 1mg of pyridostigmine) or atropine (0.1mg per 1mg of pyridostigmine) -glycopyrolate가 더 선호됨

  23. Edrophonium Edrophonium • Physical structure

  24. Edrophonium • Dosage & Packaging -neostigmine의 1/10의 potency -0.5-1mg/kg-solution of 10mg/10mL • Clinical Considerations -higher dose : action duration을 1시간 이상 연장 -rapid onset of action (1-2min), shortest duration of effect -mivacurium blockade의 reversal에 효과적 -intense neuromuscular blockade에는 부적합 -atropine(0.014mg/1mg of edrophonium)

  25. Physostigmine Physostigmine • Physical structure -lipid soluble, BBB통과

  26. Physostigmine • Dosage & Packaging -0.01-0.03mg/kg -solution containing 1mg/1mL • Clinical Considerations -lipid solubility, CNS penetration -nondepol. blockade reversal agent로 유용성 제한 -central anticholinergic toxicity의 치료에 효과적 (atropine과 scopolamine의 overdose로 인한 ) -benzodiazepine과 흡입 마취제로 인한 CNS depression과 delirium의 reversal에 사용

  27. Physostigmine -0.04mg/kg: postop. shivering에 효과적 -morphine induced respiratory depression을 antagonize -Side effect :excessive salivation, vomiting, convulsion - plasma esterase에 의해 완전히 대사되므로 renal excretion은 중요치 않음

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