Anticholinesterases 1. Reversible anticholinesterases 2. Irreversible anticholinesterases.

AnticholinesterasesAnticholinesterases

1. Reversible anticholinesterases1. Reversible anticholinesterases

2. Irreversible anticholinesterases2. Irreversible anticholinesterases

• anionic site esteratic siteanionic site esteratic site

• Acetylcholinesterase is the mechanism Acetylcholinesterase is the mechanism of terminating ACh effectsof terminating ACh effects

Reversible anticholinesterasesReversible anticholinesterases

Action of acetylcholinesteraseAction of acetylcholinesterase

Acetylcholinese:Acetylcholinese: structure for interaction with substratestructure for interaction with substrate

Neostigmine Neostigmine 新斯的明新斯的明

CH3 NCOO

CH3

N +(CH3)3

Neostigmine Neostigmine 新斯的明新斯的明


• 1. 1. Pharmacological effectsPharmacological effects

• binding to AChE, but slowly hydrolysisbinding to AChE, but slowly hydrolysis• inhibiting AChE activityinhibiting AChE activity

• Properties of EffectsProperties of Effects• stronger effect on skeletal musclesstronger effect on skeletal muscles• AChE (-), ACh release, stimulating NAChE (-), ACh release, stimulating NM M receptrecept

oror

• effective on GI tract and urinary bladder effective on GI tract and urinary bladder • more polar and can not enter CNSmore polar and can not enter CNS• relatively ineffective on CVS, glands, eyerelatively ineffective on CVS, glands, eye


Effect of neostigEffect of neostigmine on AChEmine on AChE

Action of neostigmine on acetylcholinesteraseAction of neostigmine on acetylcholinesterase

• 2. 2. Clinical usesClinical uses

• (1) Myasthenia gravis(1) Myasthenia gravis （（重症肌无力重症肌无力）） :: symptomatisymptomatic treatment, overdose: cholinergic crisisc treatment, overdose: cholinergic crisis

• (2) Paralytic ileus and bladder(2) Paralytic ileus and bladder （（手术后肠道及膀胱麻手术后肠道及膀胱麻

痹痹）） : : post operative abdominal distension and upost operative abdominal distension and urinary retentionrinary retention

• ((3) Antidote for nondepolarizing skeletal muscle 3) Antidote for nondepolarizing skeletal muscle relaxants poisoningrelaxants poisoning （（解除非除极化型肌松药中毒解除非除极化型肌松药中毒））

• (4) Paroxysmal superventricular tachycardia(4) Paroxysmal superventricular tachycardia （（阵阵发性室上性心动过速发性室上性心动过速））


• 3. 3. Adverse effectsAdverse effects

• （（ 11 ）） Cholinergic effects: Cholinergic effects: muscarinic and nicomuscarinic and nicotinic effects, treated with atropine (muscarinic)tinic effects, treated with atropine (muscarinic)

• （（ 22 ）） ContraindicationsContraindications ：：• mechanical ileusmechanical ileus （（机械性肠梗阻机械性肠梗阻））• urinary obstructionurinary obstruction （（尿路阻塞尿路阻塞））• bronchial asthmabronchial asthma （（支气管哮喘支气管哮喘））• poisoning of depolarizing skeletal muscle relaxapoisoning of depolarizing skeletal muscle relaxa

ntsnts• （（除极化型肌松药中毒除极化型肌松药中毒））


• Other reversible anticholinesterOther reversible anticholinesterasesases

• Pyridostigmine (Pyridostigmine ( 吡斯的明吡斯的明 ): ): myasthenia gramyasthenia gravis, paralytic ileus and bladdervis, paralytic ileus and bladder

• Physostigmine (Physostigmine ( 毒扁豆碱毒扁豆碱 ): ): glaucomaglaucoma

• Edrophonium chloride (Edrophonium chloride ( 依酚氯铵依酚氯铵 )) ：： myastmyasthenia gravishenia gravis

• Galantarmine (Galantarmine ( 加兰他敏加兰他敏 )) ：： myasthenia gramyasthenia gravisvis


• Anticholinesterases improving meAnticholinesterases improving memorymory

• Tacrine (Tacrine ( 他克林他克林 )) ：： improving memory / improving memory / hepahepatic toxicitytic toxicity

• Donepezil (Donepezil ( 多奈哌齐多奈哌齐 ) ) andand rivastigmine ( rivastigmine ( 利凡斯的明利凡斯的明 ): ):

• improving menory;improving menory; used in mild/moderate Alzheimer used in mild/moderate Alzheimer

patientspatients

• Huperzine (Huperzine ( 哈伯因，石杉碱甲哈伯因，石杉碱甲 )) ：： myasthenia gravis, myasthenia gravis, imimproving memoryproving memory


Irreversible anticholinesterasesIrreversible anticholinesterases and cholinesterase reactivatorsand cholinesterase reactivators

• 1. 1. OrganophosphatesOrganophosphates （（有机磷酸酯类有机磷酸酯类））• (1) Toxicology(1) Toxicology

• Irreversible binding to esteric site of ACIrreversible binding to esteric site of AChE by covalent attachmenthE by covalent attachment －－ phosphoryphosphorylatedlated AChEAChE －－ agingaging

• ACh accumulated in the synaptic sites, aACh accumulated in the synaptic sites, and caused toxic effectsnd caused toxic effects

Irreversibly binding to esteric site of AChE by Irreversibly binding to esteric site of AChE by covalent attachmentcovalent attachment －－ phosphorylated AChEphosphorylated AChE

• (2) Toxic symptoms(2) Toxic symptoms

• Acute intoxicationAcute intoxication• Muscarinic symptomsMuscarinic symptoms eye, exocrine glandeye, exocrine gland

s, respiration, GI tract, urinary tract, CVSs, respiration, GI tract, urinary tract, CVS

• Nicotinic symptoms Nicotinic symptoms NNNN: : elevation of BP, inelevation of BP, in

crease of HR;crease of HR; NNMM: : tremor of skeletal musclestremor of skeletal muscles

• Central symptomsCentral symptoms excitation, convulsion; excitation, convulsion; depression (advanced phase)depression (advanced phase)


• Chronic intoxicationChronic intoxication

• usually occupational poisoningusually occupational poisoning

• plasma ChE activity plasma ChE activity ↓↓

• weakness, restlessness, anxietweakness, restlessness, anxiety, tremor, miosis, ……y, tremor, miosis, ……


• (3) Detoxication(3) Detoxication

• Elimination of poison; Supportive therapElimination of poison; Supportive therapyy

• AntidotesAntidotes • AtropineAtropine －－ antagonizing muscarinic effects; antagonizing muscarinic effects;

early, larger dose, and repeated useearly, larger dose, and repeated use• Cholinesterase reactivatorsCholinesterase reactivators －－ reactivation oreactivation o

f phosphorylated AChE; f phosphorylated AChE; moderate-severe patiemoderate-severe patients, early use, combined with atropinents, early use, combined with atropine


• 2. 2. Cholinesterase reactivatorsCholinesterase reactivators

Pyraloxime methoiodidePyraloxime methoiodide碘解磷定碘解磷定 , , PAMPAM

NCH N OH. I -

CH3

+Recognizing aRecognizing and binding to nd binding to

AChEAChE

oxime groupoxime group Conjugated Conjugated with organo-with organo-phosphatesphosphates


• (1) Pharmacological effects(1) Pharmacological effects

• a.a. Recognizing and binding to AChE, conj Recognizing and binding to AChE, conjugating with organophosphate by oxime grougating with organophosphate by oxime group (up ( 肟基肟基 ))

• b.b. Conjugation with free organophasphate Conjugation with free organophasphatess

• c.c. Rapid reactivation of AChE of neuromu Rapid reactivation of AChE of neuromuscular junctions scular junctions


11

22

• (2) Clinical uses(2) Clinical uses

• a. a. Moderate-severe patientsModerate-severe patients• b.b. Early use, Early use, ineffective for aged phosphineffective for aged phosph

orylated AChEorylated AChE • c.c. More effective on tremor More effective on tremor• d.d. Combination with larger dose of atropiCombination with larger dose of atropi

nene


• (3) Adverse effects(3) Adverse effects

• a.a. Central reactions: Central reactions: i.v.i.v. > 500 mg/ > 500 mg/minmin

• b.b. Iodine toxic effects Iodine toxic effects

• c.c. overdose: inhibiting AChE overdose: inhibiting AChE


• Other Cholinesterase ReactivatorsOther Cholinesterase Reactivators

• Pralidoxime chloride (Pralidoxime chloride ( 氯解磷定氯解磷定 ):):

• saver than PAMsaver than PAM

• Obidoxime chloride (Obidoxime chloride ( 双复磷双复磷 ):):

• two active oxime groups; two active oxime groups;

• central active; central active;

• overdose: inhibiting AChEoverdose: inhibiting AChE


Anticholinesterases 1. Reversible anticholinesterases 2. Irreversible anticholinesterases.

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