Part 2 Parasympathomimetics Cholinoceptor agonists: M, N Anticholinesterase inhibitors

Part 2Part 2

ParasympathomimeticsParasympathomimetics

Cholinoceptor agonists: Cholinoceptor agonists: M, NM, N

Anticholinesterase inhibitorsAnticholinesterase inhibitors

A A Muscarinic receptor Muscarinic receptor agonistsagonists

A A Muscarinic receptor agonistsMuscarinic receptor agonists

1. 1. Choline Esters Choline Esters ((胆碱酯类胆碱酯类 ))

Acetylcholine Acetylcholine 乙酰胆碱乙酰胆碱 Carbachol Carbachol 卡巴胆碱卡巴胆碱 Methacholine Methacholine 醋甲胆碱醋甲胆碱 Bethanechol chloride Bethanechol chloride 氯贝胆碱氯贝胆碱

2.2. Natural Alkaloids Natural Alkaloids ((生物碱类生物碱类 ))

PilocarpinePilocarpine 毛果芸香碱（匹罗卡品）毛果芸香碱（匹罗卡品） Muscarine Muscarine 毒蕈碱毒蕈碱

Pilocarpine Pilocarpine 毛果芸香碱（匹罗卡品）毛果芸香碱（匹罗卡品）

O NO

H5C2 CH2 CH3

H3C

H3C

H3CCH2CH2OCOCH3N

+

�Pilocarpine Pilocarpine 毛果芸香碱毛果芸香碱


1. 1. Pharmacological effectsPharmacological effects（（ 11 ）） EyesEyes MiosisMiosis （（缩瞳缩瞳）） :: contraction of sphincter muscle

of iris

Lowing intraocular pressureLowing intraocular pressure （（降低眼内压降低眼内压）） :: enlarging angle of anterior chamber, increasing drainage of aquous humor

Spasm of accommodationSpasm of accommodation （（调节痉挛调节痉挛）） :: contraction of ciliary muscle, contraction for near vision


Iris, cilliary musIris, cilliary muscles, and Schelecles, and Schele

mm canalmm canal

Aqueous humor drainageAqueous humor drainage

PilocarpinePilocarpine

AtropineAtropine

（（ 22 ）） Promoting secretion of exocrine glPromoting secretion of exocrine glandsands （（外分泌腺体外分泌腺体））

especially in sweat, salivary and tear glandsespecially in sweat, salivary and tear glands


2. 2. Clinical usesClinical uses（（ 11 ）） Ophthamological usesOphthamological uses Glaucoma:Glaucoma: narrow- narrow- oror wide-angleswide-angles Iritis:Iritis: miotics/mydriaticsmiotics/mydriatics

BOXBOX GlaucomaGlaucomaAcute congestive glaucomaAcute congestive glaucoma （（ narrow-narrow-

angleangle ））Chronic simple glaucomaChronic simple glaucoma （（ wide-anglewide-angle ））


（（ 22 ）） Systemic useSystemic use

Dry mouth: Dry mouth: radiotherapyradiotherapy Antidote for atropine poisoning Antidote for atropine poisoning


3. 3. Adverse effectsAdverse effects

（（ 11 ）） Local (eye): Local (eye): pain, tearspain, tears

（（ 22 ）） Systemic: Systemic: secretion of exocrinsecretion of exocrine glands, treated with atropine e glands, treated with atropine


B B AnticholinesterasesAnticholinesterases

1. Reversible anticholinesterases1. Reversible anticholinesterases

2. Irreversible anticholinesterases2. Irreversible anticholinesterases

anionic site esteratic siteanionic site esteratic site

Acetylcholinesterase is the mechanism of terAcetylcholinesterase is the mechanism of terminating ACh effectsminating ACh effects

B-1 B-1 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 receptorreceptor

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）） :: symptomatic trsymptomatic treatment, overdose: cholinergic crisiseatment, overdose: cholinergic crisis

(2) Paralytic ileus and bladder(2) Paralytic ileus and bladder （（手术后肠道及膀胱麻痹手术后肠道及膀胱麻痹）） : : post operative abdominal distension and urinary retepost operative abdominal distension and urinary retentionntion

((3) Antidote for nondepolarizing skeletal muscle relax3) Antidote for nondepolarizing skeletal muscle relaxants poisoningants 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 （（阵发性阵发性室上性心动过速室上性心动过速））


3. 3. Adverse effectsAdverse effects

（（ 11 ）） Cholinergic effects: Cholinergic effects: muscarinic and nicotimuscarinic and nicotinic effects, treated with atropine (muscarinic)nic 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 relaxantspoisoning of depolarizing skeletal muscle relaxants （（除极化型肌松药中毒除极化型肌松药中毒））

B -1 B -1 Reversible anticholinesterasesReversible anticholinesterases

Other reversible anticholinesteraseOther reversible anticholinesterasess

Pyridostigmine (Pyridostigmine ( 吡斯的明吡斯的明 ): ): myasthenia gravis, myasthenia gravis, paralytic ileus and bladderparalytic 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 )) ：： myasthemyasthenia gravisnia gravis

Galantarmine (Galantarmine ( 加兰他敏加兰他敏 )) ：： myasthenia gravismyasthenia gravis


Anticholinesterases improving memorAnticholinesterases improving memoryy

Tacrine (Tacrine ( 他克林他克林 )) ：： improving memory / improving memory / hepatic thepatic toxicityoxicity

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 patientused in mild/moderate Alzheimer patient

ss

Huperzine (Huperzine ( 哈伯因，石杉碱甲哈伯因，石杉碱甲 )) ：： myasthenia gravis, myasthenia gravis, improviimproving memoryng memory


B-2 B-2 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 AChE bIrreversible binding to esteric site of AChE by covalent attachmenty covalent attachment －－ phosphorylatedphosphorylated ACAChEhE －－ agingaging

ACh accumulated in the synaptic sites, and cACh accumulated in the synaptic sites, and caused toxic effectsaused 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 intoxicationMuscarinic symptomsMuscarinic symptoms eye, exocrine glands, respeye, exocrine glands, resp

iration, GI tract, urinary tract, CVSiration, GI tract, urinary tract, CVS

Nicotinic symptoms Nicotinic symptoms NNNN: : elevation of BP, increase elevation of BP, increase

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

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



Chronic intoxicationChronic intoxication

usually occupational poisoningusually occupational poisoning

plasma ChE activity plasma ChE activity ↓↓

weakness, restlessness, anxiety, treweakness, restlessness, anxiety, tremor, miosis, ……mor, miosis, ……



(3) Detoxication(3) Detoxication

Elimination of poison; Supportive therapyElimination of poison; Supportive therapy

AntidotesAntidotes AtropineAtropine －－ antagonizing muscarinic effects; antagonizing muscarinic effects; earear

ly, larger dose, and repeated usely, larger dose, and repeated use Cholinesterase reactivatorsCholinesterase reactivators －－ reactivation of phreactivation of ph

osphorylated AChE; osphorylated AChE; moderate-severe patients, earlmoderate-severe patients, early use, combined with atropiney 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, conju Recognizing and binding to AChE, conjugating with organophosphate by oxime group gating with organophosphate by oxime group (( 肟基肟基 ))

b.b. Conjugation with free organophasphates Conjugation with free organophasphates

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 phosphorylineffective for aged phosphoryl

ated AChEated AChE c.c. More effective on tremor More effective on tremor d.d. Combination with larger dose of atropineCombination with larger dose of atropine



(3) Adverse effects(3) Adverse effects

a.a. Central reactions: Central reactions: i.v.i.v. > 500 mg/min > 500 mg/min

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



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Part 2 Parasympathomimetics Cholinoceptor agonists: M, N Anticholinesterase inhibitors