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

9. Action of neostigmine on acetylcholinesterase

10. 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）

11. 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）

12. 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

13. 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

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

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

16. Irreversible anticholinesterases and cholinesterase reactivators
(2) Toxic symptoms
Acute intoxication
Muscarinic symptoms eye, exocrine glands, respiration, GI tract, urinary tract, CVS
Nicotinic symptoms NN: elevation of BP, increase of HR; NM: tremor of skeletal muscles
Central symptoms excitation, convulsion; depression (advanced phase)

17. Irreversible anticholinesterases and cholinesterase reactivators
Chronic intoxication
usually occupational poisoning
plasma ChE activity ↓
weakness, restlessness, anxiety, tremor, miosis, ……

18. Irreversible anticholinesterases and 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

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

20. Irreversible anticholinesterases and 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

21. 2 1

23. Irreversible anticholinesterases and 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

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

25. Irreversible anticholinesterases and 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