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Cholinesterase-lnhibiting Drugs
Department of pharmacology
Zhu ling (朱玲)
2010.3
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
The indirect-acting agents produce their
primary effects by inhibiting the action of
acetylcholinesterase (AchE), which
hydrolyzes acetylcholine to choline and
acetic acid.
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Cholinesterase-lnhibiting Drugs

Anticholinesterases are drugs that inhibit or
inactivate acectylcholinesterase, causing the
accumulation of acetylcholine at the
cholinergic receptors. This produces effects
similar to prolonged stimulation of
cholinergic fibers.
 Classified by the stability of the enzyme-drug
complex (marked differences in duration of action)
Reversible Cholinesterase-lnhibiting Drugs
neostigimine
physostigimine
Irrevesible Cholinesterase-lnhibiting Drugs
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organophosphates
Neostigmine 新斯的明
1 Pharmacokinetics
Quaternary ammonium agent
Oral absorption is predictable poor
much larger doses (at least 10 multiple) are
required for oral administration than for
parenteral injection
Distribution into the CNS is negligible
(difficult penetrate blood-brain barrier)
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Neostigmine 新斯的明
2 Mechanism of action
inhibit acectylcholinesterase, causing the
accumulation of acetylcholine at the
cholinergic receptors.
muscarinic and nicotinic action
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‘-’ anionic site
(process 150ms)
‘ser-o’ hydrolyzable covalent bond at the eseratic site
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‘-’ anionic site
(process hours)
‘ser-o’ hydrolyzable covalent bond at the eseratic site
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Neostigmine 新斯的明
 3.Effects and clinical uses
1) skeletal muscle :contraction
inhibit AchE， accumulation of Ach
at the cholinergic receptors;
activate neuromuscular nicotinic
cholinoceptors directly in addition to
blocking cholinesterase;
promote motor nerve to release Ach
* therapy of myasthenia gravis
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Neostigmine 新斯的明

Myasthenia gravis
A disease affecting skeletal muscle neuromuscular
junction. An autoimmune process causes production
of antibodies that decrease the number of functional
nicotinic receptor on the postjunctional endplates.
Symptoms: weakness and fatigability (remit with rest
and worsen with exercise); affect skeletal muscle
(small muscle: ptosis
all muscle:dyspnea)

therapy: usually oral administration，severe
or emergency subcutaneously or i.m.
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Neostigmine 新斯的明
2) gastrointestinal and bladder smooth muscle
exciting (muscrinic effect)
* therapy: postoperative abdominal distention
(postoperative ileus,atony or paralysis of the stomach
or bowel following surgical manipulation) and
urinary retention (atony of the urinary bladder)
3) * therapy: treatment of overdose of the
nondepolarizing neuromuscular relaxants;
reverses the peripheral signs of antimuscarinic
drug intoxication (eg. atropine)
(central signs use Physostigimine)
4) modest bradycardia
*
treatment of paroxysmal supraventricular
tachycardia (in the past)
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Neostigmine 新斯的明
4.toxicity
 Therapeutic dosage : few side effects
 Excessive drug therapy :cholinergic crisis
（ worsen myasthenic signs ）
small dose of edrophonium used to distinguish,
emergency and support systems avilable

contraindication：asthma, atrioventricular
block, mechanical obstruction
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Cholinesterase-lnhibiting Drugs
Physostigimine
(eserine)
clinic- glaucoma
al uses refresh after
anesthetics
(analeptic)
action
tertiary nitrogens
Lipid-solubility
Pyridostig- Edrophon- ambenoniu
mine
ium(tensil m
on)
myastheni myastheni myasthenia
a gravis
a gravis
gravis
diagnose
and
Distinguish
long
rapid and
similar to
duration
short effect neostigmine
poor selectivity
weak effect weak effect long
Local
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duration
medication
Irreversible Cholinesterase-lnhibiting
Drugs
organophosphates
Organophosphates inhibitor poisoning and
treatment
1. Insecticides and chemical warfare
pesticides: isoflurophate (DFP), parathion,
malathion, DDVP(dichlorvos) , dipterex, rogor
“nerve (war) gas” soman, sarin, tabun et al.
2. Mechanism of organophosphates inhibitor
poisoning
‘-’ anionic site
(process hundreds of hours)
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‘ser-o’ covalent bond at the eseratic site (stable and slow hydrolyze)
3 signs of organophosphates inhibitor
poisoning
Muscarinic signs ：eye, gland, smooth muscle
 Nicotinic signs ： N1
ganglia excite (all of
autonomic nerve excite)
N2
neuromuscular junction (skeletal
muscle contraction muscle tremble)
 CNS effects：stimulate (tremor, emesis, mania,
stimulant respiratory center et al)
inhibit (convulsion coma)

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1) Muscarinic effect
cardiovascular system↓
miosis
glands secretion ↑
smooth muscle↑
2) nicotinic effect
to excite ganglia
adrenal medulla secrete Adr
cardiovascular system: ↑
smooth muscle ↑
glands secretion ↑
skeletal muscle ↑
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4. Treatment of organophosphates
inhibitor poisoning

Maintenance of vital signs—respiration in
particular may be impaired
 Decontamination to prevent further
absorption removal of all clothing,
washing of the skin and stomach,
conducting of rushing down ,et al
 Therapy includes treatment with atropine
and cholinesterase reactivators
 Others
sedation et al
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cholinesterase reactivators

cholinesterase reactivators
a class of oxime compounds, capable of
regenerating active enzyme (AchE) from
the organophosphorus-cholinesterase
complex, available for the treatment of
organophosphates poisoning inhibit.
These oxime agents include
Pralidoxime PAM-Cl（氯解磷定）
Pralidoxime iodide PAM（碘解磷定）
iacetylmonoxime DAM and others
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cholinesterase reactivators
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cholinesterase reactivators
1 treatment
 Obviously reverse nicotinic effects，
rapidly inhibit skeletal muscle tremble
 Poorly control muscarinic effects
 relieve part of CNS effects
2 principle of application
 Early, large dose (enough dose), repeat
administration
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cholinesterase reactivators
3. Mechanism
1) reactivating active enzyme (AChE) by splitting off
the phosphorus from the
organophosphoruscholinesterase complex
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2) binding of free organophosphates
cholinesterase
reactivators
3. Mechanism
1) organophosphates+ AchE
Phosphorylated AchE
Phosphorylated PAM
regenerating active
AchE
PAM
2) PAM +organophosphates
Phosphorylated PAM
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cholinesterase reactivators
4. adverse reaction
 Local prickle (ache)
 Instead inhibit AchE when overdosage
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