INDIRECT-ACTING
CHOLINOMIMETICS
(ANTICHOLINESTERASE)
ANS PHARMACOLOGY
LECTURE 3
Dr. Hiwa K. Saaed HD, MSc. PhD
Department of Pharmacology & Toxicology

Basic Pharmacology of the Indirect-Acting
Cholinomimetics
Q. How do they work?
 By inhibiting ChE, protect Ach from hydrolysis.
 Their pharmacodynamic properties are almost
identical.
 The chief differences between members of the group
are chemical and pharmacokinetic.
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Chemistry
(1) Simple alcohols bearing a quaternary ammonium
group, e.g., edrophonium
(2) Carbamic acid esters of alcohols bearing
-Quaternary ammonium groups (e.g., neostigmine)
-Tertiary ammonium groups (e.g., physostigmine).
(3) Organic derivatives of phosphoric acid
(organophosphates, e.g., echothiophate).
Physostigma venenosum3

Reversible Irreversible bind covalently to ChE.
Carbamates Acridine organophosphates
Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Rivastigmie
Donepezil
tacrine Dyflos (DFP) , Echothiophate Drug
Parathion, Malathion (insecticide)
Diazinon, Tabun, sarin, soman (nerve
gases for chemical warfare)
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Cholinesterase inhibitors

Irreversible cholinesterase inhibitors
 Irreversible: Only the organophosphate inhibitors,
 because they bind covalently to ChE, and can
permanently inactivate the enzyme.
 The effects of organophosphates can last as long
as a week, which is approximately the time,
needed to synthesize a new molecule of ChE.
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In most cases, no.
 however, if Pralidoxime “2-PAM”
(a cholinesterase reactivator) is given
before a process called aging;
 Aging: the organophosphate binds
to ChE and loses one of its alkyl
groups, then it may be possible to
remove the organophosphate from
ChE.
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Q. Is it at all possible to reverse the
effects of organophosphates?

 Edrophonium, Neostigmine,
Pyridostigmine:
 Absorption from the
conjunctiva, skin, and lungs is
predictably poor.
 Distribution into the CNS is
negligible.
 Physostigmine (lipid
soluble):
 is well absorbed from all
sites and can be used
topically in the eye.
 It is distributed into the
CNS and is more toxic
Synthetic quaternary ammonium
agents
Naturally occurring tertiary
amine:
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Absorption, Distribution, and Metabolism
of
All are well absorbed from the skin, lung, gut, and conjunctiva except for
echothiophate; Therefore, dangerous to humans and highly effective as
insecticides.
The organophosphate cholinesterase inhibitors

Thiohosphate (parathion, malathion, and related compounds)
The thiohosphate insecticides (parathion, malathion,
and related compounds) are:
 quite lipid-soluble
 rapidly absorbed by all routes.
They must be activated in the body by conversion to
the oxygen analogs, a process that occurs rapidly in
both insects and vertebrates.
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 are also rapidly metabolized
(detoxify) by other pathways to
inactive products in birds and
mammals but not in insects and
Unfortunately, fish ; these agents
are therefore considered safe
enough for sale to the general
public.
 is not detoxified
effectively in
vertebrates; thus, it is
considerably more
dangerous than
malathion to humans and
livestock and is not
available for general
public use.
Malathion and a few other
organophosphate insecticides Parathion
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Thiohosphate (parathion, malathion, and related compounds)

Actions of AChE Inhibitors
1. CNS:
• Low doses: CNS activation
• High: coma and respiratory arrest
2. Eye, respiratory tract, GI & urinary tract: The same as
muscarinic agonists
3. Cardiovascular:
• Heart: Bradycardia, ↓contraction, ↓COP
• Blood vessels? No effect
4. Neuromuscular junction:
• low dose ↑ force of contraction
• high dose Muscle fasciculation and depolarizing blockade
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The major therapeutic uses of the
cholinomimetics:
1. Eye:
 glaucoma,
 accommodative esotropia
2. Gastrointestinal & Urinary tracts:
 postoperative atony,
 neurogenic bladder
3. Neuromuscular junction:
 myasthenia gravis,
 curare-induced neuromuscular paralysis
NB. Cholinesterase inhibitors, but not direct-acting acetylcholine
receptor agonists; are extremely valuable as therapy for
myasthenia.
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Drugs Used in Myasthenia Gravis
Drug Duration of Action
Diagnosis:
Edrophonium I.V (improvement) 5-15 min
Treatment:
Neostigmine (do not cross BBB) 0.5-2 hours
Pyridostigmine 3-6 hours
Ambenonium 4-8 hours
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Treatment of AChE Poisoning
AChE Adverse effects:
 Excessive cholinergic stimulation
1. Atropine: Reverses muscarinic but not nicotinic
2. Pralidoxime (2-PAM):
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