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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.
2
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)
4
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.
5
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.
6
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:
7
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.
8
 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
9
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
10
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.
11
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
12
Treatment of AChE Poisoning
AChE Adverse effects:
 Excessive cholinergic stimulation
1. Atropine: Reverses muscarinic but not nicotinic
2. Pralidoxime (2-PAM):
13

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L3:cholinomimetics

  • 1. INDIRECT-ACTING CHOLINOMIMETICS (ANTICHOLINESTERASE) ANS PHARMACOLOGY LECTURE 3 Dr. Hiwa K. Saaed HD, MSc. PhD Department of Pharmacology & Toxicology
  • 2. 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. 2
  • 3. 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
  • 4. 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) 4 Cholinesterase inhibitors
  • 5. 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. 5
  • 6. 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. 6 Q. Is it at all possible to reverse the effects of organophosphates?
  • 7.  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: 7 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
  • 8. 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. 8
  • 9.  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 9 Thiohosphate (parathion, malathion, and related compounds)
  • 10. 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 10
  • 11. 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. 11
  • 12. 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 12
  • 13. Treatment of AChE Poisoning AChE Adverse effects:  Excessive cholinergic stimulation 1. Atropine: Reverses muscarinic but not nicotinic 2. Pralidoxime (2-PAM): 13