1.
Cholinergic Agonists
‘Cholinomimetic agents’
Lecture 2
Dr. Hiwa K. Saaed
Department of Pharmacology & Toxicology
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2.
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Cholinergic Agonists

3.
Classification
A. Pharmacologically: by their spectrum of action.
1. Muscarinic agonists:
 Bethanechol
 Methacholine
 Pilocarpine
2. Nicotinic agonists:
 nicotine
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4.
B. mode of action
1. Direct-acting: bind directly to and activate
muscarinic or nicotinic receptors,
Also subdivided chemically:
A. Esters of choline (including acetylcholine,
bethanechol, methacholine and carbachol)
B. Alkaloids (such as muscarine, pilocarpine and
nicotine).
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Classification

5.
2. Indirect-acting:
by inhibiting the hydrolysis of endogenous
acetylcholine. also subdivided to
A. Reversible:
neostigmine, physostigmine, pyridostigmine,
ambenomium, edrophonium, donepezil,
galantamine, rivastigmine, tacrine.
B. Irreversible
echothiophate, isoflurophate
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Classification

6.
Indirect and direct
Some quaternary cholinesterase inhibitors also
have a modest DIRECT action as well,
example, neostigmine, which activates
neuromuscular nicotinic cholinoceptors directly
in addition to blocking cholinesterase.
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7.
Basic Pharmacology of Direct-acting
 Muscarinic and Nicotinic agents
Acetylcholine & Carbachol: have effects on both
receptors.
 muscarinic agents;
‘Pilocarpine and Bethanechol’ preferentially bind
to muscarinic receptors.
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8.
Pharmacokinetics
 All the direct-acting cholinergic drugs have
longer durations of action than Ach.
 Choline esters are poorly absorbed and
poorly distributed into the CNS because they
are hydrophilic.
 The tertiary cholinomimetic alkaloids
(pilocarpine, nicotine, lobeline) are well
absorbed from most sites of administration.
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9.
Pharmacokinetics
 Although all are hydrolyzed in the
gastrointestinal tract (and less active by the oral
route).
 they differ markedly in their susceptibility to
hydrolysis by cholinesterase.
1. Acetylcholine is very rapidly hydrolyzed.
2. Methacholine 3 times more resistant to
hydrolysis
3. Carbachol & Bethanechol are extremely
resistant to hydrolysis.
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10.
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 Pharmacology of Ach-like agonist

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 Although, it affects almost every system within
the body. it is therapeutically of no
importance!!!! because of
1. its multiplicity of actions,
2. and its rapid inactivation by the cholinesterases.
A. Acetylcholine (Ach)
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12.
Acetylcholine (Ach)
 CVS: it ↓s heart rate, contractility, and blood
pressure.
 GIT: it ↑s motility of the GIT and bladder.
 Pulmonary system: it ↑s secretions of the
bronchioles
 Eye: miosis and accommodation.
 PNS: contraction of skeletal muscle
 CNS: it affects neurotransmission
 Endocrine system: it causes release of
epinephrine from the adrenal medulla (via Nn
receptors).
 And it stimulates sweat gland secretions.
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13.
Response mediated by Muscarinic
receptors
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14.
Response mediated by Nicotinic
receptors
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15.
Adverse effects:
excessive generalized cholinergic stimulation
DUMBLES:
• Diarrhea and decreased BP,
• Urination,
• Miosis,
• Bronchoconstriction,
• Lacrimation,
• Excitation of skeletal muscle,
• Salivation and Sweating
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B. Bethanechol
 It has duration of action of about one hour.
 Its major action on the smooth musculature of the bladder
and GIT, causing increased intestinal motility and tone.
 (BBB- Bethanechol stimulates the Bladder and Bowel)
Therapeutic Uses:
 to stimulate the atonic bladder in postoperative, non-
obstructive urinary retention.
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C. Carbachol actions:
 Systemically: Carbachol has profound effects on both
the CVS and the GIT
 because of its ganglion (Nn receptor) stimulating
activity, and it may first stimulate and then depress
these systems.
 It can cause release of epinephrine from the adrenal
medulla by its nicotinic action.
 Locally instilled into the eye, it mimics the effects of
Ach, causing miosis and a spasm of accommodation.
 is rarely used therapeutically except in the eye to treat
glaucoma. Because of its high potency, and relatively
long duration of action.
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 Act on muscarinic receptors
 Used in diagnosis of asthma and
bronchial hyperreactivity
D. Methacholine
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E. Pilocarpine (an alkaloid)
 is a tertiary amine, and is stable not hydrolyzed
by AchE.
 It is far less potent compared with Ach and its
derivatives.
 Pilocarpine exhibits muscarinic activity
 is used primarily in ophthalmology, topically
produces a rapid miosis and contraction of the
ciliary muscle; a spasm of accommodation; the
vision is fixed at some particular distance, making
it impossible to focus.
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E. Pilocarpine action

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 Pilocarpine is one of the most potent
stimulators of secretions such as sweat, tears,
and saliva,
 but its lack of selectivity (adverse effects)
limited its use:
1. can enter the brain and causes CNS
disturbances.
2. It stimulates profuse sweating and salivation.
Pilocarpine actions:
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22.
Sjogren syndrome
 Sjogren syndrome, immunologic disorder with
destruction of the exocrine glands leading to
the mucosal dryness (dry mouth and lack of
tears)
 is usually treated with cevimeline, a cholinergic
drug that also has the drawback of being
nonspecific.
 Recent studies have shown that mouth sprays
of Pilocarpine are beneficial in promoting
salivation in patients with Xerostomia (dryness
of the mouth).
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is the DOC in the emergency lowering of IOP of both narrow-angle
and a wide-angle glaucoma.
Therapeutic use in glaucoma:
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is extremely effective in
opening the trabecular
meshwork around
Schlemm canal result in
an increased drainage of
aqueous humor

24.
Organ system effects of cholinergic agonists
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25.
INDIRECT-ACTING
CHOLINOMIMETICS
(ANTICHOLINESTERASE)
Dr. Hiwa K. Saaed
Department of Pharmacology & Toxicology

26.
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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27.
Chemistry of the Indirect-Acting
Cholinomimetics
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 venenosum27

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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

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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.
Q. Is it at all possible to reverse the effects of organophosphates? In
most cases, no.
However, if Pralidoxime “2-PAM” (a cholinesterase reactivator) is
given before a process called aging.
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 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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Aging:

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 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
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

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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)
• 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.

33.
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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34.
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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36.
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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