Chapter 11

Cholinomimetic Drugs
2
The Direct-acting Cholinoceptor
Stimulants
The direct-acting cholinomimetic drugs can
be divided on the basis of chemical
structure
esters of choline (including acetylcholine)
alkaloids (such as muscarine and nicotine)
3
Acetylcholine
acetylcholine is synthesized from choline
and acetyl Co-A (AcCoA) by the
enzyme choline acetyltransferase

O
N
O
CH
3
CH
3
C H
3
C H
3
4
5
Organ system effects
Most of the direct organ system effects of
muscarinic cholinoceptor stimulants are
readily predicted from a knowledge of the
effects of parasympathetic nerve
stimulation and the distribution of
muscarinic receptors.
6
1. Eye
M-R agonist cause contraction of the smooth
muscle of the iris sphincter (resulting in miosis)
and of the ciliary muscle (resulting in
accommodation).
the iris is pulled away from the angle of the
anterior chamber, and the trabecular meshwork
at the base of the ciliary muscle is opened.
Both effects facilitate aqueous humor outflow into
the canal of Schlemm, which drains the anterior
chamber.
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2. Cardiovascular system
Intravenous infusions of minimally effective
doses of acetylcholine in humans cause
vasodilation, resulting in a reduction in
blood pressure, often accompanied by a
reflex increase in heart rate.
Larger doses of acetylcholine produce
bradycardia and decrease atrioventricular
node conduction velocity in addition to
hypotension.
9
3. Respiratory system
ACh contract the smooth muscle of the
bronchial tree. In addition, the glands of
the bronchial mucosa are stimulated to
secrete. This combination of effects can
occasionally cause symptoms, especially
in individuals with asthma.
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4. Gastrointestinal tract
ACh increases the secretory and motor
activity of the gut. The salivary and gastric
glands are strongly stimulated; the
pancreas and small intestinal glands less
so.
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5. Central nervous system
The central nervous system contains both
muscarinic and nicotinic receptors, the
brain being relatively richer in muscarinic
sites and the spinal cord containing a
preponderance of nicotinic sites.
12
6. Peripheral nervous system
Autonomic ganglia are important sites of
nicotinic synaptic action. The action is the
same on both parasympathetic and
sympathetic ganglia. The initial response
therefore often resembles simultaneous
discharge of both the parasympathetic and
the sympathetic nervous systems.
13
In the cardiovascular system, the effects of
ACh are chiefly sympathomimetic.
Dramatic hypertension is produced by
activation of N
N
-R.
In the gastrointestinal and urinary tracts, the
effects are largely parasympathomimetic:
nausea, vomiting, diarrhea, and voiding of
urine are commonly observed.
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N
N
O
O
C H
3
CH
3
Pilocarpine
15
Pharmacological actions:
selectively activate M-R
1.Eye
miosis
decrease intraocular pressure
cyclospasm
2. Glands secrete increasingly
16
The anterior chamber is the site of several
tissues controlled by the ANS.
These tissues include three different
muscles (pupillary dilator and constrictor
muscles in the iris and the ciliary muscle)
and the secretory epithelium of the ciliary
body.
17
Pilocarpine mediate contraction of the
circular pupillary constrictor muscle and of
the ciliary muscle. Contraction of the
pupillary constrictor muscle causes miosis,
a reduction in pupil size.
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pupilloconstrictor
(cholinergic nerve)
dilator muscle of pupil
(noradrenergic nerve )
19
Aqueous humor, a transparent fluid produced by the ciliary
epithelium of the ciliary body, flows from the posterior
chamber through the pupil to the anterior chamber. It then
flows peripherally and filters through the trabecular
meshwork to the canal of Schlemm, through which the
fluid enters venous circulation.
20
Ciliary muscle contraction also puts tension
on the trabecular meshwork, opening its
pores and facilitating outflow of the
aqueous humor into the canal of Schlemm.
Increased outflow reduces intraocular
pressure, a very useful result in patients
with glaucoma.
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22
Ciliary muscle contraction causes
accommodation of focus for near vision.
Marked contraction of the ciliary muscle,
which often occurs with cholinesterase
inhibitor intoxication, is called cyclospasm.
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Clinical uses
1.Glaucoma
Glaucoma is actually a group of diseases that
are distinguished by an increase in
pressure inside the eye that causes
damage to the optic nerve and to the retina.
angle-closure glaucoma
open-angle glaucoma
2.iritis
Anticholinesterase agents

26
Acetylcholinesterase (AChE) terminates the action
of acetylcholine (ACh) at the junctions of the
various cholinergic nerve endings with their
effector organs or postsynaptic sites. Inhibitors
of AChE, or anticholinesterase (anti-ChE) agents,
cause ACh to accumulate in the vicinity of
cholinergic nerve terminals and thus can
produce effects equivalent to excessive
stimulation of cholinergic receptors throughout
the central and peripheral nervous systems.
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28
Reversible anticholinesterase agents
such as Neostigmine.
Irreversible anticholinesterase agents
The organophosphorus inhibitors (e.g., DFP),
form stable conjugates with AChE.

29
Steps in the hydrolysis of ACh by AChE
30
Acetylcholine (ACh) catalysis:
Binding of ACh, formation of a transition state,
formation of the acetyl enzyme with liberation of
choline, rapid hydrolysis of the acetyl enzyme
with return to the original state.
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Reversible Anticholinesterase agents
Neostigmine
N O
O
C H
3
CH
3
N
CH
3
CH
3
CH
3
32
Neostigmine reaction with and inhibition of
acetylcholinesterase (AChE): reversible binding
of neostigmine formation of the dimethyl
carbamoyl enzyme slow hydrolysis of the
dimethyl carbamoyl enzyme.
33
Pharmacologyical Properties
Eye
cause constriction of the pupillary
sphincter muscle around the pupillary
margin of the iris (miosis).
cause constriction of the ciliary muscle
(block of accommodation reflex with
resultant focusing to near vision).
Intraocular pressure falls, as the result of
facilitation of outflow of the aqueous
humor.
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Gastrointestinal Tract
Neostigmine enhances gastric contractions,
increases the secretion of gastric acid.
Neostigmine augments GI motor activity; the
colon is particularly stimulated. Propulsive
waves are increased in amplitude and
frequency, and movement of intestinal
contents is thus promoted.
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Neuromuscular Junction
inhibition of AChE at neuromuscular
junctions.
direct action of neostigmine on skeletal
muscle: activation of the N
M
receptor.
Promote the release of ACh
36
Actions at Other Sites
Low doses of anti-ChE agents augment
secretory responses to nerve stimulation;
higher doses actually produce an increase in
the resting rate of secretion.
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Therapeutic Uses
Paralytic Ileus and Atony of the Urinary
Bladder
In the treatment of both these conditions,
neostigmine generally is preferred among
the anti-ChE agents.
Neostigmine should not be used when the
intestine or urinary bladder is obstructed,
when the viability of the bowel is doubtful,
or when bowel dysfunction results from
inflammatory bowel disease.
38
Myasthenia Gravis
Myasthenia gravis is a neuromuscular
disease characterized by weakness and
marked fatigability of skeletal muscle.
39
Myasthenia gravis is caused by an
autoimmune response primarily to the ACh
receptor at the postjunctional endplate.
These antibodies reduce the number of
receptors detectable by receptor-binding
assays and electrophysiological
measurements of ACh sensitivity.
40
myasthenia gravis
41
In a subset of 10% of patients with
myasthenic syndrome, muscle weakness
has a congenital rather than an
autoimmune basis, with mutations in the
ACh receptor that affect ligand-binding
and channel-opening kinetics.
Administration of anti-ChE agents does not
result in subjective improvement in most
congenital myasthenic patients.
42
Neostigmine can increase the response of
myasthenic muscle to repetitive nerve
impulses, primarily by the preservation of
endogenous ACh.
43
Intoxication by Anticholinergic Drugs
In addition to atropine and other muscarinic
agents, antihistamines, and
antidepressants have central and
peripheral anticholinergic activity.
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The End!