Chapter 11 Cholinomimetic Drugs

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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)

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Acetylcholineacetylcholine is synthesized from choline

and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase

ON

OCH3

CH3

CH3

CH3

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Organ system effects Most of the direct organ system effects of m

uscarinic cholinoceptor stimulants are readily predicted from a knowledge of the effects of parasympathetic nerve stimulation and the distribution of muscarinic receptors.

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1. Eye M-R agonist cause contraction of the smooth musc

le 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 systemIntravenous 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.

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3. Respiratory system ACh contract the smooth muscle of the bron

chial 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 activ

ity 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 m

uscarinic and nicotinic receptors, the brain being relatively richer in muscarinic sites and the spinal cord containing a preponderance of nicotinic sites.

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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.

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In the cardiovascular system, the effects of ACh are chiefly sympathomimetic. Dramatic hypertension is produced by activation of NN-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

OO

CH3

CH3

Pilocarpine

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Pharmacological actions: selectively activate M-R 1.Eye miosis decrease intraocular pressure cyclospasm2. Glands secrete increasingly

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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.

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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 )

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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.

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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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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

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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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Reversible anticholinesterase agents such as Neostigmine. Irreversible anticholinesterase agentsThe organophosphorus inhibitors (e.g., DFP),

form stable conjugates with AChE.

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Steps in the hydrolysis of ACh by AChE

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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 agentsNeostigmine

N O

O

CH3

CH3

N

CH3

CH3

CH3

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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.

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Pharmacologyical PropertiesEye • 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 juncti

ons. • direct action of neostigmine on skeletal mu

scle: activation of the NM receptor.• Promote the release of ACh

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Actions at Other Sites Low doses of anti-ChE agents augment secr

etory responses to nerve stimulation; higher doses actually produce an increase in

the resting rate of secretion.

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Therapeutic UsesParalytic Ileus and Atony of the Urinary Bl

adderIn the treatment of both these conditions, ne

ostigmine 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.

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Myasthenia GravisMyasthenia gravis is a neuromuscular

disease characterized by weakness and marked fatigability of skeletal muscle.

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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.

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myasthenia gravis

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In a subset of 10% of patients with myasth∼enic 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.

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Neostigmine can increase the response of myasthenic muscle to repetitive nerve impulses, primarily by the preservation of endogenous ACh.

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Intoxication by Anticholinergic DrugsIn addition to atropine and other muscarinic

agents, antihistamines, and antidepressants have central and peripheral anticholinergic activity.

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The End!