Cholinergic Drugs

CHOLINERGIC DRUGS

(Cholinomimetic, Parasympathomimetic)

These are drugs which produce actions similar to that of ACh, either by directly interacting with cholinergic receptors (cholinergic agonists) or by increasing availability of ACh at these sites (anticholinesterases).

     CHOLINERGIC AGONISTS

Choline esters           Alkaloids

Acetylcholine           Muscarine

Methacholine            Pilocarpine

Carbachol                 Arecoline

Bethanechol

Actions (Of Ach As Prototype)

Depending on the type of receptor through which it is mediated, the peripheral actions of ACh are classified as muscarinic or nicotinic. The central actions are not so classifiable and are described separately.

A. Muscarinic

1.  Heart

ACh hyperpolarizes the SA nodal cells and decreases the rate of diastolic depolarization. As a result, rate of impulse generation is reduced—bradycardia or even cardiac arrest may occur.

At the AV node and His-Purkinje fibres refractory period (RP) is increased and conduction is slowed: PR interval increases and partial to complete AV block may be produced. The force of atrial contraction is markedly reduced and RP of atrial fibres is abbreviated. Due to nonuniform vagal innervation, the intensity of effect on RP and conduction of different atrial fibres varies— inducing inhomogeneity and predisposing to atrial fibrillation or flutter.

Ventricular contractility is also decreased but the effect is not marked. The cardiac muscarinic receptors are of the M₂ subtype.

2. Blood vessels

All blood vessels are dilated, though only few (skin of face, neck, salivary glands) receive cholinergic innervation. Fall in BP and flushing, especially in the blush area occurs. Muscarinic (M₃) receptors are present on vascular endothelial cells: vasodilatation is primarily mediated through the release of an endothelium dependent relaxing factor (EDRF) which is nitric oxide (NO). It may also be due to inhibitory action of ACh on NA release from tonically active vasoconstrictor nerve endings.

Stimulation of cholinergic nerves to the penis causes erection by releasing NO and dilating cavernosal vessels through M₃ receptors. However, this response is minimal with injected cholinomimetic drugs.

3.  Smooth Muscle

Smooth muscle in most organs is contracted (mainly through M₃ receptors). Tone and peristalsis in the gastrointestinal tract is increased and sphincters relax → abdominal cramps and evacuation of bowel.

Peristalsis in ureter is increased. The detrusor muscle contracts while the bladder trigone and sphincter relaxes → voiding of bladder.

Bronchial muscles constrict, asthmatics are highly sensitive → dyspnoea, precipitation of an attack of bronchial asthma.

4. Glands

Secretion from all parasympathetically innervated glands is increased via M₃ and some M₂ receptors: sweating, salivation, lacrimation, tracheobronchial and gastric secretion. The effect on pancreatic and intestinal glands is not marked. Secretion of milk and bile is not affected.

5. Eye

Contraction of circular muscle of iris → miosis.

Contraction of ciliary muscle → spasm of accommodation, increased outflow facility, reduction in intraocular tension (especially in glaucomatous patients).

B. Nicotinic

1. Autonomic Ganglia

Both sympathetic and parasympathetic ganglia are stimulated. This effect is manifested at higher doses. High dose of ACh given after atropine causes tachycardia and rise in BP due to stimulation of sympathetic ganglia and release of catecholamines.

2. Skeletal Muscles

Iontophoretic application of ACh to muscle endplate causes contraction of the fibre. Intraarterial injection of high dose can cause twitching and fasciculations, but i.v. injection is generally without any effect (due to rapid hydrolysis of ACh).

C. CNS

ACh injected i.v. does not penetrate bloodbrain barrier and no central effects are seen. However, direct injection into the brain, or other cholinergic drugs which enter brain, produce a complex pattern of stimulation followed by depression.

The important features of other choline esters are summarized in Table 7.5.

Interactions

Anticholinesterases potentiate ACh markedly, methacholine to less extent and have only additive action with carbachol or bethanechol, depending upon the role of ChE in the termination of action of the particular choline ester. Atropine and its congeners competitively antagonize muscarinic actions.

Adrenaline is a physiological antagonist.

Uses

Choline esters are rarely, if ever, clinically used. ACh is not used because of evanescent and nonselective action. Methacholine was occasionally used to terminate paroxysmal supraventricular tachycardia but is obsolete now.

Bethanechol has been used in postoperative/ postpartum nonobstructive urinary retention, neurogenic bladder, congenital megacolon and gastroesophageal reflux. Side effects are prominent: belching, colic, involuntary urination/ defecation, flushing, sweating, fall in BP, bronchospasm.

Dose: 10–40 mg oral, 2.5–5 mg s.c.; UROTONIN 25 mg tab.