Medical Pharmacology Topics   

Preliminary Outline

Cholinergic Agonists   Muscarinic and Nicotinic          Acetylcholine          Carbanylcholine   Muscarinic Only      Quaternary N          Muscarine          Acetyl-beta-             methylcholine          Bethanechol      Tertiary N          Arecholine          Pilocarpine   Nicotinic Only          Nicotine

Cholinergic Receptors and Agonists

Acetylcholine serves as a neurotransmitter at parasympathetic postganglionic terminals, selected sympathetic postganglionic terminals (most sweat glands), all autonomic preganglionic terminals and the neuromuscular junction in skeletal muscle.

Acetylcholine is synthesized in the presynaptic nerve terminals by choline acetyl transferase from acetyl CoA and choline. It is stored in vesicles for later release at the nerve terminal. Acetylcholine in the synaptic cleft is rapidly degraded by cholinesterase.

Key features of cholinergic systems to be exploited with drugs are receptor heterogeneity and rapid degradation of the neurotransmitter by cholinesterase.

Intravenous injection of acetylcholine will exert maximum effect first in the cardiovascular system, second in glands and smooth muscle, third in ganglia, and finally at the neuromuscular junction. Muscarine will exert cholinergic effects in the same sequence but with much larger concentrations needed to show response at ganglia and skeletal muscle. Nicotine will show effects first on ganglia, second at the neuromuscular junction, and at much larger concentrations will show cardiovascular effects and on glands and smooth muscle. According to these responses, cholinergic receptors are classified as muscarinic or nicotinic.

Muscarinic cholinergic receptors (M) are G-protein linked. There are five subtypes (M1 - M5) but to date the only clinically useful selective agent is pirenzepine, a competitive antagonist at M1 receptors.

Nicotinic cholinergic receptors are ligand-gated ion channels that mediate rapid increases in Na+ and K+ permeability, resulting in membrane depolarization. Ganglionic nicotinic receptors (NG) are found in all autonomic gangly, the adrenal medulla and the CNS. Neuromuscular nicotinic receptors (NM) are located at the neuromuscular junction of skeletal muscle.

Many toxins act by disrupting or destroying cholinergic nerve terminals , including botulism toxin (used clinically as botox) and black widow spider venom (alpha-latrotoxin). A variety of compounds synthesized from plants and fungi have agonist activity at muscarinic receptors. Muscarine itself is found in certain mushrooms and is responsible for "fast" mushroom poisoning, characterized by a wide range of parasympathetic effects: bradycardia, hypotension, hypotension due to action on uninervated receptors in blood vessels, and other.

Both acetylcholine and muscarine have quaternary nitrogens, making them hydrophilic (no CNS activity). Other muscarinic agonist, like arecholine and pilocarpine, have nonpolar tertiary nitrogens, making them lipophilic and able to act on cholinergic receptors in the CNS. Arecholine is the active ingredient in areca or betel nut, which is chewed for its intoxicating effects in Asia and the Pacific islands. Pilocarpine is another naturally occurring cholinomimetic used in the treatment of open angle glaucoma, with PNS and CNS side effects if absorbed systemically (should be administered in a slow-release formula).

Acetylcholine is not a very useful drug because it acts on both muscarinic and nicotinic receptors, and is rapidly metabolized. Synthetic cholinomimetics are used clinically for GI stimulation, treatment of urinary retention, pupillary constriction during surgery and treatment of glaucoma. Examples of cholinomimetic drugs include: carbanylcholine, acetyl-beta-methylcholine (M only) and bethanechol (M only, resistant to esterases). Contraindications for these agents include asthma, peptic ulcer and coronary insufficiency. They should not be given parenteraly because of the danger of acute respiratory distress and cardiovascular collapse.

The effects of nicotine on NG receptors may reflect stimulation or blockade. Cholinergic receptors act fast because acetylcholine is quickly removed from the synaptic cleft, allowing membranes to repolarize. But nicotine lingers and does not allow repolarization, blocking transmission. Therefore, effects seen with lower levels of nicotine include stimulation, vomiting, AD release (due to CNS effects), increased heart rate and blood pressure (due to ganglionic SNS stimulation), increased GI motility and glandular secretions (due to ganglionic PNS stimulation), and loss of muscular tone (due to neuromuscular blockade).At higher levels nicotine blocks the PNS, decreasing GI and gland activity. Acute nicotine toxicity displays convulsions, hypertension, arrhythmias, coma and neuromuscular failure.

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