13. Cholinergic Antagonists

Cholinergic antagonists Cholinergic antagonists are divided in two subgroups on the basis of their specific receptor affinities: ● Muscarinic antagonists (i.e. antimuscarinic drugs). The most useful of these agents selectively block the muscarinic synapses of the parasympathetic nerves. The effects of parasympathetic innervations are thus interrupted, and the actions of sympathetic stimulation are left unopposed.

● Nicotinic antagonists (i.e. ganglion-blocker and neuromuscular junction blocker).

Antimuscarinic agents Antimuscarinic agents (atropine, scopolamine, ipratropium) block muscarinic receptors causing inhibition of all muscarinic functions. In addition, these drugs block the few exceptional sympathetic neurons that are cholinergic, such as those innervating sweat glands.

Atropine

a. Atropine Atropine, a belladonna alkaloid, has a high affinity for muscarinic receptors, where it binds competitively, preventing acetylcholine from binding to that site. Atropine is both a central and peripheral muscarinic blocker. Its general actions last about 4 hours except when placed topically in the eye, where the action may last for days.

Mechanism of action Atropine causes reversible blockade of cholinomimetic actions at muscarinic receptors- i.e., blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist. Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at non-muscarinic receptors are generally undetectable clinically.

Ocular effects Atropine blocks all cholinergic activity on the eye, resulting: Mydriasis: Dilation of the pupil Photophobia: Intolerance of light Cycloplegia: Inability to focus for near vision In patients with glaucoma, intraocular pressure may rise dangerously which is not significant in normal individuals.

Therapeutic uses: In the eye, topical atropine exerts both mydriatic & cycloplegic effects and permits the measurement of

Atropine is isolated from the plant Atropa belladonna. ‘Bella donna’ means ‘beautiful woman’. In the old days, in Italy atropine was used by young women to augment their looks before attending festivities. It widens the pupils of the eyes, and it prevents sweating, therefore leading to accumulation of heat and to red cheeks. At higher dosages, it also causes hallucinations, which may or may not be helpful with falling in love.

Smooth muscle Relaxation of all smooth muscle: GIT: reduction of tone and peristalsis. Therefore, gastric emptying time is prolonged, and intestinal transit time is lengthened. (produce constipation) Lungs: relaxation of bronchial smooth muscle but not as β-adrenoreceptor agonist. Bladder: reduce hypermotility states of the Therapeutic urinary bladderuses: Atropine is used as an antispasmodic agent to relax the gastrointestinal tract and bladder.

Exocrine glands Salivary: Decrease salivation significantly (dry mouth). Gastric: Gastric secretion is blocked less effectively: the volume and amount of acid, pepsin, and mucin are all reduced, but large doses of atropine may be required. Pirenzepine and a more potent analog, telenzepine, reduce gastric acid secretion with fewer adverse effects than atropine and other less selective agents.

Sweat: Decrease sweating. In adults, body temperature is elevated by this effect only if large doses are administered, but in infants and children even ordinary doses may cause “atropine fever”. Bronchial: Decrease bronchial secretion. Antimuscarinic drugs are frequently used prior to administration of inhalant anesthetics to reduce the accumulation of secretions in the trachea and the possibility of laryngospasm.

Therapeutic uses: Antisecretory agent: The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery.

Cardiovascular effect Atropine produces divergent effects on the cardiovascular dose.

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At low doses the predominant effect is a decreased cardiac rate (bradycardia). Originally thought to be due to central activation of vagal efferent outflow. [Parasympathetic innervation of the heart is mediated by the vagus nerve] With higher doses of atropine, the cardiac receptors on the SA node are blocked, and the

Antidote for cholinergic agonists Atropine blocks the effects

of excess acetylcholine that results from inhibition of acetylcholinesterase by drugs such as physostigmine. Massive doses of antagonists may be required over a long period of time to counteract the excess acetylcholine.

Adverse effects: Depending on the dose, atropine may cause dry mouth, blurred vision, "sandy eyes", tachycardia, and constipation. Effects on the CNS include restlessness, confusion, hallucinations, and delirium, which may progress to depression, collapse of the circulatory and respiratory systems and death. In older individuals, the use of atropine to induce mydriasis and cycloplegia is considered too risky since it may exacerbate an attack of glaucoma in someone with a

b. Scopolamine Scopolamine is another belladonna alkaloid, produces peripheral effects similar to those of atropine. However, scopolamine has greater action on the CNS and a longer duration of action in comparison to those of atropine. Scopolamine also has the unusual effect of blocking short-term memory. Actions: Scopolamine is one of the most effective anti-motion sickness drugs available. In contrast to atropine, scopolamine produces sedation, but at higher doses can instead

Therapeutic action: Though similar to atropine, its therapeutic use is limited to prevention of motion sickness and blocking of short-term memory.

c. Ipratropium Inhaled ipratropium, a quaternary derivative of atropine, is useful in treating asthma and chronic obstructive pulmonary disease in patients unable to take adrenergic agonists. Ipratropium is also used in the management of chronic obstructive pulmonary disease.

Atropin

Ipratropiu

The hallucinations are, obviously, caused by atropine entering the central nervous system. The central effects are lessened by derivatization of the tertiary amine found in atropine to a quaternary amine, as in ipratropium. Because of its permanent charge, ipratropium does not easily cross the blood brain barrier by ‘non-ionic diffusion’, and it is therefore often preferred over atropine in clinical medicine.