Cholinergic Antagonists Overview

Cholinergic Antagonists:

• Cholinergic antagonists are drugs that block the effects of acetylcholine (ACh) at cholinergic receptors.
• They are divided into antimuscarinic (M receptor blockers) and antinicotinic (Nicotinic receptor blockers).
• Most clinically useful are antimuscarinic agents and neuromuscular blocking agents.
• Ganglionic blockers have limited clinical usefulness due to their broad actions and lack of selectivity.

Antimuscarinic Agents:

• Antimuscarinic agents, also called parasympatholytics, block the effects of parasympathetic autonomic discharge.
• They competitively bind to M cholinergic receptors, inhibiting ACh’s stimulatory effects.
• They also block some sympathetic neurons that are cholinergic, like those innervating salivary and sweat glands.
• Antimuscarinic agents are beneficial in various clinical situations.
• They do not block N cholinergic receptors, therefore they lack skeletal neuromuscular or autonomic ganglia effects.

Atropine:

• Atropine is a tertiary amine alkaloid ester of tropic acid.
• It is found in plants like Atropa belladonna and Datura stramonium.
• At therapeutic doses, atropine acts mainly peripherally, with minimal CNS effects.
• Tissues most sensitive to atropine are salivary, bronchial, and sweat glands.
• Atropine's duration of action is around 4 hours, but its effects in the eye can last for days.

Atropine - MOA:

• Atropine and its related compounds have a higher affinity for M receptors.
• They bind competitively to the common site on cholinergic receptors, blocking ACh and other cholinergic agonists.
• Atropine's blockade can be overcome by increasing the concentration of ACh or using a muscarinic agonist.
• Atropine is highly selective for M receptors, with much lower potency at N receptors, but does not discriminate between M1, M2, and M3 receptors.

Atropine – Physiological Actions:

• Eye: Atropine blocks cholinergic activity of the pupillary sphincter muscles and ciliary muscles, causing mydriasis (dilated pupil), unresponsiveness to light, cycloplegia (paralysis of ciliary muscles), and inability to focus for near vision.
• Antisecretory agent: Used to block secretions in the respiratory tract prior to surgery.
• Anaesthesia: Used with neostigmine to reverse skeletal muscle relaxation after surgery.

Atropine - PK:

• Atropine is readily absorbed from the GIT and the conjuctival membrane, and well distributed throughout the body, including the CNS.
• It is partially metabolized by the liver with a plasma half-life of 2-4 hours.
• Its effects on parasympathetic function decline rapidly in all organs except the eye.
• About 60% of the dose is eliminated unchanged in the urine.

Atropine - A/E:

• Poisoning manifests as dry mouth, blurred vision, tachycardia, hot & flushed skin, urinary retention, and constipation.
• Body temperature is often elevated.
• CNS effects include restlessness, confusion, hallucinations, delirium, depression, circulatory/respiratory collapse, and death.
• Atropine's use for mydriasis and cycloplegia in older individuals is risky due to potential glaucoma exacerbation.

Scopolamine:

• Scopolamine is another belladonna alkaloid with peripheral effects similar to atropine, but has greater CNS action and a longer duration of action.

Scopolamine – Physiological Actions:

• Scopolamine has marked central effects, producing drowsiness and amnesia (loss of short-term memory) at therapeutic dosages.

Ganglionic Blockers:

• Ganglionic blockers act by blocking the transmission of nerve impulses through autonomic ganglia.
• They have limited clinical usefulness due to their diffuse actions and lack of selectivity.
• Examples include trimethaphan, mecamylamine, hexamethonium, and tetraethylammonium.

Cardiovascular Effects of Ganglionic Blockade:

• Decreased arteriolar and venous tone, leading to a gradual decrease in BP.
• Moderate tachycardia may occur due to decreased parasympathetic dominance at the sinoatrial node.

Other Organ System Effects of Ganglionic Blockade:

• GIT: Reduced secretions and profound inhibition of motility, potentially causing constipation.
• Genitourinary: Ganglionic blockade can precipitate urinary retention in men with prostatic hyperplasia.
• Sexual functions: Impaired erection and ejaculation.
• Thermoregulatory sweating is blocked.

Clinical Application of Ganglionic Blockers:

• Rarely used due to the availability of selective autonomic blocking agents.
• Mecamylamine has been studied for use in reducing nicotine craving, treating moderate to severe hypertension, and as an alternative therapy for hypertensive crises.
• Trimethaphan is occasionally used in the treatment of hypertensive crises.

Neuromuscular Blocking Drugs:

• These drugs block cholinergic transmission at the neuromuscular junction of skeletal muscle, resulting in muscle relaxation.
• They are divided into nondepolarising (competitive) blockers and depolarizing blockers.
• Clinically useful during surgery to achieve muscle relaxation.
• Other muscle relaxants include centrally acting agents like diazepam and baclofen, and peripherally acting agents like dantrolene and botulinum toxin.

Nondepolarising (Competitive) Blockers:

• They act by competitively binding to the N receptors at the neuromuscular junction, blocking the action of ACh.
• Examples include curare, tubocurarine, pancuronium, mivacurium, metocurine, doxacurium, vecuronium, and rocuronium.
• They have variable potencies in producing ganglionic blockade, with tubocurarine being the least selective.
• Some, like pancuronium, have vagolytic action due to muscarinic receptor blockade and lead to tachycardia.

Therapeutic Uses of Nondepolarising Blockers:

• Used as adjuvant drugs to relax skeletal muscle during surgery and orthopedic procedures.
• Employed in procedures like intubation, bronchoscopy, and esophagoscopy.
• Used in psychiatry to prevent trauma during electroconvulsive therapy (ECT).
• Control of muscle spasms – botulinum toxins are preferred.

PK of Nondepolarising Blockers:

• All are injected IV due to poor oral absorption.
• They penetrate membranes poorly and do not enter cells or cross the BBB.
• Most are excreted unchanged in the urine.
• Atracurium is degraded spontaneously in plasma and by ester hydrolysis.
• Atracurium has been replaced by cisatracurium due to histamine release and laudanosine formation, which can cause seizures.
• Vecuronium and rocuronium are deacetylated in the liver, with prolonged clearance in patients with hepatic disease.

Drug Interactions:

• Cholinesterase Inhibitors: These drugs increase ACh concentrations, potentially overcoming neuromuscular blockade. Examples include neostigmine and pyridostigmine.
• Antibiotics: Some antibiotics can potentiate neuromuscular blockade. Examples include aminoglycosides (e.g., gentamicin) and macrolides (e.g., erythromycin).
• Anesthetics: Volatile anesthetics can enhance neuromuscular blockade.
• Other Drugs: Diuretics, lithium, and corticosteroids can also increase the effects of nondepolarising blockers.

Depolarizing Blockers:

• They cause depolarisation of the muscle membrane, initially leading to a brief period of muscle twitching followed by paralysis.
• The main example is succinylcholine.
• Short duration of action and rapid onset.
• Used for rapid intubation, and in combination with non-depolarizing agents to prolong paralysis.

Depolarising Blockers – MOA:

• Succinylcholine binds to the N receptors at the neuromuscular junction, mimicking ACh and causing a prolonged depolarization.
• This prolonged depolarization prevents further ACh binding, resulting in paralysis.

PK of Depolarizing Blockers

• Rapidly hydrolyzed by plasma cholinesterase.
• Short duration of action.
• Has a phase I (depolarizing) and phase II (desensitisation) effect.
• Metabolic breakdown is affected by atypical cholinesterase activity.

A/E of Depolarizing Blockers

• Hyperkalemia.
• Malignant hyperthermia.
• Rhabdomyolysis.
• Muscle pain.
• Cardiovascular effects (bradycardia).

Interactions of Depolarizing Blockers

• Cholinesterase inhibitors can prolong the effects of succinylcholine.
• Antibiotics may enhance the effects.
• Anesthetics may influence the effect.
• Other drugs may interact.

Adverse Effects of Antimuscarinic Agents:

• Dry mouth, blurred vision, photophobia, tachycardia, urinary retention, constipation, CNS effects (restlessness, confusion, hallucinations, delirium), and hyperthermia.
• Contraindications include narrow-angle glaucoma, urinary retention, and megacolon.

Adverse Effects of Neuromuscular Blocking Agents:

• Respiratory depression, muscle weakness, and prolonged paralysis.
• Contraindications include myasthenia gravis, and hypersensitivity.

This quiz covers cholinergic antagonists, focusing on their classification into antimuscarinic and antinicotinic drugs. It highlights the properties, mechanisms, and clinical utility of antimuscarinic agents, particularly atropine. Test your understanding of these important pharmacological agents.