Cholinergic agents

Classification: stimulants and blockers

Pharmacological targets in the cholinergic synapse allow drugs to be divided into two main groups: those that stimulate transmission and those that inhibit it.

Agents that stimulate transmission:

• Cholinomimetics (direct stimulants). They mimic the effects of acetylcholine by binding to receptors. They are subdivided into M-cholinomimetics (stimulate muscarinic receptors, e.g., pilocarpine) and N-cholinomimetics (act on neuronal-type nicotinic receptors in ganglia).
• Anticholinesterase agents (indirect stimulants). They act as inhibitors of the enzyme acetylcholinesterase. As a result, the neurotransmitter is not degraded, its concentration in the synaptic cleft increases, and it exerts a potent and prolonged effect on both receptor types (M and N simultaneously).

Agents that block transmission:

• Antimuscarinics (M-blockers) — switch off M-receptors.
• Ganglionic blockers — selectively block $N_n$-receptors in autonomic ganglia, adrenal medulla, and carotid bodies.
• Curare-like agents (muscle relaxants) — act peripherally by blocking skeletal muscle $N_m$-receptors.

Application of cholinergic transmission stimulants

The choice of a specific drug largely depends on its ability to cross the blood-brain barrier (BBB) and the duration of its effect.

• Ophthalmology. M-cholinomimetics and anticholinesterase agents constrict the pupil (miosis) and improve aqueous humor outflow. This is critical for lowering intraocular pressure in glaucoma.
• Atony and myasthenia. Peripheral cholinesterase inhibitors (neostigmine, pyridostigmine) increase the tone of the smooth muscles of the gastrointestinal tract and urinary bladder, as well as skeletal muscle. In myasthenia gravis, pyridostigmine is prescribed for long-term maintenance therapy, while neostigmine is used for the rapid management of a myasthenic crisis.
• Alzheimer's disease. Only centrally acting anticholinesterase drugs (donepezil, rivastigmine, galantamine) are used because they readily penetrate the brain. Quaternary compounds are useless for this purpose.

Anticholinergics in clinical practice

Blockers are used in various fields of medicine, allowing for the targeted inhibition of parasympathetic influence:

• Ophthalmology: short-acting drugs are required for pupil dilation (diagnostic mydriasis) and induction of cycloplegia.
• Pulmonology: blockade of $M_3$-receptors eliminates the cholinergic component of bronchospasm in asthma.
• Cardiology: M-blockers accelerate heart rate and improve conduction in bradyarrhythmias and heart blocks.
• Gastroenterology: the selective $M_1$-receptor blocker pirenzepine and the non-selective blocker atropine are used for hyperacid conditions and peptic ulcer disease. Notably, pirenzepine produces significantly fewer systemic side effects.
• Neurology: central M-blockers (trihexyphenidyl) are used as antiparkinsonian drugs. They effectively reduce tremor and muscle rigidity.
• Anesthesiology: ganglionic blockers and muscle relaxants provide muscle relaxation for surgical procedures, facilitate intubation, and enable controlled hypotension.

Important interactions and toxicology

Understanding the mechanisms of action of these drugs is essential for managing poisonings and overdoses.

• Decurarization. Anticholinesterase agents displace nondepolarizing muscle relaxants from receptor binding, terminating their effect. However, with depolarizing muscle relaxants (suxamethonium), they act as synergists, dangerously enhancing and prolonging the block.
• Organophosphate poisoning. In intoxication with organophosphorus compounds (irreversible inhibitors), cholinesterase reactivators are used. Quaternary ammonium compounds (dipiroxime) act only peripherally, whereas tertiary amines (isonitrozine) cross the BBB and protect the CNS. Important: reactivators are contraindicated in poisoning by reversible inhibitors (carbamates).
• Overdose of M-cholinomimetics. Managed by the administration of pharmacological antagonists — atropine and atropine-like drugs.
• Inversion of the acetylcholine effect. If atropine is administered beforehand (blocking M-receptors), subsequent administration of acetylcholine causes an increase rather than a decrease in blood pressure. This occurs due to the unmasking of the stimulating N-cholinergic effect on ganglia and the adrenal medulla.

Class and exam questions

What else to study on this topic

• Mechanisms of cholinergic receptor coupling with G-proteins and cellular functions.
• Stages, pathogenesis, and clinical presentation of poisoning by organophosphorus compounds (OPCs) and mushrooms (Amanita).
• Toxic effects of nicotine, dependence development, and management strategies.
• Differential diagnosis of cholinergic and myasthenic crises during drug overdose.
• Resorptive effects of cholinesterase inhibitors on exocrine glands and the cardiovascular system.

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