In the vast network of the human nervous system, communication happens in milliseconds through chemical messengers known as neurotransmitters. Among these, acetylcholine (ACh) stands out as one of the most vital — controlling muscle movement, memory, and autonomic functions. The study of cholinergic neurotransmitters forms a crucial foundation for pharmacology and drug design, influencing therapies for disorders like Alzheimer’s disease, myasthenia gravis, and Parkinson’s disease.
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Biosynthesis and Catabolism of Acetylcholine
Acetylcholine is synthesized in the nerve endings by an enzyme called choline acetyltransferase, which catalyzes the reaction between choline and acetyl coenzyme A (acetyl-CoA). Once synthesized, ACh is stored in synaptic vesicles and released when a nerve impulse arrives at the axon terminal.
After performing its role in transmitting signals across synapses, acetylcholine is rapidly broken down by the enzyme acetylcholinesterase (AChE) into choline and acetic acid. This catabolic process ensures that neurotransmission remains precise and controlled, preventing overstimulation of muscles or glands.
Cholinergic Receptors: Muscarinic and Nicotinic
Cholinergic neurotransmission occurs through two main receptor types:
Muscarinic receptors – Found mainly in smooth muscles, cardiac tissues, and glands, these receptors mediate the actions of the parasympathetic nervous system, such as slowing the heart rate and stimulating glandular secretions.
Nicotinic receptors – Located in the neuromuscular junction and certain brain regions, these receptors are responsible for fast synaptic transmission, especially in skeletal muscle contractions.
Understanding the distribution of these receptors is critical for developing drugs that selectively target specific sites, minimizing side effects.
Parasympathomimetic Agents and Their Structure-Activity Relationship (SAR)
Parasympathomimetic agents, also known as cholinomimetics, mimic the action of acetylcholine by activating cholinergic receptors. They are classified into direct-acting and indirect-acting agents based on their mechanism of action.
Direct-Acting Agents
These compounds directly bind to cholinergic receptors and produce similar effects to acetylcholine. Examples include:
Acetylcholine – The natural neurotransmitter itself, but rarely used therapeutically due to its rapid degradation.
Carbachol and Bethanechol – Synthetic analogues resistant to enzymatic breakdown, used in conditions like urinary retention.
Methacholine – A diagnostic agent for bronchial hyperreactivity.
Pilocarpine – A plant alkaloid used in treating glaucoma by stimulating ocular secretions.
Indirect-Acting Agents (Cholinesterase Inhibitors)
These drugs inhibit acetylcholinesterase, prolonging the action of acetylcholine at synaptic junctions. They are further classified as reversible and irreversible inhibitors.
Reversible inhibitors: Physostigmine, Neostigmine, Pyridostigmine, and Edrophonium chloride – often used in myasthenia gravis and post-operative paralytic conditions.
Irreversible inhibitors: Isofluorphate, Echothiophate iodide, Parathione, and Malathion – organophosphates that form stable enzyme complexes, used in specific medical and agricultural settings.
One notable antidote to organophosphate poisoning is Pralidoxime chloride, a cholinesterase reactivator, which restores enzyme function by cleaving the bond between the inhibitor and acetylcholinesterase.
Cholinergic Blocking Agents and Their Pharmacological Roles
Opposing the action of parasympathomimetics, cholinergic blocking agents (anticholinergics) inhibit acetylcholine’s binding to its receptors. Their Structure-Activity Relationship (SAR) provides valuable insights into designing selective antagonists for clinical use.
Solanaceous Alkaloids and Analogues
These naturally derived compounds include Atropine sulphate, Hyoscyamine sulphate, and Scopolamine hydrobromide—well-known for their role in treating motion sickness, asthma, and pupil dilation during eye examinations. Synthetic analogues like Ipratropium bromide and Homatropine hydrobromide are commonly used in respiratory therapy.
Synthetic Cholinergic Blocking Agents
A wide range of synthetic derivatives has been developed for various therapeutic purposes:
Tropicamide and Cyclopentolate hydrochloride – ophthalmic agents for eye dilation.
Clidinium bromide and Dicyclomine hydrochloride – used in gastrointestinal disorders.
Glycopyrrolate and Propantheline bromide – control salivation and gastric secretions.
Benztropine mesylate, Procyclidine hydrochloride, and Orphenadrine citrate – serve as antiparkinsonian drugs by balancing neurotransmitter activity in the central nervous system.