How Drugs affect Neuromuscular Transmission?

(i) Drugs affecting acetylcholine release include botulinus toxin, which is associated with food-poisoning and interferes with the synthesis or release of ACh. In this way it produces muscular paralysis; black widow spider toxin, which stimulates secretion of massive amounts of ACh, leading to its depletion and consequent motor paralysis, and hemicholiniums, which block the choline transport system and inhibit choline uptake. Prolonged treatment with hemicholiniums depletes the store of transmitter and ultimately decreases the ACh content of the quanta.

(ii) Drugs inactivating acetyl cholinesterase are called anticholinesterases (anti-ChE). These drugs bind to AChE, thereby preventing ACh from binding to the same sites. The AChE is freed only when the anti-ChE bound to it is hydrolyzed. By inactivating AChE, anti-ChE drugs permit large amounts of ACh to accumulate within the myoneural cleft. In the presence of an anti-ChE, the EPP is larger (more depolarization) and dramatically prolonged. Initially the depolarization results in a persistent muscle contraction (spasm) but after sometime it makes the motor end-plate inexcitable due to channel desensitization. Anti-ChE is of two types. Drugs like neostigmine, which are hydrolyzed by AChE in a few hours, are called reversible inhibitors. Thereafter, the AChE becomes available once again for inactivating ACh. Reversible inhibitors are used in the treatment of myasthenia gravis and in curare poisoning. Organophosphate compounds like Malathione and Baygon (insecticides) and isopropyl phosphofluoridate or DFP (a nerve-gas used in chemical warfare) are poorly hydrolyzed by ACh-E and therefore remain attached to the ACh-E for several weeks. These are called irreversible inhibitors. In presence of these irreversible inhibitors, ACh is unable to bind to the inactivated ACh-E. Hence, irreversible AChE inhibitors produce deadly paralysis.

(iii) Drugs binding to acetylcholine receptors are of two types. Drugs like succinylcholine produce neuromuscular block by depolarizing the end plate (depolarizing neuromuscular block). In moderate dosage, these drugs (called cholinomimetic drugs) bind to ACh receptors in the motor end-plate and depolarize the end plate resulting in muscle spasm. In high dosage, however, it will induce desensitization of the ACh-gated channels with consequent paralysis. Succinylcholine, is commonly used during surgery as a muscle relaxant and to reduce movements during electroconvulsion treatment of psychotic patients. Drugs like d- tubocurarine bind to the ACh receptors but do not stimulate them, and therefore, do not depolarize the membrane. They therefore block neuromuscular transmission without depolarizing the end-plate (non-depolarizing neuromuscular block). They only keep the ACh receptors blocked so that ACh is unable to bind to them. Bungarotoxin found in the venom of the krait also produces non-depolarizing block.