Neuromuscular junction Flashcards
(8 cards)
intro - ACh mediates comms
The neuromuscular junction (NMJ) is a key site where acetylcholine (ACh) mediates communication between motor neurons and skeletal muscle. Drugs that act at this cholinergic synapse play essential roles in clinical medicine, particularly in anaesthesia and the treatment of neuromuscular disorders. These drugs function either as agonists, enhancing ACh activity, or as antagonists, inhibiting it—each with distinct mechanisms and therapeutic applications.
2nd para - nicotinic acetylcholine
At the NMJ, ACh is released from presynaptic terminals and binds to nicotinic acetylcholine receptors (nAChRs) on the postsynaptic membrane. These ligand-gated ion channels open upon binding, allowing sodium influx and membrane depolarisation, ultimately triggering muscle contraction
. Most cholinergic drugs interact with these receptors through reversible, non-covalent binding, affecting the receptor’s function without forming permanent bonds
3rd para - cholinergic agonists
Cholinergic Agonists include both direct- and indirect-acting agents. Direct agonists such as suxamethonium (succinylcholine) bind to nAChRs and mimic ACh. Suxamethonium causes prolonged depolarisation of the muscle membrane by activating the receptor but not detaching quickly, leading to transient paralysis. It is commonly used for rapid muscle relaxation during intubation. Unlike ACh, it is not rapidly degraded by acetylcholinesterase (AChE), making it more clinically useful in this context
4th para - indirect agonists
Indirect agonists work by inhibiting AChE, the enzyme responsible for breaking down ACh. Neostigmine is a well-known example. By preventing ACh degradation, neostigmine increases its availability in the synaptic cleft. This is particularly important in conditions like myasthenia gravis (MG), an autoimmune disease marked by reduced nAChR function. Neostigmine improves neuromuscular transmission and is also used to reverse the effects of non-depolarising muscle relaxants after surgery
5th para - Cholinergic antagonists
Cholinergic Antagonists, particularly non-depolarising neuromuscular blockers such as tubocurarine and pancuronium, act as competitive inhibitors at nAChRs. They bind to the receptor without activating it, blocking ACh from exerting its effect and resulting in muscle relaxation. These agents are used during general anaesthesia to induce controlled paralysis. Their effects can be reversed with anticholinesterases, which increase ACh levels to outcompete the blocker
6th para - clinical use of these drugs
The clinical use of these drugs is guided by their pharmacodynamics and receptor interactions. Full agonists like suxamethonium produce maximal receptor activation, whereas partial agonists only achieve submaximal responses. Antagonists have binding affinity but no activating ability. Understanding these properties helps clinicians choose the appropriate agent for each scenario—whether for short procedures, long-term paralysis, or disease treatment
7th para - from a practical standpoint
From a practical standpoint, cholinergic agents are widely used across clinical contexts. Suxamethonium is valued for its rapid onset and short duration in emergency intubations. Non-depolarising blockers like atracurium and pancuronium are selected for their predictability and duration of action during surgery. Anticholinesterases such as neostigmine and pyridostigmine remain essential for MG management and for reversing muscle blockade postoperatively
8th para - specificity of drug action at NMJ
The specificity of drug action at the NMJ is dose-dependent. At therapeutic doses, drugs selectively bind their intended targets, but higher concentrations may reduce specificity and increase the risk of side effects. This is particularly relevant for agents with narrow therapeutic windows, such as suxamethonium and neostigmine, where small dosing errors can lead to significant toxicity
