Neuromuscular Blocking Drugs
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These include drugs that block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end-plate of skeletal muscle. These neuromuscular blockers are structural analogs of acetylcholine and act either as antagonists (nondepolarising type) or agonists (depolarising type) at the receptors on the end-plate of the neuromuscular junction. Neuromuscular blockers are clinically useful during surgery to produce complete muscle relaxation.
a) Nondepolarising (competitive) blockers: These agents constitute the majority of the clinically-relevant neuromuscular blockers. They act by blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors
Actions: Tubocurarine, found in curare of the South American plant Pareira, is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (>5 min) and a long duration of action (1–2 hours). Side effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator, as well as its effect of blocking autonomic ganglia. It is excreted in the urine.
Therapeutic Uses: These blockers are used therapeutically as adjuvant drugs in anaesthesia during surgery to relax skeletal muscle.
Pharmacokinetics: All neuromuscular blocking agents are injected intravenously since their uptake via oral absorption is minimal. They penetrate membranes very poorly and do not enter cells or cross the BBB. Many of the drugs are not metabolised, their actions are terminated by redistribution. For example, tubocurine, pancuronium, mivacurium are excreted in the urine, unchanged.
Adverse Effects: The drug Tubocurine needs to block about 70-80% of the Ach receptors for neuromuscular conduction to fail, and hence, for an effective blockade to occur. At this stage, end-plate potentials (EPPs) can still be detected, but are too small the reach the threshold potential needed for activation of muscle fiber contraction.
b) Depolarising blocking agents: These agents act by depolarising the plasma membrane of the skeletal muscle fiber. This persistent depolarisation makes the muscle fiber resistant to further stimulation by ACh.
There are two phases to the depolarizing block.a) Nondepolarising (competitive) blockers: These agents constitute the majority of the clinically-relevant neuromuscular blockers. They act by blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors
Actions: Tubocurarine, found in curare of the South American plant Pareira, is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (>5 min) and a long duration of action (1–2 hours). Side effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator, as well as its effect of blocking autonomic ganglia. It is excreted in the urine.
Therapeutic Uses: These blockers are used therapeutically as adjuvant drugs in anaesthesia during surgery to relax skeletal muscle.
Pharmacokinetics: All neuromuscular blocking agents are injected intravenously since their uptake via oral absorption is minimal. They penetrate membranes very poorly and do not enter cells or cross the BBB. Many of the drugs are not metabolised, their actions are terminated by redistribution. For example, tubocurine, pancuronium, mivacurium are excreted in the urine, unchanged.
Adverse Effects: The drug Tubocurine needs to block about 70-80% of the Ach receptors for neuromuscular conduction to fail, and hence, for an effective blockade to occur. At this stage, end-plate potentials (EPPs) can still be detected, but are too small the reach the threshold potential needed for activation of muscle fiber contraction.
During phase I (depolarizing phase), they cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons. At this point, full neuromuscular block has been achieved.
Actions: Respiratory muscles are paralysed last. Succinylcholine initially produces short-lasting muscle fasciculations, followed within minutes by paralysis. The drug does not produce a ganglionic block, except in high doses, although it does have weak histamine-releasing action.
Therapeutic Uses: Succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia. It is also employed during electroconvulsive shock treatment.
Pharmacokinetics: Injected intravenously. Its brief duration of action (several minutes) results from rapid hydrolysis by plasma cholinesterase. It is therefore usually given by continuous infusion.
Adverse Effects: Hyperthermia and apnea.
Category: Acetylcholine , Pharmacology Notes
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