Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine (ACh) synthesis or release, or by acting postsynaptically at the acetylcholine receptor. While there are drugs that act presynaptically (such as botulin toxin and tetrodotoxin), the clinically-relevant drugs work postsynaptically.
Clinically, neuromuscular block is used as an adjunct to anesthesia to induce paralysis, so that surgery, especially intra-abdominal and intra-thoracic surgeries, can be carried out with fewer complications. Because neuromuscular block may paralyze muscles required for breathing, mechanical ventilation should be available to maintain adequate respiration.
Tubocurarine, found in curare of the South American plant genus Strychnos, 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.
This drug needs to block about 70-80% of the Ach receptors for neuromuscular conduction to fail, and hence, for 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.
|Agent||Time to onset |
|Mivacurium (Mivacron)||90||12-18||No longer manufactured secondary to marketing, manufacturing, financial concerns||refrigerated|
|Atracurium (Tracrium)||90||30 min or less||widely||refrigerated|
|Cisatracurium (Nimbex)||90||60-80||causes release of histamine||refrigerated|
|Vecuronium (Norcuron)||60||30-40||Few, may cause prolonged paralysis and promote muscarinic block||widely||non-refrigerated|
|Rocuronium (Zemuron)||75||45-70||may promote muscarinic block||non-refrigerated|
|Pancuronium (Pavulon)||90||180 or more|
|Tubocurarine (Jexin)||300 or more||60 - 120||rarely|
|gallamine (Flaxedil)||300 or more||60 - 120|
|Pipecuronium||90||180 or more|
There are two phases to the depolarizing block. 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.
The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (5-10 minutes) because of hydrolysis by various cholinesterases. Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but rarely, used in clinical practice.
Inhibition of acetylcholinesterase may be used to cause the same effect as a depolarizing neuromuscular block.
The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently-high frequencies of electrical stimulation.
Additionally, these drugs may exhibit cardiovascular effects, since they are not fully selective for the nicotinic receptor and hence may have effects on muscarinic receptors. If nicotonic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs may cause autonomic symptoms. Additionally, neuromuscular blockers may facilitate histamine release, which causes hypotension, flushing, and tachycardia.
In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of potassium from muscle fibers. This puts the patient at risk for life-threatening complications, such as hyperkalemia and cardiac arrhythmias.
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