Neuromuscular blocking drugs

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Global view of a neuromuscular junction:
1. Axon
2. Motor end-plate
3. Muscle fiber
4. Myofibril

Detailed view of a neuromuscular junction:
1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion

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.

Patients are still aware of pain even after full conduction block has occurred; hence, general anesthetics and/or analgesics must be given to prevent anesthesia awareness.

Classification

These drugs fall into two groups:

• Non-depolarizing blocking agents: 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.

• Depolarizing blocking agents: These agents act by depolarizing the plasma membrane of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

Non-depolarizing blocking agents

All of these agents act as competitive antagonists against acetylcholine at the site of postsynaptic acetylcholine receptors.

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.

Comparison of neuromuscular blocking agents

Agent	Time to onset (seconds)	Duration (minutes)	Side-effects	Clinical use	Storage
Rapacuronium	Ultra short-acting
Mivacurium (Mivacron)	90	12-18	hypotension (transiently), by release of histamine	No longer manufactured secondary to marketing, manufacturing, financial concerns	refrigerated
Atracurium (Tracrium)	90	30 min or less	hypotension, transiently, by release of histamine Toxic metabolite called laudanosine, greater accumulation in individuals with renal failure	widely	refrigerated
Doxacurium		long	hypotension, transiently, by release of histamine Toxic metabolite called laudanosine, greater accumulation in individuals with renal failure
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	tachycardia (slight) (no hypotension)	widely	non-refrigerated
Tubocurarine	300 or more	60 - 120	hypotension (by ganglion-block and histamine release) Bronchoconstriction (by histamine release)	rarely
gallamine	300 or more	60 - 120	tachycardia
Pipecuronium	90	180 or more	tachycardia (slight) (no hypotension)		non-refrigerated

Depolarizing blocking agents

Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.

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.

Comparison of drugs

The main difference is in the reversal of these two types of neuromuscular-blocking drugs.

• Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs since they are competitive antagonists at the ACh receptor so can be reversed by increases in ACh.
• The depolarizing blockers already have ACh-like actions, so these agents will have prolonged effect under the influence of acetylcholinesterase inhibitors. The administration of depolarizing blockers will initially exhibit fasciculations (a sudden twitch just before paralysis occurs). This is due to the depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers.

The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently-high frequencies of electrical stimulation.

• Non-depolarizing blockers will have this effect on patients.
• Depolarizing blockers will not.

Adverse effects

Since these drugs may cause paralysis of the diaphragm, mechanical ventilation should be at hand to provide respiration.

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.

Certain drugs such as aminoglycoside antibiotics and polymyxin and some fluoroquinolones also have neuromuscular blocking action as their side effect.

External links

• Neuromuscular+blocking+agents at the US National Library of Medicine Medical Subject Headings (MeSH)

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