Neuromuscular-blocking drugs 2729485 225528814 2008-07-14T04:17:20Z Arcadian 104523 /* Classification */ wik [[Image:Synapse diag3.png|thumb|Global view of a neuromuscular junction:<BR>1. [[Axon]]<BR>2. Motor end-plate<BR>3. [[Muscle fiber]]<BR>4. [[Myofibril]]]] [[Image:Synapse diag4.png|thumb|Detailed view of a neuromuscular junction:<BR>1. [[Presynaptic]] terminal<BR>2. [[Sarcolemma]]<BR>3. [[Synaptic vesicle]]<BR>4. [[Nicotinic acetylcholine receptor]]<BR>5. [[Mitochondrion]]]] '''Neuromuscular-blocking drugs''' block neuromuscular transmission at the [[neuromuscular junction]], causing [[paralysis]] of the affected [[skeletal muscle]]s. This is accomplished either by acting [[presynaptic]]ally via the inhibition of [[acetylcholine]] (ACh) synthesis or release, or by acting [[postsynaptic]]ally 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 (physiology)|respiration]]. Patients are still aware of pain even after full conduction block has occurred; hence, [[general anesthetic]]s and/or [[analgesic]]s must be given to prevent [[anesthesia awareness]]. ==Classification== These drugs fall into two groups: *'''[[Non-depolarizing blocking agent]]s''': 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.<ref name="pmid8866353">{{cite journal |author=Bufler J, Wilhelm R, Parnas H, Franke C, Dudel J |title=Open channel and competitive block of the embryonic form of the nicotinic receptor of mouse myotubes by (+)-tubocurarine |journal=J. Physiol. (Lond.) |volume=495 ( Pt 1) |issue= |pages=83–95 |year=1996 |pmid=8866353 |doi=}}</ref> *'''[[Depolarizing blocking agent]]s''': These agents act by [[Depolarization|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 antagonist]]s 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]],<ref name="pmid2429800">{{cite journal |author=Inada E, Philbin DM, Machaj V, ''et al'' |title=Histamine antagonists and d-tubocurarine-induced hypotension in cardiac surgical patients |journal=Clin. Pharmacol. Ther. |volume=40 |issue=5 |pages=575–80 |year=1986 |pmid=2429800 |doi=}}</ref> as well as its effect of blocking [[autonomic ganglion|autonomic ganglia]].<ref name="pmid2682131">{{cite journal |author=Ostergaard D, Engbaek J, Viby-Mogensen J |title=Adverse reactions and interactions of the neuromuscular blocking drugs |journal=Medical toxicology and adverse drug experience |volume=4 |issue=5 |pages=351–68 |year=1989 |pmid=2682131 |doi=}}</ref> 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 potential]]s (EPPs) can still be detected, but are too small the reach the [[threshold potential]] needed for activation of muscle fiber contraction. {|class="wikitable sortable" |+Comparison of neuromuscular blocking agents !Agent |'''Time to onset''' <br> (seconds) |'''Duration''' <br> (minutes) !Side-effects !Clinical use |Storage |- |[[Rapacuronium]] |Ultra short-acting | | | |- |[[Mivacurium]] (Mivacron) |90 |12-18<ref name=Rang151/> | *[[hypotension]] (transiently), by release of histamine<ref name=Rang151/> |No longer manufactured secondary to marketing, manufacturing, financial concerns |refrigerated |- |[[Atracurium]] (Tracrium) |90 |30 min or less<ref name=Rang151/> | *[[hypotension]], transiently<ref name=Rang151/>, by release of histamine *Toxic metabolite called [[laudanosine]], greater accumulation in individuals with renal failure |widely<ref name=Rang151/> |refrigerated |- |[[Doxacurium]] | |long<ref name=Rang151/> | *[[hypotension]], transiently<ref name=Rang151/>, 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<ref name=Rang151/> |Few<ref name=Rang151/>, may cause prolonged paralysis<ref name=Rang151/> and promote muscarinic block |widely<ref name=Rang151/> |non-refrigerated |- |[[Rocuronium]] (Zemuron) |75 |45-70 |may promote muscarinic block | |non-refrigerated |- |[[Pancuronium]] (Pavulon) |90 |180 or more | *[[tachycardia]] (slight)<ref name=Rang151/> (no hypotension)<ref name=Rang151/> |widely<ref name=Rang151/> |non-refrigerated |- |[[Tubocurarine]] |300 or more<ref name=Rang151> {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} Page 151 </ref> |60 - 120<ref name=Rang151/> | *[[hypotension]] (by [[ganglion-block]] and histamine release)<ref name=Rang151/> *[[Bronchoconstriction]] (by histamine release)<ref name=Rang151/> |rarely<ref name=Rang151/> | |- |[[gallamine]] |300 or more<ref name=Rang151/> |60 - 120<ref name=Rang151/> | *[[tachycardia]] | | |- |[[Pipecuronium]] |90 |180 or more | *[[tachycardia]] (slight)<ref name=Rang151/> (no hypotension)<ref name=Rang151/> | |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 [[fasciculation]]s (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 [[motoneuron]]s. 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 (anatomy)|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 receptor]]s.<ref name="pmid2682131">{{cite journal |author=Ostergaard D, Engbaek J, Viby-Mogensen J |title=Adverse reactions and interactions of the neuromuscular blocking drugs |journal=Medical toxicology and adverse drug experience |volume=4 |issue=5 |pages=351–68 |year=1989 |pmid=2682131 |doi=}}</ref> If nicotonic receptors of the [[autonomic ganglion|autonomic ganglia]] or [[adrenal medulla]] are blocked, these drugs may cause autonomic symptoms. Additionally, neuromuscular blockers may facilitate [[histamine]] release, which causes hypotension, [[Flushing (physiology)|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 arrhythmia]]s. Certain drugs such as [[aminoglycoside ]] antibiotics and [[polymyxin]] and some [[fluoroquinolones]] also have neuromuscular blocking action as their side effect. ==References== {{reflist}} ==External links== * {{MeshName|Neuromuscular+blocking+agents}} {{-}} {{Receptor agonists and antagonists}} {{Muscle relaxants}} [[Category:Muscle relaxants]]