The ideal neuromuscular blocker drugs (NMB) would be rapid in onset, have a predictable offset, be nontoxic, lack deleterious cardiovascular or autonomic effects, undergo a defined means of metabolism and excretion preferably independent of end-organ function, and be inexpensive. Many of these characteristics are found in clinically available drugs like cisatracurium.
To briefly review, neuromuscular blockade occurs via one of two different pharmacologic modes. Neuromuscular blocker drugs that act as a prolonged agonist at the nicotinic acetylcholine (nACh) receptor are called depolarizing agents (e.g., succinylcholine).
Succinylcholine attaches to each of the alpha subunits of the nACh receptor and mimics the action of acetylcholine, thus depolarizing the postjunctional membrane. Neuromuscular blockade develops because a depolarized postjunctional membrane cannot respond to subsequent release of acetylcholine.
A second group of WMB agents that bind noncovalently and competitively to nACh receptors and inhibit neuromuscular transmission are called nondepolarizing Neuromuscular blocker drugs. In high doses, these drugs may act by blocking the ion receptor channels.
Occupation of as many as 70% of the nACh receptors does not produce evidence of neuromuscular blockade. Neuromuscular transmission, however, fails when 80% to 90% of the receptors are blocked.
Nondepolarizing Neuromuscular blocker drugs may be classified on the basis of their structure and duration of action. Clinically available nondepolarizing drugs can be grouped into two basic structural categories.
The benzylisoquinolinium drugs (atracurium, cisatracurium, mivacurium, tubocurarine) tend to be potent (and therefore slower in onset) Neuromuscular blocker drugs that are eliminated by the kidneys or by Hofmann elimination and may trigger histamine release. Conversely, the aminosteroid compounds (pancuronium, vecuronium, rocuronium) are less potent, have a faster onset of action, are eliminated by the liver with active metabolites, and lack significant histamine release or autonomic interactions.
Neuromuscular blocker drugs also may be classified as short (succhinylcholine, mivacurium), intermediate (atracurium, cisatracurium, vecuronium, rocuronium), or long-acting (tubocurarine, pancuronium) on the basis of their duration of action.
This is the purified form of one of the ten stereoisomers of atracurium. Cisatracurium has an ED95 of 50 Âµg/kg and has an onset of action of 3 to 5 minutes and duration of neuromuscular blockade lasting 20 to 35 minutes.
Neuromuscular blockade is easily maintained at a stable level by infusion at a constant rate and does not diminish over time. In contrast to vecuronium, the rate of spontaneous recovery from cisatracurium-induced neuromuscular blockade is not influenced by length of infusion in patients requiring mechanical ventilation.
Cisatracurium undergoes spontaneous nonenzymatic degradation at normal body temperature and pH by a base-catalyzed reaction termed Hofmann elimination, to form laudanosine and monoquaternary acrylate. Hofmann elimination represents a chemical mechanism of elimination accounting for 77% of the clearance of cisatracurium, whereas renal clearance is responsible for another 16%.
The organ-independent clearance of cisatracurium means that this nondepolarizing Neuromuscular blocker drugs can be administered to patients with hepatic or renal dysfunction without a change in its neuromuscular blocking profile. The pharmacokinetics of cisatracurium is only marginally influenced by advanced age.
The metabolites of cisatracurium by Hoffman elimination are inactive at the neuromuscular junction (NMJ). In contrast to atracurium, plasma concentrations of laudanosine after administration of 2 Ã— ED95 dose of cisatracurium are fivefold less than that present after a 1.5 Ã— ED95 dose of atracurium (Lien et al., 1996).
Cisatracurium, in contrast to atracurium, is devoid of histamine-releasing effects such that cardiovascular changes do not accompany the rapid intravenous (IV) administration of even large doses (8 Ã— ED95) of cisatracurium. Cisatracurium administered to adult neurosurgical patients produces less cerebral hemodynamic changes compared with equipotent doses of atracurium.
This is among long-acting aminosteroid nondepolarizing Neuromuscular blocker drugs with an ED95 of 70 Âµg/kg that has an onset of action in 3 to 5 minutes and a duration of neuromuscular blockade lasting 60 to 90 minutes.
An estimated 80% of a single dose of pancuronium is eliminated unchanged in the urine. In renal failure, the plasma clearance is decreased 33% to 50%. An estimated 10% to 40% undergoes hepatic deacetylation.
The 3-desacetylpancuronium metabolite is approximately 50% as potent as pancuronium at the NMJ. Patients with total biliary obstruction and hepatic cirrhosis have an increased volume of distribution, decreased plasma clearance, and prolonged elimination half-time of pancuronium.
This is among intermediate-acting aminosteroid nondepolarizing Neuromuscular blocker drugs with an ED95 of 50 Âµg/kg that produces an onset of action in 3 to 5 minutes and a duration of neuromuscular blockade lasting 20 to 35 minutes.
Vecuronium undergoes both hepatic metabolism and renal excretion. The 3-desacetylvecuronium metabolite is approximately one half as potent as the parent compound. The elimination half-time is prolonged in patients with renal failure. In patients with cholestasis, hepatic cirrhosis, or alcoholic liver disease, the administration of vecuronium, 0.2 mg/kg, results in a prolonged elimination half-time and increased duration of action.
Rocuronium is an intermediate-acting aminosteroid with an ED95 of 0.3 mg/kg that has an onset of action in 1 to 2 minutes and a duration of neuromuscular blockade lasting 20 to 35 minutes. Rocuronium is largely excreted unchanged (up to 50% in 2 hours) in the bile.
Liver disease increases the volume of distribution of rocuronium and could result in a longer duration of action, especially with repeated doses or prolonged IV administration. Renal excretion of rocuronium may be >30% in 24 hours, and administration of this drug to patients in renal failure may produce a modestly prolonged duration of action.