The intermediate-acting steroid muscle relaxants (eg, vecuronium and rocuronium) tend to be more dependent on biliary excretion or hepatic metabolism for their elimination. These muscle relaxants are more commonly used clinically than the long-acting steroid-based drugs (eg, pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function.
Atracurium (Figure 27–3) is an intermediate-acting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes). It readily crosses the blood-brain barrier, and high blood concentrations may cause seizures and an increase in the volatile anesthetic requirement. During surgical anesthesia, blood levels of laudanosine typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL.
Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most common muscle relaxants in use today. Although cisatracurium resembles atracurium, it has less dependence on hepatic inactivation, produces less laudanosine, and is much less likely to release histamine. From a clinical perspective, cisatracurium has all the advantages of atracurium with fewer adverse effects. Therefore, cisatracurium has virtually replaced atracurium in clinical practice.
Gantacurium represents a new class of nondepolarizing neuromuscular blockers, called asymmetric mixed-onium chlorofumarates. It is degraded nonenzymatically by adduction of the amino acid cysteine and ester bond hydrolysis. Gantacurium is currently in phase 3 clinical trials and not yet available for widespread clinical use. Preclinical and clinical data indicate gantacurium has a rapid onset of effect and predictable duration of action (very short, similar to succinylcholine) that can be reversed with neostigmine or more quickly (within 1–2 minutes), with administration of l-cysteine. At doses above three times the ED95, cardiovascular adverse effects (eg, hypotension) have occurred, probably due to histamine release. No bronchospasm or pulmonary vasoconstriction has been reported at these higher doses.
B. Depolarizing Relaxant Drugs
The extremely short duration of action of succinylcholine (5–10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. The primary metabolite of succinylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction. In addition, because there is little if any plasma cholinesterase at the motor end plate, a succinylcholine-induced blockade is terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels of plasma
TABLE 27–1 Pharmacokinetic and dynamic properties of neuromuscular blocking drugs.
1Nonenzymatic and enzymatic hydrolysis of ester bonds. 2Butyrylcholinesterase (pseudocholinesterase).
cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate.