Page 491 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 27 Skeletal Muscle Relaxants 477

biliary excretion or hepatic metabolism for their elimination.
O These muscle relaxants are more commonly used clinically than
the long-acting steroid-based drugs (eg, pancuronium). The
OC CH 3
CH 3 H duration of action of these relaxants may be prolonged signifi-
N + cantly in patients with impaired liver function.
H
CH 3
+ N CH 3 H CH 3 Atracurium (Figure 27–3) is an intermediate-acting iso-
quinoline nondepolarizing muscle relaxant that is no longer
H H H
O in widespread clinical use. In addition to hepatic metabolism,
CH 3 CO H H atracurium is inactivated by a form of spontaneous breakdown
Pancuronium known as Hofmann elimination. The main breakdown products
are laudanosine and a related quaternary acid, neither of which
O
possesses neuromuscular blocking properties. Laudanosine is
slowly metabolized by the liver and has a longer elimination half-
C CH 3
O
CH 3 life (ie, 150 minutes). It readily crosses the blood-brain barrier,
H +
N and high blood concentrations may cause seizures and an increase
N CH 3 H H CH 3 in the volatile anesthetic requirement. During surgical anesthesia,
blood levels of laudanosine typically range from 0.2 to 1 mcg/mL;
H H H
O H however, with prolonged infusions of atracurium in the ICU,
laudanosine blood levels may exceed 5 mcg/mL.
CH 3 CO H Atracurium has several stereoisomers, and the potent isomer
Vecuronium
cisatracurium has become one of the most common muscle
O relaxants in use today. Although cisatracurium resembles atracu-
rium, it has less dependence on hepatic inactivation, produces less
OC CH 3
CH 3
laudanosine, and is much less likely to release histamine. From a
CH 3 clinical perspective, cisatracurium has all the advantages of atra-
+
N N
CH 3 + CH 3 H curium with fewer adverse effects. Therefore, cisatracurium has
N N CH 3
CH 3 H H virtually replaced atracurium in clinical practice.
Gantacurium represents a new class of nondepolarizing
CH 3 CO H neuromuscular blockers, called asymmetric mixed-onium
O chlorofumarates. It is degraded nonenzymatically by adduc-
Pipecuronium tion of the amino acid cysteine and ester bond hydrolysis.
Gantacurium is currently in phase 3 clinical trials and not yet
O
available for widespread clinical use. Preclinical and clinical data
CH 3 C indicate gantacurium has a rapid onset of effect and predict-
O
CH 3 able duration of action (very short, similar to succinylcholine)
H
O + that can be reversed with neostigmine or more quickly (within
N
H CH 3 H 1–2 minutes), with administration of l-cysteine. At doses
N H
H H CH 2 CH CH 2 above three times the ED , cardiovascular adverse effects (eg,
95
hypotension) have occurred, probably due to histamine release.
HO No bronchospasm or pulmonary vasoconstriction has been
H H
Rocuronium reported at these higher doses.
B. Depolarizing Relaxant Drugs
FIGURE 27–4 Structures of steroid neuromuscular blocking The extremely short duration of action of succinylcholine
drugs (steroid nucleus in color). These agents are all nondepolarizing (5–10 minutes) is due to its rapid hydrolysis by butyrylcho-
muscle relaxants.
linesterase and pseudocholinesterase in the liver and plasma,
respectively. Plasma cholinesterase metabolism is the predominant
pathway for succinylcholine elimination. The primary metabolite
neuromuscular blockade during or after anesthesia. However, if of succinylcholine, succinylmonocholine, is rapidly broken down
the parent compound is administered for several days in the ICU to succinic acid and choline. Because plasma cholinesterase has
setting, the 3-hydroxy metabolite may accumulate and cause an enormous capacity to hydrolyze succinylcholine, only a small
prolonged paralysis because it has a longer half-life than the percentage of the original intravenous dose ever reaches the neuro-
parent compound. The remaining metabolites possess minimal muscular junction. In addition, because there is little if any plasma
neuromuscular blocking properties. cholinesterase at the motor end plate, a succinylcholine-induced
The intermediate-acting steroid muscle relaxants (eg, blockade is terminated by its diffusion away from the end plate
vecuronium and rocuronium) tend to be more dependent on into extracellular fluid. Therefore, the circulating levels of plasma