Neuromuscular Blocking Drugs (see
Chapter 13
)
In contrast to the scant pharmacokinetic data described earlier
for opioids and intravenous anesthetics, more comprehensive information is available
regarding the impact of cirrhosis on the pharmacokinetics and pharmacodynamics of
muscle relaxants. Vecuronium is a steroidal muscle relaxant that undergoes hepatic
elimination[71]
[72]
and has decreased clearance, a prolonged elimination half-life, and prolonged neuromuscular
blockade in patients with cirrhosis ( Fig.
55-4
).[73]
[74]
The impact of alcoholic liver disease is less definite, with clearance and elimination
half-lives typically unchanged.[75]
Rocuronium,
another steroidal muscle relaxant with a faster onset of action than vecuronium has,
also appears to undergo hepatic metabolism and elimination.[76]
Hepatic dysfunction can increase the volume of distribution of rocuronium, thus
prolonging its elimination half-life[76]
and producing
a longer clinical recovery profile and return of normal twitch tension.[76]
[77]
Although the initial clinical recovery of
neuromuscular
function is not affected by
Figure 55-4
Disappearance of vecuronium from plasma after a single
bolus dose of 0.2 mg/kg. A semilogarithmic plot of plasma concentration versus time
shows that the vecuronium concentration remained at a much higher level during the
elimination phase in patients with cirrhosis (open circles)
than in normal control patients (black circles).
This difference reflects the markedly decreased plasma clearance of vecuronium,
increased elimination half-life, and increased duration of neuromuscular blockade
in patients with cirrhosis versus normal individuals. (From Lebrault C,
Berger JL, D'Hollander AA, et al: Pharmacokinetics and pharmacodynamics of vecuronium
(ORG NC 45) in patients with cirrhosis. Anesthesiology 62:601–605, 1985.)
liver disease, larger initial doses or repeated administration will typically prolong
the effect of rocuronium in the presence of significant hepatic dysfunction.[76]
The increased volume of distribution for some drugs observed in
cirrhotic patients can also prolong the elimination half-life of pancuronium[78]
and the time of onset of pipecuronium,[79]
although
elimination of pipecuronium appears to be unchanged. Muscle relaxants that undergo
organ-independent elimination, such as atracurium (nonspecific ester hydrolysis)
and cisatracurium (Hofmann elimination), have similar elimination half-lives and
clinical durations of action in normal patients and those with end-stage liver disease.
[80]
[81]
[82]
Cirrhosis also does not appear to decrease the plasma clearance of rapacuronium
or prolong the clinical recovery of neuromuscular function, although given the recent
Food and Drug Administration removal of rapacuronium from the market, this information
is largely of historical interest.[83]
[84]
The unique elimination of mivacurium by plasma cholinesterase is, however, altered
by cirrhosis.
Mivacurium is associated with significantly longer recovery of
twitch tension and has a longer elimination half-life (18 versus 34 minutes in normal
versus cirrhotic patients, respectively) and a longer residence time in patients
with hepatic failure than in normal patients, a finding closely correlated to reduced
plasma cholinesterase activity in cirrhotic patients.[85]
[86]
[87]
This
reduced
activity appears to be related to reduced clearance by plasma cholinesterase of the
two active isomers of mivacurium, cis-trans and trans-trans.
[87]
Infusion rates of mivacurium should be adjusted
accordingly in patients with advanced liver disease. The changes observed with mivacurium
are predictably expected with succinylcholine if decreased plasma cholinesterase
levels are present because of advanced liver disease. Lowered cholinesterase levels
have been observed in these individuals[88]
and
may prolong the effect of succinylcholine.
In summary, cirrhosis and other forms of advanced liver disease
will predictably reduce the elimination of vecuronium, rocuronium, and mivacurium
and prolong the duration of neuromuscular blockade, especially after repeated doses
or the use of prolonged infusions. Atracurium and cisatracurium are not dependent
on hepatic elimination and can be used without modification of dosing in patients
with end-stage liver disease. Careful monitoring of neuromuscular function is recommended
whenever muscle relaxants are used in this patient population.
