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Hepatobiliary Disease (also see Chapter 56 )

Patients with hepatobiliary disease may exhibit prolonged blockade with dTc,[730] pancuronium,[296] doxacurium,[346] vecuronium,[231] rocuronium,[353] [357] and mivacurium.[172] [228] In the case of pancuronium,[295] vecuronium,[231] and mivacurium,[172] [228] this prolonged action is associated with decreased plasma clearance of the drug. However, this relationship is not consistent, and many studies have described a reduction in clearance without a prolonged duration of action. In the case of atracurium, one study even reports increased clearance in patients with cirrhosis, but the duration of action was normal.[330]

The influence of hepatobiliary disease on the pharmacokinetics of neuromuscular blockers is complex ( Table 13-15 ). In most studies, hepatic disease is associated with an increased volume of distribution, and as a result, patients have an apparent resistance to the effect of dTc,[330] [735] pancuronium,[297] [736] atracurium,[737] and rocuronium.[732] The effect of hepatic disease on the
TABLE 13-15 -- Pharmacokinetics of neuromuscular blocking drugs in patients with normal liver function or hepatobiliary disease

Plasma Clearance (mL/kg/min) Volume of Distribution (mL/kg) Elimination Half-Life (min)


Normal Disease Normal Disease Normal Disease Hepatic Pathology Reference
Short-Acting Drugs
Mivacurium isomers





Cirrhosis [172]
  Cis-trans 95 44 * 210 188 1.53 2.48 *

  Trans-trans 70 32 * 200 199 2.32 11.1 *

  Cis-cis 5.2 4.2 266 237 50.3 60.8

Intermediate-Acting Drugs
Atracurium 5.3 6.5 159 207 * 21 22 Hepatorenal [712]

6.6 8.0 * 202 282 * 21 25 Cirrhosis [330]
Cisatracurium 5.7 6.6 * 161 195 * 23.5 24.4 Transplantation
Vecuronium 4.26 2.73 * 246 253 58 84 * Cirrhosis [231]

4.30 2.36 * 247 206 58 98 * Cholestasis [731]

4.5 4.4 180 220 58 51 Cirrhosis [304]
Rocuronium 2.79 2.41 184 234 87.5 96.0 Cirrhosis [353]

217 217 16.4 23.4 * 76.4 111.5 * Mixed [356] †

296 189 151 264 * 56 98 * Cirrhosis [732] †

3.70 2.66 * 211 248 92 143 * Cirrhosis [357]
Long-Acting Drugs
Doxacurium 2.7 2.3 220 290 99 115 Transplantation [346]
Pancuronium 123 59 * 261 307 * 133 267 * Cholestasis [296] †

1.86 1.45 * 279 416 * 114 208 * Cirrhosis [294]

1.76 1.47 284 425 * 141 224 * Cholestasis [732]
Pipecuronium 3.0 2.6 * 350 452 111 143 Cirrhosis [299]
Gallamine 1.22 0.90 237 259 162 220 Cholestasis [733]

1.20 1.21 206 247 * 135 160 Cholestasis [734]
*Significant difference between normal hepatic function and hepatobiliary disease.
 †Values expressed as milliliters per minute, or liters, not weight adjusted.




pharmacokinetics of neuromuscular blockers (see Table 13-15 ) suggests that initial doses may need to be greater than for patients with normal hepatic function but that once the desired level of block has been achieved, subsequent recovery may be slower. This is illustrated in the case of vecuronium, in which doses up to 0.15 mg/kg have a normal duration of action[304] [738] [739] but a dose of 0.2 mg/kg has prolonged action (see Fig. 13-15 ).[731] [739]

Hepatic disease can alter the elimination of neuromuscular blockers by several mechanisms. The principal route of metabolism of pancuronium and vecuronium is deacetylation at the 3-position.[290] [292] This metabolic process is presumed to occur in the liver because 10% to 20% of the total dose of pancuronium and 40% percent of the total dose of vecuronium are found in the liver and bile as both parent drug and metabolite.[290] [292] [303] In hepatic disease, an increased plasma concentration of bile salts can reduce the hepatic uptake of pancuronium and vecuronium,[290] [733] which may be an explanation for the decreased clearance of these drugs observed by some investigators.[294] [296] [346] Excretion of vecuronium is diminished in the presence of decreased hepatic function.[665] The duration of action of vecuronium is longer in these patients, and recovery is slower than in young healthy individuals.

530

Atracurium and cisatracurium share organ-independent modes of elimination.[322] [323] [340] [341] [342] As a consequence, their clearance should be little affected by hepatic disease. In fact and in contrast to all other neuromuscular blockers, plasma clearance of atracurium and cisatracurium is slightly increased in patients with liver disease (see Table 13-15 ).[330] [358] Because elimination of atracurium and cisatracurium occurs outside as well as from within the central compartment, it has been suggested that a larger distribution volume should be associated with a larger clearance.[342] In two studies,[330] [358] volumes of distribution and clearance of the drugs increased with liver disease, thus lending support to this theory.[342] The increased clearance of the relaxant in patients with liver disease is not reflected in a decrease in the drugs' duration of action.[330] [358]

A concern raised about administering atracurium to patients with hepatic disease was the possible accumulation of laudanosine.[339] Although laudanosine relies principally on hepatic mechanisms for elimination, the concentrations encountered during liver transplantation are unlikely to be associated with clinical sequelae.[339] [735]

In patients with hepatic disease (most commonly cirrhosis), the distribution volume of rocuronium is increased,[353] [356] [357] [732] and its clearance may be decreased.[357] The duration of action of rocuronium is prolonged in patients with hepatic disease,[353] [357] [732] and its onset may be prolonged.[353]

In patients with severe liver disease, butyryl-cholinesterase activity is decreased because of decreased synthesis of the enzyme in the liver. [228] Consequently, plasma clearance of the isomers of mivacurium is decreased by approximately 50% (see Table 13-15 ),[172] and its duration of action is prolonged and may be almost tripled.[172] [228]

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