EFFECT OF HEPATIC DYSFUNCTION AND HEPATOBILIARY DISEASE ON ANESTHETIC DRUG PHARMACOKINETICS (see Chapter 3 )

Liver disease may have a significant impact on drug metabolism and pharmacokinetics as a result of alterations in protein binding, reduced levels of serum albumin and other drug-binding proteins, altered volume of distribution because of ascites and increased total-body water compartments, and reduced metabolism secondary to abnormal hepatocyte function. In addition, sedatives and opioids may have exaggerated effects in patients with advanced liver disease and may either induce or worsen hepatic encephalopathy.^[51] The impact of chronic alcohol ingestion on hepatic enzyme induction may also influence the ultimate effect of drugs in patients with cirrhosis.

The impact of liver disease on drug disposition depends not only on the elimination pathways for a given drug but also on the severity of the underlying hepatic dysfunction. The efficiency of drug removal by the liver is determined by several factors, including hepatic blood flow, hepatic enzyme activity and efficiency, the extent of plasma protein binding, cholestasis-induced alterations in the enterohepatic circulation and metabolism of enteral drugs, and the presence of portosystemic shunts that exclude certain drugs from elimination by the diseased liver.^[52] In addition, the influence of liver disease on drug elimination differs for enteral and parenteral drugs.^[51] In general, severe liver disease predictably alters the metabolism of drugs with large extraction ratios, such as lidocaine and meperidine, where clearance is primarily dependent on hepatic blood flow or portosystemic shunting. Conversely, the metabolism of low-extraction drugs, such as the benzodiazepines, is influenced mainly by protein binding, where unbound drug is available for elimination, and by intrinsic hepatic clearance and metabolism, which is reduced in accordance with the severity of hepatocellular dysfunction. ^{[51] [52]} However, an increased free fraction of a drug because of reduced levels of plasma proteins may counter the impact of reduced hepatic metabolism and lead to modest changes in the ultimate effect of the drug.^[52] Finally, greater free fractions of available drug as a result of reduced protein binding may lead to greater drug deposition in tissues (and a potentially increased volume of distribution), which in conjunction with reduced hepatic metabolism may increase drug half-life. ^[52] It is thus evident that drug pharmacokinetics in the presence of advanced liver disease is complex. The impact on different classes of drugs is discussed separately.

Opioids (see Chapter 11 )

The significantly reduced metabolism of morphine in patients with advanced cirrhosis leads to a prolonged elimination half-life, markedly increased bioavailability of orally administered morphine, decreased plasma protein binding, and potentially exaggerated sedative and respiratory-depressant effects.^[52] Although extrahepatic metabolism may contribute to morphine clearance in patients with cirrhosis, it is recommended that the administration interval be increased 1.5- to 2-fold in these patients and the oral dose of the drug reduced because of increased bioavailability.^[52] Similar changes occur with meperidine, where a 50% reduction in clearance and a doubling of the half-life have been observed. In addition, clearance of normeperidine is reduced, and

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In contrast to these drugs, fentanyl is a highly lipid-soluble synthetic opioid that has a short duration of action after a single intravenous bolus dose because of rapid redistribution into storage sites. With repeated administration or continuous infusions, accumulation may occur and lead to prolonged effects.^[52] Because it is almost completely metabolized in the liver, its elimination should be predictably prolonged in patients with advanced liver disease. However, limited data suggest that fentanyl elimination is not appreciably altered in patients with cirrhosis.^{[52] [53]} Whether the limited extent of liver disease in the study patients affected the pharmacokinetic data or whether continuous infusions or repeated dosing in cirrhotic patients will produce more exaggerated and pronounced effects is unknown.

Sufentanil, a more potent but similar synthetic lipophilic opioid, is also extensively metabolized by the liver and is highly protein bound. Single-dose pharmacokinetics is not significantly altered in patients with cirrhosis, although the impact of continuous infusions and reduced protein binding is as ill defined for sufentanil as for fentanyl.^[54] Alfentanil, a short-acting opioid less potent than fentanyl, is also exclusively metabolized by the liver and is highly protein bound.^[52] However, unlike fentanyl or sufentanil, the half-life of alfentanil is almost doubled in patients with cirrhosis, and higher free fractions of the drug are observed, which can potentially lead to a prolonged duration of action and enhanced effects.^{[55] [56]} Remifentanil is a synthetic opioid with an ester linkage that allows for rapid hydrolysis by blood and tissue esterases; such hydrolysis leads to high clearance, rapid elimination, and recovery that is almost independent of the dose or duration of infusions.^[52] Predictably, its clearance should be unaffected by hepatic dysfunction, and available data indicate that remifentanil elimination is indeed unaltered in patients with severe liver disease or in those undergoing liver transplantation.^{[52] [57] [58] [59]}