Hepatic Disease

Drugs that can act as hepatocellular toxins (e.g., acetaminophen, alcohol, and isoniazid) will cause elevations in liver transaminases. Mild alanine ami-notransferase (ALT) and aspartate aminotransferase (AST) elevations are common and usually benign. They require investigation only if elevated two to three times above baseline. Other drugs, such as val-proic acid, can impair the metabolic machinery of the cell disproportionate to the degree of hepatocel-lular damage. In patients with valproate-induced liver injury, low albumin, high prothrombin time (PT), and high ammonia may be seen without much elevation in liver transaminases (Bjornsson 2008).

Still other drugs (e.g., chlorpromazine and eryth-romycin) cause cholestasis without much hepatocel-lular injury or elevation in ALT or AST (Glasova and Beuers 2002; Hautekeete 1995; Velayudham and Farrell 2003). Although elevations in bilirubin or alkaline phosphatase in adults suggest involvement of the biliary tract, in children and adolescents, alkaline phosphatase is routinely elevated by related release from bones. Thus, in pediatric patients, assay of y-glutamyl transpeptidase is a better indicator of cholestasis and should be measured along with bili-rubin.

Hepatic disease may affect drug distribution due to changes in hepatic blood flow, effects on protein binding, and changes in volume of distribution due to peritoneal ascites (Beliles 2000b). The effects are reduced medication availability for metabolism and a resultant increase in serum drug levels. In acute hepatitis, there is generally no need to modify dosing because metabolism is only minimally altered and the change is transient. In chronic hepatitis and cirrhosis, however, there is destruction of hepatocytes and the likely need to modify medication dosages.

Cirrhosis may distort liver architecture and alter hepatic blood flow. In severe disease, portosystemic shunting may affect 60% or more of portal vein flow that diverts circulating drugs away from the liver, resulting in decreased drug extraction and first-pass metabolism (Bosch 2007). In contrast, hepatic blood flow may be increased in viral hepatitis and in chronic respiratory problems. Medications with high baseline rates of liver clearance (e.g., haloperi-dol, paroxetine, sertraline, nefazodone, venlafaxine, TCAs, and midazolam) are significantly affected by alterations in hepatic blood flow.

Produced in the liver, albumin and ^-glycoprotein may be reduced in infectious and inflammatory hepatic disease, whereas protein levels may be elevated as a result of surgery, trauma, or cirrhosis. Elevated bilirubin levels are found in acute viral hepatitis and primary biliary cirrhosis (Crosignani et al. 2008; Farrell 1998). Bilirubin has a strong affinity for albumin binding sites and may displace medications (e.g., divalproex sodium and phenytoin). In steady-state situations, changes in protein binding may result in elevated unbound active drug even in the presence of normal serum drug concentrations. Because it is often difficult to predict changes in protein binding, it is important to maintain attention to the effects of psychotropic medications and not rely exclusively on serum drug concentrations.

It is often necessary to use lower dosages of medications in patients with hepatic disease. Initial dosing of medications should be reduced in patients with hepatic disease, and titration should proceed slowly. For drugs that have significant hepatic metabolism, intravenous administration may be preferred (see Table 30-1). Parenteral administration of drugs avoids first-pass metabolic effects, such that the dosing and action of drugs are similar to those in patients with normal hepatic function.

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