Drug Dosing Issues and Resources

As with renal impairment, all pharmacokinetic processes may be affected by hepatic disease and must be considered in dosage administration. Unfortunately there is not a dosing calculator which can encompass these elements, and individualized assessment is needed. The primary process affected by hepatic impairment is the metabolism of drugs. This can affect bioavailability (increases) and systemic clearance/removal of drug (decreases) from the circulation. Both of these effects lead to increased concentrations in the body. As with renal impairment, the potential accumulation of drugs and an increase in adverse effects/toxicity which may occur is the primary concern. Specific dosage precautions must be considered.

It is important to evaluate the degree of liver impairment. Just like in renal impairment, liver impairment is not an “all-or-none” phenomenon, and must be evaluated in relative terms. Unlike renal impairment, there is no quick way to estimate hepatic function. Sometimes that is better, since it requires a more thoughtful and complete analysis. Liver function CAN be evaluated by looking at what the liver does from a physiologic standpoint.

Elevation of hepatic transaminases (AST and ALT) is not a very reliable indicator of function. These enzymes are released from hepatic cells and serve as an indication of acute injury. But the liver has a large redundancy and damage which occurs over long period of time can lead to serious impairment even in the absence of transaminase elevations.

The liver is responsible for synthesis of proteins, including albumin and clotting factors. Elevated prothrombin/INR and/or low serum albumin concentrations indicate that the synthetic capacity of the liver is diminished. The liver is also responsible for excretory functions through the conjugation of bilirubin. Elevations in bilirubin may indicate impairment of this function. There are also other indicators of hepatic function, such as serum ammonia. There is a classification scheme (the Pugh-Child scale) which takes several of these factors into account and may be used to classify the degree of liver impairment into mild, moderate, and severe levels. Specific dosage adjustment and/or contraindications have been published using these criteria for some drugs.

 
It is important to note that medicine interactions are not obvious in evaluating hepatic impairment. Interactions which block a metabolic pathway may be considered as a type of transient, functional hepatic impairment.