Pharmacokinetic Changes in Liver Failure and Impact on Drug Therapy.

P harmacokinetics is a term that describes the time course and fate of a drug in the body. The term encompasses drug absorption, distribution, metabolism, and elimination and is often referred to as drug disposition.1 Absorption is defined as the process by which a drug enters the systemic circulation, distribution is the movement of the drug between body compartments, and metabolism encompasses the activation or inactivation of the drug through biotransformation reactions. Elimination is the removal of the drug from the body through different routes, including in urine, feces, and bile.2 Critically ill patients pose several challenges to health care providers that are related to medication pharmacokinetics. These challenges are due to the complex interactions of the patient’s multiple disease states and often are due to the presence of multiorgan dysfunction. Organ dysfunction affects the safety and effectiveness of medications because many organs are involved in drug disposition.1 Metabolism occurs in multiple areas of the body; however, the liver plays a central role in drug metabolism because of the high concentrations of multifunctional enzymes. The liver has hepatocytes that contain the necessary enzymes for metabolic pathways that activate or inactivate the drug.1 The disposition of many medications relies on hepatic function for metabolism and elimination, and these processes may be hampered when physiological factors impair liver function.3 Common drug classes that are highly dependent on the liver for metabolism include analgesics, sedatives, antibiotics, and anticoagulants. In order to better predict the impact of hepatic dysfunction on medication pharmacokinetics, it is important to understand the factors affecting hepatic metabolism. The liver’s ability to eliminate drugs from the body is dependent on blood flow to the liver and its enzymes’ ability to metabolize drugs. Medications are classified as those whose metabolism is dependent on hepatic blood flow (eg, morphine) and those whose metabolism is dependent on liver enzyme activity (eg, diazepam). Drugs that are dependent on blood flow for metabolism are very sensitive to changes in perfusion such as episodes of hypotension, hypovolemia, or shock.3-6 In the setting of hypotension or shock, hepatic blood flow is decreased, resulting in reduced metabolism and increased