13.15: Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow

Chronic liver disease significantly impacts drug metabolism due to alterations in hepatic blood flow and enzyme accessibility. This disruption affects the body's pharmacokinetics—the movement and processing of drugs within the system. Key enzymes crucial for metabolizing medications become less accessible, changing how drugs are processed and utilized. Furthermore, liver disease influences the synthesis of plasma proteins, such as albumin and globulins, which play critical roles in drug binding and distribution. These proteins are essential for the proper transportation and effectiveness of medications in the bloodstream.

In severe cases, cirrhosis may progress to fibrosis, leading to the development of intra- or extrahepatic shunts. These shunts can significantly alter the drug extraction process, reducing the liver’s ability to filter out medications and thereby increasing their bioavailability. This alteration necessitates a recalibration of drug dosages to avoid toxicity.

Calculating a drug’s hepatic clearance becomes crucial in managing these conditions. To ensure accuracy, clinical assessments must corroborate these calculations. These calculations help adjust dosages to accommodate the liver's diminished processing capacity.

Given these complexities, the treatment protocol for patients with hepatic failure typically starts with low drug doses. This conservative approach, coupled with continuous plasma level monitoring, helps safeguard against potential drug toxicity while ensuring therapeutic efficacy.

Although useful for detecting liver damage, liver function tests do not provide insights into the functionality of specific enzymes like cytochrome P450, which are pivotal for drug metabolism. Consequently, drugs that depend on these enzymes are often administered in reduced doses to compensate for impaired liver function. Additionally, drugs that require flow-dependent clearance are generally avoided in patients with liver failure, or their doses are significantly reduced to minimize the risk of adverse effects. This tailored approach in drug administration is essential to manage effectively and safely the complexities introduced by chronic liver disease.

Chronic liver disease disrupts hepatic blood flow, altering enzyme accessibility and affecting drug pharmacokinetics.

It also impacts the synthesis of plasma proteins like albumin and globulins, affecting drug binding and distribution.

Severe fibrosis can progress to cirrhosis. This results in the development of intrahepatic and extrahepatic shunts, which can reduce drug extraction while increasing drug bioavailability.

Tissue damage and blood flow changes can alter a drug’s hepatic clearance. Hepatic clearance is influenced by the blood flow, intrinsic clearance, and their interaction. The overall clearance can also be expressed as the product of the blood flow and the extraction ratio. These values must be corroborated with clinical assessment, such as physical examination and liver function tests.

Given these challenges, in hepatic failure patients, treatments often begin with low doses while monitoring plasma levels to ensure a safer and more effective therapy.

As liver function tests typically show only liver damage and not the cytochrome P450 enzyme functionality, the enzyme-dependent drugs are often given in reduced doses.