Читать книгу Clinical Pharmacology and Therapeutics - Группа авторов - Страница 66

In low extraction drugs, the rate of metabolism is so sufficiently low that hepatic clearance is relatively insensitive to changes in hepatic blood flow, and dependent mainly on the capacity of the liver enzymes. Examples include chloramphenicol, paracetamol and theophylline. The hepatic clearance of drugs in this group that are also highly protein‐bound, such as diazepam, tolbutamide, phenytoin and valproic acid, depends on both the capacity of the enzymes and the free fraction. It is thus difficult to predict the consequences of hepatic disease on total drug concentration. However, as with renal disease, care must be taken in the interpretation of concentrations of highly protein‐bound drugs such as phenytoin.

The influence of liver disease on drug elimination is complex; the type of liver disease is critical. In acute viral hepatitis, the major change is in hepatocellular function, but drug‐metabolising ability usually remains intact and hepatic blood flow can increase. Mild to moderate cirrhosis tends to result in decreased hepatic blood flow and portosystemic shunting, while severe cirrhosis usually shows reduction in both cellular function and blood flow. Cholestasis leads to impaired fat absorption with deficiencies of fat‐soluble vitamins and impairment of absorption of lipophilic drugs. Alcoholic liver disease is common and chronic ethanol abuse is associated with increased activity of the microsomal ethanol‐oxidising system. This effect is a result primarily of induction by ethanol of a specific cytochrome P450 (CYP2E1) responsible for enhanced oxidation of ethanol and other P450 substrates and, consequently, for metabolic tolerance to these substances. This may lead to enhanced clearance and, hence, decreased response to certain drugs such as benzodiazepine sedatives, anticonvulsants (phenytoin) and warfarin. By contrast, simultaneous alcohol ingestion may decrease clearance of drugs metabolised via the P450 (CYP2E1) enzyme system.

Comment. Unlike the measurement of creatinine clearance in renal disease, there is no simple test that can predict the extent to which drug metabolism is decreased in liver disease. A low serum albumin, raised bilirubin and prolonged prothrombin time give a rough guide.

The fact that a drug is metabolised by the liver does not necessarily mean that its pharmacokinetics is altered by liver disease. It is not easy, therefore, to extrapolate the findings from one drug to another. This is because superficially similar metabolic pathways are mediated by different forms of cytochrome P450.

The documentation of modestly altered pharmacokinetics does not necessarily imply clinical importance. Even normal subjects show quite wide variations in pharmacokinetic indices and therefore pharmacokinetics should not be viewed in isolation from alterations in drug effect, which are much more difficult to assess. However, if a drug is known to be subject to substantial pharmacokinetic changes, clinical significance is much more likely.

If it is clinically desirable to give a drug that is eliminated by liver metabolism to a patient with cirrhosis, it should be started at a low dose and the drug levels or effect monitored very closely.