Abstract

ABSTRACTBoth old age and liver disease may affect the disposition and elimination of drugs and in the case of sedatives and tranquilizers such abnormalities may be associated with exaggerated sedation. Diazepam (Valium) elimination half-life (T) increases with advancing age and it correlates with increased volume of distribution but not with plasma clearance. Chlordiazepoxide (Librium) T is also increased in the elderly, the increase being related to decreased drug clearance. By contrast, age has no effect on the disposition and elimination of oxazepam (Serax) or lorazepam (Ativan). Similarly, in the presence of significant liver disease the elimination of certain members of the benzodiazepine class of drugs is strikingly impaired. Diazepam T is increased twofold or more in acute viral hepatitis and in cirrhosis of the liver as plasma clearance is correspondingly decreased. Diazepam metabolism is also impaired in chronic active hepatitis and in hepatic neoplasm, but not in extrahepatic cholestasis. The disposition and elimination of chlordiazepoxide are also impaired in the presence of liver disease. The changes in T or plasma clearance of these drugs, however, do not correlate with any of the conventional liver function tests. Apart from pharmacokinetic changes it has also been shown that cirrhotic patients, especially those with previous encephalopadiy, are more sensitive to the CNS effect of agents like diazepam than are normal controls. Unlike diazepam and chlordiazepoxide, oxazepam disposition and lorazepam clearance are not affected in liver disease. Other members of the benzodiazepine group of drugs are still to be studied. Based on pharmacokinetic data, oxazepam and lorazepam would seem to be more suitable than diazepam and chlordiazepoxide for use in the elderly and in patients with liver disease. In view of the present state of knowledge, in general, the administration of tranquilizers to geriatric and hepatic patients should be handled with prudence.