The effects of liver disease and aging on the disposition of diazepam, chlordiazepoxide, oxazepam and lorazepam in man

The benzodiazepines constitute a class of drugs of considerable disparity in a number of potentially clinically important ways. They are also used so widely that the characteristics of the patient population important in overall drug responsiveness vary considerably, also. The possibility, therefore, exists that one drug may have more desirable qualities than another related benzodiazepine when used in a particular group of patients. A clinical response has both pharmacokinetic and pharmacodynamic components, and as an initial exploration of the latter hypothesis the disposition of a number of benzodiazepines has been investigated with respect to the effects of aging and liver disease on the involved processes. Considerable differences exist between the drugs when studied in a group of young and old individuals aged usually below 30 and above 60 years. With diazepam and chlordiazepoxide aging leads to a 3‐ to 6‐fold prolongation in the elimination half‐life from about 20–30 hours to 60–80 hours and 6–8 hours to 30–36 hours, respectively. In both cases this involves an age‐related increase in the distribution volume, but in addition the plasma clearance of chlordiazepoxide decreases about 3‐fold. In contrast, the removal of both oxazepam and lorazepam from the body, appears to be unaffected by aging, whether expressed by the half‐life or plasma clearance. Similar differences between these drugs also exist with respect to the effects of liver disease on their disposition. Cirrhosis produces a 2‐ to 3‐fold increase in the half‐life of both diazepam and chlordiazepoxide relative to age‐matched controls. The predominant cause of this is a significant reduction in plasma clearance but the distribution of the drugs is slightly increased due to a reduction in plasma binding. Acute viral hepatitis has a similar but slightly smaller effect upon plasma clearance, which is reversible upon clinical recovery. Neither of these diseases has a significant effect on the disposition of oxazepam and lorazepam. The aging process and liver disease, therefore, affect the disposition of these closely related benzodiazepines quite differently. The fact that the pharmacokinetics of benzodiazepines which are eliminated by glucuroni‐dation are relatively unaffected by the investigated disease processes suggests that they may be more clinically advantageous than perhaps similar drugs which are oxidatively metabolized. However, well designed clinical studies including assessment of any pharmacodynamic alterations will be required to test whether this is indeed correct.