Benzodiazepines are on the Beers criteria. They can have significant adverse effects like sedation, confusion, the risk for dependence, and increased fall risk. We like to avoid benzodiazepines if we can, but what if we do feel that it is necessary (i.e. hospice or other situation)? I have been asked this question before and will be comparing lorazepam and diazepam to demonstrate how different medications in each class can have different pharmacokinetics in the body.
Let’s start with lorazepam as this is the benzodiazepine that I see used the most in our elderly population. Lorazepam is altered by a process called conjugation. Do you need to know what conjugation is? Not really as long as you know that in the case of lorazepam, the process ultimately leads to an inactive compound. What is also cool about conjugation compared to renal elimination or other elimination processes is that age doesn’t have as great of an effect on the speed and functionality of this process.
This is great, but who cares and how does it affect my patient? Bottom line, lorazepam does not have any active metabolites and the breakdown of the drug is fairly consistent as a patient ages from 46 to 86. This can lead to less patient variability in response and risk of adverse effects.
Active metabolites can make a drug’s activity challenging to predict. Diazepam is a good example of this problem. Diazepam has an active metabolite called desmethyldiazepam. While the half-life of diazepam is relatively long at around 40-50 hours, desmethyldiazepam’s half-life can be over 100 hours and this can be even longer in our elderly population!
Complicating things further, the formation of desmethyldiazepam is done by the enzymes CYP3A4 and 2C19. As we learn more about drug interactions and pharmacogenetics, you can begin to appreciate how complicated the kinetics of diazepam are. There are hundreds (maybe more) of drugs that could alter the activity of 3A4 or 2C19. Genetic variations could certainly lead to an alteration in the formation of this active metabolite. This is challenging because it is REALLY difficult to predict how each patient will respond to the drug. Large variability in how one patient will respond compared to the next is problematic and does not allow us to rest easy at night.
Hopefully, this example of comparing lorazepam to diazepam was helpful in learning more about pharmacokinetics! I did have a previous post on benzodiazepines that may be of interest as well.
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