How can medications with very short half lives (~2 hours) ever be effective given that a non-negligible steady state is never achieved unless dosed like 6 times/day?

Question

There are some medications, like buspirone, that have a very short half-life of 2-3 hours. Even if you took it twice a day, you’d only end up achieving a steady state of about 3-5% of the original dose. It’s very easy to do the math on Excel: [here’s an example of a 2 hour half-life medication taken twice a day](https://i.imgur.com/2N7HbmT.png).

One possible solution is taking the medication a ridiculous number of times per day, which is simply not going to happen (it’s hard enough to get daily compliance out of patients).

A second possible solution is prescribing a dose that’s like 10-50x larger than the desired steady-state level. For example, let’s say taking 100mg (2x/daily) of a medication provides a steady state of about 1-3% of that dose (as is approximately the case for a 2x/daily medication with a ~2 hour half life). If the *desired* steady state is 75% of that dose, you could achieve that steady-state by instead prescribing **2500mg** 2x/daily.

The problem with that, I assume, is that a 25x larger dose of almost *any* medication would have intolerable side effects.

But obviously these medications are approved, prescribed, used, and apparently actually do work. **But how?** I just don’t see how it’s possible. I’m sure I’m just missing something.

In: Biology

Answer 1

You’re missing a huge piece of the puzzle, which is active metabolites. Active metabolites are metabolic byproducts of a drug that continue to to produce the effects of the drug even after the parent drug has been metabolized. Active metabolites can not only have half-lives much longer than the parent drug, but can also be more potent than the parent drug itself.

To use your example of buspirone, it has several active metabolites. The main ones are 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-(2-pyrimidinyl)piperazine.