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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 5 of 5. This is the beginning of the thread.
Posted by Mishal on December 30, 2007, at 23:07:32
If you can help me,
It confuses me when I look at many drugs's half-lifes and the dosage prescribed. For example, Serzone the antidepressant has a very short half-life of maximum 4 hours. Yet it is advised to take twice daily. If the half life of a medicine is only 4 hours, then by taking it twice daily would only make it work for eight hours. Roughly one third of a day (24 hours) Isn't it so?
Or is there any difference between half-life and the duration of drug action?
Posted by Maxime on December 31, 2007, at 0:54:04
In reply to Half-life means duration of drug action?, posted by Mishal on December 30, 2007, at 23:07:32
Hi
A medication's half-life is the time it takes for the plasma concentration of a drug to reach half of its original concentration. So the half-life of a drug is how long it takes for half of it to be eliminated from the bloodstream.Once you have been taking the med, it takes about 4 half-life units for the concentration of a med in the system to reach a steady state. And that's what you are aiming for.
Maxime
Posted by Mishal on December 31, 2007, at 3:11:34
In reply to Re: Half-life means duration of drug action? » Mishal, posted by Maxime on December 31, 2007, at 0:54:04
> Hi
> A medication's half-life is the time it takes for the plasma concentration of a drug to reach half of its original concentration. So the half-life of a drug is how long it takes for half of it to be eliminated from the bloodstream.
>
> Once you have been taking the med, it takes about 4 half-life units for the concentration of a med in the system to reach a steady state. And that's what you are aiming for.
>
> Maxime
Hi Maxime,I know what half-life means. But what I need to know is how can a med with a very short half life work for the whole day taking it once or twice daily. Like the example of Serzone, its half-life is roughly four hours. That means, taking Serzone twice daily amounts to 4 + 4 x 2 = 16 hours. Therefor duration of action (here in the case of Serzone) is 16 hours. Still 8 hours are there with the med not being in our system.
Am I right? Or do I miss something?
Posted by Larry Hoover on December 31, 2007, at 5:40:28
In reply to Half-life means duration of drug action?, posted by Mishal on December 30, 2007, at 23:07:32
> If you can help me,
>
> It confuses me when I look at many drugs's half-lifes and the dosage prescribed. For example, Serzone the antidepressant has a very short half-life of maximum 4 hours. Yet it is advised to take twice daily. If the half life of a medicine is only 4 hours, then by taking it twice daily would only make it work for eight hours. Roughly one third of a day (24 hours) Isn't it so?No, that's a limited view of the effect of half-life drug concentration. A drug does not stop working once it reaches its half-life.
> Or is there any difference between half-life and the duration of drug action?
There's a lot more to consider.
In the simplest model, drug metabolism occurs at a fixed rate, dependent only on the initial drug concentration. Whatever concentration you start with, at the half-life period, there will have been half the drug eliminated (1/2 remaining). Go forward another half-life period, and there will be only a quarter of the original dose remaining (1/2 of 1/2 remaining). And so on.
If you take the drug again, at the half-life period, and then take it again at the second half-life period, then your blood concentration will be: 1 (from the third dose) + 1/2 (from the second dose) + 1/4 (from the first dose) = 1 3/4 times the concentration arising from a single dose. After four doses, it's 1 7/8. After five, it's 1 15/16. The effect is that the maximum blood concentration approaches twice that occurring from a single dose, and falls close to that from a single dose, if you take the drug as frequently as the half-life period. In general use, this stable pattern develops after 5 doses. But there's a lot more to consider.
One issue is the presence of active metabolites. Just because a drug is no longer present in its parent form is not evidence that it's stopped working. Yes, Serzone has a very short half-life of perhaps four hours, but it has an equally active metabolite, hydroxynefazodone. This drug's effects are not limited to the parent molecule, nefazodone.
Then one must consider kinetic effects. Recall that I said we model the half-life as a linear process (well, linear when plotted as the natural logarithm). That model suggests a limiting value of twice the dosed blood concentration, after 5 (or more) consecutive doses. Serzone does not follow that model's prediction. In a dose-dependent relationship, the maximum blood concentration increases from a low of 3 times, to a maximum up to about 7 times that predicted by our model (i.e. two times). In effect, what we see is that Serzone inhibits its own metabolism. That may be why it can cause fulminant liver failure, as the liver is programmed to self-destruct if it cannot metabolize a toxin. Our individual capacity to metabolize toxins varies considerably, and some livers can't handle nefazodone.
Another factor to consider with respect to drug effects are compartment issues. The dataset for half-life considerations is developed from blood samples. We cannot assume that identical concentration fluctuations occur outside the bloodstream. Behind the blood/brain barrier, the local half-life could be a very different value. And again, we must also allow for the variable effects of the parent and metabolites.
At best, a blood half-life determination serves as a guide. But clinical practise guidelines are developed from the Phase 1 and 2 clinical trials, which would have revealed the atypical performance of Serzone. The twice daily dosing is quite appropriate for this particular drug, notwithstanding its half-life.
Does this answer your questions?
Lar
Posted by Mishal on December 31, 2007, at 22:15:37
In reply to Re: Half-life means duration of drug action? » Mishal, posted by Larry Hoover on December 31, 2007, at 5:40:28
This is the end of the thread.
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