Dose and half-life

[ProteinTreasure]

I am having difficulty with half-life and dose of the psychiatric medications. Tried to read a few pharmacology textbooks and I am still struggling.

For example, does half-life depend on the dose? Sometimes in reference books there are 20-30 hours of half-life but not sure how exactly that translates into clinical practice, and is it still the same regardless of the dose.

Thank you.

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[clausewitz2]

I am having difficulty with half-life and dose of the psychiatric medications. Tried to read a few pharmacology textbooks and I am still struggling.

For example, does half-life depend on the dose? Sometimes in reference books there are 20-30 hours of half-life but not sure how exactly that translates into clinical practice, and is it still the same regardless of the dose.

Thank you.

The point of even talking about half-lives is to abstract away from specific dosages and concentrations. If first-order kinetics hold (and they do for most drugs we use) elimination is directly proportional to concentration.

The question of the relationship between absolute serum levels and therapeutic effect is much thornier.

 

[whopper]

Adding to the confusion, depending on your genetics, you might metabolize the meds faster or slower than others. E.g. some people are slow or rapid metabolizers so dosages need to be adjusted accordingly but over 99% of the time the physician won't know what type of metabolizer you are because it's not yet part of the standard to get the testing done nor will insurance pay for it most of the time.

 

[Amygdarya]

No, half-life doesn't depend on the dose or concentration of the drug; it's a constant that is mostly determined by intrinsic properties of the drug that affect drug distribution and elimination (eg., drug hydrophobicity that affects distribution, specific metabolic mechanisms that dictate rate of metabolism and elimination routes etc).

The variation in half-life values that you can see in the tables is not due to different drug doses but to patient-related drug elimination factors (eg., if they are slow or fast metabolizers as described above, if there is any hepatic or renal impairment that leads to slower elimination etc).

To make it more concrete, for a patient A it will take 20 hours to eliminate half of the drug from the body regardless of the dose. If you give that patient 5 mg of the drug, there'll be a total of 2.5 mg of the drug in 20 hours; if you give him/her 10 mg, it'll be 5 mg in 20 hours.
However, in a patient B with significant renal impairment the half-life of the same drug is 30 hours. Thus it takes 30 hours to go from 5 mg to 2.5 mg and from 10 mg to 5 mg.

 

[NickNaylor]

The only thing I'd add to @Amygdarya's post would be to mention that some medications - CBZ being the classic example - are autoinducers, so the dose can "affect" the drug's metabolism/half-life in that way. Beyond that case, I don't know of any medication with a variable half-life dependent on dose.

The other thing to consider is that half-lives are notoriously variable. If you ever look at actual pharmacological data, it's almost useless for many medications. I think it's worthwhile to have a general - perhaps only qualitative - understanding of the half-lives of most medications, but I'm not sure that it's critical for clinical practice to know if an individual drug's half-life is 20 vs. 30 hours other than knowing trivia. The one exception would be medications that require plasma level monitoring since the half-life will obviously be important to knowing when to check levels and how to interpret levels (sort of).

 

[clausewitz2]

The only thing I'd add to @Amygdarya's post would be to mention that some medications - CBZ being the classic example - are autoinducers, so the dose can "affect" the drug's metabolism/half-life in that way. Beyond that case, I don't know of any medication with a variable half-life dependent on dose.

The other thing to consider is that half-lives are notoriously variable. If you ever look at actual pharmacological data, it's almost useless for many medications. I think it's worthwhile to have a general - perhaps only qualitative - understanding of the half-lives of most medications, but I'm not sure that it's critical for clinical practice to know if an individual drug's half-life is 20 vs. 30 hours other than knowing trivia. The one exception would be medications that require plasma level monitoring since the half-life will obviously be important to knowing when to check levels and how to interpret levels (sort of).

Zer

No, half-life doesn't depend on the dose or concentration of the drug; it's a constant that is mostly determined by intrinsic properties of the drug that affect drug distribution and elimination (eg., drug hydrophobicity that affects distribution, specific metabolic mechanisms that dictate rate of metabolism and elimination routes etc).

The variation in half-life values that you can see in the tables is not due to different drug doses but to patient-related drug elimination factors (eg., if they are slow or fast metabolizers as described above, if there is any hepatic or renal impairment that leads to slower elimination etc).

To make it more concrete, for a patient A it will take 20 hours to eliminate half of the drug from the body regardless of the dose. If you give that patient 5 mg of the drug, there'll be a total of 2.5 mg of the drug in 20 hours; if you give him/her 10 mg, it'll be 5 mg in 20 hours.
However, in a patient B with significant renal impairment the half-life of the same drug is 30 hours. Thus it takes 30 hours to go from 5 mg to 2.5 mg and from 10 mg to 5 mg.

While half-life does not depend on concebtraconc, rate of elimination certainly does, e.g., at higher doses the drug is eliminated at a faster rate. If this was not the case, half-life would not be a coherent concept. And indeed for zero-order kinetics (like EtOH) there is just a static rate of elimination regardless of dose and so we can't talk about a half-life.

For some drugs at sufficiently high doses all transporters/receptors involved in elimination are saturated so higher drug doses the elimination rate ceases to scale proportionately and the kinetics become non-linear.

Fluoxetine is actually an example of a drug that inhibits its own metabolism (half-life is 1-3 days after a single dose, 5-7 days after chronic dosing) in a way that substantially impacts real-world steady state levels, which are not achieved until 4-5 weeks of dosing.

Of course there is not a clear relationship between serum levels of SSRIs and anything meaningful regardless, but saying dose is irrelevant to metabolism of all the drugs we deal with is not quite right.

 

[Georgit]

The question of the relationship between absolute serum levels and therapeutic effect is much thornier.

The brain is made of fat, the serum is a water solution.
So the half-life can be a bad indicator for the duration of the effects of a lipophilic drugs binding in the brain, that can be much shorter ( two-compartment model). An extreme example of this is THC, another could be diazepam. No you will be not stoned for days smocking a joint, also if the THC half-life measured in urine is up to 1 week.