Basic Pharmacology

[9point75]

I'm getting myself all confused over something that seems very simple. If a medication has a half-life > 24 hours (like abilify) and we dose it every day, aren't we increasing the total body levels a little bit each day as the input would vastly outdo the output? I feel like I'm having the biggest mindjob right now...

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[billypilgrim37]

Nope! http://en.wikipedia.org/wiki/Geometric_series

With fixed dosing, you're at 88% of the steady state dose after about 3 half-lives, 94% after 4 half-lives, 97% after 5, and so on.

 

[393656]

Nope! http://en.wikipedia.org/wiki/Geometric_series

With fixed dosing, you're at 88% of the steady state dose after about 3 half-lives, 94% after 4 half-lives, 97% after 5, and so on.

This has no relation to the guys questions bro.

Half life is kind of irrelevent once you hit steady state in regards to accumulation of the drug. Half life is important in predicting how long a drug will take to get to the point of amount in=amount out (steady state) but once that state is reached, the kinetics of the drug take over and only so much can be absorbed before so much is excreted at the same time so you never reach a level higher than X. which is determined by those specific kinetic factors. Half life really has nothing to do with this aspect.

The factor that can screw with that transiently is things like protein bound drugs and free drug levels with displacement. You can increase free drug levels for example without changing total drug amount and transiently influence kinetic factors to cause the set level to be different but in time it will re-adjust and once again balance in=out

 

[firedoor]

Excellent question.

So the kinetics of absorption, metabolism and elimination are independent of half-life once steady state is reached?

What about drug elimination from the body once steady state is reached and no more drug is administered...is the plasma decay dependent upon half-life, the drug's steady state kinetics, or some other factor(s)?

 

[393656]

Excellent question.

So the kinetics of absorption, metabolism and elimination are independent of half-life once steady state is reached?

What about drug elimination from the body once steady state is reached and no more drug is administered...is the plasma decay dependent upon half-life, the drug's steady state kinetics, or something else?

Yes of course once drug is being stopped, the remaining drug lingering is based on half-life. I think that is a different point than the OP's question thought regarding whether there is an accumulating effect of a drug and that accumulation is not dependant on half life once SS is reached. But of course ultimate drug excretion is dependent on half life-that is the essence of what half life is!

 

[billypilgrim37]

This has no relation to the guys questions bro.

You can't talk about steady state without talking about the rate of something going in and the rate of something going out. We talk about the rate of something going out when we talk about half-lives. We reach steady state because most of our drugs work on first order kinetics. They don't stop working on first order kinetics once they reach steady state. (Most of our drugs anyway. Alcohol and phenytoin et al have their own non-first order rules.)

To the OP, instead of thinking about how we daily dose Abilify though it has a half-life longer than 24 hours, consider something like lithium, which we regularly dose 2-3x daily, though it has a half-life of about 18-24 hours in adults. Just like lithium does not continue to accumulate over time, you wouldn't expect Abilify to do so either. At some point, as defined in a geometric series, given fixed dosing at fixed intervals, you simply level off.

So it makes sense to talk about being at 94% at 4 half-lives, 97% at 5 half-lives, 98.4, 99.2, 99.6, 99.8, 99.9, etc. The additional increase in level each day is offset by the increase in elimination rate (as in first order kinetics, the elimination rate is related to the substrate concentration). This DIRECTLY answers the OP's question as to whether we are adding more drug each day. We're not. And that's why. The input does not exceed the output, because the output increases with the input.

 

[firedoor]

To the OP, instead of thinking about how we daily dose Abilify though it has a half-life longer than 24 hours, consider something like lithium, which we regularly dose 2-3x daily, though it has a half-life of about 18-24 hours in adults. Just like lithium does not continue to accumulate over time, you wouldn't expect Abilify to do so either. At some point, as defined in a geometric series, given fixed dosing at fixed intervals, you simply level off.

It's like freakin game theory.

 

[393656]

All you did billy boy was state how many half lifes to steady state. I am pretty sure the OP knows what steady state is and how many half-lives it takes. He was asking about drug accumulation which you did not even touch in at first.

Also lithium is not a good comparison because the only reason people dose it multiple times per day is nothing to do with its half life or its steady state levels but purely because once a day dosing of regular release lithium has a high peak concentration that borders on toxic side-effects that are poorly tolerated. It is simply dosed multiple times per day due to tolerability with once daily unless its ER dosing that lacks the high peaks

 

[billypilgrim37]

All you did billy boy was state how many half lifes to steady state. I am pretty sure the OP knows what steady state is and how many half-lives it takes. He was asking about drug accumulation which you did not even touch in at first.

I also linked to the concept of a geometric series, which was the whole point: a limit is reached.

Also lithium is not a good comparison because the only reason people dose it multiple times per day is nothing to do with its half life or its steady state levels but purely because once a day dosing of regular release lithium has a high peak concentration that borders on toxic side-effects that are poorly tolerated. It is simply dosed multiple times per day due to tolerability with once daily unless its ER dosing that lacks the high peaks

WHY we dose lithium 1-3x/daily is a completely different discussion. The fact that you don't expect to reach steady state any quicker whether you dose it daily or 2-3x per day is the relevant idea. I have people who (against my recommendation) split their Abilify pill into 2-3 doses through the day. This doesn't effect their steady state, but it makes it more tolerable for them.

 

[393656]

I also linked to the concept of a geometric series, which was the whole point: a limit is reached.



WHY we dose lithium 1-3x/daily is a completely different discussion. The fact that you don't expect to reach steady state any quicker whether you dose it daily or 2-3x per day is the relevant idea. I have people who (against my recommendation) split their Abilify pill into 2-3 doses through the day. This doesn't effect their steady state, but it makes it more tolerable for them.

Billy bob you continue to make no sense. Is english your native?

 

[Suedehead]

Billy bob you continue to make no sense. Is english your native?

ah, the wallstreet show.

 

[whopper]

aren't we increasing the total body levels a little bit each day as the input would vastly outdo the output?

Dude, remember the concept of equilibrium! There's plenty of forces going on in the body such as protein binding, metabolism of the kidneys and/or liver, etc.

 

[9point75]

Okay, I think I made it straight in my brain. Pills are are static quantity in terms of their doses and hence the input. The output or half life is not a fixed quantity. The half life amount cleared from the blood is a proportion of whatever the blood levels are. That's why it doesn't accumulate ad inifinitum and will always steady out.

 

[Manicsleep]

Okay, I think I made it straight in my brain. Pills are are static quantity in terms of their doses and hence the input. The output or half life is not a fixed quantity. The half life amount cleared from the blood is a proportion of whatever the blood levels are. That's why it doesn't accumulate ad inifinitum and will always steady out.

AMDE is a good acronym to remember if you like that type of thing. Absorption, metabolism, displacement and excretion (maybe elimination).

Steady state is simply when intake and excretion are equal. You can overload your body by taking in more than it can metabolize or excrete in other ways. Different drugs have different pharmacokinetics which can change over time and can also change with overdose.

The amount cleared really varies on a lot of factors. For example. Alcohol with its zero order kinetcs is not removed based on concentration. However, the amount removed per/time is still subject to AMDE.

 

[393656]

Okay, I think I made it straight in my brain. Pills are are static quantity in terms of their doses and hence the input. The output or half life is not a fixed quantity. The half life amount cleared from the blood is a proportion of whatever the blood levels are. That's why it doesn't accumulate ad inifinitum and will always steady out.

Dude you would laugh at the "basic" science stuff I forget on a daily basis. I LOVE pharm but sometimes I will realize I either forget or do not understand the most basic process. Pharm ( a true understanding) is an elusive science that very few truly know very well, including myself to much degree. I have read every psychopharm book one can find as well as regular pharm books and there are just subtle points to pharm that are really hard to ever "get"

Dont feel bad-glad it clicked!

 

[firedoor]

Okay, I think I made it straight in my brain. Pills are are static quantity in terms of their doses and hence the input. The output or half life is not a fixed quantity. The half life amount cleared from the blood is a proportion of whatever the blood levels are. That's why it doesn't accumulate ad inifinitum and will always steady out.

Ahhhhh...so elimination is dependent upon the plasma concentration half life, not the "pill half life", is this correct? Awesome insight !!!

 

[billypilgrim37]

Well, the rate of elimination is a function of the plasma concentration and the half-life. So, yeah.

 

[393656]

Well, the rate of elimination is a function of the plasma concentration and the half-life. So, yeah.

Billy boy again spreading bad info.

the RATE does not change with plasa conc. Its completely dependent on kinetics-half life.

The AMOUNT that is eliminated is dependant on conc in blood up until a point where you reach its saturday for elimination

 

[billypilgrim37]

he RATE does not change with plasa conc. Its completely dependent on kinetics-half life.

No, the rate increases exactly the way I said. That's the definition of a first order reaction, that the rate is dependent upon the substrate concentration.

Are you confusing rate and half-life?

Look at any high school chemistry book or http://en.wikipedia.org/wiki/Rate_equation#First-order_reactions.

 

[Reductio]

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3–5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization ... When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels. This phenomenon is due to the long half life of aripiprazole, and is responsible for many of the adverse side effects that appear after multiple days of dosing (whereas the first dose normally does not cause these side effects).

BillyP's first posts are helpful in explaining why it takes 10 - 14 days to get to SS, which also happen to be how long it takes to get to therapeutic levels. He also pointed out that Aripiprazole follows first-order kinetics. Once in SS, an entire QD dose (half of which was administered 75 hours prior), will be eliminated each day.

 

[Reductio]

Billy boy again spreading bad info.

the RATE does not change with plasa conc. Its completely dependent on kinetics-half life.

The AMOUNT that is eliminated is dependant on conc in blood up until a point where you reach its saturday for elimination

Yes it does, and no it isnt.

Rate of elimination is dependent on (plasma) concentration, because the amount eliminated is not fixed. It itself depends on the concentration... thats first order kinetics.

 

[nitemagi]

Yes it does, and no it isnt.

Rate of elimination is dependent on (plasma) concentration, because the amount eliminated is not fixed. It itself depends on the concentration... thats first order kinetics.

Concur. I think WS is confusing rate with % eliminated.