How Do Medications Metabolize?

[Christina]

I'm not asking for (and don't want) personal advice, but I want to know more about how medications metabolize and the difference between those that work immediately and those that have to reach a certain level in your bloodstream to be effective. I'm even not sure that I mean bloodstream, just wherever it is that the levels are building up. Why is it that drugs like aspirin work almost as soon as you digest them and others like psych meds have to reach a certain point before you get to what they call a "therapeutic level" to be effective? What affects the speed at which an individual metabolizes medications and why do some people metabolize medicines too quickly for them to reach maximum effectiveness or too slowly for them to work in a reasonable amount of time compared to others?

I really hope that coffee isn't mentioned in any of the answers but I've braced myself for it just in case.

[Ray Moscow]

I expect that the explanations are very complex, since the mechanisms by which the drugs work are many, varied, and in some cases still unknown.

Aspirin -- possibly the most commonly used medicine -- apparently has several mechanisms of action (http://en.wikipedia.org/wiki/Aspirin#Mechanism_of_action) which were only unraveled recently.

You can probably read up on particularly drugs and learn how each is thought to work.

[BioBeing]

Different medicines are metabolized in different ways.

Some go straight into the bloodstream (as they are rapidly absorbed from the gut) and get carried to the target organ and go to work. Inhalation is also a very quick way of getting the drug into the blood: see cigarettes and inhalers (and other things I know nothing about).

Some drugs are not soluble in water: these have a hard time getting into blood, but may get into cells well. Others will be readily soluble in blood, but need to get into the cells to work. These might have to be metabolized to begin working. This often happens in the liver. So the drug has to get carried around your body one time, hit the liver, be found by the correct activating enzyme, then pass round the bloodstream again to get to where it needs to be.

Others are more slowly released. They may get absorbed slowly by the gut. Others are coated to slow down the release and extend the therapeutic dose time.

Others have to accumulate in a certain place. Like crossing over the "blood-brain" barrier, which can take time.

Others will use various combinations of these techniques...

Your own DNA is going to cause you to take up some drugs faster or slower than other people might, depending for example on the levels of cytochromes you have in your liver.

You own intestinal flora and fauna can also affect the way drugs get taken up and work. Some drugs are worked on by microbes in your gut to activate them, or at least convert them to byproducts that might cause side effects.

It is a very complicated topic!

[Christina]

Thanks. I think that I can read more about the particular medication that I metabolize too fast and come back and ask more specific questions about things I don't understand. It's hard to find sources that are more than trivial but don't require much of a background to get.

At least it was a complicated question and not an obvious one that I should have found on the first google expedition.

[BioBeing]

Thanks. I think that I can read more about the particular medication that I metabolize too fast...

You don't metabolize it "too fast". You have the wrong dose/schedule.

and come back and ask more specific questions about things I don't understand. It's hard to find sources that are more than trivial but don't require much of a background to get.

At least it was a complicated question and not an obvious one that I should have found on the first google expedition.

If you find a page too technical, give us a link, and we'll try to translate!

[Christina]

You don't metabolize it "too fast". You have the wrong dose/schedule.

Yes - I should have expanded that and said that my combination of dosage and schedule doesn't seem to be as effective as it could be to raise my levels to what seems to be more typical for my dosage from what I've read. I've been thinking about what behavioral things I can do to help in terms of when I take them and when I eat, sleep and work out instead of or in addition to increasing the dosage as my doctor will surely recommend if my next blood test is the same.

In general, does taking them with food make a difference compared to taking them on an empty stomach?

[Christina]

This article in RxList (http://www.rxlist.com/depakote-drug.htm) says this:

Metabolism

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.

The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
I don't even know what question to ask other than "huh?".

It goes on to say this:

... For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly.

Is an enzyme-inducing antiepileptic drug the same as an anticonvulsant? I take one of those too.

I'm going to talk to my doctor about all this but I don't see him for a while and I don't want to make an appointment just to ask questions.

[BioBeing]

What that first bit means is that there is nothing you can do, by yourself, to change the way the drug is metabolized by your body.

The second bit means that finding an effective dosing regimen is going to be tricky.

The third bit relates more to the chemical nature of the drugs. Different chemical "groups" (parts of the overall drug) are processed differently by the liver (and the same group is processed in the same way). What this means is that if say the drug has a carboxylic acid group on it that is the main target of metabolizing enzymes, then other drugs that contain a carboxylic acid group are going to get metabolized in the same way.

Now: think about a simple drug like ethanol. You have probably heard that when you drink a lot, you get elevated levels of alcohol dehydrogenase in your liver. Your body reacts to excess alcohol by making more of the enzyme that destroys alcohol.

Same with other drugs. Stimulate one pathway with one drug, and another drug of similar chemical group is going to be destroyed faster too.

An important note here is that drug metabolites (the partially broken down/modified bits of the original drug) can cause side effects before they get kicked out of the body. So, imagine you are on drug X, that doesn't normally get metabolized by pathway Y. Add drug Z, which kicks pathway Y into high gear, and X may now be a substrate for it, giving new metabolites and different side effects. It is why drug interactions are important to note, and tell your doctor of any drugs (even "natural" ones) you are taking.


BTW - this is all my understanding as a biochemist. I am not a pharmacist nor a pharmacologist (a person who actually studies these pathways for a living).

[ofro]

As a general rule, water-soluble drugs or drug metabolites are excreted by the kidney, as part of the natural process of the kidney where the blood is filtered (all small molecules are let through, but not proteins and cells) and the metabolically important molecules are reabsorbed.

Having said that, one of the main strategies in the liver is to make foreign compounds as water soluble as possible. This is done by attaching ("conjugation") several different types of charged small molecules that increases the solubility. Some fat-soluble toxins that cannot be made sufficiently water-soluble get excreted in the stool.

Another strategy is to chemically modify the compounds by oxidizing them and possibly breaking them down into smaller molecules. These make up the majority of the drug metabolites, some of which can be more toxic than the original compound.

One example is acetaminophen, the active ingredient in Tylenol. In small amounts, it is readily conjugated and thus eliminated through the urine. In the case of an overdose, there is enough acetaminophen around to overwhelm the conjugating enzyme and another set of enzymes called cytochrome P450 gets to modify it chemically into a toxic compound which, if not eliminated rapidly enough, damages the liver cells. Under certain conditions, such as in diabetes and with smokers, the detoxification mechanisms are not as efficient, and that person is much more susceptible to acetaminophen toxicity.

One more point of interest. You may have heard that when you are on blood thinners (specifically, coumadin) you should not eat grapefruit. The reason is that grapefruit contains a substance that inhibits the cytochrome P450 enzyme that degrades coumadin. As a consequence, it does not get excreted as normal but accumulates in the body to higher levels and may cause the blood to become too thin (it no longer can coagulate and leads to unstoppable bleeding). Cytochrome P450 also degrades other drugs such as some cholesterol lowering drugs. It's not as bad as with coumadin, but if you are on statins, don't eat two grapefruit in one sitting.

[Christina]

This all makes sense on a general level and more or less matches my experiences. Meds that were working perfectly well for one thing stop working in the same way when combined or another med is added for different symptom. Weaning off some like I've been doing may affect how the other works. It's always going to be tricky since it's not an exact science or well understood yet and we're a moving target in the first place. We can change faster than the meds can take effect. It's frustrating because I want someone to stick me under a scan and tell me exactly which neurotransmitters are out of whack and what each med does to affect them, and then I want a new one to look at every month to see how it changes. I should volunteer to be a guinea pig somewhere and let them poke around at my brain as long as they will explain all of the results.

[dancer_rnb]

This article in RxList (http://www.rxlist.com/depakote-drug.htm) says this:


I don't even know what question to ask other than "huh?".

It goes on to say this:



Is an enzyme-inducing antiepileptic drug the same as an anticonvulsant? I take one of those too.

I'm going to talk to my doctor about all this but I don't see him for a while and I don't want to make an appointment just to ask questions.

You might consider asking your pharmacist.

Some drugs are activated or deactivated by an enzyme. Insulin glargine, a 24 hour insulin which I take, is an example of a drug that has to have a chemical group removed by an enzyme to be effective. If my level of that enzyme changes, the rate of conversion from an inactive to active form will change. It can also work the other way, with an enzyme deactivating a drug by cleaving part of it away, which would also be dependent on the level of the deactivating enzyme.

[Christina]

When my psychiatrist, psychologist and GP discuss things everyone is on the same page in about an hour. When my pharmacist is brought into the discussion I could die before she decides what cold medicine I should take. Oddly enough, it's my psychologist that appears to know the most about med combos. I feel fine, but right now I'm not sure which med is doing what and I don't like that. I want to do something logical like start with one, add the next and see what happens, stabilize on that and add another and know which one has what effect, kind of like the way you would test hardware. It IS hardware. I'm not having any problem other than I just want to know.

[Brianna]

I remember from my pharmacology classes back in the day.

Anyone wanna explain half life?

Eta: this is the best explanation I could find.
http://www.wisegeek.com/what-does-a-drugs-half-life-mean.htm

[Christina]

When they do my blood tests all they need to know is when I took my last dose and how much it was. I do have another question as well. If a med works by reaching a certain blood level, does taking a dose have even a small immediate effect as as you digest it? Between confirmation bias,the placebo effect and wishful thinking, I can't tell. I have a list of these questions to ask my psychologist on Friday.

[Ray Moscow]

It seems to me that medicines have to enter the bloodstream to have an effect (except a placebo effect). That takes time.

It's natural to feel better if you expect to feel better. That's the placebo effect. But isn't that what we want -- to feel better?

[Brianna]

When they do my blood tests all they need to know is when I took my last dose and how much it was. I do have another question as well. If a med works by reaching a certain blood level, does taking a dose have even a small immediate effect as as you digest it? Between confirmation bias,the placebo effect and wishful thinking, I can't tell. I have a list of these questions to ask my psychologist on Friday.

It depends on the drug (capsule, quick release or coated), how much food you have in your system, and what you drank it with.

Most drugs take at least 20 minutes to enter your blood stream and get were they are going.

My stimulant takes more like 15 cause I can feel my heart rate increase.

Your psychologist might know some of this because they have a doctorate. It however would be better to talk to your psychiatrist who has had pharmacology or a pharmacist.

[Christina]

It's natural to feel better if you expect to feel better. That's the placebo effect. But isn't that what we want -- to feel better?

Yep, and I don't care how usually but I'm on this geek thing this week that I want to know specifically how it all works. Can you imagine having a process going on inside your mind you that you don't understand? Not that it's horrible, but it's fascinating and I can't seem to quit picking at it and trying to analyze it like I would any other thing that I'm interested in. The problem is that the only tool I have to analyze it with is the same dysfunctional tool that I'm trying to analyze. Does that make sense?

I don't get little manic-tweaky episodes very often anymore but when I do I try to imagine that the next med dose is going to knock it down even though I'm pretty sure that it has no immediate effect like the one that knocks me out at night does. The placebo effect is fine but I'm fairly sure that gardening, snuggling with the animals or working out until I drop do just as good of a job at slowing things down again.

[dancer_rnb]

You could try reading the medical inserts :evil:
And hope it doesn't state : method of action unknown
or some such.

I'm not sure what to tell you. It's all biochemistry of one sort or another.

[Joykins]

This article in RxList (http://www.rxlist.com/depakote-drug.htm) says this:


I don't even know what question to ask other than "huh?".

It goes on to say this:



Is an enzyme-inducing antiepileptic drug the same as an anticonvulsant? I take one of those too.

I'm going to talk to my doctor about all this but I don't see him for a while and I don't want to make an appointment just to ask questions.

Try reading the section on Absorption/Bioavailability and not metabolism -- metabolism is how your body clears the drugs, which doesn't sound like what you're asking.

[Christina]

Thanks. It sounds like taking it several times a day instead of 4 times a day may increase absorption but not necessarily efficacy since they hadn't studied that for mania, just epilepsy. It will be interesting to see what my blood tests show.