cytochrome P450 & 3A4 Enzymes.

Posted
by MmacFN (Member)

Specializes in I know stuff ;).

Ok so reading creates questions.

If there is a genetically determined variability in people which apparently, can be as great as 40X, how do you account for this?

Is there any test avaliable for this variation is it simply something you titrate for? Sortof "plan for the worst hope for the best" situation?

When has this become and issue for you in anesthesia, also, are their any common diseases etc which cause this to occur?

PS. didnt mean to put those seperate on the title should be all togeather but cannot edit it!

rn29306

533 Posts

Ok so reading creates questions.

If there is a genetically determined variability in people which apparently, can be as great as 40X, how do you account for this?

Is there any test avaliable for this variation is it simply something you titrate for? Sortof "plan for the worst hope for the best" situation?

When has this become and issue for you in anesthesia, also, are their any common diseases etc which cause this to occur?

PS. didnt mean to put those seperate on the title should be all togeather but cannot edit it!

There is one three letter word that sums it up: TTE

Titrate

To

Effect

I don't think there is a standardized test for variation. When we do heavy MACs, I will often give a "test dose" of propofol prior the start of the procedure and once we are on the table, monitors, etc. Give about 30-40 of propofol and see what happens. Some people get snowed. Others sit there and blink at ya. This guides further dosing and gives you an idea of what the patient needs.

Same with alcohol I guess. Some were born light-weights and pansies. Others aren't. Sometimes I think it would be nice to be able to get buzzed on 1/2 a drink. Saves calories and assures you won't be the DD for that night.

Oh yeah, the other three letter word that makes me smile everytime I write it is: SAR. See Anesthesia Record.

Comes in mighty useful when we are giving blood in the OR and I don't have to write out the q 15 minute VS. I can just put a "SAR" over the space.

Nitecap

334 Posts

Some folks may just chew right thru all the drugs you give them. Your like damn this person should be out but they are just chillen. So you give more.

MmacFN

Specializes in I know stuff ;). 556 Posts

freaky isnt it?

I wonder if they are deficient in this enzyme if the drug dosent take effect as quickly, does it hang around longer? If its isnt being metabolized then isnt there a longer avalibility? Or does it just get metabolized out without effect?

platon20

268 Posts

freaky isnt it?

I wonder if they are deficient in this enzyme if the drug dosent take effect as quickly, does it hang around longer? If its isnt being metabolized then isnt there a longer avalibility? Or does it just get metabolized out without effect?

First off, CYP450 and 3A4 are the same thing. 450 is a general class of hepatic enzymes, and 3A4 is the isoform variant that is most responsible for oxidative metabolism.

The vast majority of drugs are given in active form, so if they are metabolized by CP450/3A4 they are rendered inactive and cleared from the body. There are a few drugs in which the presented drug is inactive, but converted to an active metabolite by CP450 or other enzymes.

Thats why in clinical practice you are more worried about slow metabolizers rather than rapid. Slow metabolizers = low CP450 activity = longer half life of drug = higher potential for toxicity.

Bioavailability is independent of hepatic metabolism. Bioavailability is simply the ratio of drug that is presented to the GI or integumentary system vs how much is absorbed into the bloodstream.

MmacFN

Specializes in I know stuff ;). 556 Posts

Hey plant, thanks for the explanation.

I do understand that they are the same thing, actually said that at the bottom of the first post but cannot edit the title here:

PS. didnt mean to put those seperate on the title should be all togeather but cannot edit it!

I also understand that those will less emzymes will be at higher risk for prolonged drug effects, that was the statement/question in the second post i made here:

I wonder if they are deficient in this enzyme if the drug dosent take effect as quickly, does it hang around longer? If its isnt being metabolized then isnt there a longer avalibility?

I was not referring to bioavailability. In the second post i simply used the work "availability" for lack of a better word, to explain how a low enzymatic response would increase the length of time drug effects would hang around. I was intending the longer half-life that you mentioned :)

However, i do thank you for trying to edumacate me :)

First off, CYP450 and 3A4 are the same thing. 450 is a general class of hepatic enzymes, and 3A4 is the isoform variant that is most responsible for oxidative metabolism.

The vast majority of drugs are given in active form, so if they are metabolized by CP450/3A4 they are rendered inactive and cleared from the body. There are a few drugs in which the presented drug is inactive, but converted to an active metabolite by CP450 or other enzymes.

Thats why in clinical practice you are more worried about slow metabolizers rather than rapid. Slow metabolizers = low CP450 activity = longer half life of drug = higher potential for toxicity.

Bioavailability is independent of hepatic metabolism. Bioavailability is simply the ratio of drug that is presented to the GI or integumentary system vs how much is absorbed into the bloodstream.

Nitecap

334 Posts

freaky isnt it?

I wonder if they are deficient in this enzyme if the drug dosent take effect as quickly, does it hang around longer? If its isnt being metabolized then isnt there a longer avalibility? Or does it just get metabolized out without effect?

Metabilism of drug via CYP450's is frequetly refered to as a phase I. It inserts a functional group into the drug molecule changing its chemical make up. It may insert. Typicallt it it will take an O from the system and oxidize the drug. an OH group is usually inserted into the drug. This may or may not inactivate it.

Yes the CYP450's can be induced(upregulated) or inhibited (down regulated) by certain drugs, pathology ect that effects the liver.

For instance the H2 antagonist Cimetedine (tagament) is culprit in signifigantly inhibiting the CYP450's. Drugs that are metabilized via this route will hang around. This can potentially be lethal. Its scary that you can buy this drug at your local walmart.Ketoconazole also freq inhibits.

Other hand some drugs such as rifampin, phobarb induce the system (rev in up). SO other drugs metabolized this way will be metabolized faster and have a decreased duration of action.

After phase I the drug may be eliminated but many times it undergoes a phase II. refered to as conjugation reactions. This sysyem which is different that the CYP450's insert possible a glucoronic acid, amino acid, acetate. Its goal is the make the molecue highly polor so it will be carried to the kidneys and eliminated.

MmacFN

Specializes in I know stuff ;). 556 Posts

Hey nite

Sweet!

Now thats some good info! Especially the tagamet stuff!

Metabilism of drug via CYP450's is frequetly refered to as a phase I. It inserts a functional group into the drug molecule changing its chemical make up. It may insert. Typicallt it it will take an O from the system and oxidize the drug. an OH group is usually inserted into the drug. This may or may not inactivate it.

Yes the CYP450's can be induced(upregulated) or inhibited (down regulated) by certain drugs, pathology ect that effects the liver.

For instance the H2 antagonist Cimetedine (tagament) is culprit in signifigantly inhibiting the CYP450's. Drugs that are metabilized via this route will hang around. This can potentially be lethal. Its scary that you can buy this drug at your local walmart.Ketoconazole also freq inhibits.

Other hand some drugs such as rifampin, phobarb induce the system (rev in up). SO other drugs metabolized this way will be metabolized faster and have a decreased duration of action.

After phase I the drug may be eliminated but many times it undergoes a phase II. refered to as conjugation reactions. This sysyem which is different that the CYP450's insert possible a glucoronic acid, amino acid, acetate. Its goal is the make the molecue highly polor so it will be carried to the kidneys and eliminated.

subee, MSN, CRNA

Specializes in CRNA, Finally retired. Has 50 years experience. 3,499 Posts

Hey nite

Sweet!

Now thats some good info! Especially the tagamet stuff!

And another inhibitor is grapefruit juice so all patients need to look at drug inserts closely because something as simple as this juice can get patients into a lot of trouble.

MmacFN

Specializes in I know stuff ;). 556 Posts

Thanks Subee!

very interesting stuff!

And another inhibitor is grapefruit juice so all patients need to look at drug inserts closely because something as simple as this juice can get patients into a lot of trouble.
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