What are the factors that affect drug metabolism? Well, you have genetic differences of
cytochrome P450, you can have competitive inhibition of cytochrome P450, you can have
direct inhibition, you can have induction, you can inhibit P-glycoprotein, and you can alter
blood flow. So all of these things are going to affect the way that we metabolize our
drugs. Now, racial factors affect cytochrome P450 activation. So for example, let's talk
about 2D6. So, 2D6 is one of the iso-enzymes, it has 4 different phenotypes. There are
the poor metabolizers. These guys are men and women who have 2 inactive alleles.
Then you have the intermediate metabolizers. These are heterozygotes. They inherited
1 active allele from their mother and perhaps an inactive allele from their father.
So they have 1 active, 1 inactive allele so they're heterozygotes. They have a moderate
amount of activity. You have extensive metabolizers. So they inherited from each parent
an active allele. So these are very extensive metabolizers, they will bring down the
drug level and convert it to the daughter drug very quickly. There's a 4th category.
These are the ultra rapid metabolizers. Some patients will have multiple copies of their
genes that will code for very active cytochrome systems. Here is an example of what
we're talking about. So this is a drug called nortriptyline. It's an antidepressant.
And let's take a look at a person who has zero functional 2D6 genes. There is the
concentration curve. Okay? Now let's look at a concentration curve when a person has
1 functional gene or 2 functional genes or 3 functional genes or in fact 13 functional genes.
So the more functional genes for that 2D6 you have, the lower your drug level and the
less active that drug is going to be in that body and the more drug you need to prescribe
for that person or perhaps just use a different drug. Cytochrome is like a bridge and
imagine you're driving in a car. As long as the bridge is empty, you can drive a car very
quick. Two drugs may compete for that same pathway. So if you have too many cars
trying to cross the bridge, it's going to take a long time getting across that bridge.
One drug may actually inhibit the metabolism of another. So if you have a person who is
driving really slow in a car, then even though there is not too many cars around, that
one person can slow down an entire chain of cars. So that's what an inhibitor does on the
cytochrome system. Now, one drug may induce the metabolism of another. So if you ever
seen ambulances, you always know that there is at least 1 idiot following the ambulance
at a really high speed. That's like an induction enzyme. You've got 1 drug that makes the
metabolism of another drug very quick. The opposite is true when the active drug is the
metabolite. So I want you to imagine now that instead of having the active drug as the
parent drug, you've got the active drug as the daughter drug. So a good example of that is
codeine. Codeine is converted to an analogue of morphine via the cytochrome system 2D6.
So people who are fast metabolizers will have a much more potent shorter term response.
So, genetic factors that we talked about earlier with our plots are going to affect how
we metabolize drugs and a really good example is that let's take a look at patients who
immigrate to the United States from ethnic Northern European countries. These patients,
10% of your ethnic European Nordic American patients will have little therapeutic effect
from codeine. So you have to use higher doses of codeine or perhaps switch to actual
morphine to treat them. On the other hand, when you take a look at patients from the
African subcontinent from the African continent, 30% of your ethnic African American
patients will be hypermetabolizers, so they will be exposed to excessively high levels of
morphine when they take a small dose of codeine. Being aware of racial differences is very
important, but also being aware of inhibitors of cytochrome system is important too.
So I'm going to go through each of these drugs in detail. Amiodarone inhibits cytochrome.
Fluconazole which is an antifungal agent, inhibits cytochrome. Cimetidine, ritonavir which is
HIV drug and grapefruit juice are all inhibitors of cytochrome system. You should memorize
this list. You need to know this list code. Okay? So, although I hate telling people to
memorize lists without thinking about them, in this particular case you need to memorize
this without thinking about it because you need to be able to rattle off these drugs,
and of course grapefruit juice as inhibitors of cytochrome. Now there are also inducers
of cytochrome system and I've put them in green so you can remember that they make
things go faster. The prototypical inducer is rifampin, it is also the most powerful inducer.
It's a drug that we almost never use in real world clinical practice, but whenever you look
at a drug the first thing that we'll say on the drug interaction list is always rifampin and
it's used as a testing agent. Carbamazepine or Tegretol is used as an antiseizure
medication. Phenobarbital is an antiseizure medication. Phenytoin or Dilantin is an
antiseizure medication. Ethanol is of course alcohol. And St. John's Wort is a herbal
product that has been particularly problematic for a lot of our patients. You should
memorize this list. Now, I'd like to talk to you quickly about St. John's Wort. St. John's Wort
is a herbal product that is used in the treatment of depression. It's somewhat effective.
In fact, its effectiveness is greatly exaggerated by the press but one of the most
important things we need to know about St. John's Wort is its effect on drugs. Now,
people can die if they take St. John's Wort in combination with their medication. Here
is a paper that was released some time ago where heart transplant rejection occurred
due to St. John's Wort so these patients who received heart transplants took St. John's
Wort and it interacted with their antirejection medications causing heart transplant
rejection, in other words death. So, it's a terrible type of drug reaction that was caused
by something that we weren't really aware of in the medical community. So it's always
important when you're talking to your patients to get them to give you a list of their
herbal products they take and preferably stop them all. Now, let's go back to that
P-glycoprotein that we were talking about, the P-glycoprotein or MDR inhibitors. So we
have a whole list of them. P-glycoprotein, I'm going to repeat this, is also called MDR1.
It is a transport protein and it moves drugs from outside of the cell into cells or into
intestinal lumen. Inhibiting MDR at the gene level causes toxic levels of a drug. So here
are inhibitors of P-glycoprotein, verapamil and grapefruit. And substrates of
P-glycoprotein are cyclosporine and digoxin. So cyclosporine can be affected quite
significantly by grapefruit or by verapamil. You need to memorize this list of P-glycoprotein
or MDR1 inhibitors and substrates. Okay, so here's a list of everything. I want to just
point out something about secobarbital and the antiseizure medications. And when you
take particular attention, the inducers are generally antiseizure medications except for
secobarbital which is inhibitor. Okay? Okay, let's do a question. This is a drug interaction
in the coronary care unit. A 55-year-old man was diagnosed with atrial fibrillation.
His cardiologist prescribed verapamil. He was later found to have atrial fibrillation
rhythm with a ventricular rate of 136 beats per minute. His nurse practitioner prescribed
digoxin to help with his rate control. Which of the following is false? A. The verapamil
and digoxin both cause a reduction in heart rate. B. The verapamil is metabolized through
the same cytochrome P450 system and may interact based on a common final pathway.
C. Verapamil is an MDR1 inhibitor and may result in digoxin toxicity. Or D. Digoxin is cleared
by the P-glycoprotein transport molecule. Which is false? Well, let's look at our list
and let's look at our answer. So the answer is B. This is wrong. The verapamil is metabolized
through the same cytochrome P450 system and may interact based on a common final
pathway. The truth is, is verapamil is an MDR1 inhibitor, it may result in digoxin toxicity.
The mechanism of verapamil is to reduce blood pressure and reduce heart rate and also
digoxin will reduce heart rate so A is correct, C is correct, and D is correct because digoxin
is cleared by P-glycoprotein. Remember that P-glycoprotein and the MDR1 we're talking
about the same thing. Let's look at another question. Rifampin relevance, realizing
rifampin relevance. I love alliterations and you'll see that commonly throughout my
lectures. A new drug is tested at Gargantua Pharmaceuticals. The scientist administers
rifampin along with a new drug to look for the risk of drug reactions. The following is true,
so pick one answer that's true. So the answer, it is induced by rifampin. So take a look
at the question. You've got a lot of inhibited there. 2D6, 3A4, 3A5 is inhibited by rifampin
and then you have one answer that's induction and then finally the 5th answer is PGP
is induced by rifampin. Well that's not true and it's certainly not an inhibitor. Rifampin
is an inducer of cytochrome and it actually induces most of the isoenzymes. So the
correct answer is D. Let's do a question on cytochrome isoenzymes. Which of the
following cytochrome isoenzymes is the most active in metabolizing drugs? Is it 1A2?
Is it 2C9? 2C19? 2D6? Or 3A4 and 5? The answer is always 3A4 and 5. And when you're
looking at an exam, 3A4 and 5 is going to be your answer and when you're out in clinical
practice you're going to need to know if your drug is metabolized through 3A4 and 5
because almost certainly that patient's other drugs will be too. Okay, let's look at a
question for inducers of cytochrome P450. Which of the following drugs is the most
powerful inducer of cytochrome P450? Is it abciximab? Is it verapamil? Is it phenobarbital?
Is it acetaminophen? Or is it rifampin? The answer is rifampin. So remember rifampin
is your prototypical inducer. It is also the most widespread inducer and the most
powerful inducer. Let's do a question on a common problem. A 45-year-old male with
epilepsy is placed on the cholesterol-lowering agent, simvastatin. He returns with severe
myalgias and elevated liver enzymes. You suspect that he developed statin toxicity.
Which of these medications could be causing this? Could it be rifampin? Could it be
carbamazepine? Could be an increased in alcohol intake? Could it be phenytoin? Or
could it be secobarbital? The answer is secobarbital. So remember that secobarbital is
different from the other antiseizure medications. Look at that. A suicide inhibitor,
secobarbital, the other antiseizure medications are inducers. Okay, let's do a question
on suicide inhibitors of cytochrome P450. Which of the following is not a suicide inhibitor?
Is it secobarbital? Phenobarbital? Ethinyl estradiol? Spironolactone? Or propylthiouracil?
Good. You answered B, phenobarbital. It's really important to remember that you have
a choice between secobarbital and phenobarbital. And secobarbital is a suicide inhibitor.
It is one of those rare antiseizure medications that is an inhibitor. Most other antiseizure
medications are inducers. The suicide inhibitors are allopurinol, ethinyl estradiol,
propylthiouracil, and secobarbital. And I would definitely recommend that you memorize
this list of drugs. Well, that's it. Thank you very much.