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
isoenzymes. It has four different phenotypes. They are the
poor metabolizers. These are men and women who have two
inactive allelles. Then you have the intermediate
metabolizers. These are heterozygotes. They inherited one
active allelle from their mother and perhaps an inactive
allelle from their father. So they have one active one
inactive allelles. So they are 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
is a fourth category. These are the ultrarapid 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 are talking about. So this a drug called
nortriptyline it's an antidepressant. Let's take a look at a
person who has 0 functional 2D6 genes. There is the binding
curve, okay. Sorry it's a concentration curve. 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 are
driving in a car. As long as the bridge is empty, you can drive
across it 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 eventhough 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
ambulance, as you always know that there is at least a one 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 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 plants 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 which 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 cedeine. 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 this 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 memorise this list. You need to
know this list cold, okay. So although I hate telling people to
memorise lists without thinking about them, in this particular
case you need to memorise 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.
Cytochrome P450 also has suicide inhibitors. So what's a suicide
inhibitor? It means that it's permanently inhibiting things.
So spirinolactone which is a antihypertensive agent is a
suicide inhibitor. Ethinyl estradiol which is a hormone agent
and is also used as a contraceptive agent is one. Allopurinol
is another. Propylthiouracil which is an anti-thyroid medication
and secobarbital which is an antiepileptic. Now I just want
to mention something special about secobarbital.
This antiepileptic drug is always the one that trips up medical
students and it certainly gotten me when I wrote my exam.
So I got this wrong. And we're going to spend a little bit of
extra time on secobarbital and the other antiepileptics
with respect to the cytochrome system and I'll show you why
later. Once again I want you to memorise this list of drugs.
You need to know them for your exam and honestly you need to
know them for a clinical practice as well. 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 will say
on the drug interaction list is always Rifampin. And it's used
as a testing agent. Carbamazepine or Tegretol is used as an
anti-seizure medication. Phenobarbital is an anti-seizure
medication. Phenytoin or Dilantin is an anti-seizure
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 memorise 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 it's efectiveness
is greatly exagerrated by the press. But one of the most important
things that we need to know about St.John's Wort is it's
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 occured
due to St.John's Wort. So this 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 were'nt
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 the 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 MDR-1. It is a
transport protein and it moves drug from outside 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 cyclosporin
can be affected quite significantly by grapefruit or by verapamil.
You need to memorise this list of P-Glycoprotein or MDR-1
inhibitors and substrates. Okay, so here is a list of everything.
I want to just point out something about secobarbital and the
anti-seizure medications. And when you take particular attention
the inducers are generally antiseizure medications except for
secobarbital which is a suicide inhibitor, okay. So all seizure
medication, all antiseizure medications are inducers of cytochrome.
You can see carbamazepine, phenobarbital, phenytoin and ethanol.
Ethanol is'nt really an antiseizure med but you know what I
mean. Secobarbital is a suicide inhibitor. It is different.
It's very important to remember that and it's often things
that trip up medical students. 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 bpm.
His nurse practitioner prescribed digoxin to help with his
rate control. Which of the following is false?
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. Verapamil is a MDR-1 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 MDR-1 inhibitor. It may result
in digoxin toxicity. The mechanism of verapamil is to reduce
blood pressure and to 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 MDR-1 we are talking about
the same thing. Let's look at another question.
Realizing Rifampin relevance. I love illiterations and
you will see that commonly with my lectures.
A new drug is tested at Gargantua Pharmaceuticals. The scientist
administers rifampin along with the new drug to look for the risk
of drug interactions. 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 fifth answer
is P-GP 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 of cytochrome
isoenzymes. Which of the following cytochrome isoenzymes
is the most active in metabolizing drugs. Is it 1A2; Is it
2C9: 2C19; 2D6 or 3A4/5. The answer is always 3A4/5
and when you're looking at an exam, 3A4/5 is going to be your
answer. And when you're out in clinical practice, you are
going to need to know if your drug is metabolized through 3A4/5
because almost certainly that patient's other drug 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 increase 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; phenobarbitol; ethinly estradiol; spirinolactone
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 anti-seizure 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 reccomend that you memorise this list of drugs.
Well that's it, thank you very much.