Many types of drug interactions can occur within the human body. Having
a good working knowledge of this complex subject represents a huge
opportunity for pharmaceutical representatives both to educate their
customers and to better present their products.
A drug interaction can be defined as an increase or decrease in the
available amount -- and therefore the effect -- of a medication caused
by another medication, food or chemical that is simultaneously present
in the body.
Sites of interaction
There are four main sites of interaction in the body.
The gastrointestinal tract. The
gastrointestinal tract plays an important role in drug interactions.
Some medications, such as cisapride, increase GI motility and therefore
decrease the time other medications spend in contact with the lining of
the stomach or intestines. This causes decreased absorption of those
medications and an effective reduction in dose. Another interaction
that can occur at the GI level is when some medications combine with
ions found in foods and, as a result, form poorly absorbed complexes.
This is why many antibiotics should not be taken with milk. Some
medications bind to each other in the GI tract and thus decrease the
availability of either or both drugs. Such drugs (like cholestyramine
and warfarin) must be dosed several hours apart.
The liver. The human liver
utilizes a mechanism called the P450 cytochrome system, which enables
it to metabolize certain medications, foods and chemicals. The system
uses heme-containing proteins called "cytochromes" to metabolize
various substances.
The key human cytochromes are 3A4, 2D6 and 1A9. Approximately 50% of
the medications that pass through the system are metabolized through
3A4, and about 30% of medications going through the system do so
through 2D6. A substance that is metabolized by a particular cytochrome
is said to be a "substrate" of that cytochrome. So, for example,
buproprion, a substrate of cytochrome 2B6, is broken down by that
cytochrome as it passes through the liver. An "inducer" of the P450
system is any substance that makes a cytochrome work more efficiently.
An "inhibitor" of the system makes a cytochrome work less effectively.
Inducers and inhibitors change the amount of metabolism that substrates
are subjected to; inducers increase metabolism, resulting in less
active substrate than usual, and inhibitors decrease metabolism,
resulting in more remaining active substrate. To conceptualize this
system more easily, think of the liver as a trash compactor with
multiple chutes for each individual cytochrome. The substrate
medications go down their appropriate chutes and are then metabolized.
These substrates are metabolized more than usual if an inducer is also
on board or less than usual if an inhibitor happens to be on board.
Using the trash compactor analogy, the inducers can be thought of as
increasing the "electricity" applied to the compactor, thus making for
more efficient "trash compacting" and less active available medication.
The reverse could be said of inhibitors (less "electricity," less
efficient "compacting," more available active medication). This
explains how inhibitors of P450 cytochromes can potentially cause
accumulation of substrates and potential toxicity.
It is very important to realize that medications and other substances
passing through the P450 system can be both substrates and inducers or
inhibitors, often of different cytochromes. So, for instance, a
medication that is a substrate of 3A4 can also be an inhibitor of 2D6
and an inducer of 2B6.
The blood. As medications
travel through the blood, some of them bind to certain blood
components, particularly the protein albumin. The portion of the drug
that is "protein-bound" is inactive, unlike the free part that
continues to go where it's needed. When two drugs that tend to bind to
albumin (referred to as "tightly" or "highly" protein-bound) are on
board at the same time, they compete for the limited number of albumin
binding sites. The result can be that too much of either or both of
those medications winds up spilling into the blood, possibly causing
toxicity. So the concurrent use of two or more tightly protein-bound
drugs -- such as NSAIDs, valproic acid and coumadin -- should be done
with caution.
The kidneys. Vasoconstriction
to the kidneys (and/or the liver) can reduce the metabolism of certain
medications and therefore increase their effective doses, sometimes to
toxic levels. Changes in the pH of urine, toward either more acidity or
more alkalinity, can affect how some medications are reabsorbed into
the renal tubules. This, in turn, can alter the effective dose of such
medications. Finally, certain chemically similar medications compete to
be excreted by the kidneys. The kidneys ultimately "favor" one of them,
possibly resulting in high levels of the other.
Understanding how these interactions occur will give you more insight
into your product and make you a better resource to the physicians you
call on.
About the Author
Neil Berliner, M.D.
Dr. Berliners new book, A Franchise of One: Strategies for Pharmaceutical Sales, is now available. Order online at www.xlibris.com. Dr. Berliner can be booked directly for representative training: nb@reptrainer.com
Articles by Neil Berliner, M.D.
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