Asked & Answered: 15.0

The majority of my readers (I would say vast majority but that would imply a vast number of readers) are of, shall we say, advanced age.  Being of advanced age has its benefits — for instance, my age allows me to completely ignore what passes for pop music these days and no one, except maybe James Corden, will criticize me for it — but advanced age also has its drawbacks.  One of them is the ever-growing list of prescription drugs that people my age find themselves ingesting on a regular basis.

Don’t get me wrong, I’m not anti-medical-science.  In fact I feel fortunate when I consider the array of drugs developed in the last 40, 30, 20, 10 years to address the many maladies of civilized life.  These drugs range from lisinopril (high blood pressure, approved in 1987, generic since 2002) to omeprazole (acid reflux, approved in 1988, generic since 2001) to ropinirole (restless legs, approved in 1997, generic since 2008) to aflibercept (wet macular degeneration, approved in 2011 and now costing Medicare $2.9 billion a year) to apixaban (anti-coagulant for atrial fibrillation, approved in 2012 and costing $10 billion a year).

Being of suitably advanced age and other circumstances, I partake of all of these drugs, and more.  Not like it’s fun, but it would be less fun otherwise.

But what I really want to talk about is how these wondrous pharmacologicals are handled inside our bodies.  We down these pills as if they simply melt in our tummies, magically do their respective jobs for the day, and then discreetly leave the scene.  But that would not be the case at all.

I became interested in how drugs are processed in our bodies after a recent, and brief, trial of the diuretic chlorthalidone, a blood-pressure medicine that has been in use since 1960.  In my case, the drug is unreasonably effective.  In just two days, my blood pressure fell nearly 30 points and I lost about 6 pounds, despite drinking lots of water to stay hydrated.  I had to stop the trial to keep my blood pressure and weight from falling even further.

I wondered how chlorthalidone could have such a drastic, powerful effect on me — could there have been some interaction with another of my several prescription medicines?

• • • 

When drug interactions occur, it’s not because the drugs chemically react with one another in your bloodstream, but typically because they (a) have the same effect, (b) have opposing effects, or (c) use the same metabolic path through your gut or liver– in effect, competing with each other for your body’s metabolic resources.  This is actually pretty common.

Another type of interaction is when you ingest something, drug or otherwise, that thwarts the metabolic process itself.  You’ve probably heard, for example, that drinking grapefruit juice is a bad idea when you are taking certain medications.  This is because…

… grapefruit juice inhibits the CYP3A4 enzyme of the cytochrome P450 system in the intestinal mucosa, increasing the bioavailability of drugs with a high first pass metabolism. [British Journal of Medical Practitioners, 2012]

If I may clarify — and please do, you say!  According to the National Library of Medicine, CYP3A4 is the name of a gene on human chromosome 7.  This gene directs various cells to manufacture an enzyme (one of the P450 enzymes) that is “involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin, diazepam, erythromycin, and chloroquine.  The enzyme also metabolizes some steroids and carcinogens.”

Here, metabolism means the process of breaking down a drug into smaller molecules that can be eliminated by the body.  Simply put, the CYP3A4 enzyme helps us deactivate many toxins and drugs.  In fact, drug manufacturers rely on CYP3A4 to remove their drugs from the bloodstream, which allows medicines to be taken on a daily, high-compliance basis.

If your CYP3A4 enzymes get blocked or disabled, then the drugs that are designed to be broken down by CYP3A4 will circulate in your system at higher levels than the drug-maker intended.  This can in turn produce toxic effects.

The CYP3A4 enzyme (below, per the RCSB Protein Data Bank) looks like a Rorschach test designed by Jackson Pollock:

That mammals, over the eons, evolved a way to manufacture a toxin-neutralizing enzyme as complex as this is beyond my comprehension — and also beyond the scope of this post. But clearly, the evolution of CYP3A4 wasn’t shaped by grapefruit juice.  (The chemical in grapefruit juice, bergamottin, that deactivates the CYP3A4 enzyme was not conclusively identified until 2012.)

Grapefruit juice is not the only inhibitor of CYP3A4 (see this list) and is only one of many food-based inhibitors (fresh-ground black pepper is another).  I don’t use much pepper or drink grapefruit juice, so that would not explain any unusual drug responses I might have.  It would be more likely for my medications to be fighting over my CYP3A4 enzymes.

Curious, I made a list of the 11 (yes, that many) medications and supplements that I take on a daily and/or occasional basis, and then searched the web to see how many of them use the CYP3A4 pathway.  I found that 6 of the 11 rely on CYP3A4 for their metabolism, and two of those can even inhibit CYP3A4.  Just to complicate things.

I have no control which drugs have first dibs on my CYP3A4 reserves.  I guess I have to trust that, if I’m not having issues, then my body is doing its best to handle the drug traffic down there.  But it pays to be vigilant, especially when adding or adjusting medicines.

• • • 

What about my not-so-friendly friend, chlorthalidone?  Turns out that CYP3A4 was not a factor here — chlorthalidone is hardly metabolized at all but instead is very slowly filtered out by the kidneys.  By slowly, I mean that it takes over 40 hours to eliminate half of it.

This is probably one reason why, as I just learned, that diuretics like chlorthalidone are on the American Geriatric Society’s Beers List of “potentially inappropriate drugs” for older (sorry, advanced age) adults.

I know now that the dosage of chlorthalidone I was prescribed (25mg) was way too high; as I discovered, it would have been more prudent for my doctor to have started me out on one-quarter of that dose, given my age.  Doctors know a lot of things, but they can’t keep up with everything.  It doesn’t mean you doubt them, but you have more time and energy to research your specific situation than your doctor does — you can add to her knowledge.

If this post has given you a slightly better sense of what goes on inside you after you take your pills, and helps you appreciate the complexities of medical management for seniors, then great.  Thanks for hanging in here until the end.