Primer: Drug-Drug Interactions

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

For a combination of reasons, there are quite a few folks out there today that have a cocktail of drugs pumping through their blood stream.  The elderly, for example, at any given time, can be taking upwards of 10 different medications to manage their back pain, arthritis and blood pressure…and then the depression they feel because they are on so many drugs.  It’s bad enough that they have to be on so many meds, but then when they go to the hospital with another problem, the doctors have to slowly pull them off the drugs they are already on in order to isolate the problem, and then come up with a new cocktail of drugs.  This is especially a problem because so many people have multiple different doctors, some of which aren’t aware of what medications (i.e. type and dosage) their patients are taking.  And those doctors will sometimes disagree with each other and change the medications back and forth depending on which doctor sees them on a given visit.

But that’s a different discussion.  🙂

All doctors and pharmacists are aware of what are called “Drug-Drug Interactions,” which is basically the idea that one drug you are taking can counteract the effects of another, either by directly interacting with the drug itself, or with the receptors that another drug is trying to access.  Very commonly, especially in the case of the elderly, it can also occur during metabolism, the act of breaking down a drug so it can be excreted from the body, and effectively inactivated.

The common example of a drug-drug interaction involving metabolism (as taught in graduate school and medical school) is that of grapefruit.  Terfenadine, for example, was a very popular antihistamine that is metabolized by action of a specific cytochrome P450 enzyme, CYP3A4.  It turns out that components of grapefruit juice (and the antibiotic erythromycin, amongst others) are also metabolized by cytochrome P450, specifically CYP3A4.  In order for Terfenadine to be effective, it has to be converted by CYP3A4 into its “active metabolite” (i.e. the drug that actually helps you isn’t terfenidine itself, it’s the metabolite of terfenidine).  If you are drinking lots of grapefruit juice, you don’t get that active metabolite formed and you keep excess terfenidine around in your body.  Unmetabolized terfenidine, unfortunately, causes arrhythmias of the heart (which is what led to its withdrawal from the market).

So in this case, something as simple as grapefruit juice caused a drug to not function properly, leading to unwanted, and unsafe, side-effects.

Another example of drug-drug interactions via metabolism is the combination of acetaminophen (Tylenol) and alcohol.  Acetaminophen is primarily metabolized by cytochrome P450 isoforms CYP2E1 and CYP1A2 to a compound called NAPQI, which is then further converted using glutathione to innocuous bi-products.  NAPQI can cause severe liver damage if it hangs around too long.  It turns out that the process of metabolizing alcohol also takes advantage of glutathione.  If you are drinking alcohol and you take acetaminophen, it’s very likely that your liver will produce more NAPQI than it can deal with (i.e. due to decreased glutathione levels caused by the alcohol), thus causing acute liver toxicity.

Those are a few examples of how metabolism of one drug can affect another drug.  How about absorption of drugs then, eh?

Tetracycline is an antibiotic that many of us have taken or will take within our lifetimes.  It is formulated so that it tends to have metal ions in with the pills you take.  You shouldn’t take tetracycline along with antacids, however, as antacids tend to also contain aluminum.  Aluminum ions from antacids, or iron from supplements, can form what they call a “chelate” with tetracycline, reducing the ability of your body to take it up into the blood stream.  The same thing happens with calcium ions, so you can’t take tetracycline along with milk, yogurt, or other dairy products.

You can also get what we call “additive” or “synergistic effects” when you take two drugs that do effectively the same thing in a different way.  For example, people take nitroglycerin in order to cause vasodilation, and it does so by producing nitric oxide that then elevates cGMP in vascular smooth muscle cells (ultimately, cGMP is responsible for relaxation of muscle cells, thus allowing your blood vessels to open up further).  Sildenafil (Viagra) elevates cGMP by inhibiting one of its primary metabolizing enzymes.  Moral of the story is: if you are taking Viagra, and you also take some kind of nitrate like nitroglycerin, you can give yourself catastrophic hypotension (i.e. a huge drop in blood pressure).

Warfarin is an anticoagulant with a very small “therapeutic window,” which means that too much or too little of the drug can cause some serious damage to your body.  You have to be very careful when you’re on warfarin, because any variation can cause you to either form a blood clot, causing a stroke, or not clot enough, causing you to bleed out.  Aspirin is a drug a lot of elderly folks take just to help with their heart.  Typically in a low-dose form, aspirin is good to help limit your risk for heart attack and stroke, but if you take any aspirin while you’re also taking warfarin, you can dramatically increase your chances of bleeding, especially gastrointestinal bleeding: taking them together can increase your risk almost four-fold.

All of the preceding examples illustrate how one drug or compound can affect the ability of another drug to work or to be broken down, or in some cases can actually increase the effect of another drug or compound on your body.  The moral of the story is to remain cognizant of what drugs you are on and in what dosage.  Most medical professionals are aware of potential interactions between different drugs, and the examples listed above hopefully illustrate why they need to be aware of what you are taking and why.  If you have elderly parents or grandparents, it is extremely important that they keep a list of medications that they are currently taking with them at all times, especially if they see different doctors for different ailments.  If they were involved in a car accident and needed to go to the emergency room, it would save time and effort to have an up-to-date list of their medications with them, rather than having E.R. docs search to figure out what they are taking.

Of course, if you, yourself, are taking multiple medications now, or know others that are, it is equally important for you, too.  Most drugs will have warning labels on the side of the packaging that help you know what you can take a drug with and what you can’t.

Just bear in mind that, if you really like drinking a vodka and grapefruit juice before bed every night, you may need to tell your doctor before they prescribe anything to you.  🙂

6 Replies to “Primer: Drug-Drug Interactions”

  1. Ah Viagra. A very interesting drug indeed. My 28-year-old friend who is waiting for a heart transplant is on Viagra and makes her dad pick up the prescription for her. I’ve heard it’s a bit of an odd conversation for nurses to have with the parents of pediatric patients who have to be put on a Viagra drip. Perhaps you could do a primer on this one next!

    1. There was another drug they were working on to treat high blood pressure called “Minoxidil,” but they found that it had the side-effect of causing hair growth throughout your body. As you’ve no doubt figured out, they reformulated it as a topical medication under the brand “Rogaine.” 😛

      Those drugs are really interesting. Lots of companies trying to figure out good medications for high blood pressure that work differently than beta blockers, yet their side-effects tend to prove more useful than the ones they’re intended for!

  2. Isn’t the term for drug-drug interaction called “contraindication”? I think the tylenol/alcohol one should be part of any college freshman orientation… I wonder how GABA interacts with alcohol, because I used to take that in college… and I used N-Acetyl-Cysteine as a hangover cure. I wonder what weird things I was doing…. haha. Ultimately, I agree that you should have a list of medications AND supplements whenever you visit a doctor. Your General Physician might know what you’re on, but a specialist or ER person may not. Anyway, good read. Thanks Doc.

    1. A “contraindication” is more of what I’d consider to be a side-effect. I guess, technically, it’s any reason you’d choose not to give someone a drug (i.e. someone with liver failure, or an alcoholic, should not be given Tylenol because they wouldn’t be able to metabolize it properly).

      I could do a whole “Primer” on depressants, but long-story-short, depressants like benzodiazepines and barbiturates and sleep medications all work on the GABA-A receptor to “depress” neurons. Alcohol and many “date rape” drugs also work on the same receptor, so that’s why. You shouldn’t combine alcohol with depressants, as you risk respiratory depression (i.e. stop breathing).

      And N-acetyl-cysteine is an excellent anti-oxidant, and happens to function very similarly to glutathione, which is why you would give it to someone with acute Tylenol poisoning. Not necessarily helpful for a hangover, but definitely good if you take Tylenol, too. The best thing for a hangover, I think, is water. Take two glasses before you go to bed and you’ll limit your hangover considerably, as most of the metabolism your body needs to do requires copious amounts of water.

      Glad you enjoyed it, though. 🙂

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