This article originally appeared in the April 2004 Harvard Health Letter and is provided courtesy of Harvard Health Publications.

Bad combinations

Drug interactions you and your doctors need to worry about.
Almost half of all Americans age 65 or over take at least 5 different medications per week, and 1 in 8 take 10 or more. With so many people taking so many pills, opportunities for harmful drug interactions are more likely than ever. Several high-profile drugs have been taken off the market because of harmful interactions, as well as other toxicity problems, including Baycol (cerivastatin), one of the cholesterol-lowering statin drugs; Propulsid (cisapride), a nighttime heartburn drug; and Seldane (terfenadine), one of the early non-sedating antihistamines.

But there’s also a great deal of uncertainty about how big a problem this really is. There’s no central clearinghouse of information on drug interactions or standardized reporting requirements. The FDA does have a reasonably good system for reporting “adverse drug events,” but interactions make up just a fraction of those.

Compounding the confusion is the absence of criteria and definitions. Harold DeMonaco, a drug therapy expert at Massachusetts General Hospital (MGH), says, “Drug reactions are like beauty: They are in the eye of the beholder.”

The ambiguity has caused problems. Hospitals have had to reprogram their computers because even the remotest possibility of an interaction was triggering an alert that doctors then had to override. They took lists of hundreds of possible interactions and boiled them down to a couple of dozen.

Some interactions don’t occur because the medications are no longer used very much — partly because they caused interactions. In other cases, a possible interaction has been identified but the risk may be largely theoretical. For example, an article published in Circulation in 2003 suggested that Lipitor (atorvastatin), the popular cholesterol-lowering statin, may cancel out the effects of Plavix (clopidogrel), a drug that prevents blood clotting. But the Lipitor-Plavix problem is a “formulated but untested hypothesis,” according to an article written by Robert Hallisey, a pharmacist at MGH. Hallisey noted that researchers haven’t seen the interaction in the numerous studies of Plavix.

Dr. David Bates, a Harvard expert on adverse drug events, was one of the authors of a study published in the Journal of the American Medical Association in 2003 that helps put drug interactions in perspective. Bates and his colleagues examined the medical records of about 28,000 Medicare enrollees who were 65 or over. Of the 421 preventable adverse drug events, 56 were drug interactions, a sizable (13%) fraction. But that was considerably fewer than the 89 (21%) adverse events caused by “errors in patient adherence” — people taking the wrong dose, refusing to take a drug, and so on.

Six important drug interactions
We asked Dr. Bates, DeMonaco, and other Harvard experts to help us create a short list of important drug interactions. We picked six. Obviously, this leaves many interactions unmentioned but it highlights some of the important problems and the reasons they occur.

Warfarin (Coumadin) with antibiotics. Warfarin is a “blood thinner” that people with atrial fibrillation and other heart problems take to prevent the formation of blood clots. Many drugs, including warfarin, have a tendency to stick to albumin, a protein in the watery part of the blood. If another drug successfully competes with warfarin for that “binding site” on albumin, then the concentration of “free,” and thus active, warfarin soars — and with it the risk of serious bleeding. A common bad combination is warfarin and “sulfa” antibiotics such as cotrimoxazole (Bactrim, Septra, other brands) — particularly in nursing homes, where residents with atrial fibrillation are also frequently prescribed antibiotics for urinary tract infections and pneumonia. The warfarin dose should be lowered and the blood ’s clotting capacity closely monitored.

ACE inhibitors with NSAIDs. ACE inhibitors are used to treat hypertension and heart failure. The NSAIDs include aspirin, ibuprofen (Advil, Motrin, other brands), naproxen (Aleve), and the COX-2 inhibitors like Celebrex and Vioxx. In some patients, NSAIDs make ACE inhibitors less effective in lowering blood pressure. If you’re taking an ACE inhibitor, talk to your physician about which pain reliever to take. The occasional ibuprofen is not going to cause harm, but the long-term use of both classes of drugs could.

Digoxin with azithromycin, clarithromycin, or erythromycin. Digoxin (pronounced di-JOCKS-in) is prescribed to strengthen the heartbeat of people with heart failure. The -mycin drugs are antibiotics. Digoxin is metabolized by bacteria in the gut, so not all of it gets absorbed. But these antibiotics kill many of those bacteria, so the absorption of digoxin increases, which may cause an irregular heartbeat.

Potassium supplements with potassium-sparing diuretics. When diuretics pull water out of the bloodstream, they pull salt and potassium along with it. Low salt levels aren’t usually a problem, but low potassium levels can be, so potassium supplements are sometimes prescribed. But if you have heart failure or your blood pressure isn’t controlled by a diuretic, doctors will sometimes prescribe a potassium-sparing version (Aldactone, Dyrenium, other brands) in addition to or in place of the regular diuretic (see “Beware of low potassium levels from diuretics,” Harvard Health Letter, April 2004). If you keep taking the potassium supplements, then you’ll end up with too much potassium in your blood, and that excess can cause serious problems, including cardiac arrest. Combining ACE inhibitors with potassium-sparing diuretics sometimes also leads to high potassium concentrations.

The -azole antifungals and statins. The -azole antifungals, which include fluconazole, itraconazole, and ketoconazole, are oral drugs used to combat fungal infections in the vagina, lungs, and elsewhere. Like many other drugs, including many of the statins, the -azole drugs are metabolized in the liver by a group of enzymes called the P450 enzymes. When an -azole antifungal and a statin “share” the P450 enzymes, the concentration of the statin can shoot way up, and high levels can cause muscle damage.

The erectile dysfunction drugs and nitrates. Viagra, Levitra, and Cialis all interact with nitrate-based drugs such as nitroglycerin to produce a sudden drop in blood pressure. The interaction has been well publicized and is frequently mentioned in the many ads for these drugs.