Ask any sixth grader what 1+1 equals and you will be told the answer is 2. Ask a pharmacist, though, and you might get a very different answer.
In the Alice-in-Wonderland world of pharmaceuticals, sometimes 1+1 equals 0 or even 3. That’s because certain drugs may cancel out the benefits of other medicine or exaggerate their effects and cause toxicity. In the worst case scenario 1+1 equals death.
Clopidogrel (Plavix) and Potentially Deadly Interactions:
Clopidogrel offers a fascinating example of a complicated and serious drug interaction. When people develop serious blockage in a coronary artery surgeons frequently insert a balloon catheter to widen the passageway. In the “old” days, these procedures worked well for awhile, but not infrequently the artery closed up again. To keep it from closing later, doctors now almost always insert a stent.
Although these little metal mesh tubes help keep heart arteries open, they too may sometimes get clogged. That is why there has been great interest in a newer generation of devices called drug-eluting stents. These tiny tubes are coated with an immune-suppressing medication that keeps tissue from growing around the metal.
Drug Eluting Stents Require Anti-Clotting Drugs:
While metal stents that are coated with medication seems like an improvement, it creates problems of its own. Bare metal is more likely to trigger blood clot formation. And that’s where Plavix comes in.
This medicine prevents life-threatening blood clots from forming in coronary arteries. There’s not much room for error. Too much drug can lead to bleeding; too little can allow deadly clots to form. The patient walks a pretty narrow tightrope with no room for error.
The Boomerang Effect:
One fairly common side effect of Plavix is digestive distress. Not surprisingly, doctors used to prescribe the most popular heartburn medicines on the market. That includes Nexium (the “purple pill”) and similar proton pump inhibitors (PPIs) such as Prevacid, Prilosec and Protonix.
There is a big boomerang problem, however. When certain PPIs are combined with Plavix we may enter the zone where 1+1 don’t always equal 2. More than 16,600 stent recipients were studied by Indiana University School of Medicine and Medco Health Solutions. The data showed that patients given a PPI along with Plavix were 50 percent more likely to suffer a heart attack or a stroke than those taking Plavix alone (Pharmacotherapy, Aug, 2010).
This study was consistent with findings reported from the VA (Journal of the American Medical Association, March 4, 2009). That study also found that people taking both Plavix and a PPI were more likely to die or suffer cardiovascular complications:
Conclusion: “Concomitant use of clopidogrel and PPI after hospital discharge for ACS [acute coronary syndrome] was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use ofPPI may be associated with attenuation of benefits of clopidogrel after ACS.”
When 1+1 Equals 0:
Scientists now think they know why PPI-type heartburn drugs interfere with the effectiveness of Plavix. It turns out that clopidogrel itself is not an effective anti-clotting drug. It is considered a “prodrug.” To work, it has to be converted into an active form in the liver by specialized enzymes. Proton pump inhibitors impede that conversion and as a result appear to reduce effectiveness.
A study in the Journal of the American Heart Association (Oct. 29, 2015) clarifies this interaction and concludes: “Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events.”
Adverse cardiovascular events include heart attacks and strokes. These are life-threatening situations!
Other Deadly Drug Interactions:
Canadian physicians have been way ahead of their North American colleagues when it comes to warning about the potentially deadly combination of an antibiotic called co-trimoxazole (sold under the brand names Bactrim or Septra and containing the drugs sulfamethoxazole and trimethoprim) and a class of blood pressure medicines.
The canadians have discovered that when people take ACE inhibitors (such as captopril, enalapril, lisinopril or ramipril) or ARBs (like losartan or valsartan) together with co-trimoxazole it can lead to “increased risk of sudden death in older patients.” This work was published in the BMJ (Oct. 30, 2014). Additional research discovered the same risk between the diuretic spironalactone and co-trimoxazole (CMAJ, March 3, 2015).
A Dirty Little Secret:
Health policy experts know that doctors frequently override drug interaction alerts on their smart phones or computers. Pharmacists also override their computer alerts. So, when the computer says a particular combination of medications poses a risk, a lot of health professionals ignore the warning.
The name for this phenomenon is “alert fatigue.” What it means is that physicians and pharmacists are so inundated with these drug interaction alerts that after awhile they pay them no mind. That means patients may suffer or worse.
Even So-Called Minor Interactions Can Be Dangerous:
People who take thyroid hormone (levothyroxine, Levoxyl, Synthroid) are warned not to take calcium supplements at the same time. Calcium can interfere with absorption of the hormone. Some antibiotics may also be less effective when taken with calcium in antacids, supplements or foods.
Other drug interactions may result in unexpected toxicity. This is especially true for medicines like digoxin (Lanoxin) or warfarin (Coumadin), which interact with dozens of other drugs.
There are thousands of drug interactions that pose potential hazards. When physicians and pharmacists are too busy to look up potential conflicts, patients will need to watch out for themselves.
To learn how to do that and discover more about the crazy and confusing mine field of drug interactions, you may be interested in our book, Top Screwups Doctors Make and How to Avoid Them. Our chapter on drug interactions will provide you the tools that you or someone you love can use to reduce the likelihood that 1+1=death.