Preventing Some Serious Adverse Medication Events

By Marcus M. Reidenberg, MD, FACP
Weill Cornell CERT

A recently published study found that about two-thirds of emergency hospitalizations for adverse drug events in people over 65 years of age were due to warfarin (Coumadin), insulin, oral anti-diabetic drugs, and oral anti-platelet drugs (like aspirin and Plavix). The serious events were bleeding in the warfarin and antiplatelet groups or low blood sugar with neurologic symptoms in the diabetics causing people in each group to be admitted to hospital (1). These same problems, bleeding or hypoglycemia, occur in younger people with equally serious consequences.

The risk of episodes of bleeding and low blood sugar caused by excessive intensity of effect of these medications can be minimized by keeping everything the same from day to day. Let’s take bleeding first. Warfarin blocks the body’s formation of some of the substances in the blood that form clots. It is prescribed to prevent unwanted clotting in blood vessels or the heart. Bits of clots in these places can break off in the bloodstream and go to the lungs or brain causing real trouble. By giving the correct dose of warfarin to an individual, the risk of unwanted clotting is minimized while not increasing the risk of bleeding very much so there is real net benefit to taking warfarin.

But the warfarin dose must be carefully individualized for each person taking it. Doses for different people commonly range from 2-15 mg per day to achieve the desired degree of anticoagulation. This range of doses is due to variation between different people in rates of metabolism of the warfarin, rates of formation and degradation of the clotting factors affected by the warfarin, and sensitivity of the person to the warfarin. Some changes in what we eat as well as many medicines and environmental chemicals (such as the chemicals in cigarette smoke) can change some of these rates. Changing these rates changes the response to the same dose of warfarin. For example, slowing the body’s metabolism of warfarin keeps warfarin in the body longer which increases its effect. Grapefruit juice, some medicines and alcoholic beverages can do this. When this happens, the intensity of effect of the daily doses of warfarin increases and the risk of bleeding goes up. Some other medicines can speed up the rate of warfarin metabolism decreasing its effectiveness and often requiring an increase in dose to maintain effectiveness while taking the other medicine.

This analysis of warfarin leads to the need to understand the concept of the STEADY STATE. A person is stabilized on a maintenance dose of warfarin when the intensity of effect of the daily dose is just right, usually producing an INR (international normalized ratio) blood test of 2-3. As long as nothing changes, this maintenance dose will continue to produce this desired intensity of effect. This is the “steady state”. But when medication or diet change, a change in dose-response to warfarin can occur. The INR can become too much or too little causing bleeding or undesired clotting. Infections with antimicrobial therapy can do this. Even some viral infections can do this without antibiotic therapy. Some changes in diet can do this. Adding a new medicine or stopping an old medicine can do this. Any of these changes may affect any of the many enzymes and processes in the body that affect the response to warfarin. Thus the risk for bleeding or unwanted clotting goes up when something changes the previous steady state.

This same concept of a steady state is important for insulin and the other medicines used to lower blood sugar for diabetics. Blood sugar is the result of what one eats, one’s exercise, and one’s insulin amount and sensitivity to insulin. Changing the amount of physical activity one does, or the amount or timing of what one eats, or missing a dose of medicine and then taking two doses to “make up” changes the prior steady state and changes the effect of the diabetes medicine on the blood sugar. So again, what is important is to maintain the steady state.

A principle for people taking medicines with small margins of safety is to maintain the steady state as best you can and tell your doctor when something happens to change it. Medicines with small margins of safety are all those drugs that have had their dose carefully individualized to the specific patient using blood tests or measurement of effects. Maintaining the steady state is being constant in your diet, activities, and medications you take. When any of these change, tell the person who prescribed the drug with the small margin of safety so one can do one’s best to detect change in intensity of effect before catastrophe occurs.


  1. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002-12.

Posted 12/9/2011

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