Drug Interactions 101

How Do They Happen, And How Can We Minimize the Risk?

The 16th century French essayist Michel de Montaigne – decidedly suspicious of all of the medications served up by the physicians and apothecaries of his day – wondered aloud about the problem of drug interactions. After describing the complex potions used to treat various diseases he said, “...who could suppose that in this liquid confusion these faculties would not corrupt, confuse and alter one another?”

He was right to wonder, of course, and the problem of drug interactions has become even more serious as the number of medications has increased over the years.

There are three basic ways that drugs can interact with one another to result in harmful consequences.

1. Kinetic Drug Interactions: This occurs when one drug affects the way another drug is handled by the body. Scientists call these “pharmacokinetic” drug interactions, but we can shorten it to “kinetic” drug interactions. These drug interactions usually result in changes of the levels of the affected drug in the blood or in specific tissues.
2. Pharmacologic Drug Interactions: This usually involves two drugs having additive or antagonistic effects regarding the intended purpose for the drug. Usually the individual levels of the two drugs are not altered, but the sum of their effects can cause problems or one drug can neutralize the effect of the other.
3. Combined Toxicity: This occurs when two drugs have toxic, adverse effects on the same organ, resulting in damage to that organ that would not have occurred if either drug had been used alone.

These three types of drug interactions are described in greater detail below. Keep in mind that some interactions occur by more than one mechanism.

Kinetic Drug Interactions

Most of the harm caused by drug interactions results from one of the kinetic mechanisms. Kinetic drug interactions occur when one drug affects the way another drug is handled by the body by affecting the absorption, distribution, metabolism or excretion.

Absorption. This type of drug interaction occurs mainly when one drug affects the absorption of another drug from the gastrointestinal tract. For example, suppose your doctor wants you to take the antibiotic ciprofloxacin (CIPRO) for a bacterial infection, and you decide to wash it down with a big gulp of aluminum hydroxide and magnesium hydroxide (MAALOX) or other antacid. Bad idea! The antacid will prevent absorption by binding with the ciprofloxacin so tightly that very little of the antibiotic will get into your system, and the bacteria will celebrate their reprieve.

In addition to drugs binding to other drugs in the gastrointestinal tract, medications that drastically alter the acidity of the stomach such as omeprazole (PRILOSEC) and esomeprazole (NEXIUM) also can alter the absorption of certain medications.

Distribution. Sometimes one medication can affect how another drug is distributed in the body, either by affecting the drug’s binding in tissues or in the blood stream. This is not a common source of adverse drug interactions, but it does occasionally occur.

Metabolism. This is the most important mechanism by which adverse drug interactions occur. Most medications that we take are fat soluble, and therefore do not dissolve well in water. But in order to eliminate medications from the body, we need to somehow convert them to water soluble substances that our kidneys and liver can eliminate. Our bodies wisely consider medications foreign chemicals and do everything they can to rid themselves of these substances. So we are all equipped with a whole series of enzymes in our intestine and liver that make drugs more water-soluble by chopping off parts of the drug molecules or adding chemical groups onto the molecules to change them from fat soluble to water soluble. The process of making the medications more water soluble has the added benefit of rendering the medication partly or completely inactive so they then have reduced ability to cause toxicity.

Unfortunately, many medications interfere with this enzyme machinery that is so useful in getting rid of medications. So, for example, Drug A throws a monkey wrench into the enzymes, and Drug B that was about to be gobbled up by this machinery gets away unscathed. Then, because Drug A makes it impossible for the body to get rid of Drug B, Drug B starts to accumulate and after a few days or sometimes a few weeks, Drug B reaches a level that causes toxicity. Sometimes this toxicity is just an increase in side effects that is recognized and corrected by reducing the dose of Drug B. But other times  – depending on the drugs involved – severe or even fatal events occur because too much of Drug B accumulates in the body.

Another type of metabolism mechanism – called enzyme induction – is basically the opposite of the monkey-wrench type described above. Some drugs cause certain enzymes to go into overdrive, so that the enzymes are gobbling up other medications at a rapid rate (see “Smoking Drug Interactions” in this issue). Suppose a patient starts a drug (Drug A) that stimulates “gobbling” enzymes, and a chronic medication that was working fine (Drug B) stops working because it is being gobbled up much more rapidly than before. Sometimes this kind of interaction can be circumvented by increasing the dose of Drug B, but other times the enzyme stimulation is so strong that Drug B just stops working completely. This type of drug interaction usually takes place gradually over a week or two or even longer in some cases.

Excretion. The primary organ involved in excretion of drugs out of the body is the kidney (via the urine). Usually the enzymes in the intestine and liver convert the medication to a water soluble (inactive) form, and then the kidney gets rid of it. But some drugs normally are not metabolized before being eliminated by the kidneys. In such a case, another drug that interferes with the ability of the kidney to eliminate the nonmetabolized drug can cause toxicity. A good example is the drug lithium (ESKALITH, LITHOBID, LITHONATE), widely and effectively used to treat bipolar (manic-depressive) illness. Lithium is not metabolized, and there are several drugs that can interfere with lithium excretion by the kidneys, resulting in lithium toxicity.

Pharmacologic Drug Interactions

Pharmacologic drug interactions are more straightforward and usually result in just additive or antagonistic effects of two or more drugs. A common example would be taking a sleeping pill and alcohol at the same time. Both agents are sedative and can make you drowsy. When they are combined, the sedative effects of the sleeping pill add to those of the alcohol. Such interactions can be dangerous, and it is important to anticipate and prevent them.

There are many other examples of additive pharmacologic drug interactions, such as taking two drugs that both decrease blood pressure, which would result in an added decrease in blood pressure. Sometimes these additive effects are used intentionally. For instance, a doctor could combine two blood pressure medications to control a recalcitrant blood pressure, or use several drugs at once  in cancer chemotherapy to attack the cancer cells.

Antagonism can also occur. If you take several cups of coffee with your sleeping pill, the caffeine may be at odds with the medication used to help you sleep and the sleeping pill might not work. It must be said, however, that drinking coffee too late in the day is not infrequently the cause of sleeplessness and the precipitator for using sleeping pills. Less coffee, fewer sleeping pills!

Or if a patient with Parkinson’s disease who is taking medication to increase dopamine in his brain also takes a drug that reduces brain dopamine, the antagonistic effects of the two drugs may result in an increase in his Parkinson’s symptoms.

Combined Toxicity

When a person takes two or more drugs that cause damage to the same organ, there may be additional damage to that organ.

For example, taking two drugs that both tend to damage the kidneys may greatly increase the risk of kidney damage beyond what would occur by taking either of the drugs alone. Sometimes such interactions can be avoided by careful adjustments of the dosage or use of an alternative drug. But in some cases it can be hard to avoid combined toxicity completely, such as in cancer chemotherapy regimens where two or more of the drugs suppress the formation of white blood cells, increasing the risk of infections.

Summary

Drug interactions can take place by a variety of mechanisms: kinetic, pharmacologic and combined toxicity. Most adverse drug interactions are preventable if the interaction is anticipated and appropriate precautions are taken. Patients can reduce their risk of adverse interactions by taking the following precautions:

• Take as few drugs as possible. Make sure you let your physician and other prescribers know that you only want to take medications that are clearly necessary. Using “Worst Pills, Best Pills” (either the book, the newsletter or the Web site, www.WorstPills.org) can help you avoid unnecessary medications and medications that have a poor safety record. Interactions are listed for most of the drugs in “Worst Pills, Best Pills” and on the Web site.
• Make sure all of your physicians and your pharmacist know all of the medications you are taking, including herbal and alternative medications, many of which, such as St. John’s Wort, interact with many prescription drugs. Your health professionals cannot monitor effectively for drug interactions if they don’t know all of the medications you are on.
• Get all of your medications at one pharmacy if possible. Most pharmacies have computerized drug interaction screening programs that will raise a red flag if you are prescribed a new drug that can interact with a drug you have been previously taking. These programs do not catch everything, but your pharmacist is more likely to catch drug interactions if you consistently use one pharmacy (unless your complete medication profile is available to all of the pharmacies you use, if you use multiple pharmacies).
• Ask questions. When your physician orders a new medication, ask him or her if there are other medications, dietary or herbal supplements or foods you should avoid. When you pick up your new medications, talk to your pharmacist if you have any drug interaction questions.
• If you have a computer, you can get on the Internet and look up drug interactions of the medications you are taking. There are several free Web sites that allow you to enter all of your medications, and it will give you a list of potential drug interactions. But before acting on any of the recommendations from these Internet sites, it is best to check with your physician and/or pharmacist to get their advice. There may be good reasons why your physician has you on particular combinations of drugs.