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Drug-Drug Interaction Mechanisms

Philip Hansten, Pharm.D.

John Horn, Pharm.D.

Drug-drug interactions are possible whenever a person takes two or more medications concurrently. Recent scientific developments—particularly in the area of cytochrome P450 drug metabolizing enzymes—have revolutionized the study of drug interactions. The result has been a deluge of published drug interaction research that has overwhelmed most health care practitioners. While it is not possible for an individual health care practitioner to recognize all clinically significant drug interactions, it is possible to understand the important scientific principles and mechanisms that pertain to this topic. When discussing drug interactions, the drug affected by the interaction is called the “object drug,” and the drug causing the interaction is called the “precipitant drug.”

There are a number of mechanisms by which drugs interact with each other, and most of them can be divided into two general categories: pharmacokinetic and pharmacodynamic interactions. With pharmacokinetic drug interactions, one drug affects the absorption, distribution, metabolism, or excretion of another. When pharmacodynamic drug interactions occur, two drugs have additive or antagonistic pharmacologic effects. Either type of drug interaction can result in adverse effects in some individuals.

Pharmacokinetic Drug Interactions

Inhibition of Absorption. Drugs that act as binding agents such as cholestyramine and colestipol can impair the bioavailability of other drugs. This will result in a reduction in the therapeutic effect of the object drug. The effect can be profound with some combinations such as cholestyramine and furosemide. Some drugs such as fluoroquinolone antibiotics (e.g., Cipro) are susceptible to chelation with cations such as aluminum, magnesium, and iron. Other drugs such as itraconazole, ketoconazole, glipizide, glyburide, cefpodoxime, and cefuroxime have pH dependent absorption. The amount of these drugs that is absorbed from the gut may be increased or decreased by drugs that increase stomach pH.

Enzyme Inhibition Increasing Risk of Toxicity. Most drugs are metabolized to inactive or less active metabolites by enzymes in the liver and intestine. Inhibition of this metabolism can increase the effect of the object drug. If the increase in effect is large enough, drug toxicity may result. This is one of the most common mechanisms by which clinically important drug interactions occur. Since only a few different cytochrome P450 isozymes are involved in drug metabolism, competition between two drugs for these isozymes will occasionally occur. This competition may result in one drug interfering with the metabolism of another drug.

For example, inhibitors of CYP1A2 can increase the risk of toxicity from clozapine or theophylline. Inhibitors of CYP2C9 can increase the risk of toxicity from phenytoin, tolbutamide, and oral anticoagulants such as warfarin. Inhibitors of CYP3A4 can increase the risk of toxicity from many drugs, including carbamazepine, cisapride, cyclosporine, ergot alkaloids, lovastatin, pimozide, protease inhibitors, rifabutin, simvastatin, tacrolimus, and vinca alkaloids.

Enzyme Inhibitors Resulting in Reduced Drug Effect. A small number of drugs are not active in the form administered to patients. These drugs are known as prodrugs and require activation by enzymes in the body before they can produce their effect. Inhibition of the metabolism of these prodrugs may reduce the amount of active drug formed, and decrease or eliminate the therapeutic effect. For example, the analgesic and toxic effects of codeine appear to result from its conversion to morphine by CYP2D6. Thus, CYP2D6 inhibitors can impair the therapeutic effect of codeine. CYP2D6 inhibitors may similarly affect the analgesic effect of hydrocodone.

Enzyme Induction Resulting in Reduced Drug Effect. Some drugs—called “enzyme inducers”—are capable of increasing the activity of drug metabolizing enzymes, resulting in a decrease in the effect of certain other drugs. Examples of enzyme inducers include aminoglutethimide, barbiturates, carbamazepine, glutethimide, griseofulvin, phenytoin, primidone, rifabutin, rifampin, and troglitazone. Some drugs, such as ritonavir, may act as either an enzyme inhibitor or an enzyme inducer, depending on the situation. Drugs metabolized by CYP3A4 or CYP2C9 are particularly susceptible to enzyme induction. In some cases, especially for drugs that undergo extensive first-pass metabolism by CYP3A4 in the gut wall and liver, the reduction in serum concentrations of the object drug can be profound.

Enzyme Induction Resulting in Toxic Metabolites. Some drugs are converted to toxic metabolites by drug metabolizing enzymes. For example, the analgesic acetaminophen is converted primarily to non-toxic metabolites, but a small amount is converted to a cytototoxic metabolite. Enzyme inducers can increase the formation of the toxic metabolite and increase the risk of hepatotoxicity as well as damage to other organs.

Altered Renal Elimination. For some drugs, active secretion into the renal tubules is an important route of elimination. For example, digoxin is eliminated primarily through renal excretion, and drugs such as amiodarone, clarithromycin, itraconazole, propafenone, and quinidine can inhibit this process. Digoxin toxicity may result.

Pharmacodynamic Drug Interactions

Additive Pharmacodynamic Effects. When two or more drugs with similar pharmacodynamic effects are given, the additive effects may result in excessive response and toxicity. Examples include combinations of drugs that prolong the QTc interval resulting in ventricular arrhythmias, and combining drugs with hyperkalemic effects resulting in hyperkalemia.

Antagonistic Pharmacodynamic Effects. Drugs with opposing pharmacodynamic effects may reduce the response to one or both drugs. For example, drugs that tend to increase blood pressure (such as nonsteroidal anti-inflammatory drugs) may inhibit the antihypertensive effect of drugs such as ACE inhibitors. Another example would be inhibition of the response to benzodiazepines by the concurrent use of theophylline.

Although dramatic advances have been made in the study of drug interaction mechanisms over the past few decades, there is still much to learn. Thus, many of the mechanism concepts useful today will be refined in the future, yielding a picture closer to the truth. It also should be kept in mind that for some drug-drug interactions more than one mechanism may be occurring simultaneously.

Copyright 2003 by H&H Publications.  All rights reserved.