Drug Interactions

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Chapter 4 Drug Interactions

Drug interactions are a frequent and preventable cause of drug-related adverse events. Interactions between drugs (drug-drug interactions) are particularly common, and as the number of conditions that can be treated with drug therapy increases, polypharmacy—the use of multiple medications in a single patient—will become commonplace.

Fortunately, not all drug interactions will harm the patient. If this were the case, it would severely limit our ability to prescribe a number of very useful drugs. In the following pages you will note that a number of very commonly prescribed drugs are involved in drug interactions. Understanding the mechanisms behind these interactions will help you develop a strategy for determining which interactions are manageable and which combinations should be avoided altogether.

Mechanisms of Drug Interactions

Just as pharmacology is divided into two fundamental branches—pharmacokinetics and pharmacodynamics—the mechanisms of drug interactions can also be subdivided into these two branches. Note that there is a third type of interaction, a physical (chemical) interaction that may occur outside the body (in vitro). This last type involves direct interactions between drugs and is largely the concern of pharmacists.

Pharmacokinetic Interactions

Pharmacokinetic interactions can be subdivided into those involving absorption, distribution, metabolism, and excretion (ADME).

Absorption

A given drug may directly reduce the absorption of another drug through the following:

A given drug may also indirectly reduce absorption of another drug, by altering the following:

Metabolism

Phase I Reactions

Cytochrome P-450 Enzymes

Cytochrome P-450 (CYP450) enzymes are responsible for phase I (oxidative) metabolism of endogenous or exogenous substrates. See introductory chapter on pharmacokinetics for review.

CYP450 enzymes are categorized according to a number-letter-number system (e.g., CYP3A4). Thus 2C9 and 2C19 are more closely related than are 2C9 and 3A4. There are at least 40 CYP450 enzymes, although only a few are seen commonly, and it is only these that you need to be concerned with. The most common isozymes are 3A4, 2D6, 2C9 and 2C19, and 1A2.

Clinically significant drug interactions arise from either induction or inhibition of these enzymes.

Enzyme Inhibition

Inhibition of a CYP450 enzyme will result in increased levels of a substrate (drug) that is metabolized by that enzyme. Inhibition may be either competitive or allosteric:

Whether the inhibition is competitive or allosteric, if the enzyme is responsible for inactivating the drug in preparation for excretion from the body, then inhibiting this enzyme will lead to increased levels of active drug. All things being equal, this would likely result in increased biologic activity (or toxicity) of the drug.

Prodrugs require metabolic enzymes for transformation to an active (or more active) metabolite. In this case, an enzyme inhibitor would lead to a reduction in levels of active drug, in turn reducing the biologic activity of the drug. Few drugs are prodrugs; however, you should be aware of this twist on enzyme inhibition.