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 chelator is an organic chemical that bonds with and removes free metal ions from solutions. Typically, the molecule being chelated will be a divalent cation (e.g., Ca⁺², Mg⁺², Fe⁺²).

There are a few examples of agents that chelate drugs, reducing the absorption of both. The classic example would be tetracycline, which is chelated by calcium. This can inhibit absorption of tetracycline, reducing its antibacterial activity, but perhaps more important, tetracycline can reduce the availability of calcium, which can have dramatic effects on the developing fetus.

Drugs may also bind other drugs, although this is a relatively rare interaction. The classic example would be cholestyramine, a positively charged drug used to lower cholesterol. It lowers cholesterol by binding to negatively charged bile acids in the gut. Consequently, cholestyramine is also capable of binding other negatively charged drugs in the gut.

Note that cholestyramine is rarely used anymore, having been largely replaced by the statins.

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

• Some drugs require a very acidic environment for their dissolution. Drugs that increase gastric pH can reduce the absorption of these agents.

• Both drugs and food can alter gastrointestinal (GI) motility, enhancing or inhibiting the absorption of other agents.

The small intestine, with its large surface area, is a key area for drug absorption. Drugs such as anticholinergics, which reduce GI motility, may reduce the rate of absorption by delaying gastric emptying. Slowing the rate of absorption may have an impact on drugs that we want to work quickly, such as analgesics.

Transport proteins, such as P-glycoprotein (Pgp) (Figure 4-1)

• Pgp is one member of a superfamily of efflux transporters that are found in several regions of the body, including the GI tract and the blood-brain barrier. Pgp extrudes drug from the cell (i.e., pumps drug out of the cell).

• In the cells lining the GI tract, these efflux pumps will therefore pump some of the drug that was going to be absorbed back into the GI tract, preventing a proportion of drug from being absorbed.

• Pgps have inhibitors and inducers:

Pgp inhibition leads to retention of Pgp substrates. All things being equal, this would likely lead to increased absorption of the drug.

Pgp induction leads to an increased number of Pgp pumps, leading to increased extrusion of Pgp substrates. All things being equal, this would likely lead to decreased absorption of the drug.

Figure 4-1 P-glycoprotein.

Distribution

Plasma Protein Binding

Recall details of plasma protein binding from the introductory chapter on pharmacokinetics. It is only the unbound portion of a drug that crosses cell membranes and is able to exert a pharmacologic effect.

Drugs compete with one another for binding to plasma proteins. If a given drug, drug A, displaces drug B from its binding site, this will increase the amount of drug B that is unbound and free to exert a pharmacologic effect.

Displacement from plasma proteins plays a minimal role in drug interactions. Aside from the fact that there are few reports of clinically significant interactions of this type, there are a couple of theoretical reasons why we would not expect to see displacement from plasma proteins causing major problems in the clinical setting:

Free drug is also free to be metabolized and/or excreted from the body.

Free drug distributes very rapidly into tissue, quickly reducing plasma levels.

Therefore for a clinically significant interaction to occur, the interacting agent must also interfere with the metabolism or excretion of a given drug.

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:

Competitive inhibition (Figure 4-2)

Two drugs are metabolized by the same enzyme system, and one of the drugs binds more readily to the enzyme, resulting in the inhibition of metabolism of the other drug.

Example: Erythromycin and atorvastatin are both metabolized by CYP3A4. Erythromycin is also a CYP3A4 inhibitor; therefore it inhibits the metabolism of atorvastatin.

Allosteric (noncompetitive) inhibition

A drug inhibits an enzyme that it itself is not metabolized by. This inhibition occurs at an allosteric site (i.e., not at the site where the substrates bind) (Figure 4-3).

Figure 4-2 Competitive enzyme inhibition.

Figure 4-3 Noncompetitive (allosteric) enzyme inhibition.

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.

Enzyme Induction

An inducer stimulates increased production of a CYP450 enzyme. This effect can be seen in days but often takes 2 to 3 weeks to be established. An inducer accelerates the metabolism of substrate (drug).

If the drug is inactivated by that enzyme for the purpose of excretion, an inducer will result in reduced circulating levels of active drug. All things being equal, this will likely result in reduced biologic activity of the drug, perhaps leading to therapeutic failure.

Most cases of induction are allosteric, although rarely a drug may also induce the enzyme system by which it is metabolized.

Now imagine a scenario in which a patient’s condition has been stable on both a substrate (drug A) and another drug (drug B) that induces the metabolism of drug A.

What would happen if the patient discontinued drug B?

• This is a classic example of why monitoring should not end once an interacting drug has been discontinued. This is particularly important if the dose of drug A was increased in order to accommodate the effects of the enzyme inducer. If the dose is not adjusted back down, the patient might experience toxicity from the elevated plasma levels.

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