The topic of drug interactions is strikingly complex and rapidly evolving. Even experts in this area of pharmacology must rely on print and electronic resources pertaining to drug interactions on a regular basis. With these facts in mind, this chapter focuses on a wide variety of principles, with selected drug interactions utilized to illustrate these principles, as opposed to providing extensive lists of potential drug interactions. Furthermore, there will be an attempt to provide a stratification of risk, putting the greatest emphasis on the drug interactions with the greatest risk to individual patients.

Definitions

The most basic definition of a drug interaction is when two drugs are being administered simultaneously in a patient, and one drug alters the other’s serum/tissue levels or mechanism of action. The drug interaction can affect the efficacy or increase the likelihood of adverse effects from one or both drugs. Furthermore, a drug interaction can occur without clinically evident alteration of efficacy or adverse effects. In contrast, drug interactions which induce either a loss of drug efficacy or new adverse effects are known as adverse drug interactions. The topic of drugs interactions is important to physicians in all aspects of medicine regardless if the clinician (a) prescribes the drug “responsible” for a given drug interaction, or (b) the drug previously prescribed by this same clinician is the “victim” of a drug prescribed by another clinician.

Print and Electronic Resources

In reviewing this chapter, the reader is encouraged to strive for a “recognition recall” level of memory; no one can possibly master and retain all important drug interactions. Through learning key principles that assist in attaining the broadest possible understanding of the multitudes of potential drug interactions, a clinician may best be able to interpret and react to new clinician situations involving potential drug interactions. One should always attempt make things “make sense” using the general principles that follow. It is always acceptable to (1) call a drug information pharmacist, (2) call or e-mail an expert in drug interactions, or (3) look up possible interactions in various print and electronic resources. Selected resources for drug interactions are listed in Table 236-1.

P-Glycoprotein

The topic of P-glycoprotein and the role in drug interactions has been relatively recently documented. P-glycoprotein is most common at important points of entry into body or important body structures (gastrointestinal tract, blood brain barrier) as a means to ensure protection against various “toxins”. P-glycoprotein is important for a number of drugs with highly variable absorption, such as digoxin and cyclosporine. Although the topic is not discussed further in this chapter, the interested reader can find additional information in a review by Shapiro and Shear.1

Definitions

All drug interactions can be divided into either pharmacokinetic or pharmacodynamic interactions, which is true regardless of whether they are an adverse drug interaction or an interaction without loss of drug efficacy or the onset of new toxicity.2 Conceptually pharmacokinetics deal with “what the body does to the drug”, while pharmacodynamics deals with “what the drug does to the body”. In the most basic sense, these definitions relate to the normal pharmacology of a given drugs therapeutic effects, as well as in the clinical setting of drug interactions.

Various Subtypes of Pharmacokinetic Drug Interactions

Pharmacokinetic drug interactions are much more common than pharmacodynamic drug interactions. This category of interactions results from alterations in a drug’s serum and/or tissue levels. The ADME model (see Sections “Various Subtypes of Pharmacodynamic Interactions” and “Subtypes of Metabolic Drug Interactions”) of studying pharmacokinetics pertains to this category of interactions. The steps from entry of the drug into the body until excretion of the drug and/or its metabolites includes (1) absorption, (2) distribution, (3) metabolism, and (4) excretion. The importance of each of these steps is detailed elsewhere.2 Examples of drug interactions involving each of these steps are included in Table 236-2.

Various Subtypes of Pharmacodynamic Interactions

Pharmacodynamic drug interactions are much less common than pharmacokinetic drug interactions. This category of interactions deals with alterations in the mechanism of either the desired pharmacologic effect or mechanism for an adverse effect. The drug levels are not of central importance in this category of interactions. The two primary subtypes of interactions include (1) agonist—similar “polarity” of the pharmacologic effects for the two interacting drugs, and (2) antagonist—opposite “polarity” of the pharmacologic effects for the two interacting drugs. Both agonist and antagonist interactions can produce either a positive (improved therapeutic response) or negative (toxicity) biologic response. Selected examples to illustrate this innately confusing terminology are listed in Table 236-3. Conceptually the various aspects of drug pharmacodynamics occur between the “distribution” and “metabolism” steps of the pharmacokinetics sequence. An exception to this principle would be for any prodrug that requires metabolic conversion to the active drug form to generate a pharmacologic response. Two examples would be the conversion of valacyclovir (prodrug) to acyclovir (corresponding active drug) and of famciclovir (prodrug) to penciclovir (corresponding active drug).

Subtypes of Metabolic Drug Interactions

The four steps of the “ADME” model for drug pharmacokinetics all have potential drug interactions, with either loss of efficacy or toxicity. By far the greatest number of important drug interactions occurs at the “metabolism” step. Drugs need to be relatively lipophilic to the entire body and travel to the site(s) of intended pharmacologic effect. Subsequently drugs must be converted to relatively hydrophilic metabolites to be excreted in bile or urine. Only a small fraction of drugs are excreted in their active form.

The body has two categories of drug metabolizing enzymes to accomplish the biotransformation of a relatively lipophilic drug form to a more hydrophilic form in order to facilitate renal or biliary excretion. These categories are phase I and phase II metabolic enzymes. It is important to note that these phases do not necessarily occur in a set sequence from phase I to phase II. Phase I enzymes are primarily cytochrome P-450 (CYP) mixed function oxidative enzymes which typically create a somewhat more polar site of attachment for the subsequent phase II (conjugation) enzymes. Examples of the phase I and phase II enzymes which are of greatest importance to drug interactions are listed in eTable 236-3.1 and eTable 236-3.2. Several of these enzymes have polymorphisms of importance to explaining the spectrum of risk between various patients in various ethnic groups.3

Isoforms of CYP of Greatest Importance to Drug Interactions