Schnipper JL et al: Role of pharmacist counseling in preventing adverse drug events after hospitalization. Arch Intern Med 2006;166:565.
Trissel LA: Handbook on Injectable Drugs, 19th ed. American Society of Hospital Pharmacists, 2016.
John R. Horn, PharmD, FCCP
One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive, synergistic, or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4; the general principles of pharmacodynamics are discussed in Chapter 2.
Botanical medications (“herbals”) may interact with each other or with conventional drugs. Unfortunately, botanicals are much less well studied than other drugs, so information about their interactions is scanty. Pharmacodynamic herbal interactions are described in Chapter 64. Pharmacokinetic interactions that have been documented (eg, St. John’s wort) are listed in Table 66–1.
Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful, since the mechanism may influence both the time course and the methods of circumventing the interaction. Some important drug interactions occur as a result of two or more mechanisms.
The designations listed in Table 66–1 are used here to estimate the predictability of the drug interactions. These estimates are intended to indicate simply whether or not the interaction will occur, and they do not always mean that the interaction is likely to produce an adverse effect. Whether or not the interaction occurs (precipitant drug produces a measurable change in the object drug action) and produces an adverse effect depends on both patientand drug-specific factors. Patient factors can include intrinsic drug clearance, genetics, gender, concurrent diseases, and diet.
Drug-specific factors include dose, route of administration, drug formulation, and the sequence of drug administration. The most important factor that can mitigate the risk of patient harm is recognition by the prescriber of a potential interaction followed by appropriate action.
The gastrointestinal absorption of drugs may be affected by concurrent use of other agents that (1) have a large surface area upon which the drug can be adsorbed, (2) bind or chelate, alter gastric pH, (4) alter gastrointestinal motility, or affect transport proteins such as P-glycoprotein and organic anion transporters. One must distinguish between effects on absorption rate and effects on extent of absorption. A reduction in only the absorption rate of a drug is seldom clinically important, whereas a reduction in the extent of absorption is clinically important if it results in subtherapeutic serum concentrations. Similarly, an increase in the extent of absorption can lead to adverse patient outcomes.
The mechanisms by which drug interactions alter drug distribution include (1) competition for plasma protein binding, displacement from tissue binding sites, and (3) alterations in local tissue barriers, eg, P-glycoprotein inhibition in the blood-brain barrier. Although competition for plasma protein binding can increase the free concentration (and thus the effect) of the displaced drug in plasma, the increase will be transient owing to a compensatory increase in drug disposition. The clinical importance of protein binding displacement has been overemphasized; current evidence suggests that such interactions are unlikely to result in adverse effects. Displacement from tissue binding sites would tend to transiently increase the blood concentration of the displaced drug. (Text continues on page 1171.)
TABLE 66–1 Important drug interactions.
agents gastrointestinal tract, thus reducing absorption. Some antacids (eg, magnesium hydroxide with aluminum hydroxide) alkalinize the urine somewhat, thus altering excretion of drugs sensitive to urinary pH. H2-antagonists and proton-pump inhibitors can alter the absorption of drugs requiring gastric acidity for dissolution.