Drug-drug interactions (DDIs) occur when one drug adds to or diminishes the effect of another drug (ie, pharmacodynamic interaction) or affects the absorption, distribution, metabolism, or excretion of another drug (ie, pharmacokinetic interaction). Such interactions cause 26% of all adverse drug events (ADEs) and are associated with a significant burden on the health care system through increased hospitalizations. Some of the most common DDIs result from alterations in drug metabolism through interactions with cytochrome P450 enzymes and absorption through interactions with P-glycoproteins. Other common DDIs occur because of additive effects, including combinations of drugs that increase the risk of seizures, prolong the QT interval, increase central nervous system depression, and increase the risk of serotonin syndrome. Drug-related clinical decision support has been shown to improve the quality of patient care and decrease ADE rates. However, alerts generated by such systems should be interpreted using clinical judgment to determine the risks and benefits of certain drugs on a patient-specific basis. Family physicians can prevent clinically significant DDIs and optimize drug safety by using drug interaction software, along with a general understanding of common DDI mechanisms and collaboration with pharmacists.

Case 3. MS, a 64-year-old new patient, shows you a list of the drugs that she has been taking for years. While entering them into the electronic medical record, several alerts appear to notify you of potential drug-drug interactions. These include QTc prolongation with the combination of amitriptyline and ondansetron and the risk of serotonin syndrome with the combination of amitriptyline and tramadol. When you discuss the potential adverse effects, MS is concerned and asks if she should continue taking these drugs together.

Clinically relevant drug-drug interactions (DDIs) occur when one drug adds to or cancels the effect of another drug (ie, pharmacodynamic interaction) or affects the absorption, distribution, metabolism, or excretion of another drug (ie, pharmacokinetic interaction).⁵⁶ The risk of clinically relevant DDIs increases as the number of drugs taken increases.⁵⁷ The highest risk is among older adults who take eight or more drugs. The manifestation or progression of conditions that can change pharmacodynamic and pharmacokinetic parameters (eg, heart failure [HF], kidney disease, liver disease) also increases DDI risk.⁵⁶ Common drug-drug interactions and management recommendations are listed on Table 7.

It is estimated that DDIs cause 26% of all adverse drug events (ADEs), which are defined as any injuries resulting from use of a drug,⁵⁸ and cost the health care system $1.3 billion annually in hospitalizations.^56,59 It is estimated that up to 62% of ADEs are preventable.⁵⁹