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The use of multiple medications can result in drug–drug interactions that may increase or decrease the efficacy or toxicity of any single agent or of multiple agents. There are times when a drug–drug interaction can be predicted, such as that seen with warfarin and sulfonamides, but other drug combinations may not consistently result in the same clinically observable interaction and may vary due to dosing, differences between agents in a certain class, concomitant disease states of a patient, and duration of administration.


The mechanisms of these drug–drug interactions are pharmacokinetic and pharmacodynamic in nature.1 Pharmacokinetic drug interactions can occur in one of the four different phases of the body’s processing of medication: absorption, distribution, metabolism, and elimination. An example of an interaction that involves absorption is one that can occur with ciprofloxacin and antacids; prevention of absorption takes place through binding of ciprofloxacin to the antacid within the gut lumen.2 Another example of a drug–drug interaction involving absorption occurs with grapefruit juice and medications such as amlodipine and felodipine; the grapefruit juice inhibits intestinal epithelial cell metabolism and causes increased absorption of these drugs. Drug absorption can also be affected by alterations of gut flora (e.g., ampicillin and oral contraceptives) as well as changes in gut pH or motility (e.g., ranitidine and ketoconazole).


Distribution interactions usually involve drugs that are normally highly protein bound. Increased serum concentrations of the unbound drug can occur if the drug is displaced from its binding site by another agent. For example, sulfonamides and warfarin are both >90% protein bound, so when a patient on chronic warfarin therapy is given sulfamethoxazole, warfarin is displaced from the protein-binding site and the amount of free and pharmacologically active warfarin increases, there is greater inhibition in coagulation factor production, and the risk of bleeding increases. Phenytoin is also a highly protein-bound drug that is susceptible to interactions with other highly protein-bound drugs, such as warfarin, valproate, aspirin, and some NSAIDs. These interactions can be further magnified in patients who are malnourished, elderly, or have other risks of insufficient albumin concentrations.


Metabolism interactions can occur when a medication decreases or increases the metabolism of another agent. Of particular importance are those medications that are metabolized by the cytochrome-P450 enzyme family.1 There are two mechanisms for cytochrome-P450–mediated interactions: inhibition and induction. In an inhibition interaction, competition of drugs for a site or enzyme inactivation results in a decreased rate of drug metabolism, leading to a prolonged half-life and a potential for increased pharmacodynamic effects. For example, the concomitant use of metronidazole and warfarin decreases warfarin metabolism, resulting in an increase in an anticoagulant effect. An induction interaction is the result of decreased degradation or increased synthesis of cytochrome-P450 enzymes, thereby accelerating the conversion of active medication to its inactive metabolites or less active metabolites. For instance, nafcillin administered with warfarin induces metabolic enzymes that increase the metabolism of warfarin, resulting in a decreased ...

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