Introduction
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, or combined interactions. 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.
Pharmacokinetic Mechanisms
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, (3) alter gastric pH, (4) alter gastrointestinal motility, or (5) affect transport proteins such as P-glycoprotein. 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 will be clinically important if it results in subtherapeutic serum levels.
The mechanisms by which drug interactions alter drug distribution include (1) competition for plasma protein binding, (2) 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.
The metabolism of drugs can be stimulated or inhibited by concurrent therapy. Induction (stimulation) of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, phenytoin, primidone, rifampin, rifabutin, and St. John's wort. Enzyme inducers can also increase the activity of phase II metabolism such as glucuronidation. Enzyme induction does not take place quickly; maximal effects usually occur after 7-10 days and require an equal or longer time to dissipate after the enzyme inducer is stopped. Rifampin, however, may produce enzyme induction after only a few doses. Inhibition of metabolism generally takes place more quickly than enzyme induction and may begin as soon as sufficient tissue concentration of the inhibitor is achieved. However, if the half-life of the affected drug is long, it may take a week or more to reach a new steady-state serum concentration. Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, substances in grapefruit juice, indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton.
The renal excretion of active drug can also be affected by concurrent drug therapy. The renal excretion of certain drugs that are weak acids or weak bases may be influenced by other drugs that affect urinary pH. This is due to changes in ionization of the drug, as described in Chapter 1 under Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation. For some drugs, active secretion into the renal tubules is an important elimination pathway. The ABC transporter P-glycoprotein is involved in active tubular secretion of some drugs, and inhibition of this transporter can inhibit renal elimination with attendant increase in serum drug concentrations.
Pharmacodynamic Mechanisms
When drugs with similar pharmacologic effects are administered concurrently, an additive or synergistic response is usually seen. The two drugs may or may not act on the same receptor to produce such effects. Conversely, drugs with opposing pharmacologic effects may reduce the response to one or both drugs. Pharmacodynamic drug interactions are relatively common in clinical practice, but adverse effects can usually be minimized if one understands the pharmacology of the drugs involved. In this way, the interactions can be anticipated and appropriate countermeasures taken.
Combined Toxicity
The combined use of two or more drugs, each of which has toxic effects on the same organ, can greatly increase the likelihood of organ damage. For example, concurrent administration of two nephrotoxic drugs can produce kidney damage even though the dose of either drug alone may have been insufficient to produce toxicity. Furthermore, some drugs can enhance the organ toxicity of another drug even though the enhancing drug has no intrinsic toxic effect on that organ.
PREDICTABILITY OF DRUG INTERACTIONS
The designations listed in Table II-1 will be 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 do not always mean that the interaction is likely to produce an adverse effect. Whether the interaction occurs and produces an adverse effect or not depends upon (1) the presence or absence of factors that predispose to the adverse effects of the drug interaction (diseases, organ function, dose of drugs, etc) and (2) awareness on the part of the prescriber, so that appropriate monitoring can be ordered or preventive measures taken.
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