This article is part 1 of a 2-part series. This article reviews patients at high risk for nonprescription drug interactions and mechanisms of common drug interactions. Next month's OTC Advisor column will review common nonprescription drugs that result in interactions.
The use of nonprescription and herbal products by the public is rising, resulting in an increased potential for drug interactions. Drug-drug interactions occur when a drug interacts or interferes with another drug. This can alter the way one or both of the drugs act in the body, cause unexpected side effects, or interfere with laboratory test values. The drugs involved can be prescription medications, nonprescription medicines, and even vitamins and herbal products.
Patient awareness of drug interactions involving nonprescription agents remains low. Warnings are required on all product labels, but many patients fail to read the labels of nonprescription products before taking them, or they may not pay attention to or understand the drug interactions information. The new drug facts label will help sensitize patients to the possibility of drug interactions involving nonprescription medications, and the pharmacist's role will be to help patients select products with care.
Populations at Risk for Nonprescription Drug Interactions
All patients are at risk for drug interactions, but certain populations are at higher risk. Some are at increased risk for clinically important and sometimes serious drug interactions involving nonprescription drugs. Table 1 lists populations at high risk. Patients with chronic medical conditions (diabetes, renal or hepatic disease, hypertension, coronary heart disease) usually must take >1 medication on a long-term basis. Because the risk of experiencing a drug-drug interaction increases as the number of coadministered medications increases, these patients are particularly susceptible to drug interactions.
Physiologic changes that accompany aging can increase the risk of drug interactions in patients over 65 years of age, because the changes directly affect the pharmacokinetics of many drugs. Drug absorption is affected by changes in gastric acidity and motility. Hepatic function and blood flow and renal function may decline to varying degrees as individuals age, affecting the distribution, metabolism, and elimination of some drugs. Elderly patients are also at increased risk for pharmacodynamic interactions (additive adverse effects) because of the large number of medications they take. In addition, nonprescription drug use has increased over time in this age group, making it the most susceptible group for dangerous drug interactions.
Pediatric patients are at heightened risk for interactions involving nonprescription products. As with the elderly, nonprescription drug use is common in the pediatric population and often occurs without medical consultation.
Patients with HIV infections are particularly vulnerable to interactions with nonprescription medications. These patients typically use a staggering number of prescription and nonprescription drugs, including investigational agents for which detailed information is not always available.
Common Mechanisms of Drug Interactions Involving Nonprescription Drugs
Although most drug interactions are clinically insignificant, some pose a significant risk. A basic knowledge of the mechanisms of drug interactions can help pharmacists to identify and avert potentially risky combinations.
Drugs may interact through a variety of mechanisms. Pharmacodynamic interactions occur when drugs with additive, synergistic, or antagonistic pharmacologic effects are combined. Interactions also result when the pharmacokinetics of one or both drugs are altered. A pharmacokinetic interaction may occur by several mechanisms. In general, one drug alters the absorption, distribution, metabolism, or excretion of another drug, resulting in changes in plasma drug concentration.
Alterations in Drug Absorption
Drug interactions can occur where one drug changes the absorption characteristics of another drug. The binding of one drug to another, changes in gastric pH, and changes in gastrointestinal (GI) motility can cause those drug interactions.
The aluminum, magnesium, and calcium ions contained in antacids impair or prevent the absorption of a number of drugs, including quinolone and tetracycline antibiotics. Iron can also cause interactions of this type. It is important to counsel patients about the binding action of antacids. Not only does it affect antibiotics, but blood thinners and heart medications can be affected and not be absorbed into the bloodstream. If this happens, the medicine may not work as well?or may not work at all. In the case of binding interactions, the affected drug usually should be given at least 2 hours before or 4 to 6 hours after the binding agents.
When one drug changes the GI transit time of another, the pharmacokinetics of the drug can be altered. Drugs such as metoclopromide and laxatives, which increase gastric emptying and gastric transit generally, increase the rate of drug absorption.
Altered Gastric pH
Drugs that change the normal pH of the stomach can affect absorption characteristics of other drugs. This is an especially important point, considering the widespread use of proton pump inhibitors and histamine2 receptor antagonists. Increasing gastric pH will allow better absorption of weak bases. Diphenhydramine is an example of a weak base. Changes in pH may also change the dissolution of an oral formulation. For example, a product designed to dissolve in the normal gastric pH may not dissolve in a more neutral pH; hence, the drug may not be fully absorbed. If the gastric pH is increased, an enteric-coated product may dissolve in the stomach rather than in the intestinal tract, changing its absorption characteristics.
Alterations in Drug Distribution
The most common interaction affecting drug distribution is alteration in protein binding. When 2 agents that bind to plasma proteins are taken concurrently, one drug may displace the other, causing increased free blood concentrations and enhanced pharmacologic effects of the displaced drug. The most clinically significant interactions involve drugs that are highly protein- bound and have a narrow therapeutic index. An example of this type of important drug-drug interaction is warfarin and aspirin, where the aspirin will increase the unbound fraction of warfarin. This will increase plasma warfarin concentrations, enhance the anticoagulant effect, and heighten the risk of warfarin-induced bleeding.
Alterations in Drug Metabolism
The most clinically important types of pharmacokinetic drug-drug interactions are those altering a drug's metabolism by the cytochrome P-450 (CYP) enzyme system. Interactions involving the CYP450 enzymes are often due to either inhibition of an isoenzyme, leading to increased blood or tissue concentrations of the substrate, or induction of an enzyme, causing enhanced metabolism and lower substrate concentrations. Table 2 lists some of the common nonprescription medications, the CYP450 responsible for their metabolism, and the drug's effects on CYP450 isoenzyme inhibition. Enzyme inhibition is the mechanism most often responsible for life-threatening interactions.
Inhibition of CYP isoenzymes causes decreased metabolism and hepatic clearance of substrates of specific isoenzymes. There are 2 main types of inhibition mechanisms?competitive inhibition and complex formation. Competition between drugs at the enzyme-binding site is the most common type. The onset of the CYP450 inhibition depends on the inhibiting drug's half-life. For drugs with short half-lives, enzyme inhibition occurs quickly, and clinically significant interactions can be apparent within 1 or 2 days. Inhibition is also dosedependent. Higher doses of an inhibitory drug will cause greater amounts of competitive inhibition than lower doses. Inhibition is often reversible. Enzyme activity returns to normal after therapy with the inhibitor has been discontinued and the drug has been eliminated from the body.
Inhibition also may occur when a drug metabolite binds with an enzyme. In some cases, a complex forms and the enzyme is permanently inhibited. Inhibition by this mechanism may last longer than the competitive inhibition, because, once therapy with the inhibitor is discontinued, new CYP enzymes must be synthesized and restored.
Drugs can also induce CYP isoenzyme production, which leads to increased metabolism and hepatic clearance of all substrates of the specific isoenzyme. This process is distinctly different from the mechanisms involved in enzyme inhibition, and the time course is more difficult to predict.
Alterations in Drug Excretion
Many drugs are excreted in the urine via renal tubular excretion. Two drugs can compete for the same active secretion sites in the tubule, allowing for decreased elimination and potentially toxic serum concentration. When 2 drugs that are actively secreted by this process are taken concurrently, one or both of the drugs may interfere with the elimination of the other. Nonprescription medications that competitively inhibit the renal tubular transport system include cimetidine and salicylates.
Alteration in urine pH can also affect drug elimination. Alkalinization of the urine will decrease the elimination of drugs that are weak bases, and decreases in urine pH will increase their elimination. An example of a nonprescription medication that is a weak base is pseudoephedrine. Acidification of the urine will decrease renal elimination of drugs that are weak acids.
Pharmacists are in a unique position to counsel and educate patients about nonprescription drug interactions. They can play an important role in identifying patients at heightened risk for interactions, teaching patients that nonprescription medications should be used responsibly, assisting with nonprescription product selection, and monitoring patients for drug interactions. Finally, pharmacists should encourage patients to read the Drug Facts label for warnings.
Dr. Ferreri is a clinical assistant professor at the University of North Carolina School of Pharmacy.