Patient History

An elderly man with a history of hypertension and hyperlipidemia was prescribed itraconazole daily for the treatment of a toenail infection.^[1] Three weeks after initiating itraconazole, he experienced pain in his lower extremities that progressed to his upper extremities and neck. After noticing brown-colored urine, he discontinued all of his medications, which included simvastatin, lisinopril, and aspirin, and sought medical attention. Upon examination, he had muscle tenderness and blood pressure of 195/95 mm Hg; his blood cell counts and renal function were within normal limits. Serum creatine kinase was 2280 U/L (normal range, 32-267 U/L) and lactate dehydrogenase, aldolase, and aminotransferase levels were elevated. The urinalysis revealed amber-colored urine positive for myoglobin and occult blood. No erythrocytes were found on microscopic examination. The patient was diagnosed with rhabdomyolysis and treated with hydration and an antihypertensive. All medications were held temporarily with the exception of itraconazole, which was discontinued. Laboratory tests completed 36 hours after presentation demonstrated improvement of abnormal laboratory values.

Background and Introduction

Finding the most appropriate medication regimen for our patients is a difficult task. Patients often require multiple medications placing them at risk for drug-drug interactions (DDIs), a situation that occurs when 1 of a combination of drugs alters the effect of another drug. Drug-drug interactions may result in decreased therapeutic benefit, adverse effects, or patient harm. The frequency of potential DDIs was estimated to be from 6.2% to 6.7% per year using prescription drug claims data from 2 large health plans.^[2] Another study estimated 374,000 plan participants were exposed to clinically important potential DDIs utilizing pharmacy drug claims data for nearly 46 million participants in a pharmacy benefit management organization over a 25-month period.^[3] A review of 4 drugs -- warfarin, digoxin, cyclosporine, and simvastatin/ lovastatin -- found that an estimated 1.3-2.7 million insured adults were prescribed a potentially interacting combination.^[5] Non-prescription medications, herbal preparations, and complementary medications also contribute to patient polypharmacy and the potential for DDIs.

This activity will provide the clinician with a basic understanding of the most common types of DDIs. In addition, the activity will provide a general overview of DDI mechanisms and strategies to help the clinician identify, prevent, and manage DDIs.

DDIs contribute to patient morbidity and may cause emergency department visits, hospitalizations, and re-admissions.^[6,7] Examples of patient morbidity caused by DDIs include gastrointestinal (GI) bleeding, renal dysfunction, electrolyte imbalance, hypertension, hypotension, bradycardia, arrhythmia, drug toxicity, and decreased drug effect.^[6-8] Juurlink and colleagues^[8] performed 3 population-based, nested case-control studies to evaluate whether elderly patients taking glyburide, digoxin, or an angiotensin-converting enzyme inhibitor (ACEI) who were admitted with drug toxicity had been prescribed an interacting agent within the previous week. They found that patients on glyburide admitted for hypoglycemia were 6 times more likely to have been treated with sulfamethoxazole/ trimethoprim (SMX/TMP). Patients admitted for digoxin toxicity were 12 times more likely to have been started on clarithromycin in the previous week. Patients on ACEIs were 20 times more likely to have been started on a potassium-sparing diuretic in the previous week.

Certain medications have been removed from the market due to patient morbidity and mortality caused as result of DDIs. Development of the dangerous arrhythmia, torsades de pointes (TdP), resulted in death in several instances. Examples from the literature of mortality associated with DDIs include ciprofloxacin in fatal seizures,^[9] moclobemide-clomipramine overdose in fatal serotonin syndrome,^[10] and fatal outcome from a warfarin and nonsteroidal anti-inflammatory drug (NSAID) interaction.^[11] Other examples are fatal interactions between tranylcypromine and imipramine,^[12] and also between methotrexate and trimethoprim.^[13] Terfenadine, astemizole, and grepafloxacin are examples of drugs taken off the market due to the risk of TdP arrhythmias caused by DDIs.^[14] Removal of drugs from the market will eliminate the risk of DDIs in certain situations. Unfortunately, the elimination of all risk is impossible due to, in part, the lack of suitable drug alternatives. Many clinicians have witnessed patient harm caused by DDIs,^[15] and many interactions that have caused hospital admission for toxicity could have been avoided. However, in many cases knowledge of DDIs is lacking.^[15,16]

DDI Risk Factors to Identify in Practice

Our most complex patients are at highest risk for DDIs. Polypharmacy, narrow therapeutic range of the medication, decreased hepatic and/or renal function of the patient each may increase the risk for DDIs. Each may be identified prior to coadministration. One should consider the potential for DDIs at all steps of the drug-delivery process. In a retrospective review of patients admitted to the emergency department, patients taking 3 or more medications or patients who were 50 years or older taking 2 or more medications had a considerable risk for DDIs.^[17] Furthermore, an increasing number of medications administered further increased the risk for adverse effects. Patients taking 2 medications had a 13% risk while patients taking 5 medications had a 38% risk for DDIs. Patients taking 7 or more medications had an 82% risk of developing adverse drug interactions.

Advanced age is an additional risk factor for DDIs. Aparasu and colleagues^[4] found that the risk for DDIs increases significantly after 44 years of age and is greatest for patients over 74 years of age. The need for multiple medications often arises with advancing age that may further the risk for DDIs. Almost 25% of the elderly outpatients referred to a diagnostic clinic in The Netherlands for decreased cognition, functional dependence, or both who were taking more than 1 medication were found to have potential adverse effects or decreased drug effect possibly due to a DDI.^[4] In general, when multiple medications are prescribed in the elderly population, the risk for DDIs increases exponentially.^[18]

Other patient-related risks for DDIs noted below, include very young age, female sex, genetics, decreased organ function, use of a medication having a narrow therapeutic range (eg, warfarin, digoxin, and cyclosporine), major organ impairment, metabolic or endocrine risk conditions (eg, hypothyroidism, hypoproteinemia), and acute medical issues (eg, dehydration).^[4,6,17-19]

Patient-Related Risks for Drug-Drug Interactions

• Acute medical condition (eg, dehydration, infection);
• Age extremes (ie, the very young and the elderly);
• Decreased renal/ hepatic function;
• Female sex;
• Metabolic or endocrine condition (eg, obesity, hypothyroidism);
• Multiple medication use;
• Narrow therapeutic range of medication; and
• Pharmacogenetics.

Non-patient factors may also affect the risk for DDIs. For example, an increasing number of clinicians or pharmacists involved with the dispensing of medication may increase the risk for DDI. Risk may also increase when computer alerts are too frequent or too infrequent. Pharmacy work flow, and work load also may influence risk of DDIs.^[20]

DDIs should be considered at each step of the drug-delivery process. All members of the healthcare team should consider the risk for DDIs when a new medication is prescribed, dispensed, or administered to a patient.