A recent study in Washington found that only 67% of serious drug interactions resulted in a correct warning from a pharmacy computer system designed to warn of significant drug interactions.(1)
Causes contributing to harmful drug?drug interactions include narrow therapeutic dosage ranges associated with certain drugs and a patient?s disease state (Tables 1 and 2). For example, patients with epilepsy have increased chances of drug interaction, compared with those with other disease states.(2)Several antiepileptic agents?such as phenytoin, carbamazepine, and valproic acid?have narrow therapeutic indexes. Thus, there is little room for error when using these drugs. Compromised renal function or changes in the cytochrome P-450 enzymes also can increase the risk of experiencing a severe adverse drug event. Clearly, it is important for pharmacists to recognize and understand which drug interactions can result in significant patient harm. Understanding the pharmacokinetics and pharmacodynamics responsible for these significant interactions strengthens the pharmacist?s chances of identifying dangers and preventing patient harm. This article focuses on 10 prevalent and potentially fatal drug interactions, listed in Table 3.
Fluoxetine and Phenelzine
The interaction can result in a central serotonin syndrome.(3)This condition is characterized by mental status changes, agitation, diaphoresis, tachycardia, and death. These symptoms can develop quickly with only 1 or 2 doses of fluoxetine when combined with phenelzine. Serotonin syndrome is possible with any monoamine oxidase inhibitor (MAOI), such as phenelzine or tranylcypromine sulfate, in combination with any drug that increases serotonin levels, such as dextromethorphan, meperidine, and other selective serotonin reuptake inhibitors (SSRIs).(3)It is recommended that fluoxetine be stopped for at least 5 weeks before an MAOI is prescribed because of the long half-life of fluoxetine and its primary metabolite, norfluoxetine. Also, 2 weeks should be allowed after discontinuation of an MAOI before starting SSRI treatment.(3)
Digoxin and Quinidine
This significant drug interaction has been known for a long time, yet it continues to be a problem, often with devastating results. The interaction can lead to a marked increase in plasma concentration levels of digoxin in more than 90% of patients.(4)Significant changes in serum digoxin are noticed within 24 hours. The average increase is roughly 2-fold.(5)The effects from this interaction range from nausea and vomiting to death. The primary mechanism for this interaction is a decreased volume of distribution of digoxin, secondary to its displacement from binding sites in body tissues.(4)Quinidine also decreases renal and nonrenal excretion rates of digoxin, which leads to increased steady-state concentrations of the cardiac glycoside.(4)Ideally, patients taking digoxin should avoid the use of quinidine; however, if the combination is necessary, the patient should be closely watched. Pharmacists should anticipate the need to reduce the digoxin dose by one half.(4)
Sildenafil and Isosorbide Mononitrate
Sildenafil may markedly increase the hypotensive effects of isosorbide mononitrate.(6)More than 123 deaths have been reported since 1998, when sildenafil was made available in the United States.(6)Most deaths were among patients with 1 or more risk factors, including obesity, hypertension, and cigarette smoking. Sildenafil was developed as a phosphodiesterase-5 (PDE5) inhibitor. In the presence of PDE5 inhibitors, nitrates can cause intense increases in cyclic guanosine monophosphate and dramatic drops in blood pressure.(7)Patients taking isosorbide mono-nitrate or any nitrate, including nitroglycerin, should be advised not to take sildenafil.
Potassium Chloride and Spironolactone
This is another significant drug interaction that has been known for a long time. The combination may result in hyperkalemia.(8)The resulting hyperkalemia can be serious and may lead to cardiac failure and death. Patients with renal impairment are especially prone to this effect. Spironolactone is a competitive antagonist of mineral corticoids, of which aldosterone is a potent example.(9)This mechanism occurs in the kidney at the distal portion of the nephron and leads to the excretion of sodium ions while saving potassium ions.(9)Patients receiving potassium-depleting diuretics, such as amiloride or triamterene, may also experience this interaction. These diuretics can interact with all absorbable forms of potassium?bicarbonate, citrate, acetate, gluconite, and iodide salts.(9)Severe hyperkalemia is dangerous, and thus patients who are prescribed spironolactone must undergo an evaluation of serum potassium levels.(9)
Clonidine and Propranolol
The combination may produce a mysterious hypertension that is unrelated to the pharmacology of either agent when administered independently.(8)A sudden withdrawal of clonidine from adjunctive therapy with propranolol may cause fatal rebound hypertension.
Clonidine is a central alpha-2 adrenergic agonist that suppresses the sympathetic nervous system from the brain.(10)This activity leads to a decrease in the norepinephrine amounts available in the synaptic cleft of the adrenergic neuron. Alpha-1 receptors then become sensitized because of less norepinephrine available in the cleft.(10)When clonidine is suddenly withdrawn, the result is a large increase in norepinephrine in the synaptic cleft of the adrenergic neuron. The sensitized alpha-1 receptors are stimulated, leading to an exaggerated vasoconstriction. The body cannot compensate for this response because the beta-2 receptors are blocked when a patient is concurrently taking propranolol. Within 24 to 72 hours, a dramatic rebound hypertension is noticed.(9)
Warfarin and Diflunisal
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diflunisal, have been shown to increase the risk for gastrointestinal (GI) bleeding and the anticoagulant response of war-farin.(5)Other NSAIDs?such as keto-profen, piroxicam, sulindac, diclo-fenac, and ketorolac?have been shown to have similar interactions with warfarin. In most patients, however, indomethacin has little effect on hypothrombinemic response.(5)Because the interaction between warfarin and diflunisal can lead to GI bleeding or even fatal hemorrhaging, an alternative to diflunisal is suggested. Acetaminophen is the alternative of choice. Yet, if an NSAID is needed, nonacetylated salicylates?such as magnesium salicylate or salsalate?are safer because of minimal effects on platelets and gastric mucosa.(5)
Theophylline and Ciprofloxacin
Concurrent administration may lead to toxic increases in theophylline.(11)This problem occurs because the hepatic metabolism of theophylline is inhibited by ciprofloxacin via the cytochrome P-450 enzyme system. Theophylline is metabolized by CYP1A2 and to a lesser extent by CYP3A4. Ciprofloxacin and other drugs, including clarithromycin, erythromycin, fluvoxamine, and cimetidine, are all potent inhibitors of CYP1A2. Because they have little effect on CYP1A2, levofloxacin or ofloxacin should be considered as an alternative to ciprofloxacin.(5)Theophylline toxicity is a serious condition; several deaths have been linked with serum concentrations as low as 25 mcg/mL.(11)Signs of theophylline toxicity include headache, dizziness, hypotension, hallucinations, tachycardia, and seizures.(11)
Pimozide and Ketoconazole
Pimozide alone can prolong the QT interval, and it has been linked with ventricular arrhythmias (torsades de pointes).(5)When pimozide is combined with ketoconazole, the combination can be deadly. Pimozide is a CYP3A4 enzyme substrate, and ketoconazole is a potent inhibitor of CYP3A4. This leads to marked increases in pimozide serum levels.(5)Other drugs?such as itraconazole, clarithromycin, erythromycin, diltiazem, and nefazodone?are also potent inhibitors of CYP3A4 and should not be administered with pimozide.(5)Fluconazole is weaker, but in larger doses it also inhibits CYP3A4. Terbin-afine is a safer choice because it does not affect CYP3A4.(5)
Methotrexate and Probenecid
When probenecid is administered with antineoplastic doses of metho-trexate, the result can be a 2- to 3-fold increase in methotrexate levels.(5)Probenecid acts as an active tubular secretion inhibitor and prevents methotrexate from being excreted, thus potentially causing toxicity. The symptoms of severe methotrexate toxicity include diarrhea, vomiting, diaphoresis, and renal failure, and it may result in death.(9,12)This interaction with methotrexate also occurs with penicillins (eg, amoxicillin, carbeni-cillin) and salicylates.(5)The risk with low-dose methotrexate (commonly used for arthritis) is lower; in fact, NSAIDs in combination with low-dose methotrexate are often prescribed purposely.(5)
Possible alternatives include aceta-minophen, as opposed to salicylates or NSAIDs. Celecoxib does not affect methotrexate pharmacokinetics and could be an alternative. However, rofecoxib produces some increases in methotrexate serum concentrations and therefore should be avoided.(5)
Bromocriptine and Pseudoephedrine
The interaction can lead to severe peripheral vasoconstriction, ventricular tachycardia, seizures, and possibly death.(5,13)Bromocriptine is an ergot-derived dopamine agonist with several uses, including antiparkinsonian therapy. New treatment guidelines for Parkinson?s disease recommend a first-line therapy change from levodopa to bromocriptine or other dopamine agonists, such as ropinirole, pramipexole, or pergolide.(14)Notable side effects of bromocriptine include thickening of bronchial secretions and nasal congestion.(11)This is significant because it increases the likelihood of a patient taking bromocriptine to self-medicate with an OTC decongestant such as pseudoephedrine. Patients receiving bromocriptine should be advised to avoid all sympathomime-tics.(5)
The mission of pharmacy practice is to help patients make the best use of their medication. This means providing safe, effective, timely, and cost-conscious therapy. From the safety viewpoint, the pharmacist has the legal duty to warn about potentially harmful drug interactions.(15)The warning should be directed to the prescribing physician in a manner that will increase the chances of avoiding the drug interaction.
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