How to Prevent Harmful Drug Interactions

Emerg Med 40(12):25, 2008

By Collin S. Goto, MD, Sing-Yi Feng, MD, and Robert A. Wiebe, MD

To help you stay alert to pharmaceutical pitfalls, the authors discuss and illustrate red-flag issues ranging from grapefruit juice effects to warfarin potentiation.

The emergency department can be a chaotic, high-risk environment, and the fact that many patients are on multiple medications only adds to the risk of a wrong diagnosis or treatment. Adverse drug reactions are a major source of morbidity and mortality in emergency department patients. Drug interactions—a specific type of adverse drug reaction—are the adverse effects that can occur when two drugs are used together. These drugs can be prescription medications, over-the-counter (OTC) remedies, vitamins, herbal supplements, or even foods and chemicals.

Emergency physicians must be vigilant in recognizing and treating drug interactions, but doing so can be challenging. For one thing, patients may have signs and symptoms that mimic other disease states. For example, an elderly patient with a drug interaction may present with agitation, confusion, somnolence, weakness, tremors, or frequent falls. Another problem is the lag time that may occur between a change in medication regimen and the onset of symptoms. On top of this, emergency physicians may inadvertently cause new interactions when they prescribe additional medications to treat a patient’s condition. The most significant interactions generally occur with drugs that have a low therapeutic index and serious toxicity and in situations where the disease being controlled by the drug is serious or potentially fatal if undertreated.

This article aims to raise awareness of drug interactions by reviewing the pharmacologic mechanisms that lead to these interactions and providing recommendations for prevention. Several case studies are included that highlight important principles to improve safety in the emergency department.

DEFINING LOW RISK

Emergency physicians are under constant pressure to quickly treat acutely ill patients. Frequent interruptions and incomplete information from patients only add to the problem. Many patients are also on multiple medications, especially the chronically ill, medically fragile, and elderly. Unfortunately, there is often very little time to review all of a patient’s medications, much less all possible drug interactions. With new medications rapidly entering the market and new drug warnings constantly being released, a new drug’s adverse reactions are not always completely known. Consequently, physicians must rely on postmarketing surveillance and reporting to detect new drug interactions.

Thousands of patients in the United States die each year from drug interactions, but the true incidence is unknown because of frequent lack of recognition and underreporting. Many patients treated in the emergency department present with a preexisting drug interaction or are treated with medications that lead to a new adverse event. The risk of drug interactions increases dramatically with the number of medications used. For example, if a patient is taking two medications, the risk of a drug interaction is approximately 15%. At least 25% of Americans over age 65 take three or more medications daily, often prescribed by different doctors. The average nursing home resident takes at least six medications daily, raising the risk of drug interactions to more than 80%. Children with special health care needs probably have a similar risk when on multiple medications.

Besides asking about prescription medications, emergency physicians must take a thorough history of OTC drugs, vitamins, and herbal remedies. Even food-drug interactions can have serious consequences. At least 40% of Americans regularly take vitamins or herbal supplements, often in combination with prescription or OTC medications, and usually without the knowledge of their doctors or pharmacists. Many people mistakenly believe that because they are “natural,” all vitamins, supplements, herbs, and foods are safe. However, these items may interact with medications, causing harmful effects.

Mechanisms of drug interactions

Prescription drugs can interact with other prescription drugs, OTC remedies, vitamins, herbal supplements, foods, or chemicals in several ways. These mechanisms may seem complex, but a review of basic pharmacologic principles will help simplify the approach to safe emergency drug management. It is important to understand the pharmacokinetic, pharmacodynamic, and pharmacogenetic factors that result in drug interactions.

Pharmacokinetics refers to changes in drug concentration in the body with respect to drug absorption, distribution, metabolism, and elimination. There are many examples of drug interactions that are related to each of these stages (see table below).

Pharmacodynamics refers to the physiologic and biochemical effects of a drug. The effects of many drugs are related to their interactions with physiological receptors. Pharmacodynamic interactions occur when one drug potentiates or antagonizes another drug’s pharmacologic action. 

Pharmacogenetics refers to genetic differences (polymorphisms) that affect the pharmacokinetic or pharmacodynamic responses to a drug due to inherited variations in the genes’ encoding for drug transporters, metabolizing enzymes, or receptors. While factors such as age, organ function, concomitant therapy, and disease process all influence the effects of medications, it is important to recognize that individual patients will have unique responses to medications due to genetic differences.

The five cases that follow illustrate how pharmacokinetic, pharmacodynamic, and pharmacogenetic factors result in drug interactions and highlight important principles that can increase patient safety in the emergency department.

Case #1: Ceftriaxone-calcium

A 4-week-old girl is brought to the emergency department with a one-day history of fever, decreased activity, and poor feeding. On examination, she is lethargic and tachycardic and has prolonged capillary refill time. A full sepsis work-up is performed and intravenous ceftriaxone is administered. The patient requires three intravenous fluid boluses and is started on pressors for continued signs of poor tissue perfusion. In addition, she is given intravenous calcium gluconate for a low serum ionized calcium level.

Following admission to the pediatric ICU, the patient is intubated for mechanical ventilation, but she continues to deteriorate and expires after 24 hours. In addition to sepsis, the autopsy reveals the presence of calcium-ceftriaxone crystals occluding small arteries in the lungs and kidneys.

This is an example of a pharmacokinetic interaction affecting drug absorption, in which ceftriaxone and calcium combined to form an insoluble precipitate. Ceftriaxone is not recommended for neonates because it has high protein binding and can displace bilirubin from protein-binding sites, resulting in neonatal hyperbilirubinemia. In addition, ceftriaxone is less soluble than many other cephalosporins and has been known to precipitate in the biliary system, causing ceftriaxone gallstones. An increased risk of nephrolithiasis has also been reported in children who have been treated with ceftriaxone.

On July 5, 2007, the Food and Drug Administration and Roche Laboratories issued a new warning to health care professionals about fatal reactions involving the combination of intravenous ceftriaxone and calcium. Deaths occurred in both full-term and premature neonates and were related to the formation of insoluble precipitates of calcium-ceftriaxone, which caused occlusion of small pulmonary and renal arteries.

Although the risk for this dangerous interaction appears to be highest in neonates, it could theoretically occur in older patients as well. Therefore, the warning recommends that ceftriaxone and calcium-containing solutions should not be administered within 48 hours of each other to any patient, regardless of age, even through different infusion lines at different sites. The emergency physician must be aware that many parenteral products contain calcium, including total parenteral nutrition formulations and even intravenous solutions such as lactated Ringer’s solution.

case #2: Serotonin Syndrome

A 14-year-old girl presents to a community emergency department with a one-day history of nausea, vomiting, agitation, and tremors. She has been taking fluoxetine and buspirone for depression and recently had her dose of fluoxetine increased by her psychiatrist. On arrival, she is agitated and hyperreflexic but otherwise has no focal neurologic symptoms. Her vital signs demonstrate fever, tachycardia, hypertension, and tachypnea. Laboratory data and radiographic studies are unremarkable.

The patient is admitted to the hospital, where her antidepressant medications are discontinued. She receives an antiemetic, a benzodiazepine, and intravenous fluids to treat her symptoms. Her nausea, vomiting, agitation, and fever gradually resolve  and after 72 hours she is discharged home.

Serotonin syndrome is a rare, potentially fatal adverse drug reaction resulting from overstimulation of 5-HT1A and possibly 5-HT2A serotonin receptors in the central gray nuclei and medulla of the brain. Single use or, more commonly, combinations of selective serotonin reuptake inhibitors (SSRIs), tricyclic an- tidepressants, monoamine oxidase inhibitors, or other serotonergic agents (see table below) usually are the cause of serotonin syndrome. Medications with serotonergic activity, such as meperidine and dextromethorphan, are often prescribed and administered in the emergency department.

Serotonin syndrome has a wide spectrum of clinical severity. Patients with mild cases can present with nonspecific symptoms, such as nausea, vomiting, tachycardia, and agitation. Patients with life-threatening reactions can present with coma, seizures, elevated body temperatures (above 104°F), and cardiac arrest. 

Serotonin syndrome is an example of a pharmacodynamic drug interaction because the combination of more than one drug with serotonergic properties results in serotonergic excess. Many commonly prescribed medications with serotonergic properties have the potential to cause serotonin syndrome when used in combination.

Case #3: Prolonged QT interval

A 15-year-old boy presents to the emergency department after a syncopal episode. Half an hour before presentation, he was playing soccer with some friends. He initially complained of chest pain and shortness of breath, then lost consciousness for one minute. On arrival in the emergency department, he is awake and alert with normal vital signs. His physical examination is unremarkable. He has a history of depression treated with imipramine. Three days earlier, the patient was also in the emergency department and was prescribed erythromycin for a sinus infection.

Laboratory data are unremarkable, but his ECG shows a corrected QT interval of 525 msec. He is admitted to the hospital for observation, his erythromycin is discontinued, and repeat ECGs demonstrate that his QT interval has returned to normal.

QT prolongation is a cardiac condition caused by prolonged repolarization following ventricular depolarization. It may be congenital or acquired. Acquired QT prolongation is usually drug induced, although certain patient risk factors, such as bradycardia or hypokalemia, can exacerbate the problem. QT prolongation is potentially life-threatening because it may result in ventricular arrhythmias, especially torsades de pointes (TDP) and sudden cardiac death.

Many types of medications are known to prolong the QT interval (see table below). Antiarrhythmics have the highest potential to cause QT prolongation, especially sotalol. Other medication classes include psychiatric medications, antihistamines, antibiotics, as well as few other medications, including cisapride and methadone.

Drug interactions can result in QT prolongation and TDP due to the additive effects of two medications that prolong the QT interval (a pharmacodynamic interaction) or due to one drug interfering with the metabolism of the other (a pharmacokinetic interaction). Inhibited metabolism of a drug that prolongs the QT interval may lead to elevated drug concentrations, resulting in TDP. Medications reported to interfere with the metabolism of other drugs that are associated with TDP include antifungals, antidepressants, antiretrovirals, calcium channel blockers, and antibiotics. Medications that cause electrolyte abnormalities (such as diuretics) may also result in acquired QT prolongation. The emergency physician must be aware of these important drug interactions when prescribing medications that cause QT prolongation.

Case #4: Warfarin Interactions

An 80-year-old woman presents to the emergency department with bleeding gums, hematuria, and melena. Four days earlier, she was seen there for fever and dysuria, diagnosed with a urinary tract infection, and prescribed ciprofloxacin. Today, her laboratory data reveal a hemoglobin of 9 gm/dl, a prothombin time of 48 seconds, and an international normalized ratio (INR) of 12. She has been on warfarin for atrial fibrillation for 15 years. The patient is admitted to the hospital, her antibiotic is discontinued, and vitamin K is administered.

Warfarin is the most common oral anticoagulant in the United States and is also one of the most frequently implicated causes of drug interactions. Warfarin inhibits synthesis of the vitamin K-dependent clotting factors (II, VII, IX, and X). It has a narrow therapeutic index, and INR values greater than 4.0 are associated with a higher incidence of major bleeding complications, such as intracranial hemorrhage and gastrointestinal bleeding.

Many drug-drug interactions and drug-food interactions occur in patients taking warfarin (see table above). Certain drugs alter warfarin’s metabolism, potentiating its anticoagulant effects (a pharmacokinetic interaction). The most common medications associated with this mechanism include antibiotics (especially ciprofloxacin) and anti-inflammatory agents. However, these metabolic effects also depend on genetic polymorphisms of cytochrome P 450 enzymes (a pharmacogenetic interaction).

Herbal medications such as dong quai, which contains natural coumarins, can also enhance warfarin’s anticoagulant properties. In addition, diets with high quantities of green leafy vegetables containing vitamin K can reverse the anticoagulant effect of warfarin. These are both examples of pharmacodynamic interactions.

Case #5: Food-drug and herb-drug interactions

A 45-year-old woman is brought to the emergency department after being found unconscious in her bedroom. She is bradycardic, comatose, and hypotensive. While she is being resuscitated, her husband tells you that she has been on the same dose of felodipine, a calcium channel blocker, for hypertension for more than five years and that this is the only drug she takes. On further questioning, the husband states that the patient is in excellent health and has not overdosed on her medications. As you question him further, the husband recalls that the patient recently began drinking grapefruit juice every morning as part of a new dietary regimen. Luckily, her bradycardia and hypotension improve with aggressive resuscitation and supportive care, but they were probably due to the interaction between grapefruit juice and the felodipine.

Certain foods and herbal preparations can alter the metabolism of medications by a variety of mechanisms. Grapefruit juice is a common food that interacts with many different medications. It contains a substance called naringenin that inhibits intestinal cytochrome P 450 enzymes and increases both the bioavailability and serum concentrations of certain medications (a pharmacokinetic interaction). These increased serum drug concentrations are associated with significant symptoms. For example, taking a benzodiazepine along with grapefruit juice can cause excessive sedation. Grapefruit juice is also associated with acquired QT-interval prolongation because it can inhibit the metabolism of medications that prolong the QT interval.

St. John’s wort (Hypericum perforatum) is a common herbal medication used to treat depression. In contrast to grapefruit juice, a substance found in St. John’s wort (hyperforin) increases the activity of cytochrome P 450 enzymes. This results in decreased drug concentrations and decreased drug effects (a pharmacokinetic interaction). In addition, St. John’s wort has serotonergic activity, so it has the potential to cause serotonin syndrome when used concurrently with antidepressant medications such as SSRIs (a pharmacodynamic interaction).

The emergency physician should be aware of the many food-drug and herb-drug interactions in order to identify and prevent adverse drug interactions. Patients also need to be educated about food-drug and herb-drug interactions so they can recognize the symptoms early and seek medical attention.

Preventing Drug interactions

As these examples demonstrate, drug interactions can cause serious, even fatal, complications in patients treated in the emergency department. Obtaining a thorough medication history on every patient is essential, including prescription drugs, OTC medications, vitamins, herbal remedies, dietary supplements, and foods that may cause significant interactions.

Emergency physicians must be able to identify dangerous drug interactions and eliminate the offending agents. Make full use of available resources, such as drug interaction charts, handbooks, Web sites, computerized data bases, pharmacists, and regional poison centers, to help identify drug interactions. However, each drug information resource has its limitations, so good clinical judgment and problem-solving skills must be exercised when applying the available information to a clinical situation.

It’s also important to reduce nonessential prescriptions, especially in high-risk patients taking multiple medications, such as the chronically ill, medically fragile, and elderly patients, as well as children with special health care needs. Medication regimens should optimize therapeutic benefits while minimizing the risk of adverse drug reactions. Finally, educating patients about potential drug interactions and instructing them to seek medical evaluation if symptoms occur is critical.

Most drug interactions are predictable and avoidable if emergency physicians use the prevention strategies described above and summarized in the box above.

back to top

Suggested Reading Boyer EW and Shannon M: The serotonin syndrome. N Engl J Med 352(11):1112, 2005. Gaddis GM, et al.: Drug interactions in at-risk emergency department patients. Acad Emerg Med 9(11):1162, 2002. Goldberg RM, et al.: Drug-drug and drug-disease interactions in the ED: analysis of a high-risk population. Am J Emerg Med 14(5):447, 1996. Holbrook AM, et al.: Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165(10):1095, 2005. Kao LW and Furbee RB: Drug-induced Q-T prolongation. Med Clin North Am 89(6):1125, 2005. Prybys KM: Deadly drug interactions in emergency medicine. Emerg Med Clin North Am 22(4):845, 2004. Rapp RP and Kuhn R: Clinical pharmaceutics and calcium ceftriaxone. Ann Pharmacother 41(12):2072, 2007. Wilkinson GR: Drug metabolism and variability among patients in drug response. N Engl J Med 352(21):2211, 2005. Xie HG and Kim RB: St John’s wort-associated drug interactions: short-term inhibition and long-term induction? Clin Pharmacol Ther 78(1):19, 2005.

Printable version of this article

E-mail this article