Causal Association Suggested Between Loperamide and Torsades de Pointes

Torsades de pointes—Is it everywhere or nowhere? It may depend on how hard one looks.

Since the early 1990s when the “Seldane alarm” went off, calling attention to the fact that some non-cardiac drugs could cause torsades de pointes (TdP), we have seen a shocking number of seemingly “safe” drugs join the growing list of drugs that can cause TdP, some even after decades of use. The latest, loperamide (Imodium), was on the market for 39 years before its cardiac toxicity was identified. Now, based on the study by Klein et al, we know that this opiate, like many others, blocks the cardiac hERG channel; that is, the action that most TdP-causing drugs have in common. Methadone was marketed for over 50 years before it was identified as an hERG blocker and a not-uncommon cause of TdP. Such delay in recognition is partially because TdP can be difficult to diagnose, especially if an ECG isn’t available for measuring the QT interval. Also, late detection can occur when the pattern of a medicine’s use changes. In the case of loperamide, it is now being taken with newer drugs that interfere with its clearance, and it is sometimes taken in markedly higher doses than recommended. Because of the large number of medicines patients today take, drug-induced TdP should be considered in the differential for any patient who develops syncope or symptoms suggestive of an arrhythmia and is taking a medication, even a very old and presumed “safe” medicine.

In 1999, when the CredibleMeds website first began posting the list of drugs that can cause TdP, only 22 drugs were listed. Even though 9 drugs have been withdrawn due to TdP, 43 marketed drugs with “Known Risk of TdP” remain on the market. Another 36 drugs are on a “Conditional Risk” list, placed there because TdP occurs in association with these drugs only under certain conditions, such as over-dosage, drug interactions, etc. Because the FDA now requires QT testing of new drugs, another 82 drugs are on the list with “Possible Risk of TdP.” For these, there is clear evidence that they can prolong the QT interval but no evidence of TdP, yet. How many of these will graduate to join one of the categories of “Known” or “Conditional Risk?” These two lists include drugs from every therapeutic category and many are among the most prescribed drugs in medical practice; for example, erythromycin, clarithromycin, levofloxacin, azithromycin, etc. For clinicians, it is impossible to memorize all of these drugs and to be aware of the many conditions that can transform a simple OTC medicine for traveler’s diarrhea (or even an essential antibiotic) into something potentially lethal. The solution to this problem must come from the new technologies that we can enlist to help us manage medical and scientific information.¹ Decision-support systems that profile the patient’s risk and surveil the patient’s list of prescribed drugs have been shown to identify patients at high risk of TdP and to reduce the prescribing of QT-prolonging drugs to these high-risk patients.^2,3 We look forward to having this type of decision support for all of our practices and, most importantly, for our patients.

References

1. Woosley RL, Whyte J, Mohamadi A, Romero K. Medical decision support systems and therapeutics: The role of autopilots. Clin Pharmacol Ther. 2016;99(2):161-164.
2. Tisdale JE, Jaynes HA, Kingery JR, et al. Effectiveness of a Clinical Decision Support System for Reducing the Risk of QT Interval Prolongation in Hospitalized Patients. Circ Cardiovasc Qual Outcomes. 2014;7(3):381-390.
3. Sorita A, Bos JM, Morlan BW, et al. Impact of clinical decision support preventing the use of QT-prolonging medications for patients at risk for torsade de pointes. J Am Med Inform Assoc. 2015;22(e1):e21-e27.