Ryan and Toxo go in depth on an old substance that has begun to resurface with new toxicity due to users taking massive amounts. Loperamide. Dive into the regulatory history, mechanisms of its toxic cardiac effects, and a brief discussion of treatment in episode 4.

Buying as much loperamide as you possibly can 

Loperamide History

1. 1969: Synthesized. (1)
2. 1976: FDA Approved as Schedule V. (2)

• "IMODIUM FDA Application No.(NDA) 017694". U.S. Food and Drug Administration (FDA). 1976.
• https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf

1. 1982: Descheduled. (3)

• Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN9780080861142.

1. 2010: Increasing poison center calls, arrhythmia cases, and hospitalizations. (4,5,6)

• Eggleston W, Marraffa JM, Stork CM, et al. Notes from the Field: Cardiac Dysrhythmias After Loperamide Abuse — New York, 2008–2016. MMWR Morb Mortal Wkly Rep 2016;65:1276–1277.
• http://dx.doi.org/10.15585/mmwr.mm6545a7

1. 2016: DEA denies rescheduling request. (7)

• https://www.chpa.org/PDF/09_05_17_CommentsCitizenPetitionLoperamide.aspx

1. 2019: FDA works with manufacturers to reduce package size to 48 tablets. (8)

• https://www.fda.gov/drugs/drug-safety-and-availability/fda-limits-packaging-anti-diarrhea-medicine-loperamide-imodium-encourage-safe-use
• Pharmacist Knowledge Gap: Awareness of abuse remains low.
• Feldman R, Everton E. National assessment of pharmacist awareness of loperamide abuse and ability to restrict sale if abuse is suspected. J Am Pharm Assoc (2003). 2020. doi:10.1016/j.japh.2020.05.021
• https://pubmed.ncbi.nlm.nih.gov/32641253/

Toxic Mechanisms

1. Inhibition of Sodium and HERG Channels:

• Kang J, Compton DR, Vaz RJ, Rampe D. Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide. Naunyn Schmiedebergs Arch Pharmacol. 2016. doi:10.1007/s00210-016-1286-7
• https://pubmed.ncbi.nlm.nih.gov/10837556/
• IC50 for HERG Ikr ~ 40 nm/l (1908 ng/dl), inhibits as low as 10 nm/l.
• Klein MG, Haigney MCP, et al. Potent Inhibition of hERG Channels by Loperamide. JACC Clin Electrophysiol. 2016. doi:10.1016/j.jacep.2016.07.008

1. Reported Fatalities:

• Marraffa JM, Holland MG, et al. Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila). 2014. doi:10.3109/15563650.2014.969371
• https://pubmed.ncbi.nlm.nih.gov/29941678/

Treatment

• Guidelines:
• Eggleston W, Palmer R, Dubé PA, et al. Loperamide toxicity: recommendations for patient monitoring and management. Clin Toxicol (Phila). 2020. doi:10.1080/15563650.2019.1681443
• https://www.sciencedirect.com/science/article/pii/S1880427611800050
• Supportive Care:
• Arrhythmia Management:
• Electrical cardioversion for torsades.
• Magnesium to prevent early after depolarizations (target Mg >2, K >4).
• Lidocaine recommended for VT (does not prolong QTc).
• Overdrive pacing (e.g., isoproterenol) if bradycardia precedes arrhythmia.
• Beta-blockers for long QT syndrome.
• Wide QRS Tachycardia: Use hypertonic sodium (1–2 amps of 8.4% Sodium Bicarbonate IV).

Where Do We Go From Here?

• Further research is needed to understand the incidence of loperamide-induced toxicity and the impact of FDA packaging changes.
• Concerned about loperamide regulation? Contact us at toxtalk1@gmail.com.

References

1. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf
2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guidelines for VT and Sudden Cardiac Death. J Am Coll Cardiol. 2018. doi:10.1016/j.jacc.2017.10.054

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