The Poison Lab

Episode #4- The Rise of Lethal Loperamide

Episode Summary

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.

Episode Notes

Buying as much loperamide as you possibly can 

• Loperamide history
  • 1969- Synthesized (1)
  • 1976 FDA Approved as schedule V (2)
  • Jaffe trial of "abuse potential"- https://pubmed.ncbi.nlm.nih.gov/7438696/
  • 1982- Descheduled (3)
  • 2010-Annually Increasing in # of poison center calls, cases of arrhythmia and hospitalization (4,5,6)
  • 2016- Submission to DEA for rescheduling of loperamide denied (7)
  • 2019- FDA works with manufactures to reduce package size to 48 tablets (8)
  • Pharmacist knowledge of abuse remains low https://pubmed.ncbi.nlm.nih.gov/32641253/
• Toxic Mechanism
  • Fun theories about co evolution of PGP and CYP https://pubmed.ncbi.nlm.nih.gov/10837556/
  • Inhibition of sodium channels, and to a higher affinity, Human Ether a Go-Go Related (HERG) channel leads to prolonged repolarization (9)
    • IC50 for HERG Ikr ~ 40 nm/l (1908 ng/dl), inhibits as low as 10 nm/l (10)
    • Case reports of conduction disturbance with level of 22 ng/ml (14)
    • Levels in fatalities vary but  reported as high as 270 ng/ml in some studies  (15)
  • Prolonged re polarization leads to torsades
    • Early after depolarizations may trigger, which are then propagated torsades via re entrant rhythms (11)
• Treatment
  • ACMT loperamide guidelines (12)
  • Supportive care
    • Arrhythmia management
      • Torsades (13)
        • Electrical cardioversion (terminates re entrant rhythm)
        • Magnesium (prevents early after depolarization)
        • Target Mg >2 and K >4
        • Lidocaine-> Recommended in 2006 Sudden cardiac death guidlines, not mentioned in 2017, however one of the only VT recommended antiarryhtmics that do not prolong QTc (others, sotalol, amiodarone, and procainamide, do)
        • If preceded by bradycardia, Overdrive pacing with isoproterenol to target HR~ 100
        • Beta blockers are recommended in patients with LQTS
      • Sodium channel blockade induced wide QRS complex tachycardia (12)
        • Hypertonic sodium to over whelm sodium channel blockade (1-2 amps of 8.4% Sodium Bicarbonate given IV)
  • Where do we go in the future?
    • More research will help us understand the true incidence of how often this occurs and what impact the FDA decisions will have
    • Any concerned citizen can submit for rescheduling of loperamide. Interested? Reach out at toxtalk1@gmail.com
      • Drug Enforcement Agency. The Controlled Substances Act. Available at: https://www.dea.gov/controlled-substances-act.

1. Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN9780080861142.
2. "IMODIUM FDA Application No.(NDA) 017694". U.S. Food and Drug Administration (FDA). 1976.
3. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf.
4. Miller H, Panahi L, Tapia D, Tran A, Bowman JD. Loperamide misuse and abuse. J Am Pharm Assoc (2003). 2017;57(2S):S45eS50.
5. Feldman R, Everton E. National assessment of pharmacist awareness of loperamide abuse and ability to restrict sale if abuse is suspected [published online ahead of print, 2020 Jul 5]. J Am Pharm Assoc (2003). 2020;S1544-3191(20)30264-8. doi:10.1016/j.japh.2020.05.021
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. DOI: http://dx.doi.org/10.15585/mmwr.mm6545a7
7. https://www.chpa.org/PDF/09_05_17_CommentsCitizenPetitionLoperamide.aspx
8. https://www.fda.gov/drugs/drug-safety-and-availability/fda-limits-packaging-anti-diarrhea-medicine-loperamide-imodium-encourage-safe-use
9. Kang J, Compton DR, Vaz RJ, Rampe D. Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(10):1133-1137. doi:10.1007/s00210-016-1286-7
10. Klein MG, Haigney MCP, Mehler PS, Fatima N, Flagg TP, Krantz MJ. Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide. JACC Clin Electrophysiol. 2016;2(7):784-789. doi:10.1016/j.jacep.2016.07.008
11. https://www.sciencedirect.com/science/article/pii/S1880427611800050
12. Eggleston W, Palmer R, Dubé PA, et al. Loperamide toxicity: recommendations for patient monitoring and management. Clin Toxicol (Phila). 2020;58(5):355-359. doi:10.1080/15563650.2019.1681443
13. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society [published correction appears in J Am Coll Cardiol. 2018 Oct 2;72(14):1760]. J Am Coll Cardiol. 2018;72(14):e91-e220. doi:10.1016/j.jacc.2017.10.054
14. Marraffa JM, Holland MG, Sullivan RW, et al. Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila). 2014;52(9):952-957. doi:10.3109/15563650.2014.969371
15. Miller H, Panahi L, Tapia D, Tran A, Bowman JD. Loperamide misuse and abuse. J Am Pharm Assoc (2003). 2017;57(2S):S45-S50. doi:10.1016/j.japh.2016.12.079