Figure - available from: Case Reports in Medicine
This content is subject to copyright. Terms and conditions apply.
EKG on presentation showing sinus bradycardia with HR 50 bpm, PR interval 198 ms, QRS duration 122 ms, QTc interval 371 ms, and QT interval 408 ms.
Source publication
Abuse of over the counter drugs often gets overlooked by health care providers. Loperamide is one such over the counter drug that is often abused by drug addicts. We present here a case of a young male attaining euphoria from taking massive doses of loperamide. He developed Torsades de Pointes and subsequent cardiac arrest. We found similarities in...
Citations
... At therapeutic dosing, cardiac conduction aberrations and dysrhythmia have not been documented with loperamide administration; thus, it is speculated that the cardiac effects noted are a dose-related anomaly cropping up only at supra-therapeutic dosing. Very recently, several instances of cardiac dysrhythmias and protraction of the QRS and QTc intervals have been attributed to loperamide misuse [93][94][95][96][97][98]. ...
Introduction
Cancer chemotherapy regimens include multiple classes of adjuvant drugs as supportive therapy. Because of
the concurrent intake of other drugs (like antiemetics, antidepressants, analgesics, and antimicrobials),
there is a heightened risk for possible QT interval prolongation. There is a dearth of evidence in the
literature regarding the usage of QT-prolonging anticancer drugs and associated risk factors that have the
propensity to prolong QT interval. The purpose was to explore the extent of the use of QT-interval-
prolonging drugs and potential QT-prolonging drug-drug interactions (QT-DDIs) in cancer patients
attending OPD in a tertiary-care hospital.
Methods
This was a hospital-based, cross-sectional, observational study. Risk stratification of QT-prolonging drugs
for torsades de pointes (TdP) was done by the Arizona Center for Education and Research on Therapeutics
(AzCERT)/CredibleMeds-lists, and potential QT-DDIs were determined with four online DDI-checker-
software.
Results
In 1331 cancer patients, the overall prevalence of potential QT-prolonging drug utilization was 97.3%.
Ondansetron, pantoprazole, domperidone, and olanzapine were the most frequent QT-prolonging drugs in
cancer patients. The top six antineoplastics with potential QT-prolonging and torsadogenic actions were
capecitabine, oxaliplatin, imatinib, bortezomib, 5-fluorouracil, and bendamustine. Evidence-based
pragmatic QTc interval prolongation risk assessment tools are imperative for cancer patients.
Conclusion
This study revealed a high prevalence of QT-prolonging drugs and QT-DDIs among cancer patients who are
treated with anticancer and non-anticancer drugs. As a result, it's critical to take precautions, stay vigilant,
and avoid QT-prolonging in clinical situations. Evidence-based pragmatic QTc interval prolongation risk
assessment tools are needed for cancer patients.
... In 2016, loperamide-induced torsade de pointes arrhythmias were reported, and several case reports, usually associated with loperamide abuse, have been subsequently reported. [1][2][3] Previous experimental studies have demonstrated that loperamide inhibited Na v 1.5, K v LQT1/minK and human Ether-ago-go Related Gene (hERG) channel currents, 4) which may support clinical observations in abusers of loperamide, such as wide QRS complex and prolonged QT interval, leading to ventricular tachyarrhythmias, including torsade de pointes or Brugada syndrome. 5) However, information is still lacking regarding in vivo electropharmacological effects of loperamide to discuss causality based on bridge between cellular actions and clinical observations. ...
... Orally administered loperamide, whose usual sustained doses are 1 to 2 mg for diarrhea, has been reported to be absorbed well from the gastrointestinal tract and is almost completely extracted and metabolized in the liver, thereby little loperamide reaches the systemic circulation (bioavailability is <2%). 12) On the contrary, excessive oral doses of loperamide, presumably leading to saturation of hepatic metabolism, might induce drug-induced ECG abnormalities, as observed in patients who took about 134-600 mg of loperamide daily, including history of heroin abuse, [1][2][3]5) which is closely associated with the current results of intravenous administration of loperamide in the isofluraneanesthetized guinea pig. We have no information regarding chronic effects of toxic doses of loperamide on ECG as well as toxicokinetic parameters, 12) which should be checked exten- sively. ...
Cardiac electropharmacological effects of an antidiarrheal drug loperamide and its antidote naloxone were assessed in isoflurane-anesthetized guinea pigs. Intravenous administration of loperamide at 0.01–0.1 mg/kg did not affect parameters of electrocardiogram (ECG) or monophasic action potential (MAP) of the right ventricle. Additional administration of loperamide at 1 mg/kg prolonged the QT interval and MAP duration of the ventricle accompanied with increments of the PQ interval and QRS width. The potency of loperamide for QT-interval prolongation was about 100-times lower than that of dofetilide, in spite that similar inhibitory effects on the human Ether-a-go-go Related Gene (hERG) K⁺ channels have been reported between loperamide and dofetilide, implying lower accessibility of loperamide to the K⁺ channels. Intravenous administration of naloxone at 0.003–0.3 mg/kg, which effectively inhibits µ-opioid receptors, did not affect ECG parameters including QT interval or MAP duration. Furthermore, the loperamide-induced cardiac electrophysiological changes were not modified in the presence of naloxone at 0.3 mg/kg. These results suggest that loperamide has a potential to delay cardiac conduction and repolarization in the in vivo condition. Since naloxone did not modify ECG parameters and loperamide-induced ECG changes, naloxone is confirmed to possess acceptable cardiac safety when used as an antidote.
Fullsize Image
... Individuals appreciating the opioid effects may present with plasma levels greater than 1,000 times the recommended concentrations [1,5]. Case reports have been reported of patients presenting with abnormal symptoms after substantial doses of loperamide, mirroring the effects of harder opioid overdoses, such as heroin [1,2,[7][8][9]. Recently, the FDA began compiling cases of presumed loperamide toxicity, citing 48 loperamide cardiac cases since the drug's approval in 1976 with half of the cases appearing in the year 2010 alone. However, because loperamide is not commonly ordered in toxicological screens, there are likely many overlooked cases [1]. ...
... Suprathreshold doses are necessary to interact with these extra-gastrointestinal channels [2,4,5,14]. Frequent excessive dosing has been shown to cause bioaccumulation of loperamide in fat deposits, which can lead to supratherapeutic tissue drug concentrations [3][4][5]8]. Figure 4 shows the proposed action potential changes from opioid toxicity. ...
... Loperamide's tendency to accumulate in fat may lead to apparently therapeutic plasma levels in the presence of toxic symptoms. While these patients can be identified by multiday persistence of therapeutic concentration despite abstinence, few patients will be hospitalized long enough to trend this finding [3,8]. ...
Reports of cardiac arrhythmia secondary to loperamide toxicity have become increasingly common in the literature. We present two patients in their mid-20s, each having overdosed on loperamide and subsequently manifesting life-threatening cardiac arrhythmias not otherwise explained by known pathology. An analysis of the limited research available indicates that loperamide's capacity to block ion channels may be responsible for these events. A better mechanistic understanding of loperamide's effects can help inform clinical management of patients with these life-threatening symptoms as at this time no set guidelines for management have yet been established.
... Loperamide is an over-the-counter medication used to treat diarrhea, however, there are reports from the United States where the drug has been used as a recreational drug; initially was acquired to control diarrhea as a symptom of heroin withdrawal in the rehabilitation clinics and subsequently consumed in search of its opioid properties (1,4).There are case reports of overdose of loperamide from 100 to 400 tablets per day and in these patients cardiotoxicity manifested as syncope due to tachyarrhythmias such as VT, torsade de pointes, long QT, Brugada pattern and sudden death; improving completely as soon as the use of the drug is abandoned around 14 to 48 hours (5). ...
... Although there are records of dangerous arrhythmias caused by the consumption of opioids and loperamide as its generic substitute, there have not been reported cases of sustained VT on an outpatient Holter monitoring. The reported cases show the appearance of these disorders in the emergency department after syncope events in patients with loperamide abuse (3)(4)(5). ...
... In these cases, VT has been shown to occur in association with bradycardia or frequent electrical pauses, and it is induced by the development of early postdepolarization and activities triggered by prolonged repolarization (3)(4)(5). This is usually due to a premature ventricular beat falling into a prolonged repolarization cycle. ...
The case of a patient with repetitive syncope episodes with a history of using loperamide at high doses for recreational purposes in search of an effect similar to heroin, is reported. In the diagnostic approach with Holter monitoring, ventricular tachycardia and ventricular fibrillation were evidenced. We also present the treatment of our case and review the literature.
... At therapeutic doses loperamide does not cross the blood-brain barrier and thus typically does not cause central nervous system effects, including the euphoric effect associated with centrally acting opiates. Recently, there have been several reports of loperamide toxicity from ingestion of supra-therapeutic doses to obtain an opiate-induced euphoric effect [2,3]. ...
A 32-year-old male developed recurrent ventricular tachycardia after taking mega doses of loperamide and famotidine in order to experience an opiate-like euphoric effect. He was taking up to 200 mg of loperamide and multiple doses of famotidine each day. He developed palpitations and syncope. Electrocardiography demonstrated ventricular tachycardia and QT interval prolongation (corrected QT interval was 597 ms). He was diagnosed with loperamide-induced QT prolongation resulting in incessant ventricular tachycardia. Loperamide was discontinued, and he was treated with electrolyte replacement, supportive care, and monitoring. After 5 days, his electrocardiogram (ECG) normalized and he had no more ventricular tachycardia. A Naranjo assessment score of 8 was obtained, indicating a probable relationship between QT prolongation and his use of loperamide. Large doses of loperamide can cause QT interval prolongation and life-threatening arrhythmias. These effects may be accentuated when histamine-2 receptor blockers are also abused.
... These reports influenced FDA to strengthen kidney warnings for diabetes medicines Canagliflozin (Invokana Invokamet) and Dapagliflozin (farxiga, Xigduo XR) and warns health care professionals to assess the kidney function prior to the use of drugs. [18][19][20] Loperamide (Imodium) is an antidiarrheal. [21] Jacqueline Argamany and Jennifer Seltzer reviewed the report of "American association of poison control centers national poison data system" from 2011-2014. ...
... Furthermore, the use of pharmacological and electrical pacing was necessary in some cases to achieve heart rate overdrive for arrhythmia control. (Marraffa et al., 2014;Marzec et al., 2015;Mukarram, Hindi, Catalasan, & Ward, 2016;O'Connell et al., 2016;Spinner et al., 2015;Upadhyay et al., 2016;Wightman et al., 2016). ...
Loperamide is a popular antidiarrheal medication that has been used for many years. It is currently gaining more attention among healthcare professionals due to its increasing potential for side effects. At present, it is considered safe enough to be sold over the counter. In contrast with other opioid agonists, loperamide is a peripherally acting μ-receptor agonist exerting its effects mainly on the myenteric plexus of the gastrointestinal longitudinal muscle layer. It decreases peristalsis and fluid secretion resulting in longer gastrointestinal transit time. The bioavailability of the drug is extremely low. Moreover, it is actively excluded from the central nervous system; hence, it lacks the central effects of euphoria and analgesia at the recommended dosages. Loperamide abuse has been steadily increasing in the United States. Abusers typically ingest high doses in desire to achieve a satisfactory central nervous system drug penetration. This has made it a potential over the counter substitute for self-treating opioid withdrawal symptoms and achieving euphoric effects.
... Prolonged QTc interval at supra-therapeutic doses can be explained by the blockade of the cardiac human ether-a-go-go (hERG) potassium channel. These channels are major regulators of the rapid delayed rectifier current (IKr) which conducts potassium (K+) out of the cardiac myocytes [11,12]. Defective function of the channels affects ventricular repolarization and leads to a prolonged relative refractory period of the cardiac myocytes [11]. ...
Loperamide is an over-the-counter antidiarrheal agent that is considered by many patients to be safe, but has been used as a drug of abuse due to its opioid properties. However, cardiotoxicity has been reported, prompting the FDA to release a warning regarding the arrhythmogenic potential of loperamide. We present a case of a 38-year-old female presenting with cardiac arrest thought to be secondary to abuse of the loperamide that she was using to alleviate the heroin withdrawal symptoms. Cardiac ischemia and other drug toxicities were ruled out. Loperamide induces QTc prolongation and cardiac dysrhythmias. She had recurrent ventricular arrhythmias with multiple cardiac arrests. The persistence of the cardiotoxicity for a longer duration than previously reported in the literature is unique in this clinical presentation. We also highlight the potential mechanisms for loperamide cardiotoxicity and its challenging management.
Abbreviations: ACLS: Advanced cardiac life support; GI: Gastrointestinal
... (21) She too had a prolonged QT interval and suffered sustained ventricular tachycardia, requiring cardiopulmonary resuscitation, multiple cardioversions, and pacemaker placement (21). A number of additional publications signaling prolonged QT intervals and ventricular dysrhythmias have since appeared (16,17,20,22,32). Swank et al. reviewed the U.S. Food and Drug Administration Adverse Event Reporting System and published literature to identify reports of cardiotoxicity. ...
Background:
Despite its opioid properties, loperamide has long been thought to have low abuse potential due to its poor absorption from the gastrointestinal tract and limited potential to cross the blood-brain barrier. A recent patient reportedly taking loperamide to avoid heroin withdrawal symptoms, at doses approximately 100 times those recommended, directed our attention to this issue.
Objectives:
1) Investigate number of cases of intentional loperamide abuse and misuse reported to poison centers between 2009 and 2015; 2) Compile reports of clinical effects of loperamide abuse; and 3) Search for evidence of increasing Internet interest in the central opioid effects of loperamide.
Methods:
For the years 2009 thru 2015, we reviewed exposure calls related to misuse/abuse of loperamide in the Texas Poison Center Network's database and the National Poison Data System. We used Google trend analysis to detect evidence of increased Internet interest in the illicit use of loperamide.
Results:
Between 2009 and 2015, the number of misuse/abuse calls related to loperamide alone nearly doubled, with about one-third of cases occurring in teens and young adults in their 20s. Of particular concern are reports of significant cardiotoxic effects (∼18% of cases), including conduction defects and various dysrhythmias, sometimes leading to death. Google Trends analysis demonstrates an increasing number of searches for "loperamide high" and "loperamide withdrawal" beginning in 2011.
Conclusions:
Loperamide misuse/abuse seems to be on the rise. Given its propensity to induce conduction disturbances and dysrhythmias at very high doses, emergency physicians should be vigilant for this form of drug abuse.
... However, supratherapeutic doses of loperamide have been promoted on multiple druguse websites and online drug forums since 2005 as a treatment for opioid withdrawal syndrome and a possible methadone alternative, as well as a drug of abuse for its euphoric effects [8][9][10][11][12]. The FDA warns that taking higher than recommended doses of loperamide, either for selftreatment of diarrhea symptoms or as an inexpensive and uncontrolled alternative to opioids, may cause serious heart problems such as QRS widening and QT interval prolongation, dysrhythmias, torsades de pointes, ventricular arrhythmias, syncope and cardiac arrest that can lead to death [13][14][15][16][17][18][19]. The risk of these heart problems, including dysrhythmia, may be increased when high doses of loperamide are ingested along with medicines that interact with it. ...
... When loperamide is used systematically at supratherapeutic doses, commonly by individuals who intentionally abuse or misuse it to achieve euphoria or to self-treat opioid withdrawal symptoms, it may produce serious cardiac effects that can be life-threatening [15,18,77]. Effects such as QRS widening, QT interval prolongation, dysrhythmias, torsades de pointes, ventricular arrhythmias, syncope, cardiac arrest or even death have been reported [13][14][15][16][17][18][19]. ...
... The patient recovered after administration of magnesium and isoproterenol. After 8 days of hospitalization, he was discharged to a drug rehabilitation facility [17]. ...
Loperamide is a phenylpiperidine derivative and an opioid agonist that was launched by Janssen Pharmaceutica in 1973. It was initially classified in the United States as a Schedule II drug and was transferred to Schedule V in 1977; it has not been listed as a controlled substance since 1982. Loperamide is used for the symptomatic treatment of diarrhea and gastrointestinal inflammation. It has a low potential for central nervous system effects when administered in therapeutic doses. However, when used in supratherapeutic doses, either for self-treatment or drug abuse (opioid substitute), it can lead to life-threatening cardiac effects. The US Food and Drug Administration and the global community are concerned about these severe side effects, suggesting the need for control worldwide. This article reviews the existing knowledge on loperamide, including its chemistry, synthesis, pharmacology, toxicology, pharmacokinetics, biotransformation, its medicinal use, dependence potential, abuse of the drug, reported intoxications, fatalities, its determinations in biological samples, and its current legal status. All available information was gathered through a detailed search of PubMed and the World Wide Web.
