Loperamide-induced severe cardiotoxicity: a toxicokinetic and toxicodynamic analysis derived from a case series and the published literature.

Introduction: Chronic loperamide overdose is associated with cardiotoxicity. We describe the toxicokinetics of loperamide and N-desmethyl loperamide, and their concentration-response relationship on cardiotoxicity in newly described and published cases.

Materials and methods: We obtained serial loperamide and N-desmethyl loperamide concentrations, and corresponding electrocardiographic intervals in three episodes (two patients) of loperamide-related cardiotoxicity. A toxicokinetic and toxicodynamic analysis was undertaken that included data from previous publications to explore the relationship between these variables.

Results: Patients presented with dizziness, bradycardia, loss of consciousness, and jerking or ventricular tachycardia after taking loperamide 320-400 mg/day for weeks or years. In one patient, ventricular tachycardia occurred on days two and three post-admission. Prolonged electrocardiographic intervals resolved after approximately five days. Admission loperamide concentrations were 5.37-288 μg/L and the terminal elimination half-lives were 21.3-38.7 h. Admission N-desmethyl loperamide concentrations were 87.67-256.34 μg/L and the terminal elimination half-life was 31.9-88.9 h. Overall, there were 42 loperamide and 35 N-desmethyl loperamide concentrations with paired electrocardiographic data, and the concentration-response relationship was derived using a maximum effect (Emax) model. Lower loperamide concentrations were associated with electrocardiographic abnormalities, compared to N-desmethyl loperamide concentrations. The total relative loperamide concentration, which combines both concentrations into a single value using in vitro inhibitory potencies at cardiac ion channels, out-performed either parent or metabolite concentrations alone for predicting cardiotoxicity on receiver operating characteristic curves.

Discussion: Loperamide and N-desmethyl loperamide have long elimination half-lives causing prolonged cardiotoxicity. Higher loperamide and N-desmethyl loperamide concentrations are associated with prolonged electrocardiographic intervals.

Conclusions: Patients with chronic loperamide overdose are at risk of cardiotoxicity that persists for days due to persistent loperamide and N-desmethyl loperamide concentrations. We believe patients with loperamide overdose need an admission electrocardiograph and continuous monitoring until electrocardiographic changes resolve.