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

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.

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.

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.

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.

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.