LAUSR

Ranolazine is an antianginal agent with a favorable safety profile [1]. We report a fatal ranolazine overdose. Forty-five minutes prior to hospitalization, a 65-year old woman with Turner’s syndrome and schizoaffective disorder reported ingestion of fifty 1000mg ranolazine tablets (her brother’s) and seven pills of quetiapine, valproate, and mirtazapine (other medications prescribed were trazadone, rivaroxaban and gabapentin). She was alert with unremarkable physical examination. Vital signs were: blood pressure (BP) 103/67mmHg; heart rate (HR) 94; temperature 98.7 F; respiratory rate 20; SpO2 98%. Laboratory values were normal. Acetaminophen, salicylate, ethanol concentrations and urine drug screen were negative. Initial electrocardiogram (ECG) showed QRS 85 milliseconds (msec) and QTc 472 msec. She received activated charcoal (50 g). One hour later, her systolic BP decreased to 89mmHg; the QTc was 485 msec. She received intravenous (IV) magnesium (3 g), IV calcium (1 g), temporary norepinephrine, and 4 liters IV crystalloid in the first eight hours for fluid responsive hypotension. After eight hours, the QTC was 506 msec (Figure 1); she developed tonic-clonic movements, somnolence, diaphoresis, hypoxia and hypotension (mean arterial pressure 40-50mmHg); norepinephrine was reinitiated. She required intubation for airway protection and displayed pulmonary edema, then developed progressive bradycardia and cardiac arrest with pulseless electrical activity. Unsuccessful resuscitation included IV vasopressin, epinephrine, phenylephrine, 20% IV lipid emulsion and 2mg IV glucagon. She expired. Serum ranolazine concentration was 50mg/L (therapeutic concentration: 0.4–6.1mg/L). Ranolazine exhibits 62–65% protein binding, p-glycoprotein transport, a volume of distribution (Vd) of 40.4–48.6 L, and CYP3A4 and CYP2D6 metabolism [2]. Polydrug p-glycoprotein interaction likely contributed to ranolazine toxicity. Ranolazine inhibits the delayed cardiac Naþ current, which persists past the peak Naþ-current of the action potential [3]. Intracellular sodium from the delayed Naþ-current exchanges for Ca2þ via a Naþ/Ca2þ antiporter resulting in calciuminduced calcium release from the sarcoplasmic reticulum [3]. By inhibiting the delayed Naþ-current and subsequent intracellular myocyte Ca2þ-loading, Ranolazine essentially acts as an indirect calcium channel blocker. In contrast, peak Naþchannel blockers cause QRS prolongation and arrhythmogenic potential (not present in this case). Ranolazine causes dose-dependent QTc prolongation [1]. Animal models demonstrate alpha-1, b-1, and b-2 adrenoreceptor inhibition and inhibition of beta-oxidation of fatty acids [1,4]. Ranolazine decreases cardiac output and systolic function in humans [5]. This patient developed hypotension, QTc prolongation without arrhythmias, tonic-clonic movements, cardiovascular collapse and death. Quantification of gabapentin, valproate, quetiapine, trazodone, and mirtazapine was therapeutic or subtherapeutic but may have contributed to toxicity (including QTc prolongation). The history, comprehensive testing and drug quantification by liquid chromatography-mass spectrometry support the primary role of ranolazine. Optimal management is unclear. Refractory shock should be anticipated. Echocardiogram may evaluate myocardial inotropy and IV fluid tolerance. IV calcium, inotropes, vasopressors, high dose insulin and extra-corporeal life support may be considered (unavailable in this case). IV fluid administration should be judicious given decreased cardiac inotropy