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A6904 - Down but Not Out: Severe Amitriptyline Overdose for Extended Duration Due to Genetic Polymorphism
Author Block: D. Gekhman, G. Marmolejos, N. Agarwal; Drexel University at Hahnemann Hospital, Philadelphia, PA, United States.
Introduction: Up to eight percent of Caucasians have Tricyclic Antidepressant (TCA) deficient metabolism due to CYP2D6 polymorphism; this mutation lowers the threshold for accumulation of toxic levels and results in prolonged intoxication. Ventricular arrhythmias due to QTc prolongation are an adverse effect of TCAs caused by blockage of sodium channels in the cardiac conduction system as well as central nervous system depression leading to coma. TCA toxicity management guidelines dictate supportive care until the drug is metabolized to non-toxic levels. Amitriptyline, in particular, has a half-life of 9-27 hours with a therapeutic range of 80-200 ng/mL. We present a unique case of TCA overdose in a deficient metabolizer without any concomitant co-ingestion.
Case Report: A 44 year old female with Human Immunodeficiency Virus infection and Bipolar disorder presented after ingesting 50 pills of 75 milligrams of Amitriptyline in a suicide attempt. Within an hour of presentation, her Glasgow Coma Scale deteriorated to a six. Mechanical ventilation and bicarbonate infusion were initiated for a goal pH of 7.5. Drug screen was positive only for TCAs. After approximately 24 hours her electrocardiogram (ECG) normalized and bicarbonate infusion was discontinued. Twelve hours later, the patient became hypotensive and repeat ECG showed recurrent QRS widening to 150 and QTc prolongation above 600 milliseconds. She required bicarbonate infusion until day six and mechanical ventilation until day fourteen of admission. No ventricular arrhythmias occurred. On days four and nine, serum TCA levels were found to be 1299 and 808 ng/mL, respectively. Genetic testing revealed the CYP2D6*4 allele mutation. On day sixteen she was transitioned to a psychiatric facility.
Discussion: Different populations have varying CYP2D6 genotype frequencies. Up to eight percent of Caucasians are considered poor metabolizers due to the CYP2D6*4 allele mutation. In addition, up to 50% of Asians are considered intermediate metabolizers due to CYP2D6*10 mutations. Although our patient was successfully managed as per established guidelines for an expected 24-32 hour toxicity, she continued to have lethal serum TCA levels resulting in prolonged critical care support. Being unaware of the high incidence of the described enzyme polymorphism, supportive care was prematurely discontinued resulting in hypotension and cardiac repolarization changes with heightened risk of fatal arrhythmias. Thus, it is imperative to consider genetic testing for certain patient populations to avoid adverse outcomes. We describe what would be the first published case of pure TCA toxicity prolonged by genetic mutation.