Discussion
We report the case of a multiple drug overdose involving Nortriptyline, Livergol, Gabapentin, and Thiamine supplement, which resulted in a QTc interval prolongation presented on ECG on arrival. According to the 2020 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, antidepressants are reported among the top 5 substance classes most frequently involved in toxic exposures, and over the past 10 years, their exposure has increased most rapidly and with more serious outcomes, by 5.84% per year or 1,793 cases per year [5]. As a class, TCAs are categorized in the top 25 classes associated with the greatest fatality [6].
Delayed clinical deterioration or even death following a relative stabilization or improvement, days after the ingestion had been previously documented. A previous case, reports a 61-year-old man presenting after an nortriptyline overdose up to 2500 mg, with QRS widening to 240 milliseconds despite the further narrowing of QRS interval, his course got complicated by repeated episodes of wide complex tachycardia and required continuous sodium bicarbonate treatment until day 14 hospitalization [7]. In another case of a patient with an initial nortriptyline level of 1518 mg/L and episodes of generalized tonic-clonic seizures, sodium bicarbonate infusion was administrated for a total of 5 days [8]. however, in all of these cases, significant initial toxicity was observed. Our patient with large ingestion of Nortriptyline still showed no delayed deterioration and responded very well on a short (12 hours) sodium bicarbonate treatment course. In line with the result of our case, in a report by Pierog and colleagues, despite a large amount of amitriptyline ingested, the patient only received therapy for 48 hours [9].
The recommended therapeutic window of NT is defined between 50 ng/mL and 150 ng/mL. Normally, medications with NT start at a low dose, and then gradually increased to reach the optimal therapeutic level. However, the plasma steady-state concentrations of TCAs in the course of treatment vary interindividual, as the therapeutic or toxic concentrations are mostly determined by NT metabolism and clearance rate. But, in general, plasma levels above 150 ng/mL are associated with the incidence of adverse effects [10]. Given that, conventional dosage regimen can lead to toxic concentration in slow metabolizer individuals, as Lee et al. reported a case presenting with adverse effects such as dizziness, dry mouth, and constipation after 6 days prescription of routine dosage of NT [11]. Drug interactions leading to the decreased metabolism rate can be observed in treatment with two or more CYP enzyme metabolizers, resulting in enzyme competition. Shim et al. reported increased blood levels of TCA in schizophrenic patients under treatment of paroxetine, a potent CYP2D6 inhibitor [12].
Several successful studies have been evaluating silymarin’s benefits as an anti-inflammatory, anti-diabetic, anti-Alzheimer, and anticancer agent. Due to the extensive therapeutic roles of Livergol in human studies and its wide use in liver diseases, its safety is very important and should be prescribed with caution, especially when co-administered with drugs that carry a narrow therapeutic window. According to pharmacological studies, silymarin was safe at therapeutic doses in humans, only transient side effects like GI discomfort were reported. Silymarin has shown limited effect on the pharmacokinetics of some drugs in vivo; inhibitory effect on cytochrome P-450 enzymes could affect warfarin metabolism. Though it did not have a major effect on drug metabolism, it is suggested that their combination should be used with caution. In total, Livergol has a good safety profile and is well tolerated even at high doses [3, 13].
One major cause of concern in the use of herbal medicine is that they mainly contain physiochemical constituents that may interact with prescription drugs. Regarding the little information available about herbal product potential for drug interaction and pharmacokinetic alternation, healthcare practitioners usually take caution against co-administration of Livergol and pharmaceutical drugs to avoid any possible clinically significant interactions [14].