Tarka® overdose in a young child

Abstract

Tarka® is a combination antihypertensive medication composed of verapamil hydrochloride and trandolapril. A 3.5-year-old female was brought to our hospital due to a sleepy condition 7 hours after an accidental ingestion of six tablets of Tarka® containing 240 mg verapamil hydrochloride and 4 mg trandolapril in each tablet. Five hours after hospitalization, her condition deteriorated and arterial pressure progressively decreased despite the treatment. Finally, a temporary pacemaker was implanted, after which the vital findings began to return to normal values. The pacemaker was removed 13 hours after implantation as normal heart rhythm was observed. There are no reports of intoxication with fixed-dose combination products, especially Tarka®, in young children in the literature. Therefore, we believe that our report can provide an insight on the toxic dose of this drug in younger children. Clinicians should keep in mind that lethargy can be the first symptom of a possible clinical deterioration, even in normotensive and normorhythmic individuals.

Introduction

Fixed-dose combination products are becoming increasingly prevalent in the treatment of essential hypertension. There are more than 20 combination products available. ¹ Tarka® is a combination antihypertensive medication composed of verapamil hydrochloride and trandolapril. Various combination dosages are available, with doses of verapamil hydrochloride and trandolapril ranging from 180 to 240 mg and 1 to 4 mg, respectively. ² Although fixed-dose combination products have many benefits, such as improved compliance and being more effective alone than the sum of the effectiveness of both products, it has some disadvantages, including the lack of flexibility with dose administration with its individual components, lack of familiarity of the individual components of fixed-dose combination products among practitioners, and lack of data on the clinical presentation and management of fixed-dose combinations in the overdose setting. ^{3 –5} Toxicological manifestations of Tarka overdose included lethargy, fatigue, impaired state of consciousness, bradycardia, hypotension, hyperglycemia, metabolic acidosis, and shock. The toxic dose of Tarka has not been known clearly, only a few case reports about Tarka overdose were available in literature. In these reports, the lethal dose of Tarka was changed to 4−7 pill which included 720 mg to 1680 mg verapamil and 8 mg to 14 mg trandolapril. But there is no report about Tarka overdose in young children. In this study, we report a case of Tarka® overdose in a 3.5-years-old-girl who presented in a somnolent state 7 hours after accidental ingestion of six tablets with 240 mg verapamil and 4 mg trandolapril in each tablet. To the best of our knowledge, this is the first report on Tarka® intoxication in a young child.

Case report

A 3.5-year-old female was brought to our hospital due to a somnolent state 7 hours after an accidental ingestion of six tablets of Tarka®, which contained 240 mg verapamil and 4 mg trandolapril in each tablet. She was referred to our emergency department from another hospital where she underwent gastric lavage and was administered activated charcoal, 1 hour before admission to our hospital. On physical examination, her body weight and height were 14 kg (25−50 percentile) and 98.5 cm (50 percentile), respectively, and the blood pressure, respiration rate, pulse rate, and body temperature were 80/60 mmHg, 32/min, 120/min, and 36.2°C, respectively. Her physical examination revealed normal findings except for the somnolence. On laboratory analyses, complete blood count, liver and renal function tests and serum electrolytes, arterial blood gas analysis, prothrombin time, and active partial thromboplastin time revealed normal values. A total of twelve doses of activated charcoal were administered with 1 g/kg at each dose. Additionally, hydration was provided with physiological serum and lactulose was administered at a dose of 5 mL, three doses a day for 2 days. Five hours after hospitalization, arterial pressure and pulse rate gradually decreased and finally arterial pressure was measured as 50/20 mmHg, pulse as 58/min, and respiratory rate as 24/min. At this stage, she had a poor condition and lethargy, flushing, bradycardia, a murmur of 2−3/6 degree at the apex, hardly measurable peripheral pulses, diminished deep tendon reflexes, bilateral extensor plantar response, and spasticity on the upper extremities on physical examination. On laboratory examination, hyperglycemia (285 mg/dL) and leukocytosis (20.000/mm³) were detected. Her electrocardiogram showed complete A-V block with prolongation of all intervals (Figures 1−3). Her condition worsened and arterial pressure decreased progressively. Fluid reconstruction was performed and dopamine was initiated at a dose of 10 µg/kg/min and the dose was increased up to 20 µg/kg/min according to response. Then, adrenalin infusion (0.1 µg/kg/min) was started and the dose was increased to 1 µg/kg/min because of unresponsive bradycardia and hypotension. In addition to these therapies, hyperinsulinemia/euglycemia therapy was administered, but unfortunately hemodynamic stability could not be achieved. Therefore, finally, a temporary pacemaker was implanted and after that, the vital findings began to approach to normal values (pulse rate: 110/min, respiratory rate: 34/min, arterial pressure: 90/60 mmHg, body temperature: 36.5°C). Adrenalin and dopamine doses decreased slowly in accordance with the status of arterial pressure and pulse rate and finally discontinued 8 hours after implantation of the pacemaker. Thirteen hours after pacemaker implantation, the pacemaker was removed because the heart rhythm returned to normal values. She was discharged with complete remission on 3rd day after hospitalization. She is now in the 6th month of follow-up and has been followed-up free of symptoms and signs.

Figure 1.

Complete A-V block of our patient before pacemaker insertion.

Figure 2.

Pacemaker rhythm.

Figure 3.

Normal sinoatrial rhythm after pulling out of pacemaker.

Discussion

Tarka® is a combination of the antihypertensive drugs verapamil hydrochloride and trandolapril. Trandolapril, which is an angiotensin-converting enzyme inhibitor (ACE-I), decreases the blood pressure by relaxing the circulatory blood vessels through the inhibition of angiotensin II. ⁶ In the human body, trandolapril is de-esterified to its main bioactive metabolite trandolaprilate. Trandolaprilate, which is eight times more potent than trandolapril, reaches peak plasma concentrations in 2–12 hours and is excreted in urine and feces. ² Verapamil, which is a calcium channel blocker (CCB), undergoes significant first-pass portal metabolism, yielding its primary bioactive metabolite norverapamil. Norverapamil has approximately 20% of the activity of verapamil. ² In healthy subjects, peak verapamil and norverapamil concentrations occur in 4–15 hours and in 5–15 hours, respectively. However, these times may be significantly delayed after ingestion of sustained-release formulas. ² The majority of verapamil and verapamil metabolites (70%) are excreted by the kidneys. ²

Patients with ACE-I toxicity typically present with hypotension and relative bradycardia. Non-cardiac symptoms including lethargy, fatigue, and impaired state of consciousness has been reported. ⁷ Severe angioedema and hypotension are the most serious side effects of trandolapril. On the other hand, overdose with CCBs results in profound bradycardia, hypotension, hyperglycemia, metabolic acidosis, and a shock state. Although rare, stroke has also been described in verapamil toxicity. ^8,9 Toxicity due to standard verapamil formulas normally occur within 2 to 4 hours after ingestion. Furthermore, symptoms of toxicity with sustained-release verapamil overdoses occur after 12 hours post-ingestion and may persist for 48 to 72 hours. ^{10 –13} The likely mechanism of death in verapamil overdose is heart failure due to decreased myocardial contractility or complete heart block. ¹⁴ In our patient, symptoms had begun 6 hours after ingestion of six tablets of Tarka® containing 1440 mg verapamil and 16 mg trandolapril corresponding to 102.8 mg/kg of verapamil and 1.14 mg/kg of trandolapril. In the present report, the first symptom was lethargy. We thought that this could be related to trandolapril overdose. However, on follow-up, hypotension, which could develop after verepamil and trandolapril overdose and flushing, complete A-V block, hyperglycemia, leukocytosis, which were thought to be related with verapamil overdose, were noted. In a manner consistent with the reports in the literature, especially flushing and atrioventricular block developed after 12 hours of ingestion, related to verapamil overdose.

In the literature, the minimal toxic doses of verapamil are well known. ¹⁴ Reported toxic doses of verapamil, including both fatal and nonfatal cases, have ranged from 800 mg to 24 000 mg. ^8,15 In another study, the mean nontoxic dose of verapamil was reported as 320 mg, whereas the mean toxic ingestion was 3.2 g. ¹⁶ The oral LF₅₀ of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality. In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed. ¹⁷ In the literature, only four reports were found about trandolapril overdose. All of them used combined preparations of trandolapril with verapamil (Tarka®) and all the cases involved adults. ^{14,18 –20} Additionally, there is no report of intoxication with fixed-dose combination products, especially Tarka®, in young children. Therefore, we believe that our data may provide an insight on toxic dose of trandolapril and Tarka® in young children. Gokel et al. ^19,20 reported two patients who presented with acute renal failure with rhabdomyolysis and thrombotic microangiopathy after administration of the fixed-dose combination, each containing 180 mg verapamil-2 mg trandolapril combined capsules. Only one of the patients reported by Gokel et al. presented with the classic presentation of hypotension and bradycardia. ^19,20 Batalis et al. ¹⁸ described an unusual case of verapamil-trandolapril toxicity. The patient was found unresponsive approximately 12 h after Tarka® overdose and subsequently died. Cohen et al. reported a 60-year-old man who experienced dizziness and fell after ingesting five tablets of Tarka®. ¹⁴ Eight hours later, he was found to be hypotensive and bradycardic. In our patient, neither rhabdomyolysis nor thrombotic microangiopathies were found. The classical symptoms of Tarka® overdose including hypotension and bradycardia were observed. On the other hand, lethargy was the first symptom. After that, on the follow-up, there was clinical worsening. Therefore, in patients with Tarka® intoxication, lethargy should lead the physician to consider a possible clinical deterioration and patients with Tarka® overdose should be hospitalized and observed for at least 24−48 hours.

As with other cases of unstable hemodynamic status due to ingestions, initial therapy in Tarka® overdose is assessment of the airway, breathing, and circulation. The first intervention for patients with hypotension is volume replacement with crystalloid or colloid solutions. ¹⁰ Decontamination with activated charcoal or whole bowel irrigation should be considered for patients with a protected airway who seek treatment within 1 hour of ingestion, ²¹ although use of activated charcoal as late as 2 hours after ingestion can prevent absorption of sustained-release verapamil. ²² Treatments such as hemofiltration and dialysis are of limited value in verapamil intoxication because of the drug’s highly protein-bound state ²³ but it can be used for trandolapril overdose. Plasmapheresis can be used to stabilize a patient’s clinical condition and allow time for hepatic detoxification. ²⁴ Calcium would seem to be a logical choice for treatment of verapamil poisoning, with the aim of overcoming competitive blockade of calcium channels in the cardiac conducting system. ^25,26 Various sympathomimetics, including dopamine, dobutamine, norepinephrine, and amrinone, have been used to counter the hypotensive effects of CCB overdose. ²⁵ Naloxone may also be effective in reversing the hypotensive effects of ACE-I. ¹⁴ Recently, on the basis of the lipophilic properties of verapamil, findings in a rat model of verapamil poisoning suggest that therapy with the lipid emulsion intralipid may provide a survival benefit. ²⁷ The use of insulin to treat CCB intoxication is another choice in the treatment of severe CCB poisoning. Insulin increases plasma levels of ionized calcium, improves the hyperglycemic acidotic state, improves myocardial utilization of carbohydrates, and exerts its own independent inotropic effect.²⁸ Hyperinsulinemia/euglycemia therapy should be reserved for patients with hypotension, complete A-V block and bradycardia refractory to fluid resuscitation, high-dose calcium, and vasopressors. ^28,29 Pacemaker use, indicated for marked bradycardia or high-grade conduction blocks, can result in positive responses in patients with CCB overdose. ³⁰ The increase in heart rate alone can increase the cardiac output. McGlinchey et al. reported three cases with CCB intoxication who were treated with pacemaker insertion. ³¹ In that study, two of three patients were treated successfully with pacemaker insertion. The remaining patient died. But, this patient was admitted to hospital 10 hours after ingestion of drug and asystole was observed before pacemaker insertion. Another patient with calcium channel antagonist overdose who was successfully treated with pacemaker insertion was reported by Punukollu et al. ³² A 28-year-old female patient who was hospitalized for cardiogenic shock and altered state of consciousness (Glasgow coma score = 4), caused by acute poisoning with beta adrenergic blocker and calcium channel antagonist, was reported by Radovanović et al. ³³ In that patient, prolonged cardiopulmonary resuscitation was applied during the first 16 hours of hospitalization and finally the patient was treated successfully with sympathomimetics, temporary pacemaker, and mechanical ventilation. In our patient, fluid resuscitation, calcium, insulin, and sympathomimetic therapies failed but with pacemaker insertion, as in the cases in the literature, successful treatment was achieved.

Conclusion

In conclusion, there are no reports of intoxication with fixed-dose combination products, particularly Tarka®, in young children in the literature. Therefore, we believe that our results may provide an insight on toxic dose of this drug in younger children. Moreover, we believe that pacemaker can be inserted in a patient with Tarka® overdose and complete A-V block and severe hypotension and who is unresponsive to fluid resuscitation, calcium, insulin, and sympathomimetic therapies. We also suggest that clinicians should keep in mind that lethargy can be the first symptom of possible clinical worsening, even in normotensive and normorhythmic individuals.