Journal of Clinical Toxicology
Open Access

Large Overdose of a Combination Antihypertensive Medication

Celine Zhong^* and Charles F Seifert ^*Correspondence: Celine Zhong, Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, Texas, USA, Email:

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Introduction

Calcium Channel Blocker (CCB) overdose is one of the leading causes of overdose death among cardiovascular medications. Though the class constitutes only 13.8% of cardiovascular drug overdoses either alone or in combination, CCB overdoses account for 42.2% of deaths in these patients [1]. Amlodipine is a commonly prescribed Dihydropyridine (DHP) CCB used to treat hypertension, angina pectoris, cardiac arrhythmias, and other cardiovascular disorders. However, unlike the other DHP CCB’s, amlodipine has a unique pharmacokinetic profile characterized by a slower onset of action (peak concentrations between 6 to 9 hours), a large volume of distribution (21 liters/ kg), and an extensive half-life (35-45 hours). Amlodipine demonstrates linear pharmacokinetics and has a strong correlation between the oral dose given and the plasma concentration-time curve [2]. The clinical picture of previously documented CCB intoxication cases consist of severe hypotension, arrhythmias, pulmonary congestion, renal failure, liver impairment, and metabolic acidosis [3,4]. Limited large overdose cases of amlodipine have been reported in the literature.

Case Presentation

A 25-year-old, Hispanic woman with no significant medical history took approximately 90 tablets of her grandmother’s antihypertensive medication Tribenzor™, a combination antihypertensive product that contains olmesartan, amlodipine, and hydrochlorothiazide (40/10/12.5 mg). The patient presented to the Emergency Room (ER) 2 hours after ingestion. On first evaluation, the patient was alert with a Blood Pressure (BP) of 100/50, Heart Rate (HR) 113, Respiratory Rate (RR) 18, oxygen saturation (O2 Sat) 96% on 4 liters of oxygen. The patient’s BP progressively declined and she was intubated for airway protection and started on assist control mode for ventilation. The ER course of treatment consisted of gastric lavage, 2 grams of intravenous calcium chloride, 50 g of activated charcoal through orogastric tube, 4 liters of normal saline boluses, norepinephrine infusion (15 mcg/kg/min titrated up to 150 mcg/kg/min while in the ER), and an insulin drip (8 units/hr, titrated up to 30-40 units/hr). A dextrose infusion was initiated to maintain euglycemia. Normal saline boluses and a norepinephrine infusion were both started for blood pressure support. After two hours, she was transferred to the Medical Intensive Care Unit (MICU) for further management. Her labs revealed a noncontributory complete blood count, anion gap metabolic acidosis, with a glucose level of 160 mg/dl and calcium concentration of 10 mg/dl. Acetaminophen, salicylate, and alcohol levels were negative.

The norepinephrine infusion was titrated upto 200 mcg/min. She was started on a dopamine drip titrated up to a significantly high dose of 50 mcg/kg/min. Phenylephrine and vasopressin were also added and titrated up to 200 mcg/ min and 0.06 units/min, respectively. The aggressive vasopressor support continued for several days (Figure 1). Additionally, the patient experienced significant hypoxia due to pulmonary edema 13 hours after admission. She required high positive end-expiratory pressure on assist/control ventilation and was started on high frequency oscillator mode. Despite being on high frequency oscillator mode, her SpO2 was around 78%. The patient was oliguric with a central venous pressure of 19 mmHg and subsequently initiated on diuretics, initially with bumetanide and later with furosemide.

Figure 1: Mean Arterial Pressure (MAP) over course of treatment. Dopamine was titrated off first, vasopressin and phenylephrine was discontinued after 4 days, and the norepinephrine was discontinued after approximately 6 days.

Adjunctively, the patient received a calcium chloride infusion with hourly serum calcium monitoring, glucagon, and insulin with dextrose infusions. Intravenous calcium was given to maintain a calcium level goal above 11 mg/dL. The patient became more responsive and on day three, the patient had improved oxygenation, increased urine output, and required less vasopressors. By day six, vasopressors were slowly weaned off and the patient was extubated. The patient remained in the ICU for 11 days and then was transferred to the floor. The patient had a full recovery. Her total hospital admission was a duration of 12.9 days.

Results and Discussion

Management of patients with severe CCB toxicity is challenging. Patients who have ingested toxic doses of CCBs commonly manifest symptoms of bradycardia, conduction delay, peripheral vasodilation, hypoinsulinemia and hyperglycemia [4]. Patients with mild to moderate CCB toxicity may experience asymptomatic bradycardia or mild hypotension. Severe toxicity can have a profound effect on heart rate and can cause dysrhythmias. Metabolic acidosis can be common as well, secondarily to poor perfusion. Combination product overdoses may present differently than a CCB or Angiotensin-Converting Enzyme Inhibitor (ACE-I) overdose alone. In the case of combination products containing both CCB and ACE-I, the ACE-I component may confound the traditional response to antidotal and supportive therapy recommended for CCB overdoses [5]. Gastric lavage and activated charcoal administration are both methods that have been previously documented for use in standard overdose treatments. Since amlodipine is highly protein bound (93% bound to plasma protein), hemodialysis is not a treatment option [6].

Administration of activated charcoal and gastric lavage should be considered for all cases of CCB overdose and is most effective when given within 1-2 hours after ingestion [7]. Regardless of whether a patient is experiencing symptoms, an aggressive approach to care for CCB overdose should be taken, depending on patient-specific factors such as age, comorbidities, coingestion of other cardiovascular medications, and the magnitude of toxic ingestion. Prompt treatment is crucial as the clinical presentation may initially be asymptomatic with delayed presentation of cardiovascular collapse. Manifestations of toxicity may be delayed up to 16 hours after the ingestion with sustained-release formulations [8]. In this case, the patient ingested a combination pill containing a CCB, ACE-inhibitor, and diuretic which may have resulted in the unusual requirement of multiple, high-dose vasopressor support.

Previous case reports regarding amlodipine overdose with coingestion of cardiovascular medications have reported treatment with fluid resuscitation, vasopressor support, diuretics, calcium gluconate, glucagon, and lipid emulsion bolus [9-11]. More recently, there is increasing use of lipid emulsions for CCB overdose patients. Previous case reports have shown benefit of use, including reduction in vasopressor requirements; however, there is certainly still a paucity of information regarding the mechanism of action and risks of use [11-13].

This patient exhibited decreased mentation and was hemodynamically unstable requiring intubation for airway protection. Refractory hypotension was initially treated with fluid boluses, and then treated with intravenous calcium, highdose insulin infusions, dextrose, glucagon and vasopressors. Administration of intravenous calcium is a standard treatment option but its clinical efficacy has not proven to be consistent and specific dosing recommendations are not known [1,10]. Close monitoring of the serum or ionized calcium concentration every two hours and serial ECGs are necessary to avoid clinically significant hypercalcemia.

Conclusion

Calcium Channel Blockers are being increasingly used for treatment of hypertension and are often combined with other antihypertensive medications in a combination pill. CCB overdose may cause severe hypotension along with bradycardia, pulmonary edema, renal failure and other signs of heart failure.

Based on this case report and review of available literature, patients with near fatal CCB ingestion and co-ingestion of additional cardiovascular medications generally have positive clinical outcomes with appropriate initiation of high-dose vasopressors, calcium, and high-dose insulin and dextrose infusions.

References

1. Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Bronstein AC, Rivers LJ, et al. 2020 Annual report of the american association of poison control centers’ National Poison Data System (NPDS): 38th annual report. Clin Toxicol. 2021;59(12):1282-1501.
2. Haria M, Wagstaff AJ. Amlodipine: A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs. 1995;50(3):560-586.
3. Rasmussen L, Husted SE, Johnsen SP. Severe intoxication after an intentional overdose of amlodipine. Acta Anaesthesiol Scand. 2003;47(8):1038-1040.
4. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and β-blocker toxicity. Toxicol Rev. 2004;23(4):223-238.
5. Huang J, Buckley NA, Isoardi KZ, Chiew AL, Isbister GK, Cairns R, et al. Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning. Clin Toxicol. 2021;59(6):464-471.
6. Leenen FH, Coletta E. Pharmacokinetic and antihypertensive profile of amlodipine and felodipine-ER in younger versus older patients with hypertension. J Cardiovasc Pharmacol. 2010;56(6):669-675.
7. Chakraborty RK, Hamilton RJ. Calcium channel blocker toxicity. In: StatPearls. 2022.
8. St-Onge M, Dubé PA, Gosselin S, Guimont C, Godwin J, Archambault PM, et al. Treatment for calcium channel blocker poisoning: A systematic review. Clin Toxicol. 2014;52(9):926-944.
9. Lam YM, Tse HF, Lau CP. Continuous calcium chloride infusion for massive nifedipine overdose. Chest. 2001;119(4):1280-1282.
10. Plumb JO, Stewart C, Eddleston M, de Beer T. Prolonged refractory hypotension following combined amlodipine and losartan ingestion responsive to metaraminol. Case Rep Med. 2011;2011:283672.
11. Walter E, McKinlay J, Corbett J, Kirk-Bayley J. Review of management in cardiotoxic overdose and efficacy of delayed intralipid use. J Intensive Care Soc. 2018;19(1):50-55.
12. Gueret G, Pennec JP, Arvieux CC. Hemodynamic effects of intralipid after verapamil intoxication may be due to a direct effect of fatty acids on myocardial calcium channels. Acad Emerg Med. 2007;14(8):761.
13. Greene SL, Gawarammana I, Wood DM, Jones AL, Dargan PI. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: A prospective observational study. Intensive Care Med. 2007;33(11):2019-2024.