Amlodipine overdose causes prolonged calcium channel blocker toxicity

Amlodipine Overdose Causes Prolonged Calcium Channel Blocker Toxicity BRUCE D. ADAMS, MD, WILLIAM 7". BROWNE, MD Amlodipine is a relatively new agent that has the longest half-life of all calcium channel blockers. This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines. (Am J Emerg Med 1998;16:527-528. This is a US government work. There are no restrictions on its use.) Calcium channel blockers (CCBs) are the leading cause of overdose death among all cardiovascular medicines. 1,2 In 1995, 8,396 CCB overdoses were reported with 69 attributed fatalities. 1 The toxicity of CCBs predominantly affects the cardiovascular system causing hypotension and arrhythmias. Other manifestations include pulmonary edema, central nervous system dysfunction, lactic acidosis, hyperglycemia, delayed gastrointestinal transit, and congestive hepatopathy. 2,3 The optimal management of CCB overdose is controversial but includes the use of high-dose calcium, glucagon, and catecholamines. General measures such as volume resuscitation, monitoring, and gut decontamination are also important. 3-6Although there is extensive experience with CCB overdose, nearly all literature reports to date concern only first generation CCBs. 2,3 Amlodipine (Norvasc ®, Pfizer Labs, New York, NY) is a relatively new dihydropyridine CCB with novel pharmacologic properties. 7 Its plasma half-life of 30 to 58 hours is several times longer than that of other CCBs. 7,8 The Toxic Exposure Surveillance System of the American Association of Poison Control Centers lists three suicide deaths from mixed drug ingestions that included amlodipine. However, clinical details are not included in these reportsJ ,9 A M E D L I N E search using the terms amlodipine, overdose, poisoning, toxicity, adverse effects, calcium channel antagonists, and calcium channel blockers found only one other case of amlodipine overdose. 1° In that case from Belgium, a 63-year-old suicidal woman ingested 70 mg of amlodipine plus an unknown amount of oxazepam. She presented in shock with jaundice, hyperglycemia, and moderate left

From the Department of Internal Medicine, Dwight D. Eisenhower Army Medical Center, Fort Gordon, GA. Manuscript received July 22, 1997, returned August 15, 1997; revision received August 25, 1997, accepted September 29, 1997. Presented at the Georgia Chapter of the American College of Physicians Associates Meeting, May 3, 1997, Stone Mountain, GA. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the US government. Address reprint requests to Dr Adams, Department of Internal Medicine, Dwight D. Eisenhower Army Medical Center, FT Gordon, GA 30905. Key Words: Amlodipine, calcium channel blockers, overdose, Swan-Ganz catheterization, glucagon, calcium, lactic acidosis. This is a US government work. There are no restrictions on its use. 0735-6757/98/1605-001250.00/0

ventricular dysfunction. She was treated with catecholamines, calcium, glucagon, colloids, atropine, and insulin, but had a difficult clinical course including severe hyperglycemia and hypercalcemia, for which the glucagon and calcium were discontinued. Subsequently, she developed irreversible shock and died in asystole 26 hours after ingestion. The authors concluded that "continued calcium and/or glucagon might have been beneficial" because the irreversible shock developed after their withdrawal. We describe an additional patient who is, to our knowledge, the first documented survivor of a massive amlodipine overdose. CASE REPORT A 76-year-old white man inadvertently ingested 100 mg of amlodipine over a period of 24 hours. He presented to our hospital with cardiovascular collapse manifested by shock, refractory hypotension, jaundice, acute renal failure, and pulmonary edema. His medical history was significant for coronary artery disease, mild congestive heart failure (baseline ejection fraction by echocardiogram was 40% to 50%), hypertension, moderate mitral regurgitation with severe mitral annular calcification by echocardiogram, and intermittent ventricular bigeminy and right bundle branch block. The patient's only surgery had been a coronary artery bypass graft and prosthetic aortic valve replacement 7 years earlier. His outpatient medicines consisted of long-term warfarin 6 to 7 mg daily, benazepril 40 mg daily, started 6 months earlier, and amlodipine 5 mg daily, started 3 months earlier. Physical examination revealed an elderly man in severe respiratory distress speaking in broken sentences. His initial vital signs were: systolic blood pressure, 90 mm Hg; pulse, 87 beats/rain; temperature, 35.5°C; and respirations, 30 breaths/min and labored. He had jugular venous distension, diffuse rales throughout his lung fields, and 3+ pedal edema. The remainder of the physical examination findings were unremarkable. Chemical laboratory analysis showed the following levels: sodium, 133 mEq/L; potassium, 4.3 mEq/L; chloride, 100 mEq/L; bicarbonate, 11 mEq/L; blood urea nitrogen, 52 mg/dL; creatinine, 2.0 mg/dL; calcium, 9.4 mg/dL; phosphorous 7.5 md/dL; magnesium, 2.5 mg/dL; total bilirubin, 6.2 mg/dL; aspartate aminotransferase, 30 U/L; alanine aminotransferase, 23 U/L; alkaline phosphatase, 113 U/L; lactate dehydrogenase, 289 U/L; albumin, 2.8 g/dL; creatine kinase, 45 U/L; serum lactic acid, 10.3 mmol/L. Serum toxicology screen for tricyclics, barbiturates, benzodiazepines, and salicylates was negative. Serum levels for warfarin and benazepril were not obtained. Hematologic analysis demonstrated a hematocrit of 38% and a white blood count of 13,800/#L with 81% segmented neutrophils, 7% band forms, 6% lymphocytes, 5% monocytes, and 1% basophils. Schistocytes were absent on the peripheral blood smear. The prothrombin time was 27.4 seconds with an international normalized ratio of 4.8; the partial thromboplastin time was 53.1 seconds. An arterial blood gas analysis on a 100% nonrebreather mask showed a pH of 6.96, Pco2 of 44.2 mm Hg, Po2 of 102 mm Hg, and oxygen saturation of 95.6%. The electrocardiogram (ECG) displayed a new first degree atrioventricu527

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lar block as well as the right bundle branch block and ventricular bigeminy that had been observed on previous tracings. His chest X-ray displayed severe pulmonary edema. The preliminary diagnosis in the emergency department was acute congestive heart failure. He was treated with 40 mg of intravenous furosemide, an albuterol nebulizer treatment, 325 mg of chewable aspirin, and rapid sequence intubation, and he was then admitted to the medical intensive care unit. An echocardiogram revealed normal valvular function, severe global hypokinesis, and an ejection fraction estimated at 10% to 20%. Myocardial infarction was ruled out because of the unchanged ECG, normal creatinine kinase level, and absence of segmental wall motion abnormalities on echocardiogram. Dopamine 3 to 20 ~tg/kg/min and dobutamine 5 to 20/ag/kg/min were started and a Swan-Ganz pulmonary artery catheter was placed. Initial hemodynamic parameters demonstrated a pulmonary capillary wedge pressure of 20 rnm Hg (normal range, 5 to 16); systemic vascular resistance of 775 dynes/sec/cm5 (normal range, 770 to 1,500); cardiac output of 3.3 L/rain (normal range, 4 to 9); cardiac index of 1.7 L/min/m2 (normal range, 2.8 to 4.2); and a mixed venous oxygen saturation of 63%. At this time we discovered that he had ingested 20 tablets of 5 mg amlodipine over 24 hours in a misplaced attempt to relieve his progressive dyspnea. Gastrointestinal decontamination was not performed. We continued resuscitation with the dopamine and dobutamine. Over the first 24 hours, we improved his hemodynamic status with these additional agents: 2,000 cc of normal saline, 500 cc of hetastarch, 7 g total of intravenous calcium gluconate and calcium chloride, glucagon infused at 5 to 10 rag/h, and norepinephrine infused at 15 to 22/ag/min. The patient required 5 to 10 days of vasoactive medicines to achieve and maintain hemodynamic stability. His jaundice, renal failure, lactic acidosis, pulmonary edema, and first degree atrioventricular block all resolved. Swan-Ganz catheter measurements showed steady improvement in cardiac output and systemic vascular resistance. Serial amlodipine assays from this period showed the following serum levels: day 1, 67 ng/mL; day 8, 32 ng/mL; and day 22, 3.1 ng/mL (therapeutic range for amlodipine is 3 to 11 ng/mL). Finally, at 10 days after ingestion, he was awake, alert, and communicative. He remained stable off of all vasoactive medicines, having successfully cleared his CCB overdose. Unfortunately he remained ventilator-dependent because of profound muscle weakness and poor nutritional status. Several weeks later, he developed sequential complications during his intensive care course that included renal failure requiring intermittent hemodialysis, a retroperitoneal hematoma, chronic adult respiratory distress syndrome, percutaneous gastrostomy tube complications, and multifocal sepsis. He ultimately died of sepsis and multiple organ failure syndrome 112 days after admission.

DISCUSSION Amlodipine is a frequently prescribed agent with the potential for causing a uniquely severe form of CCB overdose. When compared to first generation CCBs, amlodipine overdose may cause a longer duration of toxicity. Our patient suffered cardiovascular toxicity for 5 to 10 days, which was demonstrated by the corresponding requirement for vasoactive medicines and the persistent serum amlodipine levels. There are several possible mechanisms for this prolonged toxicity. The most evident explanation is amlodipine's extraordinarily long half-life of 30 to 58 hours, the longest of the CCB class. Also, failure to decontaminate our patient's gut, even after a delayed presentation, may have increased systemic absorption of drug. 5 Although there was no evidence of a concurrent benazepril overdose, drug levels

to exclude this possibility were not performed. His age and comorbidity probably worsened the clinical findings. Finally, the overdose appears to have caused passive liver congestion and hepatic dysfunction as a consequence of his severe heart failure. This may have retarded hepatic drug metabolism even further as supported by the detectable drug levels 22 days after ingestion. In the spectrum of CCB overdoses, dihydropyridines are generally considered to be less toxic than verapamil or diltiazem. 3,6,1° The class prototype nifedipine is a potent vasodilator but produces relatively little myocardial depression. 3,11However, our Swan-Ganz catheter data indicate that amlodipine's mechanism of cardiovascular collapse in this case did involve severe myocardial depression similar to that expected with verapamil and diltiazem overdose. 3Ja Interestingly, amlodipine is known to interact with the specific receptor sites of both of these drugs. 7 Therefore, amlodipine's toxicity may be more similar to the severe pattern seen with verapamil or diltiazem than it is to the less severe pattern of nifedipine. We emphasize that although our patient did not survive his l l 2 - d a y hospital course, he certainly survived his amlodipine overdose. By the second week of hospitalization his amlodipine level was therapeutic and approaching zero, his shock had resolved, he was alert and communicative, and he was hemodynamically stable without vasoactive medicines. Our patient was treated more aggressively than the Belgian patient and survived, despite his older age and larger dose. I° This difference in clinical outcome suggests that severe amlodipine overdoses may respond best to a prolonged and aggressive therapy that includes calcium, glucagon, catecholamines, and fluid management.

REFERENCES 1. Litovitz TL, Felberg L, White S, et al: 1995 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1995; 14:487-537 2. Ling LJ: Calcium channel blockers.In Tintinalli JE, Ruiz E, Krome RL (eds): Emergency Medicine: A Comprehensive Study Guide. New York, NY, McGraw-Hill, 1996, pp 803-805 3. Lip GYH, Femer RE: Poisoning with anti-hypertensive drugs: Calcium antagonists. J Hum Hypertens 1995;9:155-161 4. Hofer CA, Smith JK, Tenholder MF: Verapamil intoxication: A literature review of overdoses and discussion of therapeutic options. Am J Med 1995;95:431-438 5. Howarth DM, Dawson AH, Smith AJ, et al: Calcium channel blocking drug overdose: An Australian series. Hum Exp Toxicol 1994;13:161-166 6. Ramoska EA, Spiller HA, Winter M, et al: Aone-year evaluation of calcium channel blocker overdoses: Toxicity and treatment. Ann Emerg Med 1993;22:196-200 7. Burges R, Moisey D: Unique pharmacologic properties of amlodipine. Am J Cardiol 1994;73:2A-9A (suppl) 8. Abernathy DR: An overview of the pharmacokinetics and pharmacodynamics of amlodipine in elderly persons with systemic hypertension. Am J Cardiol 1994;73:10A-17A (suppl) 9. Litovitz TL, Felberg L, Soloway RA, et al: 1994 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1995;13:551-597 10. Koch AR, Vogelaers DP, Decruyenaere JM, et al: Fatal intoxication with amlodipine. J Toxicol Clin Toxico11995;33:253-256 11. Proano L, Chiang WK, Wang RY: Calcium channel blocker overdose. Am J Emerg Med 1995;13:444-450