Calcium channel blocker poisoning
Background: Calcium channel blockers act at L-type calcium channels in cardiac and vascular smooth muscles by preventing calcium influx into cells with resultant decrease in vascular tone and cardiac inotropy, chronotropy and dromotropy. Poisoning with calcium channel blockers results in reduced cardiac output, bradycardia, atrioventricular block, hypotension and shock. The findings of hypotension and bradycardia should suggest poisoning with calcium channel blockers.
Conclusions: Treatment includes immediate gastric lavage and whole-bowel irrigation in case of ingestion of sustainedrelease products. All patients should receive an activated charcoal orally. Specific treatment includes calcium, glucagone and insulin, which proved especially useful in shocked patients. Supportive care including the use of catecholamines is not always effective. In the setting of failure of pharmacological therapy transvenous pacing, balloon pump and cardiopulmonary by-pass may be necessary.
Salhanick SD, Shannom MW. Management of calcium channel antagonist overdose. Drug Safety 2003; 26: 65–79.
DeRoos F. Calcium channel blockers. In: Goldfrank LR. Goldfrank’s toxicologic emergencies. 7th ed. New York: McGraw-Hill Companies; 2002. p. 762– 74.
Buckley CD, Aronson JK. Prolonged half-life of verapamil in a case of overdose: implications for therapy. Br J Clin Pharmacol 1995; 39: 680–3.
Ferner RE, Odemuyiwa O, Field AB, Walker S, Volans GN, Bateman DN. Pharmacokinetics and toxic effects of diltiazem in massive overdose. Hum Toxicol 1989; 8: 497–9.
Ferner RE, Monkman S, Riley J, Cholerton S, Idle JR, Bateman DN. Pharmacokinetics and toxic effects of nifedipine in massive overdose. Hum Exp Toxicol 1990; 9: 309–11.
Roberts D, Honcharik N, Sitar DS, Tenenbein M. Diltiazem overdose: pharmacokinetics of diltiazem and its metabolites and effect of multiple dose charcoal therapy. J Toxicol Clin Toxicol 1991; 29: 45–52.
Stajer D, Bervar M, Horvat M. Cardiogenic shock following a single therapeutic oral dose of verapamil. Int J Clin Pract 2001; 55: 69–70.
Somogyi A, Albrecht M, Kliems G, Schafer K, Eichelbaum M. Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis. Br J Clin Pharmacol 1981; 12: 51–60.
Woodcock BG, Rietbrock N. Verapamil bioavailability and dosage in liver disease. Br J Clin Pharmacol 1982; 13: 240–1.
Spiller HA, Meyers A, Ziemba T, Riley M. Delayed onset of cardiac arrhythmias from sustained-release verapamil. Ann Emerg Med 1991; 20: 201.
Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann Emerg Med 1993; 22: 196–200.
Buckley NA, Whyte IM, Dawson AH. Overdose with calcium channel blockers. BMJ 1994; 308: 1639.
Howarth DM, Dawson AH, Smith AJ, Buckley N, Whyte IM. Calcium channel blocking drug overdose: an Australian series. Hum Exp Toxicol 1994; 13: 161–6.
Leesar MA, Martyn R, Talley JD, Frumin H. Noncardiogenic pulmonary edema complicating massive verapamil overdose. Chest 1994; 105: 606–7.
Humbert VH Jr, Munn NJ, Hawkins RF. Noncardiogenic pulmonary edema complicating massive diltiazem overdose. Chest 1991; 99: 258–9.
Gustafsson D. Microvascular mechanisms involved in calcium antagonist edema formation. J Cardiovasc Pharmacol 1987; 10 Suppl 1: S121–31.
Low RI, Takeda P, Mason DT, DeMaria AN. The effects of calcium channel blocking agents on cardiovascular function. Am J Cardiol 1982; 49: 547–53.
Pearigen PD. Calcium channel blocker poisoning. In: Haddad LM, Shannon MW, Winchester JF. Clinical management of poisoning and drug overdose. 3rd ed. Philadelphia: WB Saunders; 1998. p. 1020–30.
Wells TG, Graham CJ, Moss MM, Kearns GL. Nifedipine poisoning in a child. Pediatrics 1990; 86: 91–4.
Horowitz BZ, Rhee KJ. Massive verapamil ingestion: a report of two cases and a review of the literature. Am J Emerg Med 1989; 7: 624–31.
Fauville JP, Hantson P, Honore P, Belpaire F, Rosseel MT, Mahieu P. Severe diltiazem poisoning with intestinal pseudo-obstruction: case report and toxicological data. J Toxicol Clin Toxicol 1995; 33: 273–7.
Gutierrez H, Jorgensen M. Colonic ischemia after verapamil overdose. Ann Intern Med 1996; 124: 535.
Sporer KA, Manning JJ. Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann Emerg Med 1993; 22: 603–5.
Wax PM. Intestinal infarction due to nifedipine overdose. J Toxicol Clin Toxicol 1995; 33: 725–8.
Benowitz NL. Calcium antagonists. In: Olson KR. Poisoning and drug overdose. 4th ed. New York: McGraw-Hill Companies; 2004. p. 144–7.
Buckley N, Dawson AH, Howarth D, Whyte IM. Slow-release verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993; 158: 202–4.
Tenenbein M. Whole bowel irrigation and activated charcoal. Ann Emerg Med 1989; 18: 707–8.
Ter Wee PM, Kremer Hovinga TK, Uges DR, Wee PM, Kremer Hovinga TK, Uges DR, van der Geest S. 4-aminopyridine and haemodialysis in the treatment of verapamil intoxication. Hum Toxicol 1985; 4: 327–9.
Schiffl H, Ziupa J, Schollmeyer P. Clinical features and management of nifedipine overdosage in a patient with renal insufficiency. J Toxicol Clin Toxicol 1984; 22: 387–95.
Rosansky SJ. Verapamil toxicity—treatment with hemoperfusion. Ann Intern Med 1991; 114: 340–1.
Erickson FC, Ling LJ, Grande GA, Anderson DL. Diltiazem overdose: case report and review. J Emerg Med 1991; 9: 357–66.
Haddad LM. Resuscitation after nifedipine overdose exclusively with intravenous calcium chloride. Am J Emerg Med 1996; 14: 602–3.
Henry M, Kay MM, Viccellio P. Cardiogenic shock associated with calciumchannel and beta blockers: reversal with intravenous calcium chloride. Am J Emerg Med 1985; 3: 334–6.
Kuo MJ, Tseng YZ, Chen TF, Fong DE. Verapamil overdose and severe hypocalcemia. J Toxicol Clin Toxicol 1992; 30: 309–11.
Lipman J, Jardine I, Roos C, Dreosti L. Intravenous calcium chloride as an antidote to verapamil-induced hypotension. Intensive Care Med 1982; 8: 55–7.
Luscher TF, Noll G, Sturmer T, Huser B, Wenk M. Calcium gluconate in severe verapamil intoxication. N Engl J Med 1994; 330: 718–20.
Kenny J. Treating overdose with calcium channel blockers. BMJ 1994; 308: 992–3.
Pearigen PD, Benowitz NL. Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine. Drug Saf 1991; 6: 408–30.
Crump BJ, Holt DW, Vale JA. Lack of response to intravenous calcium in severe verapamil poisoning. Lancet 1982; 2: 939–40.
Enyeart JJ, Price WA, Hoffman DA, Woods L. Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coll Cardiol 1983; 2: 1228– 31.
Viccellio P, Henry MC, Yuan J. Calcium channel blockers. In: Viccellio P. Emergency toxicology. 2nd ed. Philadelphia: Lippincott-Raven Publishers; 1999. p. 695–702.
Levey GS, Fletcher MA, Klein I, Ruiz E, Schenk A. Characterization of 125Iglucagon binding in a solubilized preparation of cat myocardial adenylate cyclase. Further evidence for a dissociable receptor site. J Biol Chem 1974; 249: 2665–73.
Mery PF, Brechler V, Pavoine C, Pecker F, Fischmeister R. Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 1990; 345: 158–61.
Sauvadet A, Rohn T, Pecker F, Pavoine C. Synergistic actions of glucagon and miniglucagon on Ca2+ mobilization in cardiac cells. Circ Res 1996; 78: 102–9.
Chernow B, Zaloga GP, Malcolm D, Willey SC, Clapper M, Holaday JW. Glucagon’s chronotropic action is calcium dependent. J Pharmacol Exp Ther 1987; 241: 833–7.Parmley WW. The role of glucagon in cardiac therapy. N Engl J Med 1971; 285: 801–2.
Parmley WW, Glick G, Sonnenblick EH. Cardiovascular effects of glucagon in man. N Engl J Med 1968; 279: 12–7.
Thomas SH, Stone CK, May WA. Exacerbation of verapamil-induced hyperglycemia with glucagon. Am J Emerg Med 1995; 13: 27–9.
Howland MW. Glucagon. In: Goldfrank LR. Goldfrank’s toxicologic emergencies. 7th ed. New York: McGraw-Hill Companies; 2002. p. 826–8.
Kline JA, Leonova E, Williams TC, Schroeder JD, Watts JA. Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. J Cardiovasc Pharmacol 1996; 27: 719–26.
Kline JA, Raymond RM, Leonova ED, Williams TC, Watts JA. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res 1997; 34: 289–98.
Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993; 267: 744–50.
Devis G, Somers G, Van Obberghen E, Malaisse WJ. Calcium antagonists and islet function. I. Inhibition of insulin release by verapamil. Diabetes 1975; 24: 247–51.
Kline JA, Raymond RM, Schroeder JD, Watts JA. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol 1997; 145: 357–62.
Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995; 23: 1251–63.
Yuan TH, Kerns WP, Tomaszewski CA, Ford MD, Kline JA. Insulin-glukose as adjunctive therapy for severe calciumchannel antagonist poisoning. J Tox Clin Tox 1999; 37: 463–74.
Law WR, McLane MP, Raymond RM. Effect of insulin on myocardial contractility during canine endotoxin shock. Cardiovasc Res 1988; 22: 777–85.
Rosen OM. After insulin binds. Science 1987; 237: 1452–8.
Megarbane B, Baud F. Glucagon or insulin and glucose: when and why? J Tox Clin Tox 2004; 4: 429–30.
Zierler KL. Increase in resting membrane potential of skeletal muscle produced by insulin. Science 1957; 126: 1067–8.
Prasad K, MacLeod DP. Influence of glucose on the transmembrane action potential of guinea-pig papillary muscle. Metabolic inhibitors, ouabain, and calcium chloride, and their interaction with glucose, sympathomimetic amines, and aminophylline. Circ Res 1969; 24: 939–50.
Kones RJ, Phillips JH. Insulin: fundamental mechanism of action and the heart. Cardiology 1975; 60: 280–303.Thomas LJ. Increase of labeled calcium uptake in heart muscle during potassium lack contracture. J Gen Physiol 1960; 43: 1193–206.
Anthony T, Jastremski M, Elliott W, Morris G, Prasad H. Charcoal hemoperfusion for the treatment of a combined diltiazem and metoprolol overdose. Ann Emerg Med 1986; 15: 1344–8.
Chimienti M, Previtali M, Medicia A, Piccinini M. Acute verapamil poisoning: successful treatment with epinephrine. Clin Cardiol 1982; 5: 219–22.
Hendren WG, Schieber RS, Garrettson LK. Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med 1989; 18: 984–7.
MacDonald D, Alguire PC. Case report: fatal overdose with sustainedrelease verapamil. Am J Med Sci 1992; 303: 115–7.
McMillan R. Management of acute severe verapamil intoxication. J Emerg Med 1988; 6: 193–6.
Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993; 22: 1229–33.
Quezado Z, Lippmann M, Wertheimer J. Severe cardiac, respiratory, and metabolic complications of massive verapamil overdose. Crit Care Med 1991; 19: 436–8.
Orr GM, Bodansky HJ, Dymond DS, Taylor M. Fatal verapamil overdose. Lancet 1982; 2: 1218–9.
Sperelakis N. Cyclic AMP and phosphorylation in regulation of Ca++ influx into myocardial cells and blockade by calcium antagonistic drugs. Am Heart J 1984; 107: 347–57.
Clifton GD, Booth DC, Hobbs S, Boucher BA, Foster TS, McAllister RG Jr., et al. Negative inotropic effect of intravenous nifedipine in coronary artery disease: relation to plasma levels. Am Heart J 1990; 119: 283–90.
Reuter H, Stevens CF, Tsien RW, Yellen G. Properties of single calcium channels in cardiac cell culture. Nature 1982; 297: 501–4.
Holzer M, Sterz F, Schoerkhuber W, Behringer W, Domanovits H, Weinmar D, et al. Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med 1999; 27: 2818–23.
Braunwald E. Mechanism of action of calcium-channel-blocking agents. N Engl J Med 1982; 307: 1618–27.
Hofer CA, Smith JK, Tenholder MF. Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options. Am J Med 1993; 95: 431–8.
Ramoska EA, Spiller HA, Myers A. Calcium channel blocker toxicity. Ann Emerg Med 1990; 19: 649–53.
The Author transfers to the Publisher (Zdravniški vestnik/Slovenian Medical Journal) all economic copyrights following form Article 22 of the Slovene Copyright and Related Rights Act (ZASP), including the right of reproduction, the right of distribution, the rental right, the right of public performance, the right of public transmission, the right of public communication by means of phonograms and videograms, the right of public presentation, the right of broadcasting, the right of rebroadcasting, the right of secondary broadcasting, the right of communication to the public, the right of transformation, the right of audiovisual adaptation and all other rights of the author according to ZASP.
The aforementioned rights are transferred non-exclusively, for an unlimited number of editions, for the term of the statutory
The Author can make use of his work himself or transfer subjective rights to others only after 3 months from date of first publishing in the journal Zdravniški vestnik/Slovenian Medical Journal.
The Publisher (Zdravniški vestnik/Slovenian Medical Journal) has the right to transfer the rights, acquired parties without explicit consent of the Author.
The Author consents that the Article be published under the Creative Commons BY-NC 4.0 (attribution-non-commercial) or comparable licence.