Pediatric Calcium Channel Blocker Toxicity 

  • Author: Derrick Lung, MD, MPH; Chief Editor: Timothy E Corden, MD   more...
 
Updated: Dec 9, 2011
 

Background

Pediatric patients with calcium channel blocker toxicity should be treated in a well-equipped emergency facility or in an intensive care setting. Numerous strategies for treating patients who have ingested calcium channel blockers are available. Among the most widely prescribed drugs in America, these calcium channel blockers are marketed under many brand names and many doses in many colors. They look appealing to children, resembling candy, and are found in many households; therefore, unintentional ingestion of calcium channel blockers is common. (See Etiology and Epidemiology.)

Calcium channel blockers include ultralong-acting medications and sustained-release forms of existing preparations. As of December 2011, 9 drugs in 3 classes in multiple immediate and sustained-release preparations were available in the United States. These classes are as follows (see Etiology and Treatment):

  • Diphenylalkylamines (eg, verapamil) - These agents poison the atrioventricular (AV) node and peripheral vasculature equally
  • Benzothiazines (eg, diltiazem) - These agents are more chronotropic than vasoactive
  • Dihydropyridines (eg, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine) - These agents primarily affect the peripheral vasculature, while cardiac toxicity may be observed in overdose

These medications have different onsets of action, and many are available in sustained-release forms, which complicates the physician's decision regarding the most appropriate time to release patients with calcium channel blocker ingestion. (See Presentation and Workup.)

The current range of indications for calcium channel blockers is broad. Although most of the disease processes that respond to calcium channel blockers affect adults, pediatricians have used calcium channel blockers to treat children with congenital heart malformations, arrhythmias, hypertension, subarachnoid hemorrhage, and/or congestive heart failure.

Physiology

Calcium channel blockers function by binding to the L-subtype, voltage-sensitive, slow calcium channels in cell membranes. This binding decreases the flow of calcium into the cell, which leads to an inhibition of the phase 0 depolarization in cardiac pacemaker cells and causes the phase 2 plateau of Purkinje cells, cardiac myocytes, and vascular smooth muscle cells. Some calcium channel blockers may also demonstrate weak cross-reactivity with fast sodium channels, partially blocking these voltage-gated ion pores, which are responsible for rapid membrane depolarization. (See the image below.)

Calcium channel blocker. Calcium channel blocker.

Different calcium channel blockers work by slightly different mechanisms. Nifedipine likely "plugs" the slow calcium channel, whereas drugs such as diltiazem and verapamil are use-dependent. That is, they interact with the calcium channel after it has been depolarized to its inactivated recovery state.

Each calcium channel blocker has a certain degree of tissue specificity, but the drugs do have common properties. Calcium channel blockers are all absorbed early in the gastrointestinal (GI) system, are substantially bound by plasma proteins, and are predominantly metabolized by the liver. Therefore, impaired renal function should not alter calcium channel blocker metabolism.

Complications

Complications relating to calcium channel blocker toxicity include the following (see Prognosis, Treatment, and Medication):

  • Seizure
  • Coma
  • Death
  • Anoxic encephalopathy from prolonged central nervous system (CNS) hypoxia
  • Ileus
  • Bowel infarction or perforation from mesenteric hypotension
  • Noncardiogenic pulmonary edema
  • Aspiration pneumonia

Patient education

Educate parents who take calcium channel blocker medications about child safety. All homes should have the number of the national poison control center (800-222-1222) posted on or near their telephones for use in an emergency. Calling this number connects the caller to his or her regional poison control center.

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Etiology

As previously mentioned, calcium channel blockers are some of the most widely prescribed drugs in America. They are marketed under many brand names and many doses in many colors. Because they look appealing to children, resembling candy, and are found in many households, unintentional ingestion of these drugs is common.

Verapamil

Verapamil (Calan, Isoptin), a phenylalkylamine, has a higher affinity for calcium slow channels in the cardiac conducting system than in peripheral smooth muscle cells; therefore, it causes a greater negative inotropic effect than do other calcium channel blocker agents. Several sustained-release formulations are available (eg, Calan SR, Isoptin SR, Verelan, Covera HS).

Patients who ingest any of these preparations should be observed longer than those who consume other preparations to guard against a delayed onset of toxicity. Verapamil almost exclusively undergoes hepatic metabolism, yielding a single active metabolite, norverapamil. This compound has 20% of the pharmacologic activity of the parent drug.

Nifedipine

Nifedipine (Procardia, Procardia XL, Adalat, Adalat CC) is a dihydropyridine. Nifedipine has relatively high affinity for the calcium channels in the smooth muscle cells of vascular tissue and causes little to no AV nodal interference. The primary manifestation of nifedipine-related toxicity is hypotension secondary to loss of systemic vascular resistance. This agent has no active metabolites after hepatic metabolism and attains peak drug levels 2-6 hours after ingestion.

Nicardipine and nimodipine

Nicardipine (Cardene, Cardene SR) and nimodipine (Nimotop) are similar to nifedipine, although they demonstrate greater peripheral vascular smooth muscle effects. The selectivity of nimodipine is directed at the cerebral vasculature because of its high lipid solubility and ability to cross the blood-brain barrier. Nimodipine has been approved for use in the treatment of cerebral ischemia after subarachnoid hemorrhage. Nicardipine and nimodipine may have small, negative inotropic effects. These compounds are predominantly metabolized by the liver. They do not exhibit a large first-pass effect, as is observed with other calcium channel blockers.

Diltiazem

Diltiazem (Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Teczem, Tiazac) has properties from the drug categories mentioned above. Although diltiazem demonstrates an affinity for cardiac conductive tissues and vascular smooth muscle cells, its clinical response more closely resembles that of verapamil than of nifedipine. Diltiazem mainly undergoes hepatic metabolism with a large first-pass effect that may differ from patient to patient. Its peak plasma concentration in non–sustained-release preparations is 2-8 hours.

Amlodipine

Amlodipine (Norvasc) has a long half-life of 30-58 hours.[1] Clinical effects of amlodipine are similar to those of nicardipine. Because of its long effect time, amlodipine ingestion increases the risk of morbidity and mortality.

Felodipine

Felodipine (Plendil), another dihydropyridine, is highly protein bound and exhibits a half-life of 11-16 hours. Because of the protein binding, the drug’s elimination is prolonged. Because of its hypotensive effect, felodipine causes a reflex tachycardia.

Isradipine

Isradipine (DynaCirc) is similar to felodipine but with a smaller volume of distribution and half-life of 8 hours.

Nisoldipine

Nisoldipine (Sular) elicits predominantly hemodynamic effects and decreases systemic vascular resistance and blood pressure.

Bepridil

Bepridil (Vascor) is a unique calcium channel blocker with some sodium channel blocking activity. It is used for refractory angina and may prolong the QT interval corrected for heart rate (QTc) through a potassium channel blocking effect. Similar to other drugs with this property, Bepridil can cause torsades de pointes. Bepridil is no longer available in the United States.

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Epidemiology

Sales of calcium channel blockers have increased over the last decade. Increased availability in the home has led to an increase in the number and severity of calcium channel blocker ingestions by children.

Occurrence in the United States

According to the American Association of Poison Control Centers (AAPCC), of the nearly 3 million exposures logged in 2007, 5,027 of these cases were single or primary exposures to calcium channel blockers.[2] Approximately 1,519 (30%) of the calcium channel blocker exposures occurred in children younger than 6 years, and 274 (5.5%) occurred in children aged 6-19 years.[2]

Race-, sex-, and age-related demographics

Although calcium channel blocker ingestion has no race predilection among young children, racial trends mirror suicide attempt statistics among adolescents.

Among young children, a male predilection for calcium channel blocker toxicity is observed. In adolescence, the sex predilection again mirrors suicide attempt statistics, with more female adolescents ingesting calcium channel blocker agents than male adolescents.

Calcium channel blocker ingestions show a bimodal distribution in the pediatric age range. Infants and toddlers often unintentionally ingest tablets that they mistake for food or candy. Teenagers ingest calcium channel blocker agents as a suicide gesture.

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Prognosis

Prognosis in calcium channel blocker toxicity depends on the following:

  • Amount and formulation of drug ingested
  • Co-ingestions
  • Patient's age
  • Time elapsed before treatment begins
  • Underlying disease states
  • Specific treatments
  • Initial rhythm
  • Use of a pacemaker and time before it is placed

Morbidity and mortality

In 2009, calcium channel blockers resulted in 16 (0.3%) fatalities and 62 (1.2%) major poisonings among the 5,027 individuals primarily exposed to calcium channel blockers. The single pediatric fatality was a 16-year-old who intentionally ingested verapamil.[2]

Koren reviewed the literature and considered sustained-release calcium channel blockers to be one of the medications considered to be lethal to infants with the ingestion of a single pill.[3] Therefore, whenever a physician or parent suspects that a child has taken a calcium channel blocker, aggressive treatment in a well-equipped hospital setting should be rapidly initiated.

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Contributor Information and Disclosures
Author

Derrick Lung, MD, MPH  Fellow, Medical Toxicology, University of California, San Francisco, School of Medicine; Clinical Instructor, Division of Emergency Medicine, Stanford University Medical Center

Derrick Lung, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Mark A Silverberg, MD, MMB, FACEP  Assistant Professor, Associate Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate Medical Center

Mark A Silverberg, MD, MMB, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Timothy E Corden, MD  Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society

Disclosure: Nothing to disclose.

Additional Contributors

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose .

References
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  4. Belson MG, Gorman SE, Sullivan K, Geller RJ. Calcium channel blocker ingestions in children. Am J Emerg Med. Sep 2000;18(5):581-6. [Medline].

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  15. French D, Smollin C, Ruan W, Wong A, Drasner K, Wu AH. Partition constant and volume of distribution as predictors of clinical efficacy of lipid rescue for toxicological emergencies. Clin Toxicol (Phila). Nov 2011;49(9):801-9. [Medline].

  16. American College of Medical Toxicology. ACMT position statement: interim guidance for the use of lipid resuscitation therapy. J Med Toxicol. Mar 2011;7(1):81-2. [Medline].

  17. Varpula T, Rapola J, Sallisalmi M, Kurola J. Treatment of serious calcium channel blocker overdose with levosimendan, a calcium sensitizer. Anesth Analg. Mar 2009;108(3):790-2. [Medline].

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