eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Calcium Channel Blocker

Author: Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant 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 at Brooklyn
Contributor Information and Disclosures

Updated: May 14, 2009

Introduction

Background

Sales of calcium channel blockers (CCBs) have increased over the last decade. Newly developed Calcium channel blockers include ultralong-acting medications and sustained-release forms of existing preparations. Increased availability in the home has led to an increase in the number and severity of calcium channel blocker ingestions by children.

Many calcium channel blockers are marketed today. As of March 2009, 9 drugs in 3 classes in multiple immediate and sustained-release preparations are available in the United States. These classes are as follows:

• Diphenylalkylamines (eg, verapamil): These agents poison both the atrioventricular (AV) node and peripheral vasculature equally.
• Benzothiazines (eg, diltiazem): These agents are more chronotropic than vasoactive.
• Dihydropyridines (eg, nifedipine, amlodipine): These agents exert blood pressure–lowering effects almost entirely on the peripheral vasculature.

The generic preparations of these medicines currently available include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil. Each preparation has its own pharmacologic properties and has a slightly different effect and duration of action. 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.

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.

Pathophysiology

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 leads to 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.

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 blockers has a certain degree of tissue specificity, but they do have common properties. Calcium channel blockers are all absorbed early in the 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.

Frequency

United States

The American Association of Poison Control Centers (AAPCC) collects data annually from regional poison control centers throughout the country. In 2007, 60 of the nation's 61 regional sites contributed information, and almost 2.5 million exposures were recorded from these sites; 38.1% of the reported cases occurred in children younger than 3 years, and 51.2% of the cases occurred in children younger than 6 years.¹ Only 14% of exposures occurred in youth aged 6-19 years.

Of the 2.4 million exposures logged in 2007, 10,084 of these cases were due to various calcium channel blockers.¹ Approximately 1,349 (13%) of the calcium channel blockers exposures occurred in children younger than 6 years, and 240 (2.3%) occurred in children aged 6-19 years.

Mortality/Morbidity

According to the 2007 AAPCC data, 4.5% of adolescent exposures were fatal, whereas only 2.3% of cases occurring in children younger than 3 years were fatal.¹  This likely reflects the fact that unintentional small ingestions or tasting occurs in toddlers, whereas intentional overdoses of various sizes are responsible for cases in the adolescent population.

In 2007, calcium channel blockers resulted in 17 (1.3%) fatalities and 74 (0.7%) major poisonings among the 10,084 individuals exposed to calcium channel blockers, although the AAPCC report does not stratify that data by age.¹ 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.² 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.

Race

Although calcium channel blockers ingestion has no racial predilection among young children, racial trends mirror statistics of suicide attempts by adolescents.

Sex

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

Age

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.

Clinical

History

Whenever a patient presents with bradycardia, hypotension, and an altered mental status, gather a short and AMPLE (ie, allergies, medications, past medical history, last meal, and events of the incident) medical history.

• If the patient ingested medications, ascertain type, dose, and number or amount.
  • Determine the number of tablets that are missing from the bottle. If the number of pills in the bottle at the time of the ingestion is unknown, determine the number of pills that the bottle initially contained (ie, the maximum number of pills the child could have taken).
  • Ascertain whether the ingestion is a sustained-release preparation. Ask the patient's family members what medications they are taking because these are most likely the substances that the patient ingested.
  • Finally, try to determine the time between the ingestion and presentation to the emergency department (ED) because this interval provides an indication of how long the calcium channel blockers (CCBs) have had to be absorbed in the patient's digestive system.
• If a suicide attempt is suspected, try to determine whether other medications or alcohol could have been co-ingested. Acetaminophen or aspirin ingestion is especially important to determine because both have known medical treatment modalities.
• When calcium channel blocker ingestion is suspected, specifically question the patient or family about cardiac or pulmonary manifestations of calcium channel blocker toxicity.
  • Did the patient exhibit chest pain, diaphoresis, flushing, palpitations, weakness, peripheral edema, dyspnea, or cough?
  • Does the patient exhibit any signs of CNS involvement?
  • Does the patient have a history of drowsiness, confusion, seizure, dizziness, headache, tremor, nausea, vomiting, or syncope?

Physical

Pay particular attention to the cardiac, vascular, and neurologic examinations because calcium channel blocker toxicity manifests most physical findings in these systems. According to one study, maximal elapsed time to onset of symptoms ranged from 3 hours (seen with normal preparations) to 14 hours (in the setting of sustained-release medications).³ These onset times should be considered when discharging home patients that may or may not have ingested calcium channel blockers.

• Begin the physical examination of the patient who has ingested an unknown amount of a calcium channel blocker by checking vital signs. The heart rate may be decreased if the sinoatrial (SA) node is poisoned or may be increased if the patient is experiencing reflex tachycardia secondary to peripheral vasodilation and hypotension. Hypotension may last up to 24 hours with some sustained-release, long-acting medications.
• When examining the head, eyes, ears, nose, and throat, ensure that the patient's pupils are equal, round, reactive to light, and not pinpoint. Specifically look for signs of focal neurologic deficits.
• A detailed, 6-part neurologic examination should be performed, and the findings should be documented. With the exception of nimodipine, calcium channel blockers have poor CNS penetration. Therefore, drowsiness, seizures, or altered mental status in the absence of hemodynamic collapse should alert the physician to the possibility of co-ingestions.
• Examine the abdomen, paying particularly close attention to the right upper quadrant. With calcium channel blocker toxicity, venous congestion can lead to hepatic engorgement and stretching of the hepatic capsule, causing hepatic tenderness and hepatomegaly. Hepatojugular reflux may also be observed. Listen for bowel sounds because calcium channel blockers may cause enteric dysmotility. Bowel perforation secondary to calcium channel blocker ingestions has been reported. Peritoneal signs of rebound and guarding are ominous findings.
• Hyperglycemia may result from impaired insulin release in addition to insulin resistance. Although beta-antagonist toxicity may resemble calcium channel blocker toxicity in most aspects of the physical examination, the serum glucose level may help identify which cardiovascular toxin was ingested because beta-antagonists often lower the glucose level.

Causes

Calcium channel blocker agents are some of the most widely prescribed drugs in America. They 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, these drugs are commonly unintentionally ingested.

• 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 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 (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 (Cardene, Cardene SR) and nimodipine (Nimotop) are similar to nifedipine. They demonstrate greater peripheral vascular smooth muscle effects. The selectivity of nimodipine is directed at 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 (Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Teczem, Tiazac) has properties from the drug categories mentioned above. Although diltiazem demonstrates an affinity for both cardiac conductive tissues and vascular smooth muscle cells, its clinical response more closely resembles that of verapamil than 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 (Norvasc) is one of the newer calcium channel blocker agents. It has a long half-life of 30-58 hours.⁴ 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 (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, it causes a reflex tachycardia.
• Isradipine (DynaCirc) is similar to felodipine but with a smaller volume of distribution and half-life of 8 hours.
• Nisoldipine (Sular) elicits predominantly hemodynamic effects and decreases systemic vascular resistance and blood pressure.
• 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.
• Mibefradil (Posicor) was taken off the market after adverse drug reactions were reported. It was a selective T-channel calcium channel blocker that was supposed to have less negative inotropy than earlier drugs in its category.

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