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Toxicity, Calcium Channel Blocker

Author: B Zane Horowitz, MD, FACMT, Professor, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

Background

Calcium channel blockers (CCBs) were initially introduced for use in the United States in 1981. Sustained-release formulations were available 10 years later. Indications for use of these drugs are angina, hypertension, arrhythmias, and migraine prophylaxis.

Calcium channel blocker overdose is rapidly emerging as the most lethal prescription drug ingestion. Overdose by short-acting agents is characterized by rapid progression to cardiac arrest. Overdose by extended-relief formulations result in delayed onset of arrhythmias, shock, sudden cardiac collapse, and bowel ischemia.

Pathophysiology

Calcium channel blockers have the following 4 cardiovascular effects:

  1. Peripheral vasodilatation
  2. Negative chronotropy (decreased heart rate)
  3. Negative inotropy (decreased cardiac contractility)
  4. Negative dromotropy (decreased cardiac conduction)

Other physiologic responses to CCB overdose include suppression of insulin release from the pancreas and decreased free fatty acid utilization by the myocardium. These factors produce hyperglycemia, lactic acidosis, and depressed cardiac contractility.

Frequency

United States

In 1996, the American Association of Poison Control Centers (AAPCC) reported 8555 exposures to calcium channel blockers resulting in 58 fatalities and 225 major outcomes.

In 1997, the AAPCC reported 9077 exposures to calcium channel blockers, resulting in 44 fatalities and 232 major outcomes.

In 1998, the AAPCC reported 8666 exposures to calcium channel blockers, resulting in 61 fatalities and 277 major outcomes.

In 1999, the AAPCC reported 8844 exposures to calcium channel blockers, resulting in 61 fatalities and 243 major outcomes.

In 2000, the AAPCC reported 8975 exposures to calcium channel blockers, resulting in 44 fatalities and 317 major outcomes.

In 2001, the AAPCC reported 9264 exposures to calcium channel blockers, resulting in 60 fatalities and 286 major outcomes.

In 2002, the AAPCC reported 9585 exposures to calcium channel blockers, resulting in 68 fatalities and 365 major outcomes.

In 2003, the AAPCC reported 9650 exposures to calcium channel blockers, resulting in 57 fatalities and 339 major outcomes.1

In 2004, the AAPCC reported 10,513 exposures to calcium channel blockers, resulting in 62 fatalities and 356 major outcomes.

In 2006, the AAPCC reported 10,031 exposures to calcium channel blockers, resulting in 13 deaths and 316 major outcomes.

In 2007, the AAPCC reported 10,084 exposures to calcium channel blockers, resulting in 17 deaths and 74 major outcomes.2

Mortality/Morbidity

Premature discharge of patients with calcium channel blocker overdose, especially extended-release formulations, may result in severe morbidity or mortality.

  • In 1996, the AAPCC reported 58 fatalities and 225 major outcomes.
  • In 1997, the AAPCC reported 44 fatalities and 232 major outcomes.
  • In 1998, the AAPCC reported 61 fatalities and 277 major outcomes.
  • In 1999, the AAPCC reported 61 fatalities and 243 major outcomes.
  • In 2000, the AAPCC reported 44 fatalities and 317 major outcomes.
  • In 2001, the AAPCC reported 60 fatalities and 286 major outcomes.
  • In 2002, the AAPCC reported 68 fatalities and 365 major outcomes.
  • In 2003, the AAPCC reported 57 fatalities and 339 major outcomes.
  • In 2004, the AAPCC reported 62 fatalities and 356 major outcomes.
  • In 2007, the AAPCC reported 17 fatalities and 74 major outcomes.2

Age

  • In the last 10 years, there has only been a minimal decline in the percentage of pediatric exposures to CCBs of all cases called to Poison Centers nationally.
  • In 1996, with 8555 total exposures reported, 2299 exposures occurred in children younger than 6 years (27% of reported cases).
  • In 1997, with 9077 total exposures reported, 2560 exposures occurred in children younger than 6 years (28% of reported cases).
  • In 1998, with 8666 total exposures reported, 2197 exposures occurred in children younger than 6 years (25% of reported cases).
  • In 1999, with 8844 total exposures reported, 2304 exposures occurred in children younger than 6 years (26% of reported cases).
  • In 2000, with 8975 total exposures reported to calcium channel blockers, 2201 exposures occurred in children younger than 6 years (25% of reported cases).
  • In 2001, with 9264 total exposures reported to calcium channel blockers, 2249 exposures occurred in children younger than 6 years (24% of reported cases).
  • In 2002, with 9585 total exposures to calcium channel blockers, 2256 exposures occurred in children younger than 6 years (24% of reported cases).
  • In 2003, with 9650 total exposures to calcium channel blockers, 2198 exposures occurred in children younger than 6 years (23% of reported cases).
  • In 2004, with 10,513 total exposures to calcium channel blockers, 2378 exposures occurred in children younger than 6 years (23% of reported cases).
  • In 2006, with 10,031 total exposures to calcium channel blockers, 1363 exposures occurred in children younger than 6 years (16% of reported cases).
  • In 2007, with 10,084 total exposures to calcium channel blockers, 1349 exposures occurred in children younger than 6 years.2

Clinical

History

Generally, patients with calcium channel blocker overdose present with empty pill bottles or a witnessed ingestion. When a history is unavailable, patients present with a cardiodepressive toxidrome and decreased heart rate and blood pressure.

  • Children can become symptomatic with as little as one tablet. In young children, calcium channel blockers have the potential to be fatal with single tablet ingestions. Delayed onset of hypotension has been reported in children with extended-release tablet ingestion. All children with suspected calcium channel blocker ingestions of any amount should be evaluated in a health care facility and monitored in an ICU setting for signs of delayed toxicity.
  • Carefully question the caretakers of children who present with depressed blood pressure or heart rate to see if anyone in the household is taking blood pressure or heart medicine.
  • In adults, deliberate overdoses are more likely to involve multiple medications, and alcohol is frequently a co-ingestant.
  • Establishing the complete list of medications that the patient may have had access to is important.
  • AAPCC consensus panel recommends the following ingestion amounts be sent into a hospital for evaluation (co-ingestants must be taken into account, these amounts assume an isolated accidentalingestion of only the calcium blocking medication):1

Open table in new window

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Table
DrugAdult DosagePediatric Dosage
Amlodipine>10 mg>0.3 mg/kg
Bepridil>300 mgAny amount
Diltiazem>120 mg immediate release, >360 mg sustained release>1 mg/kg
Felodipine>10 mg>0.3 mg/kg
Isradipine>20 mg>0.1 mg/kg
Nicardipine>40 mg immediate release, >60 mg sustained release>1.25 mg/kg
Nifedipine>30 mg immediate release, >120 sustained releaseAny amount
Nimodipine>60 mgAny amount
Nisoldipine>30 mg

Any amount

Verapamil>120 mg immediate release, >480 mg sustained release>2.5 mg/kg
DrugAdult DosagePediatric Dosage
Amlodipine>10 mg>0.3 mg/kg
Bepridil>300 mgAny amount
Diltiazem>120 mg immediate release, >360 mg sustained release>1 mg/kg
Felodipine>10 mg>0.3 mg/kg
Isradipine>20 mg>0.1 mg/kg
Nicardipine>40 mg immediate release, >60 mg sustained release>1.25 mg/kg
Nifedipine>30 mg immediate release, >120 sustained releaseAny amount
Nimodipine>60 mgAny amount
Nisoldipine>30 mg

Any amount

Verapamil>120 mg immediate release, >480 mg sustained release>2.5 mg/kg

Physical

Focus the physical examination on mental status and cardiovascular assessment.

  • Hypotension
  • Bradycardia, with variable degrees of heart block
  • Altered mental status or seizures secondary to hypotension
  • Occasional cases of bowel infarction caused by mesenteric underperfusion

Causes

  • Verapamil3,4,5 (eg, Calan, Isoptin), a phenylalkylamine, produces hypotension and heart block.
    • Several extended-release formulations are available (eg, Isoptin SR, Calan SR, Verelan, Covera-HS).
    • All extended-release formulations require longer observation periods to ensure that no delayed onset of toxicity occurs.
  • Nifedipine (eg, Procardia, Procardia XL, Adalat, Adalat CC) is representative of the dihydropyridine class, which produces profound hypotension with less heart block.
    • Overdoses with CCBs in this class may present with reflex tachycardia.
    • Other drugs in the dihydropyridine class of calcium channel blockers act similarly; they include nicardipine (eg, Cardene, Carden SR), nimodipine (Nimotop), nitrendipine, isradipine (DynaCirc, DynaCirc SR), amlodipine (Norvasc),6,7 felodipine (Plendil), and nisoldipine (Sular).
    • Amlodipine has a particularly long half-life of 45 hours.
    • All dihydropyridines exert their greatest effect on vascular smooth muscle, producing vasodilatation.
    • The sustained-release or controlled-release preparations also need prolonged observation for the same reasons prolonged observation is required for extended-release formulations.
  • Diltiazem (Cardizem), the only CCB in the benzothiazepine class, produces significant antidromotropic effects.
    • Patients ingesting diltiazem typically present with heart block and lesser degrees of hypotension.
    • Delayed-release formulations include Cardizem CD, Cardizem SR, Dilacor XR, Tiamate, Teczem, and Tiazac. These require longer observation periods to insure no delayed onset of toxicity.
  • Bepridil (Vascor), used for refractory angina, is a unique calcium channel blocker with some sodium channel blocking activity.
    • Bepridil has been shown to prolong the QTc interval through its potassium channel blocking effect; therefore, it may cause torsade de pointes.
    • About 1% of patients treated with this drug experienced ventricular arrhythmias.
  • Mibefradil (Posicor), was a novel selective T-channel calcium channel blocker, which was alleged to have less negative inotropy at therapeutic concentrations; however, it has been removed from the worldwide market after multiple adverse drug interactions were reported.
    • Mibefradil is proarrhythmic and may increase levels of tricyclic antidepressants and many other medications through competitive inhibition of cytochrome P450 C4A.
    • When patients are taking mibefradil, drugs that prolong the QTc interval (eg, terfenadine) should be used cautiously or not at all.
    • Soon after mibefradil's release, a box warning was added to the package insert; it warned that AV block and bradycardia has occurred with standard use, especially if the drug is taken in conjunction with beta-blockers or other calcium channel blockers.
    • On June 8, 1998, the drug was withdrawn from the US market because of adverse drug interactions with 26 other medications. A report by Mullins et al detailed 4 life-threatening cases of cardiogenic shock when mibefradil was used at recommended doses with calcium channel blockers and beta-blockers.8

More on Toxicity, Calcium Channel Blocker

Overview: Toxicity, Calcium Channel Blocker
Differential Diagnoses & Workup: Toxicity, Calcium Channel Blocker
Treatment & Medication: Toxicity, Calcium Channel Blocker
Follow-up: Toxicity, Calcium Channel Blocker
References
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Further Reading

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Keywords

calcium channel blocker overdose, CCB overdose, CCB overdose symptoms, CCB overdose treatment, calcium channel blocker toxicity, calcium antagonists, verapamil, nifedipine, diltiazem, calcium channel blocker poisoning, calcium channel blocker exposure, angina, hypertension, arrhythmia, migraine prophylaxis

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Contributor Information and Disclosures

Author

B Zane Horowitz, MD, FACMT, Professor, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System
B Zane Horowitz, MD, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology
Disclosure: Nothing to disclose.

Medical Editor

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

 
 
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