Primarily used for treatment of angina, hypertension, supraventricular tachycardia, and migraine prophylaxis.

Calcium channel blockers are available in regular and sustained release (SR) oral medications:

Signs and Symptoms

• Common: hypotension, bradycardia and cardiovascular collapse.
• Less common: hyperglycemia and metabolic acidosis, and CNS symptoms (due to hemodynamic instability).
• Cardiovascular toxicity following overdose is more severe in patients who have co-ingested other cardiac agents (e.g. beta-blockers, digoxin) or who have underlying cardiac disease (e.g. congestive heart failure, impaired conduction).

Laboratory abnormalities

• Hyperglycemia may be seen during the first 24 hours due to blockade of insulin release.

ECG changes can include

• Reflex tachycardia is common with amlodipine and felodipine which can progress to bradycardia in severe poisoning.
• Dysrhythmias most common with verapamil and diltiazem:
  • Narrow complex junctional escape rhythms are most common.
  • AV block, AV dissociation, junctional and idioventricular rhythms may progress to asystole and death.

Typical course

• Onset occurs within 30-60 minutes; up to 6-12 hours with sustained release (SR) preparations.
• Symptoms resolve within 24-48 hours though may take several days in severe overdose or with SR preparations.
• Death usually due to cardiovascular collapse.

Mechanism of Toxicity

• Selectively inhibit calcium influx across cell membranes of cardiac muscle (diltiazem and verapamil) and vascular smooth muscle (dihydropyridines – nifedipine, amlodipine, felodipine) resulting in negative inotropic and chronotropic effects and arterial vasodilation, respectively.
• At therapeutic doses, verapamil and diltiazem affect cardiac conduction, while dihydropyridines primarily affect vascular smooth muscle with minimal direct cardiac effects. However, in overdose, selectivity for vascular smooth muscle can be lost.
• Hyperglycemia seen in CCB overdose is secondary to inhibition of calcium-mediated insulin release from pancreas and peripheral insulin resistance.

Toxic Dose

• Varies with agent, presence of co-ingestants and underlying cardiac disease. Refer to BC Drug and Poison Information Centre (DPIC) Poison Management Manual for referral indication for possible toxic exposure.

• Serum levels for calcium channel blockers are not readily available.
• All patients should have basic toxicological investigations (electrolytes, salicylates, acetaminophen, ethanol, and digoxin level where appropriate).

Clinical pitfalls

• Managing patients with congestion of other cardiotoxic drugs and/or pre-existing cardiac disease.

• Can be very complex – consult BC DPIC early.
• Asymptomatic patients
  • Vital sign and continuous cardiac monitoring for at least 6-8 hours post-ingestion of an immediate release preparation (except amlodipine).
  • Sustained release preparations: Monitor for 18-24 hours.
  • ECG should be obtained on admission and prior to discharge.
• Symptomatic patients
  • Monitor until symptoms resolve.
  • Decontamination:
    • Administer activated charcoal.
    • Gastric lavage should be considered in patients presenting within the first hour following massive ingestion of an immediate release product.
  • Whole bowel irrigation (WBI) may be considered following ingestions of sustained release preparations in stable patients, though is contraindicated in the presence of ileus or hemodynamic instability. Caution in patients with decreased LOC as it may increase risk of aspiration.
• Protect airway and assist ventilation as needed.
• Monitor vital signs, ECG, electrolytes, glucose, and renal function.
• Treatment of bradycardia and hypotension may involve different therapies that may need to be started in parallel:
  • Atropine: 0.5 – 1 mg IV q15 min to max 3 mg.
  • IV fluids.
  • Calcium may improve blood pressure but not heart rate. Calcium chloride is preferred over calcium gluconate (3 times more concentrated) but should not be given peripherally. Dose: Adult: 10-20 mL of 10% calcium chloride, or 30-60 mL of 10% calcium gluconate.
  • Vasopressors: Norepinephrine is the most appropriate initial agent: Dopamine can be used alternatively. Titrate to effect as very high doses may be required; Start at 0.1 mcg/kg/min (7-10 mcg/min) and titrate up rapidly. Epinephrine (0.1 mcg/kg/min to start) or Vasopressin (2.4 units/hour fixed dose) are reasonable second line agents.

• High-dose insulin(HDI) therapy improves cardiac function without increasing myocardial work. Early initiation of HDI therapy (start when vasopressors are started) is recommended as response may take 30-90 minutes. Start with 1 unit/kg insulin bolus with 50 mL D50W, followed by a continuous infusion of 1 unit/kg/hour, titrating by 0.5-1 unit/kg/hour every 20-30 minutes to achieve a systolic blood pressure of 90-100 mm Hg). Intravenous dextrose should be infused at 0.5 g/kg/h (Usually D10W at 100-200 mL/h).

• • Glucagon may improve bradycardia and hypotension and should be given early in treatment. Consider early addition to other therapies (e.g. HDI) as clinical effects of glucagon is transient, hospital supplies are usually limited, and glucagon may induce vomiting. Start with 3-10 mg bolus (0.05-0.15 mg/kg in children) followed by infusion.
• Lipid emulsion therapy(LET) (Intralipid ®) should be reserved for patients with cardiac arrest or cardiovascular collapse unresponsive to therapies listed above. Provide an initial bolus of 1.5 mL/kg IV of 20% lipid emulsion over 1 minute. In asystolic patients, bolus can be repeated twice at 5-minute intervals. This can be followed by an infusion of 20% lipid emulsion (Intralipid¬Æ) at 0.25 – 0.5 mL/kg/minute for 30-60 minutes. LET is NOT a first-line therapy. LET is NOT a first-line therapy.
• Other measures to consider, if not responding, include:
  • Phosphodiesterase inhibitors such as milrinone (0.125-0.250 mcg/kg/min) may be useful but use is often limited by vasodilation which can worsen hypotension.
  • Non-pharmacologic therapies:
    • Transvenous pacing may be ineffective.
    • Extracorporeal membrane oxygenation (ECMO) can be considered in severe overdoses not responding to high dose insulin and/or LET. Early consultation or referral/transfer to an ECMO center may be appropriate.

• Further specific measures may be beneficial
  • Hemodialysis may be necessary for renal failure or correction of refractory metabolic acidosis. Hemodialysis is not effective in removing calcium channel blockers due to large volume of distribution and high protein binding.

• Patients often require a higher level of care and may require transfer. Consult BC Drug and Poison Information Centre for further discussions.

Consult

• Decisions to administer specific and advanced therapies (HDI, LET, ECMO) should be reviewed with BC Drug and Poison Information Centre 604-682-5050, 1-800-567-8911, dpic.org.

• After observation, periods have been met and the patient’s psychiatric condition has been treated if the overdose was intentional.

1. Poison Management Manual, BC Drug and Poison Information Centre