DESCRIPTION

Calcium channel-blocking drugs (CCBs) are commonly used to treat hypertension and certain cardiac dysrhythmias.

FORMS AND USES

• Typical pharmaceutical formulations include verapamil (Isoptin and Calan), diltiazem (Cardizem), nifedipine (Adalat and Procardia), amlodipine (Norvasc), bepridil (Vascor), isradipine (Dynacirc), nicardipine (Cardene), and nimodipine (Nimotop).
• Sustained-release products include verapamil (Calan SR, Isoptin SR, Covera-HS, and Verelan), diltiazem (Cardizem SR, Cardizem CD, and Dilacor XR), nifedipine (Procardia XL and Adalat CC), nicardipine (Cardene SR), felodipine (Plendil), and nisoldipine (Sular R).
• Treatment of hypertension.
  • Typical adult dose of verapamil is 80 mg orally three times per day initially (maximum 360 mg/day); pediatric dose is 3 to 5 mg/kg/day orally in divided doses.
  • Adult dose of nifedipine is 10 mg three times per day initially (maximum 120 mg/day); pediatric dose is 0.25 to 0.5 mg/kg.

TOXIC DOSE

• Ingestion of a gram or more of verapamil, nifedipine, or diltiazem can produce serious toxicity and possible death in an adult.
• The other medications in this class appear less toxic, but few data are available on overdose.

PATHOPHYSIOLOGY

• CCBs inhibit entry of extracellular calcium through voltage-dependent calcium channels, thereby reducing contraction of cardiac muscle.
• CCBs also relax arterial smooth muscle but have little effect on venous beds.

EPIDEMIOLOGY

• Poisoning is uncommon.
• Toxic effects following exposure are typically mild to moderate.
• Death occurs in cases involving coingestants or a massive overdose.

CAUSES

• Toxic ingestion is usually intentional.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is older than 6 years of age.

RISK FACTORS

Elderly patients and those with underlying cardiovascular disease may be intolerant of even mild hypotension.

DRUG AND DISEASE INTERACTIONS

• Hepatic disease decreases CCB elimination.
• Coingestion of beta-blockers, digitalis, or class I antidysrhythmic agents may worsen bradycardia, dysrhythmias, and hypotension.
• Coingestion of other antihypertensives may worsen hypotension.

PREGNANCY AND LACTATION

• All CCBs. US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Verapamil and nifedipine have been used as tocolytics.
• Verapamil administered to the mother may have cardiovascular effects on the fetus.
• Verapamil, diltiazem, nifedipine, and nicardiopine are excreted in human breast milk.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxicologic causes of bradycardia or heart block that resemble CCB overdose include beta-receptor blocker, digitalis, class I antidysrhythmics, and clonidine, among others.
• Nontoxicologic causes include ischemic heart disease and severe electrolyte abnormalities such as hyperkalemia.

SIGNS AND SYMPTOMS

• CCBs suppress cardiac function to varying degrees in overdose.
  • Verapamil and diltiazem are more effective than nifedipine at suppressing sinoatrial and atrioventricular nodal firing.
  • Overdose with any of these agents may result in bradycardia and hypotension.

Vital Signs

Bradycardia and hypotension are common.

Cardiovascular

Effects may include severe bradycardia, atrioventricular block, intraventricular conduction delays, ventricular dysrhythmias, and congestive heart failure.

Pulmonary

• Respiratory depression may develop in patients with hemodynamic instability.
• Pulmonary edema and adult respiratory distress syndrome may develop after severe overdose.

Gastrointestinal

Nausea, vomiting, and ileus can occur.

Neurologic

• CNS depression and syncope can occur.
• Seizure occurs rarely.
• Coma may complicate profound hypotension.

Fluids and Electrolytes

Metabolic acidosis may develop in patients with hypotension.

PROCEDURES AND LABORATORY TESTS

Essential Tests

ECG and continuous monitoring should be performed to detect dysrhythmia or ischemia.

Recommended Tests

• Serum electrolytes, glucose, BUN, and creatinine should be assayed to detect other causes of dysrhythmia or origin of drug accumulation. Hyperglycemia resolves as CCB effects abate.
• Serum creatine kinase should be tested in patients with prolonged seizures or coma to detect rhabdomyolysis.
• Serum acetaminophen and aspirin levels should be measured in overdose setting to detect occult ingestion.
• Head CT, lumbar puncture, bacterial cultures, and other tests are used to assess altered mental status if etiology is unclear.
• Chest radiograph should be taken in a patient with pulmonary symptoms or coma.

Not Recommended Tests

CCB levels are neither easily attainable nor clinically useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Neurologic
  • Fluids and Electrolytes
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on continuous ECG monitoring and treatment of dysrhythmia or hypotension.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Bradycardia, hypotension, altered mental status, or other severe effects are present.
• Toxic effects are not consistent with CCB poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents unusual problem, or more than one daily dose for age was ingested.

Admission Considerations

Inpatient management is warranted if patient is symptomatic or has ingested sustained release preparation.

DECONTAMINATION

Out of Hospital

Emesis should not be induced; coma or seizures may develop abruptly.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if severe effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.
• Whole-bowel irrigation with a polyethylene glycol solution should be considered following significant ingestion of sustained-release preparation.

ANTIDOTES

There is no specific antidote for CCB poisoning.

ADJUNCTIVE TREATMENT

• Hypotension
  • The primary treatment is correction of dysrhythmia, if possible.
  • Patient should receive 10 to 20 ml/kg 0.9% saline intravenously and be placed in the Trendelenburg position.
  • Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
  • A vasopressor may be added if needed. Dopamine initial dosage is 2 to 5 µg/kg/min titrated upward to effect. Dosages above 20 µg/kg/min are unlikely to have further effect. Norepinephrine may be added if hypotension is unresponsive to dopamine, 0.1 to 0.2 µg/kg/min, titrated to effect.
• If hypotension is unresponsive, or bradycardia, heart block, or signs of serious toxicity are present, calcium administration is recommended.
  • Calcium chloride 10% is preferred over calcium gluconate.
  • Initial dose for an adult is one ampule (10 ml of 10% solution) infused over 5 minutes; pediatric dose is 10 to 25 mg/kg, up to one ampule per dose.
  • Dose may be repeated every 10 minutes as needed; however, if more than two additional treatments are needed, consultation with a poison center or medical toxicologist is recommended.
  • Caution: Extravasation may cause skin necrosis.
• Bradycardia or hypotension that is refractory to standard interventions, including administration of atropine, calcium, and vasopressors is treated with glucagon.
  • An intravenous bolus of 50 to 150 µg/kg (5-10 mg in an adult) of glucagon should be infused initially, followed by an infusion of 2 to 10 mg/h, titrated to effect.
  • Vomiting and hyperglycemia occur frequently.
  • If large doses are given, saline should be used to reconstitute the drug instead of the diluent included with the glucagon package.
  • Hospital pharmacies often stock insufficient amounts of glucagon.
• Overdoses unresponsive to drug therapy. Intraaortic balloon pump has been used for hemodynamic support.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

• Continuous respiratory, cardiac, and hemodynamic monitoring should be instituted.
• Serum glucose should be monitored in diabetics and children.

EXPECTED COURSE AND PROGNOSIS

• Most patients do well with gastrointestinal decontamination and supportive care.
• Course may be prolonged and complicated in patients with massive ingestion, advanced age, underlying cardiovascular disease, or coingestion of other myocardial depressant.
• Sequelae of prolonged hypotension may develop in severe cases.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Asymptomatic patients may be discharged following gastric decontamination, 6 hours of observation, and psychiatric evaluation, if needed. Ingestion of a sustained-release product usually warrants 24-hour observation.
• From the hospital. Patients may be discharged following gastrointestinal decontamination, resolution of cardiac effects, and psychiatric evaluation. if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Sustained-release products may not produce toxic effects for several hours after overdose.

TREATMENT

• Multiple modes of treatment (pressors, glucagon, isoproterenol, etc.) are often needed simultaneously in patients with severe effects.
• Elderly patients may be intolerant of even mild hypotension.

Poisoning by agents primarily affecting the cardiovascular system.

See Also: SECTION II, Hypotension chapter; SECTION III, Calcium Gluconate and Chloride and Glucagon chapters.

RECOMMENDED READING

Lewin N. Antihypertensive agents. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies, 6th ed. Norwalk, CT: Appleton & Lange, 1998.

Authors: Lada Kokan and Kennon Heard

Reviewer: Richard C. Dart