Continuing Education Activity

Calcium channel antagonists, also known as calcium channel blockers (CCBs), have been widely used for many indications. These agents are often classified into two major categories, either non-dihydropyridines or dihydropyridines. Cardiovascular indications include hypertension, coronary spasm, angina pectoris, supraventricular dysrhythmias, hypertrophic cardiomyopathy, and pulmonary hypertension. In addition to these, they are also prescribed for Raynaud phenomenon, subarachnoid hemorrhage, and migraine headaches. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of calcium channel blockade, pertinent for clinicians and other members of the interprofessional team for recognizing and being able to utilize these agents for their intended therapeutic purpose.

Objectives:

• Identify the mechanism of action of both categories of calcium channel blockers.
• Review the approved and off-label indications for various calcium channel blockers.
• Describe the adverse effects and contraindications for both classes of calcium channel blockers.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patient receiving treatment with the CCB class of medications.

Indications

In the 1970s, calcium channel antagonists, also known as calcium channel blockers, were widely used for many indications. This cardiovascular drug class is one of the leading causes of drug-related fatalities. They often classify into two major categories, either non-dihydropyridines or dihydropyridines. The non-dihydropyridines include verapamil, a phenylalkylamine, and diltiazem, a benzothiazepine. The dihydropyridines include many other drugs, most of which end in "pine" (i.e., amlodipine and nicardipine).[1][2][3][4]

Cardiovascular indications include hypertension, coronary spasm, angina pectoris, supraventricular dysrhythmias, hypertrophic cardiomyopathy, and pulmonary hypertension. In addition to these, they are also prescribed for Raynaud phenomenon, subarachnoid hemorrhage, and migraine headaches.

Mechanism of Action

Calcium channel antagonists block the inward movement of calcium by binding to the L-type “long-acting” voltage-gated calcium channels in the heart, vascular smooth muscle, and pancreas. There are two major categories of calcium channel antagonists based on their primary physiologic effects. The non-dihydropyridines have inhibitory effects on the sinoatrial (SA), and atrioventricular (AV) nodes are resulting in a slowing of cardiac conduction and contractility. This allows for the treatment of hypertension, reduces oxygen demand, and helps to control the rate in tachydysrhythmias. The dihydropyridines, in therapeutic dosing, have a little direct effect on the myocardium, and instead, are more often peripheral vasodilators, which is why they are useful for hypertension, post-intracranial hemorrhage associated vasospasm, and migraines.[5][6]

Absorption: Calcium channel antagonists are absorbed well orally, however many have low bioavailability due to hepatic first-pass metabolism, primarily by CYP3A4.

Distribution: Calcium channel antagonists are highly protein-bound, and many have high volumes of distribution.

Metabolism: In repeated doses, or overdose, the hepatic enzymes responsible for metabolism become saturated and reduce first-pass effects, which therefore increases absorption of the active drug. Modified release formulations and saturation of metabolism of these drugs increase the half-life of various calcium channel antagonists.

Excretion: Calcium channel antagonists are primarily excreted renally after metabolism.

There is the potential for drug-drug interactions because calcium channel antagonists are metabolized by CYP3A4, which is responsible for the metabolism of many other xenobiotics.

Administration

Calcium channel antagonist administration can be via the intravenous or oral routes.

Adverse Effects

Non-dihydropyridines may cause constipation, worsening cardiac output, and bradycardia.

Dihydropyridines may lead to lightheadedness, flushing, headaches, and peripheral edema. The peripheral edema is likely related to the redistribution of fluid from the intravascular space to the interstitium.

There have also been reports of gingival hyperplasia.

Contraindications

Non-dihydropyridines are contraindicated in those with heart failure with reduced ejection fraction, second or third-degree AV blockade, and sick sinus syndrome because of the possibility of causing bradycardia and worsening cardiac output.

Calcium channel antagonists are also contraindicated in patients with known hypersensitivity to the drug or its components. Other contraindications include sick sinus syndrome (except in patients with an artificial pacemaker), severe hypotension, acute myocardial infarction, and pulmonary congestion. Calcium channel antagonists may cause AV blockade or sinus bradycardia, especially if taken with agents known to slow cardiac conduction. There are reports of dermatologic reactions and hypotension with or without syncope with calcium channel antagonist use. Peripheral edema may occur within 2 to 3 weeks of initiating calcium channel blocker therapy. Use with caution in renal and hepatic impairment. Consider starting treatment at a lower dose.

Monitoring

Patients require close monitoring. The improvement of their symptoms of angina or maintenance of their blood pressure is an indication of efficacy. A patient should undergo regular assessment if the clinician is titrating these medications quickly.[7][8][9]

Toxicity

Hypotension and bradycardia are the primary features seen in calcium channel antagonist poisoning. These findings are due to peripheral vasodilatation and reduced cardiac contractility.

Hypotension may be profound and life-threatening; it results from peripheral vasodilation, bradycardia, and decreased ionotropy. Cardiac conduction may also suffer impairment with AV conduction abnormalities, complete heart block, and idioventricular rhythms.

Patients may present asymptomatic initially and progress rapidly to severe hypoperfusion and cardiovascular collapse. Symptoms may include lightheadedness, fatigue, change in mentation, syncope, coma, and sudden death. Non-cardiac symptoms may include nausea and vomiting, metabolic acidosis secondary to hypoperfusion, and hyperglycemia from the blockade of insulin release in the pancreas. The insulin blockade also impairs the uptake of glucose by myocardial cells, which further contributes to the reduction of cardiac contractility and worsens hypotension. Severe poisoning can lead to pulmonary edema, presumably as a result of precapillary vasodilation and increased transcapillary pressure.

Dihydropyridines in mild to moderate overdose may cause reflex tachycardia; however, in severe overdose, there may be a loss of receptor selectivity leading to bradycardia.

Many factors may affect the severity of overdose, including the calcium-channel antagonist dose, the formulation, ingestion with other cardioactive medications such as beta-blockers, the patient’s age, and comorbidities. These medications may also be life-threatening with as little as one tablet in small pediatric patients.

Hyperglycemia has been considered a prognostic indicator of the severity of calcium channel antagonist toxicity. Beta-islet cells in the pancreas depend on the influx of calcium through the L-type calcium channels to release insulin. In the case of calcium channel antagonist overdose, there is a reduction in the release of insulin and subsequent hyperglycemia.

As in any other overdose, it is crucial to maintain a patent airway. Obtain an electrocardiogram and place the patient on continuous monitoring, including pulse oximetry. Obtain a chest X-ray and basic labs (including acetaminophen and salicylate levels if warranted). Initiate gastrointestinal (GI) decontamination early, especially in the cases of large ingestions or those with sustained-release formulations in the appropriate settings (i.e., normal mental status, recent ingestion, among others.) Administer activated charcoal if the patient has presented early and is awake, alert, oriented, and protecting their airway. Whole bowel irrigation is an important option for those patients with massive overdoses or overdoses of sustained or extended-release formulations that do not already have an ileus.

In the case of hypotension, initial treatment with intravenous fluids requires caution in those who have congestive heart failure, pulmonary edema, or kidney disease. Intravenous calcium administration may reverse the decreased cardiac contractility. Calcium chloride 10% (10 ml for 0.1 to 0.2 ml/kg) or calcium gluconate 10% (20 to 30 ml 0.3 to 0.4 ml/kg) may be administered intravenously and may be repeated every 5 to 10 minutes. Caution must be used with calcium chloride as it may cause skin necrosis when given through a peripheral line. Atropine is a reasonable initial treatment option, but it typically does not reverse the effects of calcium channel antagonist poisoning. Give glucagon as a bolus of 5 to 10 mg intravenously with caution for nausea and vomiting, and patients may be pre-medicated with antiemetics to help avoid this. If the patient is refractory to these interventions, initiate vasopressor therapy using intravenous norepinephrine or push-dose phenylephrine while preparing hyperinsulinemia/euglycemia (HIE) therapy. HIE increases cardiac contractility by enhancing the transport of glucose into the myocardial cells, which corrects they hypo-insulinemia. Administer a bolus of insulin 1 unit/kg, followed by an infusion of 1 to 10 units/kg per hour. Monitor the patient’s glucose for hypoglycemia initially every 10 minutes and then every 30 to 60 minutes to maintain glucose between 100 to 200 mg/dL. Use a concomitant dextrose infusion to maintain these levels. If the initial glucose is less than 200 mg/dL, administer a bolus dose of glucose. Monitor glucose levels and potassium levels closely. Intravenous lipid emulsion therapy lacks clear evidence for efficacy but is a consideration if all else fails. Administer a bolus of intravenous lipid emulsion 20% 1.5 ml/kg, repeat if needed, and then start an infusion of 0.25 to 0.5 ml/kg per minute for an hour. Reports suggest that the use of methylene blue, especially in those with amlodipine overdose resulting in vasodilatory shock, may be effective. Phosphodiesterase inhibitors are also an option in calcium channel antagonist therapy. They increase cardiac output by inhibiting the breakdown of cAMP.  Extracorporeal membrane oxygenation (ECMO) has proven successful in cases refractory to all of the above interventions since it maintains perfusion to vital organs and continues hepatic metabolism.

Enhancing Healthcare Team Outcomes

Healthcare workers who prescribe calcium channel blockers should be familiar with their adverse effects. Both hypotension and bradycardia can occur in patients on calcium channel blockers and require immediate attention. Thus, patients on these agents require monitoring as long as they remain on the drugs. If side effects do occur, the patient's treatment depends on symptoms. All symptomatic patients with hypotension or bradycardia should go to the emergency department. In asymptomatic patients, the drug should be withheld, and dosage changes or an alternative medication may be required. In an ICU setting, nurses should know how to manage hypotension and bradycardia.