Continuing Education Activity

Calcium channel blockers (CCBs), also known as calcium channel antagonists, have been approved by the US Food and Drug Administration (FDA) and are widely used to treat various conditions such as hypertension, coronary heart disease, and chronic stable angina. However, despite their widespread use, this class of cardiovascular drugs is one of the primary contributors to drug-related fatalities. CCBs are often classified into 2 major categories—non-dihydropyridines or dihydropyridines. The non-dihydropyridines include verapamil, classified as a phenylalkylamine, and diltiazem, categorized as a benzothiazepine. Cardiovascular indications include hypertension, coronary spasm, angina pectoris, supraventricular dysrhythmias, hypertrophic cardiomyopathy, and pulmonary hypertension. In addition, CCBs can also be used to treat certain off-label indications, such as Raynaud phenomenon, subarachnoid hemorrhage, and migraine headaches. 

This activity reviews the indications, mechanism of action, adverse event profile, toxicity, dosing, pharmacokinetics, and monitoring of therapy using CCBs essential for the interprofessional healthcare team to recognize and utilize these agents effectively for their intended therapeutic purposes. This activity also helps clinicians distinguish CCBs from other classes of cardiovascular drugs, thereby enhancing their practice within a spectrum of medical settings and patient outcomes.

Objectives:

• Identify appropriate indications for calcium channel blockers in cardiovascular and non-cardiovascular conditions.

• Implement evidence-based dosing strategies and monitoring protocols for patients prescribed calcium channel blockers.

• Select appropriate calcium channel blocker formulations and dosages tailored to the patient's clinical condition and comorbidities.

• Collaborate with the interprofessional healthcare team to optimize the use of calcium channel blockers, coordinate patient care, and ensure their safe and effective use in clinical practice.

Indications

In the 1970s, calcium channel blockers (CCBs), also known as calcium channel antagonists, were widely used for several indications. CCBs have been approved by the US Food and Drug Administration (FDA) to treat various conditions such as hypertension, coronary heart disease, and chronic stable angina. However, despite their widespread use, this class of cardiovascular drugs is one of the primary contributors to drug-related fatalities. CCBs are often classified into 2 major categories—non-dihydropyridines or dihydropyridines. The non-dihydropyridines include verapamil, classified as a phenylalkylamine, and diltiazem, categorized as a benzothiazepine. Dihydropyridines include many other drugs, most of which end in "pine," such as amlodipine, felodipine, nisoldipine, and nicardipine.[1][2][3][4]

FDA-Approved Indications

Each drug has distinct FDA-approved indications, with some being utilized off-label. Verification is essential for each drug.

• Dihydropyridine drugs are used to treat hypertension, coronary artery disease, and chronic stable angina.

• Non-dihydropyridine drugs are used to treat hypertension, paroxysmal supraventricular tachycardia (PSVT) conversion, PSVT prophylaxis, atrial fibrillation/flutter, chronic stable angina, and vasospastic angina.

Off-Label Uses

Notably, although CCBs can also be used to treat certain off-label indications, as mentioned below, it is crucial to verify the specific agent under consideration, as discussed previously.

The off-label uses of CCBs include migraine prophylaxis, Raynaud phenomenon, hypertrophic cardiomyopathy, pulmonary hypertension, anal fissures, and high-altitude pulmonary edema.

Mechanism of Action

CCBs 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. Two major categories of CCBs are based on their primary physiological effects. The non-dihydropyridines exert inhibitory effects on the SA and AV nodes, thereby slowing cardiac conduction and contractility. This property allows for the treatment of hypertension, reduces oxygen demand, and helps to control the rate of tachydysrhythmias.

The dihydropyridines exert minimal direct effects on the myocardium and are primarily peripheral vasodilators at therapeutic doses. This property renders them useful for conditions such as hypertension, post-intracranial hemorrhage-associated vasospasm, and migraines.[5][6][7]

Pharmacokinetics

Absorption: CCBs are readily absorbed orally. However, many exhibit low bioavailability because of hepatic first-pass metabolism, primarily mediated by CYP3A4.

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

Metabolism: CCBs are extensively hepatically metabolized. In repeated doses or overdose, the hepatic enzymes responsible for metabolism become saturated and reduce first-pass effects, increasing absorption of the active drug. Modified release formulations and saturation of metabolism of these drugs increase the half-life of various CCBs. The potential for drug-drug interactions is because CCBs are metabolized by CYP3A4, which is responsible for the metabolism of many other xenobiotics.

Elimination: CCBs are primarily excreted renally after metabolism.

Administration

Available Dosage Forms and Strengths

CCBs are available in oral or injectable formulations. A selection of various agents in each class, along with their dose forms, are mentioned below.

• Dihydropyridine agents:
  • Amlodipine is available as oral tablets.
  • Felodipine is available as an extended-release (ER) oral tablet.
  • Nicardipine is available in oral capsules and injectable formulations.
  • Nisoldipine is available as an ER oral tablet.

• Non-dihydropyridine agents:
  • Diltiazem is available in oral formulations of 12- and 24-hour ER capsules, immediate-release tablets, ER tablets, and injectable formulations.
  • Verapamil is available in oral formulations such as 24-hour ER capsules (for morning dosing), 24-hour ER capsules (for evening dosing), immediate-release tablets, ER tablets, and injectable formulations.

Specific Patient Populations

Hepatic impairment: As these drugs undergo hepatic metabolism, patients with hepatic impairment often necessitate dosage adjustments. Thus, it is advisable to consult the information for the specific agent in the package insert or other reliable resources.

Renal impairment: Patients with renal impairment generally require no dosage adjustments. However, depending on the specific agent, clinicians should verify the renal dosing for that drug.

Pregnant patients: Based on limited data on human studies, fetal harm is generally not expected with either class of CCBs. Clinicians are advised to weigh the risks versus benefits when using CCBs in pregnant patients.

Breastfeeding females: Based on limited data on human studies, no infant harm is expected from either class of CCBs. However, data are unavailable to assess the effect of these drugs on milk production.

Pediatric patients: Studies have researched amlodipine and felodipine in children aged 6 to 18. Researchers found that amlodipine significantly lowered systolic blood pressure levels by 6.9 mm Hg using the 2.5 and 8.7 mm Hg with the 5-mg dose.[8] Verapamil is approved for PSVT conversion in pediatric patients. As some CCBs are occasionally used off-label in children, clinicians should exercise caution and refer to facility protocols and drug manufacturer inserts for precise dosing guidelines.

Older patients: As CCBs are excreted at a lower rate in older patients, caution is advised in those with hepatic impairment. CCBs are effective in managing hypertension in any age group and safe in older patients.[9]

Adverse Effects

The 2 classes of CCBs—dihydropyridines and non-dihydropyridines—have different adverse event profiles.

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. More severe adverse events include acute myocardial infarction (AMI), exacerbated angina, acute hypotension, syncope, erythema multiforme, and hepatitis, which can vary slightly depending on the chosen agent.[10][11]

Non-dihydropyridines may cause constipation, orthostatic hypotension, elevated liver enzymes, dizziness, constipation, and fatigue. More severe adverse reactions with non-dihydropyridine agents include bradycardia, reflex tachycardia, AV block, arrhythmias, severe hypotension, Stevens-Johnson syndrome, paralytic ileus, congestive heart failure, peripheral edema, and hepatotoxicity.[12][13] As with dihydropyridine agents, these adverse events can vary somewhat by the specific drug.

Drug-Drug Interactions

Many drug-drug interactions involving CCBs result from their extensive first-pass metabolism via the CYP450 enzyme system. The following summarizes some of the potential interactions with CCBs.[14] Reduced doses of interacting medications may be needed.

• CYP3A isoenzyme inhibition by verapamil and diltiazem:

  • Ciclosporin
  • Statins
  • Benzodiazepines
  • Buspirone
  • Sildenafil

• Inhibition of CYP3A isoenzyme:

  • Cimetidine
  • Erythromycin
  • Clarithromycin
  • Azole antifungals
  • Protease inhibitors
  • Grapefruit juice

• Induction of CYP3A isoenzyme:

  • Carbamazepine
  • Oxcarbazepine
  • Phenytoin
  • Nevirapine
  • Rifampicin
  • Pioglitazone

• P-glycoprotein inhibition by verapamil and diltiazem

  • Carbamazepine
  • Ciclosporin
  • Fexofenadine
  • Daunrubicin

Contraindications

Non-dihydropyridines are contraindicated in those with heart failure with reduced ejection fraction, second or third-degree AV blockade, systolic blood pressure <90 mm Hg, and sick sinus syndrome because of the possibility of causing bradycardia and worsening cardiac output.

CCBs 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, AMI, and pulmonary congestion. CCBs may cause AV blockade or sinus bradycardia, especially if taken with agents known to slow cardiac conduction. Reports of dermatologic reactions are pertinent, and hypotension with or without syncope with CCB use. Peripheral edema may occur within 2 to 3 weeks of initiating CCBs. They should be used with caution in cases of renal and hepatic impairment. Consideration should be given to initiating treatment at a lower dose.[15]

Monitoring

Patients on CCBs require close monitoring. Those initiating diltiazem or verapamil treatment should undergo liver function tests, blood pressure monitoring, heart rate assessment, and electrocardiogram (ECG) monitoring. For patients on dihydropyridine CCBs, monitoring blood pressure and heart rate is typically sufficient. Symptomatic improvement of angina or maintenance of blood pressure is an indication of efficacy. A patient should undergo regular assessment if the clinician is titrating these medications quickly.[16][17][18]

Toxicity

Managing CCB Overdose

Hypotension and bradycardia are the primary features of CCB poisoning, particularly with diltiazem and verapamil. These findings are due to peripheral vasodilatation and reduced cardiac contractility.[14] Hypotension may be profound and life-threatening and results from peripheral vasodilation, bradycardia, and decreased ionotropy. Cardiac conduction may also cause 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 glucose uptake by myocardial cells, which further contributes to the reduction of cardiac contractility and worsens hypotension. Severe poisoning can lead to pulmonary edema, presumably due to precapillary vasodilation and increased transcapillary pressure. Dihydropyridines in mild-to-moderate overdose may cause reflex tachycardia; however, receptor selectivity may be lost in severe overdose, leading to bradycardia.

Many factors may affect the severity of overdose, including the CCB dose, the formulation, ingestion with other cardioactive medications such as β-blockers, the patient's age, and comorbidities. These medications may also be life-threatening, with only 1 tablet in small pediatric patients.

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

As in any other overdose, it is crucial to maintain a patent airway. Healthcare providers should obtain an ECG and place the patient on continuous monitoring, including pulse oximetry. Healthcare providers should obtain a chest x-ray and conduct basic labs, including acetaminophen and salicylate levels, if necessary. Early initiation of gastrointestinal decontamination is recommended, particularly in cases involving large ingestions or sustained-release formulations, within appropriate settings, such as normal mental status and recent ingestion. Activated charcoal should be administered if the patient presents early and is awake, alert, oriented, and able to protect their airway. Whole bowel irrigation is an important option for patients with massive overdoses or overdoses of sustained or extended-release formulations that do not already cause an ileus.

Managing CCB-Induced Hypotension

In cases of hypotension, initial treatment with intravenous (IV) fluids requires caution in those with congestive heart failure, pulmonary edema, or kidney disease. IV 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 for 0.3 to 0.4 mL/kg) may be administered IV and repeated every 5 to 10 minutes. Caution is necessary with calcium chloride as it may cause dermal necrosis when given through a peripheral line.[2]

Atropine is a reasonable initial treatment option, but it typically does not reverse the effects of CCB poisoning. Glucagon may be administered as a bolus of 5 to 10 mg IV, with close monitoring for nausea and vomiting; patients may receive antiemetics as a pre-medication to mitigate these adverse effects. In cases where patients are refractory to these interventions, healthcare providers should consider initiating vasopressor therapy using IV norepinephrine or push-dose phenylephrine while simultaneously preparing hyperinsulinemia/euglycemia (HIE) therapy. HIE increases cardiac contractility through enhanced glucose transport into myocardial cells, thereby correcting hypo-insulinemia. A bolus of insulin of 1 unit/kg should be administered, followed by an infusion of 1 to 10 units/kg/h.[19][20] The patient's glucose levels should be monitored for hypoglycemia initially every 10 minutes and then every 30 to 60 minutes to maintain glucose levels between 100 and 200 mg/dL. To sustain these levels, healthcare providers should utilize a concurrent dextrose infusion as needed.

If the initial glucose is less than 200 mg/dL, a bolus dose of glucose should be administered to patients, and their glucose and potassium levels should be closely monitored. IV lipid emulsion therapy lacks clear evidence for efficacy but may be considered if all other interventions fail. A bolus of IV lipid emulsion 20% at a dose of 1.5 mL/kg should be administered, repeated if necessary, followed by an infusion of 0.25 to 0.5 mL/kg/min for 1 hour. Reports suggest that methylene blue, particularly in amlodipine overdose patients, may be effective in managing vasodilatory shock.[21] Phosphodiesterase inhibitors represent another option in CCB therapy; they increase cardiac output by inhibiting the breakdown of cAMP. In cases refractory to the aforementioned interventions, extracorporeal membrane oxygenation has succeeded as it sustains perfusion to vital organs and continues hepatic metabolism.

Enhancing Healthcare Team Outcomes

Healthcare providers responsible for prescribing, administering, or dispensing CCBs should thoroughly understand their indications, interactions, and potential adverse effects. Patients receiving CCBs are at risk of experiencing hypotension and bradycardia, which could pose life-threatening risks and necessitate immediate attention. Close monitoring of patients throughout their treatment course is imperative. Any symptomatic patients manifesting hypotension or bradycardia should be promptly transported to the emergency department. Medication administration should be suspended for asymptomatic patients, and consideration should be given to dosage adjustments or alternative medications. Nurses in intensive care settings should be proficient in managing hypotension and bradycardia.

Due to the adverse event profile and the numerous interactions associated with CCBs, optimal therapeutic outcomes and prevention of adverse events necessitate the involvement of an interprofessional healthcare team. This team comprises physicians, advanced practice practitioners, nursing staff, and pharmacists collaborating to coordinate actions, maintain open communication, and uphold meticulous record-keeping. They strive to achieve the best patient outcomes with CCB therapy by working together.