Continuing Education Activity

Diltiazem is an oral and parenteral non-dihydropyridine calcium channel blocker. It is used in many clinical scenarios as an antihypertensive, anti-arrhythmic, and as an anti-anginal. FDA-approved indications include atrial arrhythmia, hypertension, paroxysmal supraventricular tachycardia, and chronic stable angina. Diltiazem also has numerous off-label indications. This activity will highlight the mechanism of action, adverse event profile, approved and off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions of diltiazem, pertinent for members of the interprofessional team using diltiazem for any of its intended indications.

Objectives:

• Explain the mechanisms of action for diltiazem.
• Identify the approved and off-label indications for diltiazem use.
• Review the adverse events and monitoring parameters for diltiazem therapy.
• Outline the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using diltiazem.

Indications

Diltiazem is an oral and parenteral non-dihydropyridine calcium channel blocker. It is useful in many clinical scenarios as an antihypertensive, anti-arrhythmic, and as an anti-anginal.[1]

FDA-approved Indications:

• Atrial arrhythmia 
• Hypertension
• Paroxysmal supraventricular tachycardia
• Chronic stable angina

Diltiazem also has utility in numerous off-label indications. A select few are listed below.

Non-FDA-approved Indications[2]:

• Anal fissures
• Migraine prophylaxis
• Cramps in lower leg related to rest
• Pulmonary hypertension

Diltiazem is available in many dosage forms and strengths, making it imperative to be cautious when prescribing, dispensing, and administering this medication. There are numerous brand names for oral diltiazem (capsules and tablets), and available strengths include 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg.

Mechanism of Action

Diltiazem is a non-dihydropyridine calcium channel blocker. Therapeutic effects occur through various mechanisms. Primarily, diltiazem inhibits the inflow of calcium ions into the cardiac smooth muscle during depolarization. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and, therefore, decreased blood pressure. Diltiazem is a potent coronary artery vasodilator and is consequently used for chronic angina and in those patients with coronary vasospasm. Vasospasm of the coronary arteries can lead to debilitating conditions such as myocardial infarction.

Diltiazem is a negative inotrope (decreased force) and negative chronotrope (decreased rate). The combination, along with coronary artery vasodilation, leads to decreased myocardial oxygen demand, decreased heart rate, and reduced blood pressure.

Administration

In the United States, diltiazem is FDA-approved as an oral and intravenous formulation. Compounded topical preparations of diltiazem are used off-label.[3][4]

Consult the package insert for the formulation you are using by brand name because pharmacokinetics vary significantly between different brands. The following represent the dosing variances by condition using generic names under various trade names.

Recommended Dosages

Hypertension

• Diltiazem hydrochloride (various brands)
  • Initial dose:       180 mg to 240 mg once daily
  • Maximum dose: 480 mg once daily
• Diltiazem HCl (various brands)
  • Initial dose:       120 mg to 240 mg once daily
  • Maximum dose: 540 mg once daily
• Diltiazem HCl extended-release (various brands)
  • Initial dose:       180 mg to 240 mg once daily
  • Maximum dose:  540 mg once daily

 Chronic Stable Angina

• Diltiazem hydrochloride (various brands)
  • Initial dose: 30 mg four times daily*
• Diltiazem HCl (various brands)
  • Initial dose:      120 mg to 180 mg once daily
  • Maximum dose: 480 mg once daily
• Diltiazem HCl (various brands)
  • Initial dose:      120 mg to 180 mg once daily
  • Maximum dose: 540 mg once daily
• Diltiazem HCl extended-release (various brands)*
  • Initial dose:      180 mg once daily
• Diltiazem HCl extended-release (various brands)
  • Initial dose:      120 mg once daily
  • Maximum dose: 480 mg once daily

Atrial Arrhythmia/Paroxysmal Supraventricular Tachycardia

• Initial dose: IV bolus 0.25 mg/kg ABW IV over 2 minutes
  • If needed, repeat dose at 0.35 mg/kg ABW IV after 15 minutes
• Maintenance dose: IV continuous infusion 10mg/hr
  • Increase dose at 5mg/hr to max 15mg/hr
  • Max infusion time is 24 hours 

*Increase based on clinical response to 180mg to 360mg/day

Adverse Effects

Common adverse effects of diltiazem therapy include edema, bradycardia, dizziness, headache, and fatigue. Rarer, yet more severe adverse effects include congestive heart failure, myocardial infarction, and hepatotoxicity. Diltiazem is indicated for the treatment of arrhythmias and consequently, the potential to worsen or create new arrhythmias such as extrasystole and AV block. 

Diltiazem is extensively metabolized through the CYP450 system and requires careful medication profile review. Concomitant use alongside potent CYP450 inhibitors may increase diltiazem concentrations leading to adverse effects even at clinically recommended doses. Concomitant administration with agents that slow cardiac conduction can further potentiate adverse effects such as AV block or bradycardia. 

Contraindications

Specific clinical scenarios are contraindicated to the use of diltiazem. Due to its mechanism of actions, patients with a systolic blood pressure of less than 90mmHg are ineligible for diltiazem pharmacotherapy. Additional contraindications include sick sinus syndrome and second/third-degree AV block, without a functioning ventricular pacemaker and acute myocardial infarction with pulmonary congestion on X-ray.

Additional contraindications are in place for intravenous administration. These include concomitant or recent administration of intravenous beta-blockers; cardiogenic shock; atrial fibrillation or flutter associated with an accessory bypass tract (i.e., Wolff-Parkinson-White syndrome); and ventricular tachycardia. 

Monitoring

Therapeutic monitoring includes periodic assessments of blood pressure, heart rate, and electrocardiograms. When treating hypertension and arrhythmias, objective findings serve to assess the efficacy of therapy, while subjective findings, such as a patient's frequency and severity of chest pain, are used to evaluate efficacy when treating chronic angina. A complete blood count (CBC) lab test is also performed at baseline to track potential changes in electrolytes and kidney and liver function. 

For the treatment of hypertension during pregnancy, recommendations state to use an alternative agent as diltiazem has shown adverse fetal effects in animal studies. If a patient is controlled on diltiazem for the treatment of hypertrophic cardiomyopathy, diltiazem therapy may continue, but additional fetal monitoring is required. 

Additional monitoring is required when using diltiazem parenterally. When treating arrhythmias, an IV bolus is administered over two minutes. Continuous blood pressure and ECG monitoring are necessary during the bolus administration. 

Toxicity

Potential diltiazem overdose can lead to profound bradycardia and conduction delays by suppression of SA and AV nodes. These may manifest as dizziness, lightheadedness, and fatigue. Further toxicities can lead to worsened arrhythmias, hyperglycemia, and end-organ dysfunction. Moderate toxicity is treatable with fluids, but ACLS protocol may be required when treating severe bradycardia and hypotension.[5][6]

Diltiazem is a substrate of the CYP450 enzyme, and careful monitoring is warranted when given concomitantly with inducers or inhibitors. Potent inducers/inhibitors can lead to new arrhythmias or worsen existing arrhythmias. Potent inhibitors can increase diltiazem concentration leading to mentioned toxicities. A pharmacist or other clinician should conduct a medication profile review when initiating new medications for patients on diltiazem.[7]

Enhancing Healthcare Team Outcomes

Diltiazem has been widely used in practice for many clinical indications. Proper dosage and frequency are essential to enhance patient care and improve outcomes. Providers should verify drug, dose, and patient factors prior to administration. One common error that occurs with diltiazem therapy is an incorrect dose administered to the patient. Diltiazem is available in many brand names with differing recommended dosages and differing maximum daily doses. Double-checking doses can help ensure the patient is receiving appropriate therapeutic management in both the inpatient and outpatient settings. Pharmacists and other providers should also check for potential drug interactions with other medications of the patient's profile. This vigilance will limit possible drug interactions. 

Diltiazem possesses negative inotropic effects and is generally avoided in patients with congestive heart failure, but diltiazem is also on the Beers Criteria. These factors highlight the importance of avoiding diltiazem in heart failure patients, especially in the elderly, due to potential fluid retention and heart failure exacerbation.