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 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 diltiazem interactions, pertinent for interprofessional team members 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 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 anti-anginal.[1]

FDA-approved Indications

• Atrial arrhythmia

• Hypertension

• Paroxysmal supraventricular tachycardia

• Chronic stable angina

• Angina Due to Coronary Artery Spasm( Prinzmetal's or variant angina)[2]

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

Non-FDA-approved Indications

• Anal fissures[3]

• Migraine prophylaxis[4]

• Pulmonary hypertension[5][6]

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(CCB). 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. 

Hypertension

• Diltiazem primarily produces its antihypertensive effect by relaxing the vascular smooth muscle and decreasing peripheral vascular resistance. The magnitude of blood pressure reduction is related to hypertension; thus, hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.

Atrial Arrhythmia/Paroxysmal Supraventricular Tachycardia

• Diltiazem is a negative inotrope (decreased force) and negative chronotrope (decreased rate). Along with coronary artery vasodilation, the combination decreases myocardial oxygen demand results in decreased heart rate.

Angina

•  Diltiazem has been shown to increase exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and blood pressure at submaximal and maximal workloads. Diltiazem is a potent dilator of coronary arteries, both epicardial and subendocardial.[7]

Administration

In the United States, diltiazem is FDA-approved as an oral and intravenous formulation. Compounded topical preparations of diltiazem are used off-label.[8][9]

Review the package insert for the formulation 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(adjusted body weight) IV over 2 minutes
  • If needed, repeat the 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 

Renal Impairment

• No dose adjustment is necessary.

Hepatic Impairment

• No dose adjustment is likely needed for mild-moderate hepatic impairment, but diltiazem is extensively metabolized in the liver. Consequently, use with caution in hepatic impairment.[2]

Pregnancy Considerations

• Diltiazem is teratogenic in animals, and only limited data in humans exist; thus, its use is only recommended in pregnancy if the potential benefit justifies the potential risk to the fetus.[10]

Breastfeeding Considerations

• Diltiazem is excreted in human milk. Based on the current data, amounts of diltiazem ingested by the infant are small. However, due to serious adverse reactions, if diltiazem is deemed essential, the clinician should suggest an alternative method of infant feeding.[11]

Adverse Effects

• Common adverse effects of diltiazem therapy include peripheral edema, bradycardia, dizziness, headache, and fatigue.[12]

• Severe adverse effects include congestive heart failure, myocardial infarction, and hepatotoxicity.[2]

• Diltiazem is indicated for the treatment of arrhythmias and, consequently, the potential to worsen or create new arrhythmias such as extrasystole and AV block.[13]

• 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.[14]

• Concurrent administration with agents that slow cardiac conduction can further potentiate adverse effects like AV block or bradycardia.[15]

Contraindications

• Sick sinus syndrome except in the presence of a functioning ventricular pacemaker

• Severe hypotension(SBP<90 mm hg)

• Documented hypersensitivity to the drug

• Acute myocardial infarction and pulmonary congestion

• Concurrent administration of intravenous beta-blockers

• Wide complex ventricular tachycardia[16]

• Atrial fibrillation or flutter associated with an accessory bypass tract (i.e., Wolff-Parkinson-White syndrome)[17]

• Second- or third-degree AV block except in the presence of a functioning ventricular pacemaker[13]

• Cardiogenic shock[18]

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. In contrast, 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.

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. 

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 to treat hypertrophic cardiomyopathy, diltiazem therapy may continue, but additional fetal monitoring is required.[10]

Toxicity

There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases with the known outcome, most patients recovered, and in cases with a fatal outcome, the majority involved multiple drug ingestion. 

Clinical Features 

• Profound bradycardia

• Dizziness

• End organ dysfunction

• Hypotension

• AV block

• Cardiac failure

Management

• Treat according to ACLS protocol for arrhythmias and hypotension.[19][20]

• Whole bowel irrigation for gastrointestinal decontamination[21]

• Administer IV calcium gluconate or calcium chloride.[22]

• Administer IV atropine (0.60 to 1.0 mg) for bradycardia.[23]

• IV glucagon enhances intracellular levels of cyclic adenosine monophosphate and increases heart rate.[24]

• Severe toxicity may respond to hyperinsulinemia/euglycemia therapy(HIET).[25] 

• Lipid emulsion therapy in significant cardiotoxicity.[26]

• Transvenous pacemaker to assist with electrical conduction. If there are no contraindications, an intra-aortic balloon pump can be deployed.[27]

• Extracorporeal membrane oxygenation is used for  Massive diltiazem overdose.[28]

• CCBs, including diltiazem, are extremely protein-bound; consequently, extracorporeal removal by hemodialysis is ineffective.[29]

• Administer vasopressors and inotropic agents (e.g., dopamine or norepinephrine) for severe hypotension and cardiac failure.[30]

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. Diltiazem possesses negative inotropic effects and is generally avoided in patients with congestive heart failure, and diltiazem is also on the Beers Criteria.[31] These factors highlight the importance of avoiding diltiazem in heart failure patients, especially in the elderly, due to drug interactions and heart failure exacerbation.[32]

Ideally, Clinicians should verify drug, dose, and patient factors before administration. For example, one common error with diltiazem therapy is an incorrect dose administered to the patient. Double-checking doses can help ensure the patient receives appropriate therapeutic management in inpatient and outpatient settings. Pharmacists, nurses, and other providers should also check for potential drug interactions with other medications of the patient's profile. For example, Diltiazem is available in many brand names with differing recommended dosages and differing maximum daily dosesThis vigilance will limit possible drug interactions. Nursing staff should monitor for clinical improvement and any adverse drug reaction and inform the clinicians in case of any inconsistency.

In overdose, triage nurses and emergency department physicians should quickly stabilize the patient. Critical care physician supervision is necessary for severe hypotension and cardiac failure. IABP insertion requires cardiac consultation. Obtain the latest information by contacting the poison control center(800-222-1222) in the United States. As illustrated above, clinicians(MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, and other healthcare providers are involved in taking care of the patient. Hence it is vital to communicate and work collaboratively for better patient outcomes related to diltiazem therapy. An interprofessional team approach involving all the providers would maximize efficacy and minimize adverse drug reactions translating to optimal patient outcomes with minimum adverse drug reactions. [Level 5]