What are the side effects of diltiazem (calcium channel blocker)?

Side Effects of Diltiazem

Diltiazem's most common adverse effects include peripheral edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), and rash (1.3%), with the most clinically significant risks being hypotension, bradycardia, AV block, and worsening heart failure in patients with pre-existing ventricular dysfunction. 1, 2

Common Adverse Effects (Occurring in >1% of Patients)

The FDA-approved labeling identifies the following most frequent side effects from controlled trials 1:

• Peripheral edema (2.4%) - This is dose-related, more common in women, and shared by all calcium channel blockers 3, 2
• Headache (2.1%) - Related to peripheral vasodilation 1, 4
• Nausea (1.9%) 1
• Dizziness (1.5%) 1
• Rash (1.3%) 1
• Asthenia/weakness (1.2%) 1

Cardiovascular Side Effects (Most Clinically Important)

Diltiazem's effects on cardiac conduction and contractility create the most serious adverse effect profile 3:

• Bradycardia - Due to negative chronotropic effects on SA and AV nodes; risk significantly increased when combined with beta-blockers 3, 2
• AV block - First-degree AV block occurs uncommonly; second- or third-degree AV block is rare but serious 1, 5
• Hypotension - The most common adverse effect requiring clinical attention 2
• Worsening heart failure - In patients with pre-existing ventricular dysfunction or reduced ejection fraction; recent data shows 17% incidence in hospitalized patients with EF <50% versus 4.8% with preserved EF 6, 2
• Reduced left ventricular contractility - Due to intrinsic negative inotropic effects 3

Unlike dihydropyridine calcium channel blockers, diltiazem does NOT typically cause reflex tachycardia due to its direct negative chronotropic effects 3.

Gastrointestinal Side Effects

• Constipation - Particularly problematic in elderly individuals due to decreased intestinal motility 3, 7
• Anorexia, diarrhea, dyspepsia, dysgeusia - All occurring in <1% of patients 1
• Potential GERD exacerbation - Can cause noncardiac chest pain through reflux, potentially confounding clinical picture in cardiac patients 7

Hepatic Effects

• Mild elevations of liver enzymes - Alkaline phosphatase, SGOT, SGPT, and LDH 1
• Acute hepatic injury - Rare but requires monitoring if clinically indicated 2, 1

Rare but Serious Postmarketing Adverse Events

The FDA labeling identifies the following serious reactions reported after market approval 1:

• Dermatologic: Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis (proven by rechallenge), leukocytoclastic vasculitis, photosensitivity
• Hematologic: Hemolytic anemia, leukopenia, thrombocytopenia, increased bleeding time
• Cardiac: Asystole, congestive heart failure
• Other: Angioedema (including facial/periorbital), gingival hyperplasia, extrapyramidal symptoms, myopathy, retinopathy

Drug Interaction-Related Adverse Effects

Diltiazem is both a CYP3A4 substrate and moderate CYP3A4 inhibitor, creating significant interaction potential 2:

• Severe bradycardia risk - When combined with ivabradine (both metabolized by CYP3A4) 3, 2
• Enhanced bradyarrhythmias and heart block - When combined with beta-blockers 2, 5
• Increased drug levels - Of CYP3A4 substrates including apixaban, cyclosporine, simvastatin, and many others 2

Clinical Monitoring Recommendations

To detect and manage adverse effects, the American College of Cardiology recommends 2:

• Blood pressure and heart rate monitoring - Regularly during dose titration
• ECG monitoring - In patients with conduction system disease
• Signs/symptoms of heart failure - In at-risk patients, particularly those with reduced EF
• Liver function tests - If clinically indicated

Key Clinical Pitfalls to Avoid

• Do not combine with beta-blockers without careful monitoring - Risk of severe bradycardia and heart block 2, 5
• Avoid in patients with EF <50% when possible - 17% risk of worsening heart failure in hospitalized patients 6
• Never use in second/third-degree AV block without pacemaker - Absolute contraindication 2, 1
• Exercise caution in elderly patients - Higher risk of constipation and may require dose adjustment 3, 2