What drug interactions can cause bradycardia?

Drug Interactions Causing Bradycardia

The most clinically significant drug interactions causing bradycardia occur when combining drugs with sinoatrial (SA) or atrioventricular (AV) nodal blocking properties, particularly beta-blockers with calcium channel blockers (diltiazem, verapamil), or when adding CYP2D6 inhibitors to beta-blockers. 1, 2

Primary High-Risk Combinations

Beta-Blockers with Calcium Channel Blockers

• Concomitant use of beta-blockers (metoprolol, propranolol) with non-dihydropyridine calcium channel blockers (diltiazem, verapamil) produces additive bradycardia through dual SA/AV nodal blockade 1, 3
• Amiodarone should be used with caution when combined with beta-blockers or calcium channel antagonists due to possible potentiation of bradycardia, sinus arrest, and AV block 2
• This combination may require pacemaker insertion in patients who develop severe bradycardia or sinus arrest 2
• A case report documented atrial fibrillation triggered by severe bradycardia from concomitant beta-blocker and diltiazem use 4

CYP2D6 Inhibitors with Beta-Blockers

• Potent CYP2D6 inhibitors significantly increase metoprolol plasma concentrations, mimicking poor metabolizer pharmacokinetics and reducing cardioselectivity 5
• High-risk CYP2D6 inhibitors include:
  • Antidepressants: fluoxetine, paroxetine, sertraline, bupropion, fluvoxamine 5, 6
  • Antipsychotics: chlorpromazine, haloperidol, thioridazine 5
  • Antiarrhythmics: quinidine, propafenone 5
  • Antifungals: terbinafine 5, 7
• A documented case showed metoprolol-terbinafine interaction causing 37 beats/min sinus bradycardia requiring emergency management 7
• SSRIs combined with metoprolol or propranolol resulted in bradycardia in 25 cases (37.9% of adverse reactions), including one cardiac arrest with fluoxetine-propranolol 6

Additional Significant Interactions

Ivabradine-Related Combinations

• Ivabradine is contraindicated with drugs that exacerbate bradycardia 1
• Strong CYP3A4 inhibitors (clarithromycin, itraconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir) must be avoided with ivabradine 1
• Diltiazem, verapamil, and grapefruit juice should be avoided with ivabradine due to increased exposure and exacerbated bradycardia 1, 8

Sotalol Combinations

• Sotalol causes bradycardia and should not be combined with other drugs having SA/AV nodal blocking properties 1
• Contraindicated in sinus or AV nodal dysfunction without pacemaker 1

Sofosbuvir-Based Regimens with Amiodarone

• Sofosbuvir-based regimens are contraindicated with amiodarone due to risk of life-threatening bradyarrhythmias 1
• Bradycardia observed within hours to days (up to 2 weeks) after starting treatment 1
• If amiodarone cannot be avoided, wait 3 months after discontinuation before starting sofosbuvir-based regimen 1

Catecholamine-Depleting Drugs

• Reserpine and MAO inhibitors combined with beta-blockers produce additive effects causing marked bradycardia 5
• Monitor for hypotension, vertigo, syncope, or postural hypotension 5

Clonidine with Calcium Channel Blockers

• Sinus bradycardia requiring hospitalization and pacemaker insertion reported with clonidine-diltiazem combination 8
• Monitor heart rate closely with this combination 8

Monitoring and Management Algorithm

Prevention Strategy

1. Obtain baseline ECG before initiating any combination with bradycardia risk 1
2. Correct electrolyte abnormalities (hypokalemia, hypomagnesemia) before treatment 1
3. Review complete medication list for CYP2D6 inhibitors before prescribing beta-blockers 5

When Combination is Necessary

• Reduce initial dose of added agent by 30-50% when combining drugs with SA/AV nodal effects 2
• Monitor heart rate and PR interval closely 5
• Consider pacemaker placement if symptomatic bradycardia develops and drug continuation is essential 1

Management of Symptomatic Bradycardia

• Discontinue offending medication immediately 1
• Symptoms include fatigue, dizziness, presyncope/syncope, confusion, falls 1, 7
• Temporary measures: isoproterenol to maintain higher heart rates, temporary pacing 1
• Permanent pacemaker if persistent symptomatic bradycardia and no alternative therapy available 1

Common Pitfalls

• Failing to recognize that "cardioselective" beta-blockers lose selectivity when CYP2D6 is inhibited 5
• Overlooking antifungal agents (terbinafine) as potent CYP2D6 inhibitors 7
• Not waiting adequate washout period (3 months) after amiodarone discontinuation before starting sofosbuvir 1
• Assuming quaternary anticholinergics cannot cause bradycardia—they can through peripheral ganglionic blockade 9
• Missing the long half-life of amiodarone (interaction possible for months after discontinuation) 1