Can allopurinol cause bradycardia?

Allopurinol and Bradycardia

Allopurinol can cause bradycardia, but this is an uncommon adverse effect with an incidence of less than 1% and a causal relationship that remains uncertain according to FDA labeling. 1

Evidence from FDA Drug Labeling

The FDA-approved prescribing information for allopurinol explicitly lists bradycardia under adverse reactions with "Incidence Less Than 1% Causal Relationship Unknown" in the cardiovascular category. 1 This classification indicates that:

• Bradycardia has been reported in association with allopurinol use, but a definitive causal link has not been established 1
• The event occurs rarely (less than 1% of patients) 1
• Other cardiovascular effects listed with uncertain causality include pericarditis, peripheral vascular disease, thrombophlebitis, and vasodilation 1

Context from Clinical Guidelines

Multiple cardiovascular guidelines discuss drug-induced bradycardia but do not identify allopurinol as a recognized cause of clinically significant bradycardia:

• The 2017 JACC guidelines on cardiovascular complications of cancer therapy list cisplatin, irinotecan, paclitaxel, mitoxantrone, octreotide, thalidomide, methotrexate, 5-fluorouracil, and arsenic trioxide as chemotherapy agents linked to bradycardia, but allopurinol is not mentioned 2
• The 2019 ACC/AHA/HRS bradycardia guidelines discuss reversible causes of sinus bradycardia, emphasizing negative chronotropic drugs (beta blockers, calcium channel blockers, digoxin, sodium-channel and potassium-channel blocking antiarrhythmics) but do not reference allopurinol 2
• The 2015 ESC guidelines on ventricular arrhythmias note that bradyarrhythmias are common pharmacological effects of digoxin, verapamil, diltiazem, and beta blockers, without mentioning allopurinol 2

Clinical Trial Safety Data

Large-scale randomized controlled trials of allopurinol have not identified bradycardia as a significant adverse effect:

• The ALL-HEART trial (n=5,937 patients with ischemic heart disease) randomized participants to allopurinol 600 mg daily versus usual care and found no difference in cardiovascular outcomes, with no specific mention of bradycardia as an adverse event 3
• A placebo-controlled study examining allopurinol's effect on heart rate variability in chronic heart failure patients (n=16) found no significant effect on mean heart rate (difference 0.9 ± 1.4 beats/min, p=0.5) 4

Practical Clinical Implications

When evaluating a patient with bradycardia who is taking allopurinol:

• Consider more common causes first, including beta blockers, calcium channel blockers, digoxin, antiarrhythmic drugs, hypothyroidism, electrolyte abnormalities, and underlying cardiac disease 2
• Review all concurrent medications for known negative chronotropic effects, as drug-drug interactions are more likely culprits 2
• Allopurinol should not be automatically discontinued based solely on bradycardia unless other causes have been excluded and temporal relationship strongly suggests causality 1
• If allopurinol is suspected, consider dose reduction or temporary discontinuation as a diagnostic trial, but recognize that the evidence for causation is weak 1

Mechanism Considerations

Unlike drugs with established bradycardic effects that work through specific mechanisms (beta-adrenergic blockade, calcium channel blockade, enhanced vagal tone), allopurinol's primary mechanism as a xanthine oxidase inhibitor does not directly affect cardiac conduction or chronotropy 5, 6. This mechanistic disconnect supports the FDA's classification of bradycardia as having an uncertain causal relationship with allopurinol. 1