Which beta blockers do not significantly reduce heart rate?

Beta-Blockers That Do Not Significantly Reduce Heart Rate

Beta-blockers with intrinsic sympathomimetic activity (ISA), particularly pindolol, do not significantly reduce resting heart rate while still providing therapeutic benefits through beta-blockade during periods of elevated sympathetic activity. 1, 2

Mechanism of Intrinsic Sympathomimetic Activity

Beta-blockers with ISA possess partial agonist activity at beta-adrenergic receptors, meaning they simultaneously block and mildly stimulate these receptors. 1, 2 This unique property results in:

• Minimal reduction in resting heart rate (typically only 4-8 beats per minute decrease) compared to beta-blockers without ISA 1
• Preservation of resting cardiac output with smaller reductions than non-ISA agents 1, 2
• Effective blockade during elevated sympathetic tone (exercise, stress) while maintaining near-normal function at rest 3, 2

Specific Agents With Minimal Heart Rate Reduction

Pindolol (Primary Agent)

Pindolol demonstrates the most pronounced ISA among clinically available beta-blockers and causes minimal to no reduction in resting heart rate. 1, 4

• In comparative studies, pindolol did not significantly affect resting heart rate (65.37 ± 1.47 to 65.5 ± 1.44 beats/min; p = 0.9392), while propranolol significantly reduced it (69.00 ± 1.85 to 61.50 ± 1.99; p = 0.0018) 4
• Pindolol still effectively reduces heart rate during exercise (113.59 ± 3.24 to 108.12 ± 3.16; p = 0.0102), providing therapeutic benefit when needed 4
• The ISA effect is most evident in patients with lower baseline sympathetic tone (resting heart rate <80 bpm), where heart rate remains essentially unchanged 3

Other Beta-Blockers With ISA

Additional agents with partial agonist activity include:

• Oxprenolol - possesses ISA but less extensively studied than pindolol 5
• Acebutolol - has ISA with beta-1 selectivity 6
• Carteolol - demonstrates ISA properties 6

These agents show less reduction in resting heart rate and cardiac output compared to beta-blockers without ISA. 6

Clinical Context and Guideline Perspective

When ISA May Be Advantageous

The European Society of Cardiology notes that beta-blockers with partial agonist activity reduce only exercise heart rate, not resting heart rate. 7

Potential clinical scenarios where minimal heart rate reduction is desirable:

• Patients with baseline bradycardia or borderline low heart rates who still require beta-blockade 2
• Situations requiring preservation of cardiac output at rest 2
• Patients at risk for excessive bradycardia with conventional beta-blockers 1

Important Limitations

Guidelines consistently state that beta-blockers without ISA are preferred for most cardiovascular indications, particularly heart failure. 7

Critical caveats:

• ISA agents provide insufficient heart rate reduction for optimal rate control in atrial fibrillation - guidelines specifically note that nadolol and atenolol (without ISA) are most efficacious for AF rate control 7
• No proven mortality benefit in heart failure - only sustained-release metoprolol succinate, carvedilol, and bisoprolol (all without ISA) have demonstrated mortality reduction in heart failure 7
• Less effective for post-MI protection - beta-blockers without ISA are preferred for secondary prevention after myocardial infarction 7

Practical Considerations

The interaction between ISA and baseline sympathetic tone is clinically relevant:

• In patients with high sympathetic tone (heart rate ≥80 bpm), pindolol's beta-blocking effect dominates, producing modest heart rate and FEV1 reductions 3
• In patients with low sympathetic tone (heart rate <80 bpm), ISA balances the beta-blocking effect, resulting in minimal changes to heart rate or pulmonary function 3

Pindolol reduces resting plasma norepinephrine levels, unlike beta-blockers without ISA which increase or maintain norepinephrine levels. 6

Cardiovascular Effects Beyond Heart Rate

Beta-blockers with ISA offer additional hemodynamic advantages:

• Preserved ejection fraction - pindolol does not significantly reduce ejection fraction (unlike propranolol which decreased it from 0.57 ± 0.02 to 0.15 ± 0.01) 4
• Less increase in left ventricular end-diastolic volume compared to non-ISA agents 4
• Reduced peripheral resistance during chronic therapy without compromising peripheral blood flow 2
• No adverse effects on HDL/LDL cholesterol ratio, unlike non-ISA beta-blockers which may elevate triglycerides and lower HDL 6, 2

Clinical Bottom Line

While pindolol and other ISA beta-blockers minimize resting heart rate reduction, they are not recommended as first-line agents for most guideline-directed cardiovascular indications where proven mortality benefit exists with non-ISA beta-blockers. 7 Their niche role is in patients requiring beta-blockade who cannot tolerate significant resting bradycardia or reduced cardiac output. 2