Which antihypertensive agents can be administered twice daily (BID)?

Antihypertensive Agents That Can Be Administered Twice Daily

Most antihypertensive medications can be dosed twice daily, but the key distinction is whether they should be—immediate-release formulations typically require BID dosing, while extended-release versions allow once-daily administration for the same drug class.

ACE Inhibitors and ARBs

ACE inhibitors and ARBs are commonly dosed twice daily, particularly at higher doses:

• Captopril requires three times daily dosing (initial 6.25 mg TID, maximum 50 mg TID) due to its short half-life 1
• Enalapril is dosed twice daily (initial 2.5 mg BID, maximum 10-20 mg BID) 1
• Losartan demonstrates superior blood pressure control with twice-daily dosing compared to once-daily at the same total dose (50-100 mg/day divided BID), with trough-to-peak ratios of 50-95% for systolic and 60-90% for diastolic responses 2
• Valsartan is administered twice daily (initial 20-40 mg BID, maximum 160 mg BID) 1
• Quinapril requires twice-daily dosing (initial 5 mg BID, maximum 20 mg BID) 1

Beta-Blockers

Several beta-blockers are specifically formulated for twice-daily administration:

• Metoprolol tartrate (immediate-release) requires twice-daily dosing at 25-50 mg BID, up to a maximum of 200 mg daily 3
• Carvedilol must be dosed twice daily (initial 3.125 mg BID, target 25 mg BID, maximum 50 mg BID) to maintain therapeutic beta-blockade 1, 4
• Atenolol can be given once or twice daily, though the FDA label describes 50 mg BID dosing in clinical trials 5

Important caveat: Extended-release formulations (metoprolol succinate, bisoprolol) are designed for once-daily dosing and should not be split into BID regimens 3

Calcium Channel Blockers

Immediate-release calcium channel blockers require multiple daily doses:

• Immediate-release nifedipine requires three times daily dosing, with significantly increased side effects (32% to 58%) and decreased compliance (93% to 76%) compared to once-daily extended-release formulations 6
• Immediate-release diltiazem requires three times daily dosing, though a study showed 94% of patients maintained blood pressure control when switched from once-daily to TID dosing 6
• Immediate-release verapamil requires three times daily dosing, with 91% maintaining control after switching from sustained-release 6

Extended-release formulations (diltiazem CD/SR, nifedipine GITS, verapamil SR) are designed for once or twice-daily dosing and are preferred over immediate-release to enhance compliance 7, 8

Hydralazine and Isosorbide Dinitrate Combination

This combination specifically requires three times daily dosing:

• Fixed-dose combination: 37.5 mg hydralazine/20 mg isosorbide dinitrate TID initially, up to 75 mg/40 mg TID 1
• Individual components: hydralazine 25-50 mg TID or QID plus isosorbide dinitrate 20-30 mg TID or QID 1

Mineralocorticoid Receptor Antagonists

These are typically dosed once daily, not twice daily:

• Spironolactone: 12.5-25 mg once daily, maximum 25 mg BID 1
• Eplerenone: 25 mg once daily, maximum 50 mg once daily 1

Clinical Decision Algorithm

When selecting BID versus once-daily dosing:

1. Prioritize once-daily extended-release formulations when available to improve medication adherence, which is notoriously low in hypertension 1
2. Use twice-daily dosing for immediate-release formulations or when once-daily dosing fails to provide 24-hour blood pressure control 2
3. Monitor trough blood pressure (just before next dose) to ensure adequate 24-hour coverage—if trough BP is elevated, consider switching to BID dosing or extended-release formulation 2
4. Avoid bedtime dosing preference—recent trials show no benefit to evening versus morning administration 1

Critical Monitoring Considerations

• Renal function and potassium must be checked 7-14 days after initiating or changing doses of ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists 1, 9
• Never abruptly discontinue beta-blockers in patients with coronary artery disease—mortality increases 2.7-fold with abrupt cessation; taper by 25-50% every 1-2 weeks 9, 4
• Multiple-drug therapy (two or more agents at maximal doses) is generally required to achieve blood pressure targets, particularly for BP ≥150/90 mmHg 1