Are antihypertensive medications, such as diuretics (e.g. hydrochlorothiazide), beta blockers (e.g. metoprolol), Angiotensin-Converting Enzyme (ACE) inhibitors (e.g. lisinopril), and calcium channel blockers (e.g. amlodipine), more effective when administered at the same time or at separate times?

Administering Multiple Antihypertensive Medications: Same Time vs. Separate Times

For most patients requiring multiple antihypertensive medications, administering them at the same time is more effective and improves adherence compared to separating them throughout the day. 1

Rationale for Combined Administration

• Combination therapy with multiple antihypertensive agents is often necessary to achieve blood pressure control, with most patients requiring two or more drugs from different classes 1
• Single-time administration improves medication adherence, which is a critical factor in achieving blood pressure control 1
• Fixed-dose combinations (single pills containing multiple medications) further enhance adherence compared to taking multiple separate pills 1
• Drug regimens with complementary mechanisms of action can result in additive blood pressure lowering when administered together 1

Pharmacological Considerations

• When combining antihypertensive medications, it's important to use drugs with different mechanisms of action to achieve synergistic effects 1, 2
• A triple drug regimen of an ACE inhibitor or ARB, calcium channel blocker, and a thiazide diuretic is effective and generally well-tolerated 1
• Certain combinations should be avoided, such as:
  • Two drugs from the same class (e.g., two ACE inhibitors or two beta-blockers) 1
  • Two drugs that target the same blood pressure control system (e.g., ACE inhibitor with ARB) 1, 3
  • ACE inhibitor or ARB with direct renin inhibitors like aliskiren 1, 3

Morning vs. Evening Administration

• Current evidence does not support preferential bedtime dosing of antihypertensive medications 1, 4
• Previous analyses suggesting benefits of evening dosing have not been reproduced in subsequent trials 1
• Complete 24-hour control of blood pressure should be targeted using long-acting antihypertensive medications administered in a single morning dose 4

Special Considerations

• For patients with resistant hypertension (BP ≥140/90 mmHg despite three drugs including a diuretic), adding a mineralocorticoid receptor antagonist should be considered 1
• Drugs with short duration of action may lead to large variations in blood pressure lowering effect and rapid disappearance of the antihypertensive effect with missed doses 5, 6
• Using drugs with longer duration of action provides more consistent effect during actual drug intake and more persistent effect during short periods of non-compliance 5

Practical Approach

• For initial treatment of hypertension between 130/80 mmHg and 160/100 mmHg, start with a single drug 1
• For blood pressure ≥160/100 mmHg, initial treatment with two antihypertensive medications is recommended 1
• When multiple drugs are needed, a single morning dose of long-acting medications is generally preferred 4
• Monitor for potential adverse effects of combination therapy, particularly:
  • Hyperkalemia with ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists 1
  • Acute kidney injury with ACE inhibitors, ARBs, or diuretics 1

In conclusion, administering multiple antihypertensive medications at the same time is generally more effective and improves adherence compared to separating them throughout the day. The focus should be on using complementary drug combinations with long-acting formulations to achieve consistent 24-hour blood pressure control.