If taking a 3-drug combination (including an Angiotensin-Converting Enzyme (ACE) inhibitor, a calcium channel blocker, and a diuretic) in the morning, when should the 4th medication be taken?

Timing of the 4th Antihypertensive Medication

The 4th antihypertensive medication should be taken at the same time as your morning 3-drug combination—there is no evidence supporting preferential evening dosing for the 4th drug, and maintaining a consistent morning regimen improves medication adherence. 1

Rationale for Morning Dosing of All Medications

• Recent high-quality evidence definitively shows no benefit to evening dosing: The 2025 American Diabetes Association guidelines explicitly state that "preferential use of antihypertensives at bedtime is not recommended" based on large randomized trials that failed to reproduce earlier findings suggesting evening dosing benefits 1

• The 2024 European Society of Cardiology guidelines recommend dosing at a "convenient time of day for the patient to establish a habitual pattern of medication taking to improve adherence" 1

• Taking all medications together in the morning simplifies your regimen and maximizes adherence, which is the most critical factor in achieving blood pressure control 1

Step 4 Treatment: Adding the 4th Drug

When your blood pressure remains uncontrolled on a 3-drug combination (ACE inhibitor + calcium channel blocker + diuretic), the recommended 4th agent is:

• Low-dose spironolactone 25 mg once daily if your serum potassium is <4.6 mmol/L 1

• Increased thiazide-like diuretic dose if your serum potassium is >4.5 mmol/L 1

• Alternative options if spironolactone is not tolerated include: beta-blocker, alpha-blocker, or centrally acting agents 1

Critical Monitoring Requirements

• Check serum sodium, potassium, and renal function within 1 month of adding the 4th medication, then repeat as needed 1

• Monitor for hyperkalemia and acute kidney injury, which are increased risks when combining multiple agents affecting the renin-angiotensin system 1

• Reassess blood pressure every 2-4 weeks until control is achieved, with a target of <130/80 mmHg for most patients 1, 2

Common Pitfalls to Avoid

• Do not combine two RAS blockers (ACE inhibitor + ARB)—this is explicitly contraindicated due to increased risk of end-stage renal disease and stroke 1

• Avoid NSAIDs and COX-2 inhibitors, which can interfere with blood pressure control and increase renal dysfunction risk 1

• Do not assume evening dosing is superior—this outdated recommendation has been disproven by recent trials 1, 3