What are the next steps in managing a patient with uncontrolled hypertension on perindopril (Angiotensin-Converting Enzyme Inhibitor) 8mg and amlodipine (Calcium Channel Blocker) 5mg?

Management of Uncontrolled Hypertension on Perindopril 8mg and Amlodipine 5mg

Your patient has resistant hypertension requiring immediate optimization: first, add a thiazide-like diuretic (preferably chlorthalidone or indapamide) to complete the optimal triple-drug regimen, then if blood pressure remains uncontrolled, add spironolactone as the fourth agent. 1, 2

Current Regimen Assessment

Your patient is on two of the three essential drug classes for resistant hypertension management:

• ACE inhibitor (perindopril 8mg) - at maximum dose 3
• Calcium channel blocker (amlodipine 5mg) - can be increased to 10mg 4

However, this regimen is incomplete without the third essential component: a thiazide-like diuretic 1, 2

Step 1: Optimize Current Medications

Increase Amlodipine Dose

• Increase amlodipine from 5mg to 10mg once daily 4
• The maximum antihypertensive dose is 10mg, and most patients require this higher dose for adequate blood pressure control 4
• Wait 7-14 days between titration to assess response 4

Add a Thiazide-Like Diuretic

• Add chlorthalidone (12.5-25mg daily) or indapamide (1.25-2.5mg daily) as the third agent 1, 2
• These thiazide-like diuretics are superior to hydrochlorothiazide, providing greater 24-hour ambulatory blood pressure reduction with the largest difference occurring overnight 2
• This completes the optimal triple-drug regimen: ACE inhibitor + calcium channel blocker + thiazide-like diuretic 1

Important caveat: Ensure the diuretic type is appropriate for kidney function - thiazide-like diuretics maintain efficacy down to eGFR of 30 mL/min/1.73m² 1

Step 2: Confirm True Resistant Hypertension

Before adding a fourth agent, exclude pseudoresistance:

• Perform 24-hour ambulatory blood pressure monitoring to confirm uncontrolled hypertension and exclude white-coat effect 1
• Assess medication adherence - this is a common cause of apparent treatment resistance 1
• Ensure sodium intake <2400 mg/day and optimize other lifestyle interventions including weight loss and exercise 1

Step 3: Add Fourth Agent if Still Uncontrolled

If blood pressure remains >130/80 mmHg after optimizing the triple-drug regimen:

Add Spironolactone (Preferred Fourth Agent)

• Start spironolactone 25mg once daily and titrate upward as needed 1, 2
• Spironolactone provides an average additional blood pressure reduction of 25/12 mmHg when added to existing multidrug regimens 2
• This benefit is consistent across both African American and white patients 2

Alternative Fourth Agents (if spironolactone contraindicated or not tolerated)

Consider in this order 1:

• Eplerenone (if hyperkalemia risk with spironolactone)
• Amiloride
• Doxazosin
• Beta-blocker (if heart rate >70 bpm) - metoprolol succinate, bisoprolol, or carvedilol 1
• Clonidine patch weekly (if beta-blocker contraindicated) 1

Monitoring Requirements

Within 1 Month of Adding/Adjusting Therapy

• Check serum electrolytes and renal function 2
• Monitor specifically for:
  • Hyperkalemia (especially with ACE inhibitor + spironolactone combination) 2
  • Hyponatremia and hypokalemia (with thiazide diuretics) 2
  • Elevated uric acid and calcium levels 2

Blood Pressure Targets

• Target <140/90 mmHg for most patients 1, 2
• Achieve target within 3 months of treatment optimization 1
• Consider individualization for elderly patients based on frailty 1

Critical Pitfalls to Avoid

• Never combine an ACE inhibitor with an ARB - this increases risk of hyperkalemia and renal dysfunction without additional blood pressure benefit 2, 5
• Do not add a fourth agent before optimizing the triple-drug regimen - many patients will achieve control with proper dosing of the three-drug combination 1, 2
• Consider timing of medication administration - taking at least one antihypertensive at bedtime may improve 24-hour blood pressure control, particularly nighttime values 2, 5

When to Refer

Consider referral to a hypertension specialist if 1:

• Blood pressure remains uncontrolled on ≥3 optimally dosed medications
• Multiple drug intolerances occur
• Secondary hypertension is suspected
• Patient has malignant hypertension or hypertensive crisis