What other antihypertensive medication can be added for a patient with uncontrolled hypertension on current therapy?

Management of Uncontrolled Hypertension in a Patient on Multiple Antihypertensives

Add spironolactone 12.5-25 mg daily as the next antihypertensive agent for this patient with resistant hypertension (BP 150/110 mmHg on three-drug therapy including a diuretic, calcium channel blocker, and insulin-sensitizing agents). 1

Current Medication Assessment

This patient is already on:

• Amlodipine (LODIPine) 10 mg - calcium channel blocker at maximum dose
• Hydrochlorothiazide 25 mg - thiazide diuretic at standard dose
• Pioglitazone 30 mg - which has modest BP-lowering effects

The patient meets criteria for resistant hypertension: BP ≥130/80 mmHg (or ≥140/90 mmHg by older definitions) despite adherence to three antihypertensive agents of different classes, including a diuretic. 1

Recommended Treatment Algorithm

First Priority: Optimize Current Diuretic Therapy

Switch hydrochlorothiazide to chlorthalidone 12.5-25 mg daily before adding a fourth agent. 1

• Chlorthalidone provides superior 24-hour BP control compared to hydrochlorothiazide, with the largest difference occurring overnight 1
• Given the outcome benefit demonstrated with chlorthalidone in clinical trials and its superior efficacy, it should be preferentially used in resistant hypertension 1
• This switch alone may provide adequate BP control without requiring a fourth medication 1

Second Priority: Add Mineralocorticoid Receptor Antagonist

If BP remains uncontrolled after optimizing to chlorthalidone, add spironolactone 12.5-25 mg daily. 1, 2

• Spironolactone is the preferred fourth-line agent for resistant hypertension, providing significant additional BP reduction when added to existing multidrug regimens 1, 2
• In patients with resistant hypertension on an average of 4 medications (including a diuretic and ACE inhibitor/ARB), spironolactone lowered BP by an additional 25/12 mmHg (systolic/diastolic) 1
• The BP response was similar in both African American and white patients 1
• Importantly, the response was not predicted by baseline aldosterone levels, plasma renin activity, or aldosterone/renin ratio, meaning all patients with resistant hypertension may benefit regardless of aldosterone status 1

Alternative: Amiloride if Spironolactone Contraindicated

Consider amiloride 5-10 mg daily combined with hydrochlorothiazide if spironolactone is not tolerated. 1

• Amiloride antagonizes the epithelial sodium channel, functioning as an indirect aldosterone antagonist 1
• In patients with low-renin hypertension uncontrolled on multiple drugs, substitution with amiloride 2.5 mg/hydrochlorothiazide 25 mg lowered BP by 31/15 mmHg 1
• Doubling the dose provided additional reductions of 11/4 mmHg 1

Why NOT Add an ACE Inhibitor or ARB Now

Do not add an ACE inhibitor or ARB as the fourth agent in this patient. 3

• While ACE inhibitors/ARBs are typically part of guideline-recommended triple therapy (ACE inhibitor/ARB + calcium channel blocker + thiazide diuretic), this patient is not currently on a renin-angiotensin system (RAS) blocker 3
• However, the evidence strongly supports adding a mineralocorticoid receptor antagonist before adding a RAS blocker in the setting of resistant hypertension already on a calcium channel blocker and diuretic 1
• The patient's diabetes and likely chronic kidney disease (given pioglitazone use) would make a RAS blocker beneficial, but spironolactone should be added first given the resistant hypertension phenotype 1

Critical Monitoring Parameters

Before Adding Spironolactone

• Check serum potassium and creatinine - spironolactone is contraindicated if K+ >5.0 mEq/L or creatinine clearance <30 mL/min 1
• Assess for medication adherence - non-adherence is the most common cause of apparent treatment resistance 3
• Rule out secondary hypertension - particularly primary aldosteronism, renal artery stenosis, and obstructive sleep apnea 2

After Adding Spironolactone

• Recheck potassium and creatinine in 2-4 weeks - hyperkalemia risk is significant, especially in patients with diabetes and potential renal impairment 1, 3
• Monitor for gynecomastia in male patients - occurs in 6-10% of men on spironolactone 1
• Reassess BP in 2-4 weeks with target <130/80 mmHg 3, 2

Additional Considerations

Withdraw Interfering Medications

• Avoid or minimize NSAIDs - these significantly interfere with BP control and should be withdrawn or used at the lowest effective dose 1
• Monitor BP closely when NSAIDs are necessary, recognizing that antihypertensive regimen adjustments may be required 1

Lifestyle Modifications

• Sodium restriction to <2 g/day - provides additive BP reduction of 5-10 mmHg 3
• Weight loss if BMI >25 kg/m² - each 1 kg weight loss reduces BP by approximately 1 mmHg 4
• Regular aerobic exercise - 150 minutes/week of moderate-intensity activity 4

If BP Remains Uncontrolled

Consider referral to hypertension specialist if BP ≥160/100 mmHg despite four-drug therapy at optimal doses. 2

• Evaluate for secondary causes more thoroughly 2
• Consider advanced options such as catheter-based renal denervation at high-volume centers 2

Common Pitfalls to Avoid

• Do not add a beta-blocker as the fourth agent unless there are compelling indications (coronary disease, heart failure, post-MI) - beta-blockers are less effective in resistant hypertension and have more adverse effects 1
• Do not use loop diuretics (like furosemide) unless creatinine clearance <30 mL/min - thiazide-type diuretics are more effective for hypertension management 1
• Do not combine ACE inhibitor with ARB - this increases adverse events without additional benefit 3
• Do not delay treatment intensification - this patient's BP of 150/110 mmHg represents stage 2 hypertension requiring prompt action to reduce cardiovascular risk 3, 5