What to do for a patient with uncontrolled hypertension on amlodipine (calcium channel blocker) 10mg, hydrochlorothiazide (HCTZ) (thiazide diuretic) 25mg, metoprolol (beta-blocker) 100mg, and lisinopril (angiotensin-converting enzyme inhibitor) 40mg with blood pressure 160/100?

Management of Uncontrolled Hypertension on Four-Drug Regimen

Immediate Action: Exclude Pseudoresistance and Optimize Current Therapy

Before adding a fifth medication, you must first confirm this is true resistant hypertension by excluding pseudoresistance, which accounts for approximately 50% of apparent resistant hypertension cases. 1

Critical Steps to Exclude Pseudoresistance

• Verify proper blood pressure measurement technique using appropriate cuff size, correct patient positioning (seated, back supported, feet flat, arm at heart level), and multiple readings at different visits 1
• Confirm medication adherence through direct questioning, pill counts, pharmacy refill records, and home blood pressure monitoring, as non-adherence is the most common cause of apparent treatment resistance 2
• Obtain home blood pressure monitoring or 24-hour ambulatory monitoring to exclude white coat hypertension (home BP ≥135/85 mmHg or 24-hour ambulatory BP ≥130/80 mmHg confirms true hypertension) 3
• Review all medications and substances that could elevate blood pressure, including NSAIDs, decongestants, oral contraceptives, corticosteroids, stimulants, excessive alcohol, and licorice 1

Optimize Current Diuretic Therapy

Switch from HCTZ 25mg to chlorthalidone 12.5-25mg daily, as thiazide-like diuretics are superior to thiazides for resistant hypertension. 1

• Chlorthalidone has a longer half-life (40-60 hours vs 6-12 hours for HCTZ) and demonstrates superior cardiovascular outcomes in clinical trials 3
• The 2020 International Society of Hypertension guidelines specifically recommend "use of thiazide-like rather than thiazide diuretics" for resistant hypertension 1
• Monitor serum potassium and creatinine 2-4 weeks after switching diuretics 3

Screen for Secondary Hypertension

Given BP ≥160/100 mmHg on four medications, screening for secondary causes is mandatory before adding more drugs. 1

Essential Screening Tests

• Basic laboratory work: serum sodium, potassium, creatinine/eGFR, TSH, and urinalysis 1
• Consider primary aldosteronism screening (most common secondary cause in resistant hypertension): plasma aldosterone-to-renin ratio, especially given the patient is already on an ACE inhibitor which can affect results 1
• Evaluate for obstructive sleep apnea through clinical history (snoring, witnessed apneas, daytime somnolence, obesity) 1
• Consider renal artery stenosis if there was an abrupt rise in creatinine when starting lisinopril, or if patient has atherosclerotic disease elsewhere 1

Add Spironolactone as Fifth Agent

If pseudoresistance is excluded and secondary causes ruled out, add spironolactone 25mg daily as the preferred fourth-line agent for resistant hypertension. 1

Rationale for Spironolactone

• The 2020 ISH guidelines explicitly state: "Add a low dose of spironolactone as the 4th line agent in those whose serum potassium is <4.5 mmol/L and whose eGFR is >45 ml/min/1.73m²" 1
• Spironolactone addresses occult volume expansion and aldosterone excess that commonly underlies treatment resistance 2
• Clinical trials demonstrate additional BP reductions of 20-25/10-12 mmHg when added to triple therapy 3

Prerequisites and Monitoring for Spironolactone

• Check serum potassium must be <4.5 mmol/L before initiating 1
• Verify eGFR >45 ml/min/1.73m² as contraindication exists below this threshold 1
• Monitor potassium closely at 1,4,8, and 12 weeks after initiation, as hyperkalemia risk is significant when combined with lisinopril 1, 3
• Start at 25mg daily and can increase to 50mg if needed and potassium remains safe 1

Alternative Fourth-Line Agents

If spironolactone is contraindicated (hyperkalemia, eGFR <45, gynecomastia concerns) or not tolerated, alternatives include 1:

• Amiloride (potassium-sparing diuretic without hormonal effects)
• Eplerenone (selective mineralocorticoid receptor antagonist with less gynecomastia)
• Doxazosin (alpha-blocker, though less effective than spironolactone)
• Clonidine (central alpha-agonist, watch for rebound hypertension if discontinued)

Critical Medication Review

Problematic Aspects of Current Regimen

• Metoprolol is not the preferred beta-blocker for hypertension without compelling indications (post-MI, heart failure with reduced ejection fraction, angina, or rate control need) 1, 3
• Beta-blockers are generally less effective at preventing cardiovascular events compared to other antihypertensive classes when used solely for hypertension 1
• Consider discontinuing metoprolol unless there is a compelling indication, as it may be contributing to treatment complexity without optimal benefit 1

Avoid Common Pitfalls

• Do not combine lisinopril with an ARB as this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 1, 3
• Do not add moxonidine as it increased mortality in heart failure patients 1
• Do not add alpha-blockers as primary agents due to inferior outcomes in preventing heart failure 1

Target Blood Pressure and Follow-Up

• Target BP <140/90 mmHg minimum, ideally <130/80 mmHg for this patient with resistant hypertension 1, 3
• Reassess within 2-4 weeks after any medication change 3, 2
• Refer to hypertension specialist if BP remains ≥160/100 mmHg despite optimized four-drug therapy including spironolactone, or if secondary hypertension is suspected 1, 2

Lifestyle Modifications

Reinforce intensive lifestyle interventions which can provide additive BP reductions of 10-20 mmHg 1, 2:

• Sodium restriction to <2g/day (most impactful dietary change) 1, 2
• Weight management targeting BMI 20-25 kg/m² 1
• Regular aerobic exercise at least 150 minutes weekly 1
• Alcohol limitation to <100g/week 2