What is the appropriate lab and workup for a patient with resistant hypertension on amlodipine (10 mg), clonidine (transdermal patch 0.1), chlorthalidone (50 mg), and metoprolol (25 mg extended release)?

Workup for Resistant Hypertension

Before ordering any labs, confirm this is true resistant hypertension by verifying medication adherence (the most common cause of apparent resistance) and performing 24-hour ambulatory blood pressure monitoring to exclude white coat effect, which accounts for approximately 50% of apparent resistant hypertension cases. 1, 2

Immediate Medication Optimization Required

Your current regimen needs adjustment before proceeding with extensive workup:

• Switch chlorthalidone from 50 mg to 25 mg daily - you are using double the maximum recommended dose for hypertension (25 mg is the standard maximum; 50 mg increases side effects without additional benefit) 3
• Increase metoprolol ER from 25 mg to at least 50-100 mg daily - your current dose is subtherapeutic 1
• Consider replacing clonidine patch 0.1 with a more effective fourth-line agent - clonidine is generally reserved as last-line therapy due to significant CNS adverse effects 1

Essential Laboratory Tests

Obtain the following labs to screen for secondary causes and assess safety for adding spironolactone:

• Serum potassium - must be <4.5 mmol/L before adding spironolactone 1, 4, 2
• Serum creatinine with eGFR calculation - must be >45 mL/min/1.73m² for spironolactone 1, 4, 2
• Serum sodium - assess for hyponatremia from chlorthalidone 3
• Urinalysis for blood and protein 4
• Urine albumin-to-creatinine ratio - screens for diabetic/hypertensive nephropathy 1, 4
• Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) - screen for primary aldosteronism even with normal potassium, as this accounts for 8-20% of resistant hypertension cases 4, 2
• TSH - screen for thyroid dysfunction 2
• Fasting glucose or HbA1c - assess for diabetes 1

Additional Diagnostic Studies

• 12-lead electrocardiogram - assess for left ventricular hypertrophy and ischemic changes 4
• Sleep study screening questionnaire (STOP-BANG) - obstructive sleep apnea is present in 25-50% of resistant hypertension cases 4, 2
• Home blood pressure monitoring - confirm office readings with home BP ≥135/85 mmHg 5

Secondary Hypertension Screening (If Initial Labs Abnormal)

Order these only if indicated by initial results or clinical suspicion:

• Renal artery duplex ultrasound - if eGFR declining, abdominal bruit present, or flash pulmonary edema 4, 2
• 24-hour urine metanephrines - if paroxysmal hypertension, headaches, palpitations, or sweating 4
• 24-hour urine free cortisol or overnight dexamethasone suppression test - if cushingoid features present 4

Recommended Next Steps After Labs Return

If potassium <4.5 mmol/L and eGFR >45 mL/min/1.73m²: Add spironolactone 25 mg daily as your true fourth-line agent (replacing clonidine), as this is the most effective fourth-line agent supported by the PATHWAY-2 trial. 1, 2, 5

If potassium ≥4.5 mmol/L or eGFR <45 mL/min/1.73m²: Consider eplerenone 50 mg twice daily, amiloride, or a vasodilating beta-blocker (nebivolol, carvedilol, or labetalol) instead. 1, 2

Critical Monitoring After Adding Fourth Agent

• Recheck potassium and creatinine within 1-4 weeks after adding spironolactone, as hyperkalemia risk is significant when combined with ACE inhibitors or ARBs 5
• Reassess blood pressure within 2-4 weeks of any medication adjustment 2, 5
• Target blood pressure <130/80 mmHg per current ACC/AHA guidelines 1, 2

Common Pitfalls to Avoid

• Do not continue chlorthalidone at 50 mg - this exceeds the recommended maximum dose for hypertension and increases electrolyte disturbances without additional benefit 3
• Do not add spironolactone if potassium ≥4.5 mmol/L - hyperkalemia risk becomes unacceptable 1, 2, 5
• Do not skip 24-hour ambulatory BP monitoring - approximately 50% of apparent resistant hypertension is white coat effect 2
• Do not order extensive secondary hypertension workup before confirming true resistance and optimizing the regimen 1, 2

Referral Indication

Refer to a hypertension specialist if BP remains >130/80 mmHg after optimizing the four-drug regimen with lifestyle modifications, or if you identify a secondary cause requiring specialized management. 1, 2, 5