How to manage a patient with resistant hypertension on multiple antihypertensives (blood pressure medications) who presents with elevated creatinine kinase (muscle enzyme) levels?

Management of Elevated Creatinine Kinase in Resistant Hypertension

Immediately discontinue statin therapy if the patient is taking one, as this is the most likely culprit for elevated CK in a patient on multiple antihypertensives, particularly if combined with calcium channel blockers like amlodipine. 1

Immediate Assessment and Drug-Induced Causes

The first priority is identifying and eliminating the cause of elevated CK, which in the context of resistant hypertension most commonly involves:

• Stop statins immediately if the patient is on atorvastatin or other statins, especially when combined with amlodipine (a common calcium channel blocker used in resistant hypertension), as this combination significantly increases rhabdomyolysis risk 1
• Review all medications for substances that can cause muscle injury or interfere with blood pressure control, including NSAIDs, cold preparations, and certain herbal supplements 2, 3
• Assess for rhabdomyolysis by checking renal function, urine myoglobin, and trending CK levels daily while providing aggressive IV hydration with normal saline 1

Confirming True Resistant Hypertension

Before escalating antihypertensive therapy, you must exclude pseudoresistance:

• Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat effect, which accounts for approximately 50% of apparent resistant hypertension cases 2, 4
• Verify medication adherence through direct questioning, pill counts, or pharmacy records, as nonadherence is responsible for roughly half of treatment resistance 5, 6
• Confirm proper BP measurement technique using appropriate cuff size and correct positioning 2

Screening for Secondary Causes

Resistant hypertension warrants evaluation for secondary causes, particularly:

• Primary aldosteronism (screen even with normal potassium levels) 4
• Obstructive sleep apnea 4
• Chronic kidney disease and assess baseline eGFR 2, 4
• Renal artery stenosis 4
• Other endocrine disorders including thyroid dysfunction (check TSH) 2

The basic screening should include thorough history, physical examination, serum sodium, potassium, eGFR, TSH, and urinalysis 2

Optimizing the Antihypertensive Regimen

Once drug-induced CK elevation is addressed and true resistant hypertension confirmed:

Lifestyle Modifications (Critical First Step)

• Restrict sodium intake to <2400 mg/day, as high sodium significantly contributes to treatment resistance 7, 5, 4
• Encourage weight loss if overweight/obese, which can produce significant BP reductions 5, 4
• Limit alcohol to ≤2 drinks/day for men, ≤1 drink/day for women 4
• Implement regular exercise with a structured program 4

Medication Optimization

• Ensure the regimen includes a long-acting calcium channel blocker, a renin-angiotensin system blocker (ACE inhibitor or ARB), and an appropriate diuretic at maximal tolerated doses 2, 8
• Switch to thiazide-like diuretics (chlorthalidone or indapamide) rather than thiazides, as they are more effective 2
• Use loop diuretics if eGFR <30 mL/min/1.73m² or clinical volume overload is present, as volume overload is a common unrecognized cause of treatment failure 2, 5

Fourth-Line Agent

Add spironolactone 25 mg daily as the fourth-line agent if serum potassium is <4.5 mmol/L and eGFR is >45 mL/min/1.73m² 2, 7, 9

• Spironolactone has demonstrated superior efficacy as fourth-line therapy in resistant hypertension, including in the PATHWAY-2 trial 7, 8
• Monitor serum potassium and renal function 1-2 weeks after initiation, especially with existing RAS blockade 7, 4
• If spironolactone is contraindicated or not tolerated, alternatives include amiloride, doxazosin, eplerenone, clonidine, or beta-blockers 2, 8

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication adjustment 7, 4
• Check serum potassium and renal function regularly, particularly after adding spironolactone 7, 4
• Consider home BP monitoring to guide medication titration and improve adherence 4

Critical Pitfalls to Avoid

• Do not escalate antihypertensive therapy until you've addressed the elevated CK and confirmed it's not medication-related rhabdomyolysis 1
• Do not add spironolactone without first checking potassium and renal function, as hyperkalemia risk is significant with existing RAS blockade 7, 4
• Do not overlook volume overload as a cause of treatment resistance—inadequate diuretic therapy is extremely common 5, 3
• Do not fail to screen for primary aldosteronism, as aldosterone excess is common in resistant hypertension and directly treatable 4, 6

Specialist Referral

Refer to a specialist center with expertise in resistant hypertension for further evaluation and management, particularly if BP remains uncontrolled after optimizing the four-drug regimen 2