What are the causes of resistant hypertension in patients with a history of hypertension who are not responding to lifestyle modifications and multiple antihypertensive medications?

Causes of Resistant Hypertension

Resistant hypertension is almost always multifactorial, with pseudoresistance (particularly medication nonadherence and white coat effect) accounting for approximately 50% of cases, followed by lifestyle factors (obesity, excessive sodium/alcohol), interfering medications (especially NSAIDs), and true secondary causes (obstructive sleep apnea affecting 83% of resistant cases, primary aldosteronism in 17-23%, and chronic kidney disease). 1, 2

Pseudoresistance (Excludes True Resistance)

Before pursuing extensive workup, confirm true resistance by excluding these common mimics:

• Medication nonadherence represents the single most common cause, accounting for approximately 50% of apparent treatment resistance 1, 2
• White coat hypertension accounts for roughly 50% of apparent resistant cases and must be confirmed with 24-hour ambulatory blood pressure monitoring 3, 1, 2
• Inadequate BP measurement technique, including inappropriate cuff size or incorrect patient positioning, produces falsely elevated readings 1, 2
• Suboptimal medication regimen, such as inadequate doses or inappropriate drug class selection (e.g., using hydrochlorothiazide instead of thiazide-like diuretics), contributes substantially 1

Lifestyle and Dietary Factors

These modifiable factors directly elevate BP and reduce medication effectiveness:

• Obesity is one of the two strongest risk factors for uncontrolled hypertension and is highly prevalent in resistant hypertension patients 1, 2
• Excessive sodium intake (average >10 g/day in resistant patients) directly increases BP and decreases the antihypertensive effect of most drug classes 1, 2
• Excessive alcohol consumption significantly increases the risk of resistant hypertension 1, 2
• Advanced age is the other strongest risk factor for uncontrolled hypertension 1, 2

Interfering Medications and Substances

Identify and discontinue these BP-elevating agents when clinically allowable:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common interfering medications due to their frequent use 3, 1, 2
• Oral contraceptives can elevate BP 1, 2
• Certain antidepressants interfere with BP control 1, 2
• Decongestants, corticosteroids, and herbal supplements should be identified and discontinued when possible 1

Secondary Causes of Hypertension

All patients with confirmed resistant hypertension should be systematically screened for these reversible causes: 3

Most Common Secondary Causes

• Obstructive sleep apnea affects 83% of patients with resistant hypertension and induces sustained sympathetic nervous system activation 1, 2
• Primary aldosteronism has a prevalence of 17-23% in resistant hypertension and should be evaluated in all patients, even with normal potassium levels, as hypokalemia is a late manifestation 1, 2
• Chronic kidney disease/renal parenchymal disease is a major contributor to resistance and requires assessment with serum creatinine and eGFR 3, 1
• Renovascular hypertension/renal artery stenosis should be considered, particularly in younger patients (especially women suggesting fibromuscular dysplasia) or older patients at increased risk of atherosclerotic disease 3, 1

Less Common But Important Secondary Causes

• Pheochromocytoma should be screened with 24-hour urine metanephrines or plasma metanephrines if clinical presentation suggests it 3
• Cushing's syndrome should be screened if clinical features suggest hypercortisolism 3
• Thyroid and parathyroid dysfunction can contribute to resistant hypertension 4

Volume Overload States

Volume retention is an extremely common and correctable cause:

• Inadequate diuretic therapy is extremely common—ensure thiazide-like diuretics (chlorthalidone or indapamide) are used rather than hydrochlorothiazide, and switch to loop diuretics when eGFR <30 mL/min/1.73m² 3, 1
• Progressive renal insufficiency leads to volume retention 1
• Hyperaldosteronism causes sodium retention 1

High-Risk Populations

Certain demographic groups have higher prevalence and specific considerations:

• African Americans have higher prevalence of apparent resistant hypertension and greater benefit from sodium restriction 1, 2
• Men have higher prevalence compared to women 1, 2
• Patients with diabetes have significantly higher risk 1, 2
• Elderly patients have higher prevalence of sleep apnea, renal disease, and renal artery stenosis 1, 2

Critical Clinical Pitfalls to Avoid

• Do not pursue extensive secondary hypertension workup before confirming true resistance with ambulatory BP monitoring and verifying medication adherence 1
• Do not overlook volume overload—optimize diuretic therapy before adding additional agents 1
• Screen for primary aldosteronism even when potassium is normal, as hypokalemia is a late manifestation 1
• Do not perform abdominal CT for adrenal adenomas without biochemical confirmation of hormonally active tumors 3, 1
• Do not perform diagnostic renal arteriograms in the absence of suspicious noninvasive imaging 3, 1
• Reserve renal artery stenosis imaging for high-suspicion patients (young patients, particularly women; older patients with atherosclerotic risk factors; sudden deterioration in BP control) 3, 1