HYPERTENSION - Complete Gold-Medal Study Note

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PART 1: DEFINITION AND CLASSIFICATION

Blood Pressure Classification (2025 AHA/ACC - unchanged from 2017)

ESC 2024 Classification (slightly different terminology)

Key exam point: The 2025 AHA/ACC guideline retired the term "hypertensive urgency." The preferred term is now "severe hypertension without acute target-organ damage." Hypertensive emergency = severe HTN WITH acute target organ damage.

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PART 2: EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Epidemiology

• Affects ~1.3 billion adults globally; prevalence rises steeply with age
• In most Western countries, SBP rises progressively with age; in women, increase is more marked after age 50
• Primary (essential) hypertension accounts for ~90-95% of cases
• Leading modifiable risk factor for stroke, MI, heart failure, CKD, and premature death

Pathophysiology of Primary (Essential) Hypertension

1. Reduced renal sodium excretion - Kidneys fail to excrete sodium appropriately at normal perfusion pressures → volume expansion → HTN. This is the dominant hypothesis (Guyton model).
2. RAAS activation - Angiotensin II is the central effector: causes direct vasoconstriction, promotes aldosterone release (sodium retention), stimulates SNS, promotes cardiac/vascular hypertrophy.
3. Sympathetic nervous system overactivation - Increased catecholamines raise CO and TPR; renal SNS activation further impairs sodium excretion.
4. Vascular remodeling - Vascular smooth muscle hypertrophy/hyperplasia increases TPR and structural resistance.
5. Endothelial dysfunction - Reduced nitric oxide (NO) bioavailability, increased endothelin-1 and oxidative stress.
6. Genetic/polygenic factors - Multiple genes with modest individual effect; shared environment likely as important.

• Excess dietary sodium
• Inadequate dietary potassium
• Physical inactivity
• Overweight/obesity (BMI ≥25 kg/m²)
• Excess alcohol (>2 drinks/day)
• Poor diet quality (low DASH adherence)

Pathophysiology of Secondary Hypertension

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PART 3: CLINICAL EVALUATION

History

• Duration and severity of BP elevation
• Prior BP measurements and treatment
• Symptoms of target organ damage: headache, palpitations, exertional dyspnea, orthopnea, chest pain, visual disturbance, nocturia, oliguria
• Secondary cause clues: snoring/daytime sleepiness (OSA), paroxysmal sweating/palpitations (pheo), muscle weakness/cramping (hyperaldosteronism), flank bruit (RAS)
• Drug history: NSAIDs, OCPs, sympathomimetics, stimulants, liquorice, steroids, calcineurin inhibitors, cocaine
• Family history, cardiovascular risk factors

Physical Examination

• Accurate BP measurement: both arms, sitting (after 5 min rest), standing (screen for orthostatic hypotension), use validated oscillometric device
• Check for: retinal changes (Keith-Wagener-Barker classification), carotid bruits, JVP, cardiac auscultation (S3/S4, murmurs), abdominal bruits, peripheral pulses, ankle-brachial index, fundoscopy
• Signs suggesting secondary causes: cushingoid features, thyromegaly, radio-femoral delay

Keith-Wagener-Barker Retinal Classification

Investigations

• Urinalysis + urine ACR (albumin:creatinine ratio)
• Serum electrolytes (Na, K, creatinine, eGFR, uric acid)
• Fasting glucose and/or HbA1c
• Fasting lipid profile
• ECG (LVH by voltage criteria, ischemia, arrhythmia)

• Echocardiogram (LVH assessment, diastolic dysfunction)
• Renal ultrasound (size asymmetry, scarring)
• Aldosterone:renin ratio (screen for primary aldosteronism if hypokalemia, resistant HTN, adrenal incidentaloma)
• Plasma/24h urine metanephrines (if paroxysmal symptoms, pheo suspicion)
• Thyroid function tests
• Sleep study if OSA suspected
• 24h ambulatory BP monitoring (ABPM) or home BP monitoring - to confirm diagnosis, identify white coat or masked HTN

Target Organ Damage Assessment

• Heart: LVH (ECG/echo), heart failure, coronary artery disease
• Vessels: carotid intima-media thickness, peripheral arterial disease
• Kidneys: microalbuminuria, reduced eGFR, proteinuria
• Eyes: hypertensive retinopathy
• Brain: lacunar infarcts, cognitive impairment

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PART 4: TREATMENT TARGETS

2025 AHA/ACC Targets

• General target: <130/80 mmHg for all adults with hypertension, regardless of age
• Cognitive protection: SBP <130 mmHg specifically recommended to prevent mild cognitive impairment and dementia (COR 1, LOE A)
• Post-thrombectomy stroke: Target SBP ≥140 mmHg (lower targets worsen outcomes - ENCHANTED-2, OPTIMAL BP, BEST-II trials)
• Elderly with high comorbidity/limited life expectancy: individualize based on clinical judgment

ESC 2024 Targets

• General target: 120-129/70-79 mmHg for most patients <85 years
• Age ≥85 years or moderate-severe frailty: SBP <140 mmHg (or "as low as reasonably achievable")
• Initiation threshold: BP ≥140/90 mmHg in all patients <85 years; treat at ≥130/80 in those with established CVD, DM, or CKD

ESH (European Society of Hypertension) Targets

• <140/80 mmHg for most patients
• Age 18-64: 120-129/70-79 mmHg
• Age 65-79: <140/80 (lower target 120-129 if tolerated)
• Age ≥80: SBP 140-150 mmHg (130-139 if tolerated, not frail)

Key exam comparison:

• AHA/ACC (2025): uniform <130/80 for all
• ESC (2024): 120-129/70-79 for most <85 years
• ESH: age-stratified, more conservative in elderly

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PART 5: NON-PHARMACOLOGICAL MANAGEMENT (Lifestyle Modifications)

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PART 6: PHARMACOLOGICAL MANAGEMENT

When to Start Drugs (2025 AHA/ACC)

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First-Line Drug Classes (Endorsed by AHA/ACC, ESC 2024)

1. ACE inhibitors (ACEi)
2. Angiotensin Receptor Blockers (ARBs)
3. Calcium Channel Blockers (CCBs)
4. Thiazide/Thiazide-like diuretics

Beta-blockers: AHA/ACC and ESC reserve BBs for compelling indications (post-MI, heart failure with reduced EF, angina, rate control in AF). They are NOT first-line for uncomplicated hypertension.

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Drug-by-Drug Pharmacology

1. ACE Inhibitors (ACEi)

• Enalapril: 5-40 mg/day (OD or BD)
• Ramipril: 2.5-10 mg/day (OD) - preferred post-MI, CKD
• Lisinopril: 10-40 mg/day (OD)
• Perindopril: 4-8 mg/day (OD)
• Captopril: 12.5-75 mg BD/TDS (short-acting, used in hypertensive emergency)
• Fosinopril: 10-40 mg/day (OD)

• Dry cough (5-20%, due to bradykinin - class effect, switch to ARB)
• Angioedema (rare 0.1-0.7%, can be life-threatening - absolute contraindication thereafter)
• Hyperkalemia (especially with K+ supplements, K-sparing diuretics, in CKD)
• First-dose hypotension (especially if volume depleted)
• Rise in creatinine 10-30% at initiation (acceptable if stable; stop if >30% rise)

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2. Angiotensin Receptor Blockers (ARBs)

• Losartan: 25-100 mg/day (OD)
• Valsartan: 80-320 mg/day (OD)
• Olmesartan: 20-40 mg/day (OD)
• Irbesartan: 150-300 mg/day (OD)
• Candesartan: 8-32 mg/day (OD)
• Telmisartan: 40-80 mg/day (OD) - longest half-life, once daily

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3. Calcium Channel Blockers (CCBs)

• Amlodipine: 2.5-10 mg/day (OD) - gold standard, long half-life
• Nifedipine (slow-release): 30-90 mg/day
• Felodipine: 2.5-10 mg/day
• Lercanidipine: 10-20 mg/day (better tolerated, less oedema)
• Nicardipine (IV): used in hypertensive emergency

• Verapamil: 120-480 mg/day BD/TDS (also Class IV antiarrhythmic)
• Diltiazem: 120-360 mg/day BD/TDS

• Non-DHP: heart failure with reduced EF, AV block grade 2-3, sick sinus syndrome
• DHPs (fast-release) in acute MI/unstable angina

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4. Thiazide and Thiazide-like Diuretics

• Hydrochlorothiazide (HCTZ): 12.5-25 mg/day (OD) - most widely used
• Chlorthalidone: 12.5-25 mg/day (OD) - preferred (longer half-life, stronger evidence for CV outcomes in ALLHAT trial)
• Indapamide: 1.25-2.5 mg/day (OD) - thiazide-like, preferred in CKD stage 1-3, less metabolic effects
• Metolazone: 2.5-10 mg/day - useful in CKD + resistant HTN

• Hypokalemia (most common - check K+ within 4 weeks of initiation)
• Hyperuricemia (gout in predisposed)
• Hyperglycemia / new-onset type 2 DM (especially at higher doses)
• Hyperlipidemia (minor, at higher doses)
• Hyponatremia (especially in elderly)
• Hypercalcemia (increases Ca2+ reabsorption - useful in osteoporosis, avoid in hypercalcemia)
• Erectile dysfunction

Exam key: Chlorthalidone is preferred over HCTZ by most guidelines due to stronger CV outcome data and longer half-life. Indapamide preferred in CKD.

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5. Beta-Blockers (BBs) - Compelling indications only

• Atenolol: 25-100 mg/day (cardioselective, OD) - widely used but not preferred in guidelines
• Bisoprolol: 2.5-10 mg/day (cardioselective, OD) - preferred in HF (HF-rEF)
• Metoprolol succinate: 25-200 mg/day (cardioselective, OD) - preferred in HF (MERIT-HF)
• Carvedilol: 3.125-25 mg BD (non-selective + α1 block) - preferred in HF
• Nebivolol: 2.5-10 mg/day (also releases NO → additional vasodilation) - best tolerated, good in elderly
• Labetalol (IV/oral): α1 + β blocker - preferred in hypertensive emergency in pregnancy

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6. Mineralocorticoid Receptor Antagonists (MRAs) - 4th line / Resistant HTN

• Spironolactone: 25-100 mg/day (steroidal MRA) - drug of choice for resistant HTN, primary aldosteronism
• Eplerenone: 25-50 mg/day (selective MRA, fewer hormonal side effects)
• Finerenone: 10-20 mg/day (nonsteroidal MRA - new; approved for CKD + DM in heart failure)

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7. Other Drug Classes (Second/Third-line or Special Situations)

• Doxazosin: 1-16 mg/day; Prazosin: 1-10 mg BD/TDS
• SE: First-dose postural hypotension; Contraindicated in heart failure
• Useful in HTN + BPH (prostate disease)

• Methyldopa: 250-1000 mg TDS - drug of choice in hypertension in pregnancy (first-line per most guidelines)
• Clonidine: 0.1-0.8 mg/day - rarely used; rebound HTN on withdrawal is dangerous
• Moxonidine: 0.2-0.6 mg/day

• Hydralazine: 25-100 mg BD/TDS - used in pregnancy (IV for emergencies); causes reflex tachycardia + fluid retention; lupus-like syndrome at high doses
• Minoxidil: 5-100 mg/day - potent, for resistant HTN; causes hirsutism, fluid retention, reflex tachycardia

• Aliskiren: 150-300 mg/day - do NOT combine with ACEi/ARB

• Bosentan, ambrisentan - for pulmonary arterial hypertension (not systemic HTN management)

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PART 7: TREATMENT ALGORITHMS

Step-Wise Treatment (Harrison's 22E Figure 286-4)

• Start with 2-drug combination (preferred in Black adults and those with SBP >20 mmHg above target)
• Diuretic OR CCB combined with ACEi or ARB
• Single-pill combination (SPC) preferred for adherence

• Diuretic + CCB + ACEi or ARB

• Add MRA (spironolactone 25-50 mg/day) - most effective 4th agent
• Consider vasodilators (hydralazine, minoxidil) if needed
• Rule out pseudoresistance (non-adherence, white-coat effect, poor measurement technique)
• Refer to hypertension specialist

Initial Management by BP Level (Harrison's 22E)

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PART 8: COMPELLING INDICATIONS - PREFERRED DRUGS

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PART 9: RESISTANT HYPERTENSION

• True resistant HTN: applies to ~10-15% of hypertensive patients
• AHA/ACC includes patients needing ≥4 medications to maintain BP control

Evaluation Steps

1. Exclude pseudoresistance:
   • White coat effect (confirm with ABPM/home BP monitoring)
   • Poor adherence (most common reason)
   • Inadequate doses
   • Poor measurement technique
   • Volume overload (inadequate diuretic)
2. Review medications for contributors:
   • NSAIDs, COX-2 inhibitors (most important; sodium/water retention, blunt response to all antihypertensives)
   • Oral contraceptives
   • Stimulants (methylphenidate, cocaine, amphetamines)
   • Erythropoietin
   • Sympathomimetics (decongestants)
   • Calcineurin inhibitors (cyclosporine, tacrolimus)
   • VEGF inhibitors
   • Licorice
3. Screen for secondary causes (especially primary aldosteronism, OSA, renovascular disease)
4. Optimize therapy: Ensure diuretic use and adequate dose; prefer chlorthalidone over HCTZ
5. Add 4th agent: Spironolactone 25-50 mg/day (most evidence - PATHWAY-2 trial)
6. Advanced options: Renal denervation (FDA cleared in some countries), baroreceptor activation therapy

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PART 10: HYPERTENSIVE EMERGENCY

Management of Hypertensive Emergency

Severe Hypertension Without Acute TOD (Formerly "Hypertensive Urgency")

• BP >180/120 WITHOUT target organ damage
• NOT a true emergency; does NOT require aggressive IV therapy
• Restart/optimize oral antihypertensives; recheck within 24-72 hours
• Admission generally not required unless nonadherence, no follow-up, or concern about access

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PART 11: SPECIAL POPULATIONS

Hypertension in Pregnancy

• Gestational HTN: HTN arising after 20 weeks without proteinuria; resolves postpartum
• Pre-eclampsia: HTN ≥140/90 + proteinuria (≥300 mg/24h or protein/creatinine ≥0.3) after 20 weeks; or HTN + end-organ damage without proteinuria
• Eclampsia: Pre-eclampsia + seizures
• Chronic HTN: Pre-existing, or diagnosed <20 weeks, or persisting >12 weeks postpartum
• Superimposed pre-eclampsia: Chronic HTN + new proteinuria/organ damage after 20 weeks

• First-line: Methyldopa, Nifedipine (slow-release), Labetalol
• IV emergency: Hydralazine IV, Labetalol IV, Nicardipine IV - Magnesium sulfate for seizure prophylaxis in severe pre-eclampsia
• ABSOLUTELY CONTRAINDICATED: ACEi, ARBs (oligohydramnios, renal dysgenesis, calvarial ossification defects, limb contractures, neonatal renal failure), aliskiren, thiazides (not preferred)

Hypertension in CKD (Harrison's 22E)

• Target: <130/80 mmHg (in DM or proteinuria >1g/24h)
• First-line: ACEi or ARB (renoprotective - reduce intraglomerular hyperfiltration)
• Acceptable rise in creatinine <30% at initiation with ACEi/ARB - do NOT stop
• Continue ACEi/ARB even in advanced CKD (eGFR <30) - stopping is associated with increased mortality
• SGLT2 inhibitors (gliflozins) are now a mainstay for cardiorenal protection in CKD ± DM
• Avoid K-sparing diuretics; monitor K+ closely with MRAs

Hypertension in Diabetes

• Target: <130/80 mmHg
• First-line: ACEi or ARB (also benefit: microalbuminuria, nephropathy prevention)
• SGLT2 inhibitors provide additive cardiorenal and BP-lowering benefits
• BB: Use with caution (mask hypoglycemia, worsen glucose tolerance); acceptable for compelling indications

Hypertension in the Elderly

• Begin at lowest doses; titrate slowly
• Assess for orthostatic hypotension (check standing BP)
• Thiazides and CCBs preferred first step (Katzung, 16th ed)
• Target SBP <130 mmHg if tolerated (AHA/ACC 2025); ESC: <140 mmHg for ≥85 years
• Frailty: individualize; avoid aggressive lowering (syncope, falls)
• Cognitive benefit of treating to SBP <130 mmHg (SPRINT-MIND subanalysis)

Hypertension in Stroke

• Acute ischemic stroke (no thrombolysis/thrombectomy): Do not lower BP unless >220/120; treat conservatively in first 24-48h
• Post-thrombolysis: Target <180/105 for first 24h
• Post-thrombectomy (2025 AHA/ACC NEW): Do NOT target SBP <140 mmHg - may worsen outcomes (ENCHANTED-2, OPTIMAL BP, BEST-II trials stopped early)
• Secondary prevention: ACEi + indapamide (PROGRESS trial) - 28% relative risk reduction

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PART 12: FOLLOW-UP AND MONITORING

After Initiating/Changing Therapy

• Stage 2 HTN or drug change: Recheck in 1 month
• Stage 1 HTN (high CVD risk) starting drugs: Recheck in 1 month
• Elevated BP (lifestyle only): Recheck in 3-6 months
• Normal BP: Recheck in 12 months

Routine Monitoring on Treatment

• Blood pressure at every visit (standing + seated, both arms at first)
• Renal function (creatinine, eGFR, electrolytes) after starting ACEi/ARB/diuretic - at 2-4 weeks, then periodically
• Potassium especially with ACEi/ARB (hyperkalemia risk) or thiazides (hypokalemia)
• Lipids, glucose annually
• 12-lead ECG yearly if LVH present or symptoms
• Urine ACR annually (screen for microalbuminuria)
• Fundoscopy if Grade III-IV retinopathy or new visual symptoms

Patient Adherence Strategies

• Single-pill combinations (SPCs): significantly improve adherence vs. multiple pills
• Long-acting, once-daily agents preferred
• Self-monitoring with validated home BP monitors (engage patients in own care)
• Medication reminders/apps
• Simplify regimen; avoid unnecessary complex dosing
• Pill burden review at every visit

When to Refer

• Resistant hypertension (BP above target on ≥3 drugs including diuretic)
• Suspected secondary hypertension (especially primary aldosteronism, pheochromocytoma, renovascular)
• Hypertension in pregnancy (especially pre-eclampsia/eclampsia)
• Hypertensive emergency
• Hypertension with suspected end-organ damage requiring specialist management (e.g., hypertensive retinopathy grade III/IV, hypertensive nephropathy, aortic dissection)

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PART 13: SECONDARY HYPERTENSION - TREATMENT PEARLS

Primary Aldosteronism

• Bilateral hyperplasia: spironolactone (or eplerenone)
• Unilateral adenoma (Conn's syndrome): adrenalectomy (curative ~70%)
• Screen: aldosterone:renin ratio; confirm with salt loading/fludrocortisone suppression test; then CT adrenal; adrenal vein sampling to lateralize

Pheochromocytoma

• Always start alpha-blocker first (phenoxybenzamine 10-40 mg/day or doxazosin); then add BB only after alpha-blockade established (to avoid hypertensive crisis from unopposed alpha effects)
• IV phenothiazine for acute crisis
• Definitive treatment: surgical excision

Renovascular Hypertension

• FMD (fibromuscular dysplasia) in young women → percutaneous renal artery angioplasty (PTCA) curative
• Atherosclerotic RAS: medical therapy (ACEi/ARB + statin + antiplatelet); revascularization only in specific indications (flash pulmonary oedema, bilateral RAS with deteriorating renal function)

OSA-Associated HTN

• CPAP therapy is first-line; can reduce BP by 2-4 mmHg
• Drug choice: no single preferred agent; MRAs may be especially beneficial (fluid redistribution theory)

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PART 14: KEY CLINICAL TRIALS (Must Know for Exam)

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PART 15: IMPORTANT DRUG COMBINATIONS AND RATIONALE

• ACEi/ARB + CCB (dihydropyridine): Complementary - ACEi/ARB reduces Ang II-mediated vasoconstriction and aldosterone; CCB provides direct vasodilation. Also: CCB oedema is reduced by ACEi/ARB (which reduces hydrostatic pressure in capillaries). Evidence: ACCOMPLISH trial (benazepril + amlodipine > benazepril + HCTZ for CV outcomes)
• ACEi/ARB + Diuretic: Diuretic activates RAAS → adds rationale for ACEi/ARB; ACEi/ARB reduces K+ losses from diuretic
• CCB + Diuretic: Additive antihypertensive; no major interaction
• ACEi/ARB + CCB + Diuretic: Standard triple combination

• ACEi + ARB (dual RAAS blockade: no benefit, more AKI/hyperkalemia - ONTARGET)
• Non-DHP CCB (verapamil/diltiazem) + BB (risk of severe bradycardia, AV block, HF)
• BB alone in pheochromocytoma (hypertensive crisis from unopposed alpha)
• Potassium-sparing diuretic + ACEi/ARB (hyperkalemia risk)
• Thiazide + loop diuretic without indication (excessive volume depletion)
• Aliskiren + ACEi or ARB (contraindicated - hyperkalemia, renal failure)

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PART 16: MNEMONICS AND HIGH-YIELD EXAM POINTS

ABCDE Rule for Drug Indication

• A = ACEi/ARB (DM, CKD, heart failure, post-MI)
• B = Beta-blockers (post-MI, angina, HFrEF, AF rate control)
• C = CCBs (elderly, Black patients, isolated systolic HTN, angina)
• D = Diuretics (Thiazide - first-line, isolated systolic HTN, elderly, osteoporosis)
• E = Everything else (MRAs - resistant HTN; alpha-blockers - BPH; methyldopa - pregnancy)

Classic Questions

• Drug causing cough → ACEi (bradykinin)
• Drug causing gynecomastia → Spironolactone (anti-androgen)
• Drug absolutely contraindicated in pregnancy → ACEi, ARBs
• Best 4th drug for resistant HTN → Spironolactone
• Drug of choice for hypertension in pheochromocytoma → Alpha-blocker first (phenoxybenzamine)
• Drug of choice for hypertension in pregnancy → Methyldopa (oral), labetalol (IV)
• Drug of choice for hypertension + BPH → Doxazosin
• Drug of choice for hypertension in gout → Losartan (also uricosuric)
• Drug of choice for hypertension + osteoporosis → Thiazide (reduces calciuria)
• Why give BB before CCB in aortic dissection? → Reduce HR and shear stress; CCB or vasodilator alone causes reflex tachycardia which worsens dissection
• All antihypertensives cause vasodilation EXCEPT → Diuretics (primary mechanism is volume reduction; vasodilation comes later)
• Which diuretic is preferred in CKD? → Indapamide (up to stage 3-4); loop diuretics when eGFR <30
• Single most powerful step in HTN management → Adherence to medication

"Terrible Triad" of Drug Interactions

1. ACEi + ARB + MRA = triple RAAS blockade = severe hyperkalemia/AKI - AVOID
2. Non-DHP CCB + BB = AV block + severe bradycardia - AVOID
3. Alpha-blocker + PDE5 inhibitor (sildenafil) = severe hypotension - CAUTION

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SUMMARY: GUIDELINE COMPARISON TABLE (2024/2025)

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Sources cited throughout:

• Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapter 288 (Hypertension) and Chapter 289 (CKD)
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Chapter 32 (Antihypertensives)
• Braunwald's Heart Disease, 2-Vol Set - Chapter on Hypertension Management
• Rosen's Emergency Medicine - Chapter 70 (Hypertensive Emergency)
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Chapter 5
• Katzung Basic & Clinical Pharmacology, 16th Ed
• 2024 ESC Guidelines for the management of elevated blood pressure and hypertension (McEvoy JW et al., Eur Heart J, 2024; PMID: 39210715)
• 2025 AHA/ACC Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults (Jones DW et al., Hypertension, 2025; PMID: 40811516)