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HYPERTENSION - Complete Lecture Notes

Sources: Fuster and Hurst's The Heart, 15th Edition | Braunwald's Heart Disease, 2 Vol Set | Brenner and Rector's The Kidney

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1. DEFINITION AND OVERVIEW

• Systolic BP (SBP): < 120 mmHg
• Diastolic BP (DBP): < 80 mmHg
• Accurate measurement = average of ≥2 readings on ≥2 separate occasions

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2. CLASSIFICATION OF HYPERTENSION

ACC/AHA 2017 Classification (Adults ≥18 years)

Note: The older JNC 7 used a threshold of 140/90 for Stage 1. The ACC/AHA 2017 guideline lowered this threshold to 130/80 mmHg to capture higher cardiovascular risk earlier.

Isolated Systolic Hypertension

• SBP ≥ 130 mmHg with DBP < 80 mmHg
• More common in the elderly due to arterial stiffness

Hypertensive Emergency vs. Urgency

• Emergency: Severely elevated BP (>180/120) with end-organ damage (encephalopathy, MI, AKI, pulmonary edema, aortic dissection)
• Urgency: Severely elevated BP without acute end-organ damage

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3. EPIDEMIOLOGY

• Global prevalence: ~1.13-1.28 billion adults (approximately 1 in 3 worldwide adults)
• Prevalence is rising globally due to aging populations and increased obesity/overweight
• In the United States, BP control rates have been declining: controlled BP fell from 54% (2013-2014) to 44% (2017-2018) in all adults with HTN
• Control rates in low- and middle-income countries: as low as 8-14%
• Among adults on antihypertensive medication, controlled BP declined from 72% (2013-2014) to 65% (2017-2018)
• Racial disparities: Black adults less likely to have controlled BP (42%) vs. White adults (48%)
• Younger adults (18-44 years) less likely to have controlled BP compared to those aged 45-64 years
• Awareness of having HTN declined from 85% (2013-2014) to 77% (2017-2018)

Cardiovascular Disease Risk

• CVD risk is directly and continuously related to BP with no clear threshold
• Each 20 mmHg rise in SBP or 10 mmHg rise in DBP doubles the risk of cardiovascular death (over 40-70 mmHg SBP range)
• HTN is responsible for ~54% of strokes and ~47% of ischemic heart disease events globally

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4. PATHOPHYSIOLOGY

4A. Basic Hemodynamic Relationships

• CO = Heart Rate × Stroke Volume
• TPR = resistance in arterioles (main determinant of chronic BP)

4B. Short-Term vs. Long-Term BP Regulation

• Baroreceptor reflex (aortic arch, carotid sinus)
• Sympathetic nervous system (SNS)
• Renin-Angiotensin-Aldosterone System (RAAS) initiation

• Renal pressure-natriuresis is the dominant mechanism
• If kidney sodium excretion is abnormal, sustained HTN results
• The kidney "resets" its pressure-natriuresis curve upward in HTN patients

4C. Renal Mechanisms - KEY CONCEPT

1. Increased preglomerular (afferent arteriolar) resistance

• Generalized increases → salt-insensitive HTN
• Patchy increases → salt-sensitive HTN (renin suppressed in normal nephrons, cannot respond further)

1. Decreased glomerular capillary filtration coefficient (Kf)

• Reduces GFR per mmHg of perfusion pressure
• Hypertension develops to restore sodium balance

1. Nephron loss

• Surgical nephron loss alone (without excess sodium) may not cause HTN
• Ischemic nephron loss → raises renin/Ang II → HTN
• Aging accelerates nephron loss (especially after age 40-50)

1. Increased renal tubular sodium reabsorption

• Excess mineralocorticoids (aldosterone) or Ang II
• Distal tubule hyper-reabsorption → suppresses renin → salt-sensitive HTN
• Volume initially expands → pressure natriuresis corrects → TPR rises

4D. RAAS (Renin-Angiotensin-Aldosterone System)

Liver → Angiotensinogen
        ↓ (renin from juxtaglomerular cells)
     Angiotensin I
        ↓ (ACE - lung)
     Angiotensin II
        ↓
  ┌─────────────────────┐
  │ AT1 receptors:       │
  │ • Vasoconstriction  │
  │ • Aldosterone release│
  │ • Renal Na+ retain  │
  │ • SNS activation    │
  └─────────────────────┘
  Aldosterone → distal tubule Na+ reabsorption → volume expansion

4E. Sympathetic Nervous System (SNS)

• SNS activation increases: heart rate, CO, renin secretion, renal tubular Na+ reabsorption, and TPR
• Chronically elevated SNS activity (especially renal sympathetic nerve activity) maintains HTN
• SNS modulates RAAS: renal adrenergic stimulation increases renin secretion

4F. Nitric Oxide (NO) and Endothelin

• Produced by endothelium (eNOS)
• Potent vasodilator; enhances renal pressure natriuresis
• NO deficiency impairs natriuresis and raises BP
• Oxidative stress degrades NO (superoxide + NO → peroxynitrite)

• Potent vasoconstrictor produced by endothelium
• ET-A receptors: vasoconstriction
• ET-B receptors: vasodilation (via NO/prostacyclin release) + renal sodium/water excretion
• ET-1 promotes salt-sensitive HTN by reducing renal excretory capacity

4G. Atrial Natriuretic Peptide (ANP)

• Released by atria in response to volume expansion
• Enhances renal pressure natriuresis, inhibits RAAS, causes vasodilation
• ANP deficiency (e.g., in obesity due to elevated adipocyte-derived neprilysin) may contribute to salt-sensitive HTN
• Genetic knockout of ANP → salt-sensitive HTN in mice

4H. Innate and Adaptive Immunity

• T lymphocytes and macrophages infiltrate kidneys in HTN models
• T-cell activation (by Ang II, aldosterone, DOCA-salt) impairs renal function and reduces pressure natriuresis
• Immunosuppressive drugs (mycophenolate mofetil) attenuate HTN in some models
• Systemic inflammatory conditions (SLE, RA, psoriasis) associated with increased HTN risk

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5. SECONDARY HYPERTENSION (10-15% of cases)

• Age < 30 years
• Resistant HTN (BP uncontrolled on ≥3 drugs)
• Sudden worsening of previously controlled HTN
• Unprovoked hypokalemia
• Abdominal bruit

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6. SPECIAL FORMS OF HYPERTENSION

Obesity Hypertension

1. SNS activation (especially renal sympathetic) - increases renin, tubular Na+ reabsorption
2. RAAS activation - obese subjects have elevated angiotensinogen, ACE activity, Ang II, aldosterone despite sodium retention
3. Physical compression of kidneys by perinephric and intra-abdominal fat → impairs pressure natriuresis

• Leptin → POMC neurons (arcuate nucleus) → α-MSH → MC4R activation → SNS activation → ↑ renal sympathetic activity → ↑ BP

Renovascular Hypertension (Renal Artery Stenosis - RAS)

• Unilateral RAS: reduced perfusion to one kidney → RAAS activation → HTN
• Bilateral RAS: volume-dependent HTN; ACE inhibitors/ARBs can precipitate acute kidney injury

Salt-Sensitive Hypertension

• BP rises substantially with increased sodium intake
• More common in: Black individuals, elderly, obese, CKD patients
• Mechanism: impaired renal pressure natriuresis (patchy preglomerular resistance, tubular hyper-reabsorption, nephron loss)

Nondipping Blood Pressure

• Normal: 10-20% nocturnal BP fall ("dipping")
• Non-dippers: < 10% nocturnal fall → increased risk of stroke, cardiovascular mortality, total mortality
• Reverse dippers (BP rises at night) have the worst prognosis
• Mechanisms: sympathetic overactivity, sleep apnea, obesity, endothelial dysfunction, salt sensitivity

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7. DIAGNOSIS AND EVALUATION

BP Measurement Techniques

Clinical Evaluation

• Duration and prior BP readings
• Medications (especially those causing HTN)
• Family history of HTN, CVD, CKD
• Diet (sodium, potassium, alcohol, caffeine)
• Physical activity level
• Symptoms suggesting secondary causes

• BP in both arms (difference >10-15 mmHg suggests subclavian stenosis or coarctation)
• BP sitting and standing (orthostatic hypotension)
• BMI and waist circumference
• Fundoscopy (hypertensive retinopathy)
• Carotid bruits
• Cardiac exam (S4 gallop, displaced apex = LVH)
• Abdominal bruits (RAS)
• Peripheral edema, pulses

• Grade I: Increased arteriolar light reflex (copper/silver wiring)
• Grade II: AV nicking
• Grade III: Flame hemorrhages + cotton wool spots
• Grade IV: Papilledema

Baseline Investigations

• Urinalysis (proteinuria, hematuria, casts)
• Serum electrolytes (Na+, K+ - low K+ suggests hyperaldosteronism)
• Renal function (creatinine, eGFR)
• Fasting glucose / HbA1c
• Fasting lipid panel
• ECG (LVH, arrhythmia)
• Uric acid (gout risk with thiazides)

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8. TARGET ORGAN DAMAGE

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9. MANAGEMENT

9A. Blood Pressure Targets

SPRINT Trial (Systolic Blood Pressure Intervention Trial): Intensive BP target (SBP < 120) reduced major cardiovascular events and cardiovascular mortality vs. standard target (SBP < 140) in high-risk, non-diabetic patients.

9B. Lifestyle Modifications (Cornerstone of Treatment)

9C. Pharmacological Therapy - When to Initiate

• Elevated BP + lifestyle modifications: First-line
• Stage 1 HTN (130-139/80-89): Drug therapy if 10-year ASCVD risk ≥10% OR pre-existing CVD
• Stage 2 HTN (≥140/90): Drug therapy in all patients (plus lifestyle)
• BP ≥160/100: Consider combination therapy from initiation

9D. First-Line Antihypertensive Drug Classes

1. Thiazide Diuretics

• Agents: Chlorthalidone (preferred over HCTZ for 24h duration), Hydrochlorothiazide (HCTZ), Indapamide
• Mechanism: Inhibit Na+/Cl- cotransporter in distal convoluted tubule → natriuresis → ↓ volume → ↓ CO (acute); long-term: ↓ TPR
• Indications: First-line for most patients, especially Black patients, elderly, isolated systolic HTN
• Side effects: Hypokalemia, hyponatremia, hyperuricemia (gout), hyperglycemia, hyperlipidemia, erectile dysfunction, photosensitivity
• Contraindications: Gout (relative), severe hyponatremia

2. ACE Inhibitors (ACEi)

• Agents: Lisinopril, Enalapril, Ramipril, Perindopril, Captopril
• Mechanism: Block conversion of Ang I → Ang II; also ↓ bradykinin degradation → vasodilation, natriuresis, ↓ aldosterone
• Indications: First-line; preferred in: diabetes with proteinuria, CKD, HF with reduced EF, post-MI, high CVD risk
• Side effects: Dry cough (10-15%, due to bradykinin accumulation), angioedema (rare; more common in Black patients), hyperkalemia, acute kidney injury (especially bilateral RAS), teratogenic (Category D/X - avoid in pregnancy)
• Contraindications: Bilateral RAS, pregnancy, prior angioedema, hyperkalemia

3. Angiotensin Receptor Blockers (ARBs)

• Agents: Losartan, Valsartan, Irbesartan, Candesartan, Olmesartan, Telmisartan
• Mechanism: Block AT1 receptors of Ang II → same downstream effects as ACEi but no bradykinin accumulation → no cough
• Indications: Same as ACEi; preferred when ACEi not tolerated (cough); also preferred in: diabetic nephropathy, HF (when ACEi intolerant), LVH
• Side effects: Hyperkalemia, ↑ creatinine, angioedema (less common than ACEi), teratogenic
• Note: Do NOT combine ACEi + ARB (↑ hyperkalemia, AKI without added cardiovascular benefit)

4. Calcium Channel Blockers (CCBs)

• Agents: Amlodipine, Nifedipine (long-acting), Felodipine, Nicardipine
• Mechanism: Block L-type Ca2+ channels in vascular smooth muscle → vasodilation → ↓ TPR
• Indications: First-line; preferred in: Black patients, elderly, isolated systolic HTN, angina (coronary artery disease), Raynaud phenomenon
• Side effects: Peripheral edema (ankle), reflex tachycardia (DHP), flushing, gingival hyperplasia

• Agents: Verapamil, Diltiazem
• Mechanism: Block Ca2+ channels in both vascular smooth muscle AND heart → ↓ HR + ↓ AV conduction + vasodilation
• Indications: HTN + AF with rate control, HTN + angina (not HFrEF)
• Side effects: Bradycardia, AV block, constipation (verapamil), negative inotropy
• Contraindications: HFrEF (negative inotropic effect), combined with beta-blockers (→ AV block)

9E. Second-Line Antihypertensive Drug Classes

5. Beta-Blockers

• Agents: Metoprolol (cardioselective β1), Atenolol (cardioselective), Carvedilol (α1+β1+β2), Nebivolol (β1 + NO release), Bisoprolol
• Mechanism: Block β-adrenergic receptors → ↓ HR, ↓ CO, ↓ renin secretion
• Indications: HTN + coronary artery disease, post-MI, HFrEF, tachyarrhythmias; not first-line for uncomplicated HTN (less effective in preventing stroke)
• Side effects: Fatigue, cold extremities, sexual dysfunction, bradycardia, bronchoconstriction (non-selective), masking hypoglycemia, dyslipidemia, weight gain
• Contraindications: Asthma/COPD (non-selective), severe bradycardia, AV block (2nd/3rd degree), decompensated HF

6. Aldosterone Antagonists / MR Antagonists

• Agents: Spironolactone (steroidal), Eplerenone (selective), Finerenone
• Mechanism: Block mineralocorticoid receptors → ↓ distal tubule Na+ reabsorption → natriuresis
• Indications: Resistant HTN (uncontrolled on ≥3 drugs - most effective add-on), primary hyperaldosteronism, HFrEF (improves mortality)
• Side effects: Hyperkalemia, gynecomastia and sexual dysfunction (spironolactone - anti-androgenic; less with eplerenone)
• Contraindications: Hyperkalemia, severe CKD (eGFR < 30), pregnancy

7. Loop Diuretics

• Agents: Furosemide, Bumetanide, Torsemide
• Mechanism: Inhibit NKCC2 in thick ascending limb of loop of Henle → potent natriuresis
• Indications: HTN + HF, HTN + CKD (especially when eGFR < 30, where thiazides less effective), fluid overload states
• Side effects: Hypokalemia, hypomagnesemia, ototoxicity (high doses), hypovolemia

8. Alpha-1 Blockers

• Agents: Doxazosin, Prazosin, Terazosin
• Mechanism: Block α1 receptors in vascular smooth muscle → vasodilation
• Indications: HTN + benign prostatic hyperplasia (BPH) - dual benefit
• Side effects: First-dose orthostatic hypotension, reflex tachycardia, dizziness, fluid retention
• Note: Not first-line due to inferior outcomes in ALLHAT trial (increased HF risk vs. chlorthalidone)

9. Central Alpha-2 Agonists

• Agents: Clonidine, Methyldopa, Guanfacine
• Mechanism: Stimulate central α2 receptors → ↓ SNS outflow → ↓ HR, ↓ TPR
• Indications: Methyldopa - drug of choice in pregnancy HTN; Clonidine - adjunct in resistant HTN
• Side effects: Sedation, dry mouth, bradycardia; rebound HTN with abrupt clonidine withdrawal

10. Direct Vasodilators

• Agents: Hydralazine, Minoxidil
• Mechanism: Direct arteriolar dilation → ↓ TPR
• Indications: Hydralazine + nitrates in HFrEF (especially in Black patients); Hydralazine in pregnancy (IV for acute severe HTN); Minoxidil for refractory HTN
• Side effects: Hydralazine: reflex tachycardia, fluid retention, lupus-like syndrome (high doses); Minoxidil: hypertrichosis, pericardial effusion, fluid retention (requires concurrent diuretic + beta-blocker)

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10. COMBINATION THERAPY

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11. RESISTANT HYPERTENSION

• Poor medication adherence
• White coat effect
• Suboptimal technique / poorly calibrated device
• Drug interactions (NSAIDs, OCPs, steroids)

• Confirm with ABPM
• Assess and optimize lifestyle
• Rule out secondary causes (primary hyperaldosteronism - most common)

• Add spironolactone 25-50 mg/day (most effective 4th agent)
• Consider eplerenone if spironolactone not tolerated
• Renal denervation (RDN) - investigational/approved in some regions

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12. HYPERTENSION IN SPECIAL POPULATIONS

Diabetes

• Target BP: < 130/80 mmHg
• Preferred agents: ACEi or ARB (reduce proteinuria, slow CKD progression)
• Avoid: Thiazides and beta-blockers may impair glucose control (use with caution)

Chronic Kidney Disease (CKD)

• Target BP: < 130/80 mmHg
• ACEi/ARB preferred (reduce proteinuria, delay CKD progression - caution if bilateral RAS)
• Loop diuretics preferred when eGFR < 30 (thiazides less effective)
• Monitor: K+ and creatinine after initiating ACEi/ARB

Heart Failure with Reduced EF (HFrEF)

• ACEi (or ARB if intolerant) + Beta-blocker + MR antagonist + SGLT2 inhibitor = core therapy
• Avoid: DHP CCBs (except amlodipine, felodipine), Non-DHP CCBs (negative inotropes)

Coronary Artery Disease (CAD)

• Beta-blockers + ACEi preferred
• Long-acting CCBs acceptable for additional BP control or angina

Elderly Patients

• Target SBP: 130-140 mmHg (individualized; lower targets acceptable if tolerated)
• Diuretics + CCBs particularly effective
• Avoid: Alpha-1 blockers and central alpha-2 agonists (orthostatic hypotension risk)
• Be cautious with very low DBP (< 60-65 mmHg) in those with CAD (J-curve phenomenon)

Pregnancy

Stroke

• Acute ischemic stroke: Avoid aggressive lowering in first 24h (cerebral autoregulation impaired); allow permissive HTN up to 220/120 mmHg (or 185/110 if thrombolysis)
• Post-stroke (secondary prevention): Target < 130/80 mmHg; ACEi + Thiazide diuretic combination preferred

Black Patients

• Higher prevalence and more severe end-organ damage
• More salt-sensitive; often low-renin HTN
• Thiazide diuretics and CCBs are more effective as monotherapy
• ACEi/ARBs less effective as monotherapy but added to diuretics/CCBs show benefit
• Higher risk of ACEi-induced angioedema (3x more common in Black patients)

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13. HYPERTENSIVE EMERGENCIES

• Hypertensive encephalopathy
• Acute pulmonary edema (LV failure)
• Acute coronary syndrome (MI, unstable angina)
• Aortic dissection
• Acute kidney injury
• Stroke (hemorrhagic)
• Eclampsia

• Target: Reduce mean arterial pressure (MAP) by 25% in first hour, then gradually to 160/100 over 2-6 hours (except aortic dissection - see below)
• Use IV antihypertensive agents; switch to oral once BP stabilized

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14. HYPERTENSION AND OBESITY - TREATMENT SUMMARY

1. SNS blockade: Beta-blockers, Central alpha-2 agonists (but limited evidence in obesity)
2. RAAS blockade: ACEi/ARB most effective (RAAS is inappropriately activated in obesity despite volume expansion)
3. MR antagonism: Spironolactone superior to most antihypertensives in obese patients with resistant HTN
4. Weight loss: Even modest weight loss (5-10 kg) significantly reduces BP

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15. PATIENT MANAGEMENT PLAN - KEY POINTS

• Clear written visit summary with BP readings and targets
• Lifestyle change contract with achievable goals
• Home BP monitoring training (validated device)
• Medication list with dosages
• Telehealth follow-up consideration
• Family/social support engagement
• Management of all coexisting CVD risk factors (lipids, diabetes, smoking)

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QUICK REFERENCE SUMMARY TABLE

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