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Hypertension: Basics to Clinical Medicine

1. Definition

"Like height and weight, blood pressure is a continuously distributed variable; moreover, detrimental consequences increase progressively as the pressure rises, with no rigidly defined threshold dependably predicting total safety." - Robbins & Kumar Basic Pathology, p. 547

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2. Classification (ACC/AHA 2017 Guidelines)

Special Forms

• Isolated systolic hypertension: SBP ≥ 140 with DBP < 90. Common in the elderly due to arterial stiffening.
• White coat hypertension: Elevated only in clinical settings; normal on ambulatory monitoring.
• Masked hypertension: Normal in office; elevated on ambulatory monitoring.
• Resistant hypertension: BP ≥ 130/80 on ≥ 3 antihypertensive agents (including a diuretic) at maximal doses, or controlled BP on ≥ 4 agents.
• Hypertensive urgency: Severely elevated BP (often > 180/120) without acute end-organ damage.
• Hypertensive emergency: Severely elevated BP WITH evidence of acute end-organ damage (brain, heart, kidneys, retina, large vessels).
• Malignant hypertension: BP > 200/120 with bilateral advanced retinopathy (flame hemorrhages, papilledema).

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3. Epidemiology

• Over 40% of U.S. adults are hypertensive by ACC/AHA 2017 criteria (approx. 116 million adults).
• 73.9% of hypertensives in the U.S. have uncontrolled BP.
• For non-hypertensive individuals aged 55-65 years, lifetime risk of developing hypertension is 90%.
• African Americans have the highest prevalence in the U.S. due to combined genetic and environmental factors.
• Without treatment, ~50% of hypertensives die from ischemic heart disease or heart failure; ~33% from stroke.
• Nearly one-third of the world's adults have hypertension.

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4. Etiology and Types

Primary (Essential) Hypertension

• Accounts for 90-95% of all cases.
• No single identifiable cause; multifactorial (genetic + environmental).
• Key contributing factors: obesity/visceral adiposity, sedentary lifestyle, high sodium intake, insulin resistance, excessive alcohol, stress.

Secondary Hypertension (5-10%)

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5. Pathophysiology

The Core Formula

Renal-Pressure Natriuresis (The Long-Term Regulator)

• Black patients
• The elderly
• Patients with CKD
• Those with low plasma renin activity

Renin-Angiotensin-Aldosterone System (RAAS)

1. Reduced renal perfusion or sympathetic activation → renin released from juxtaglomerular cells
2. Renin cleaves angiotensinogen → Angiotensin I
3. ACE (in lungs) converts Ang I → Angiotensin II (Ang II)
4. Ang II effects:
   • Vasoconstriction (AT1 receptor) → ↑ TPR
   • Adrenal cortex → aldosterone → Na+ and water retention → ↑ blood volume → ↑ CO
   • Proximal tubule → Na+/H+ exchange → ↑ Na+ reabsorption
   • CNS → vasopressin release, sympathetic activation, thirst

Sympathetic Nervous System

• Catecholamines cause vasoconstriction (α1) and increase heart rate/contractility (β1)
• Chronic sympathetic overactivation is a feature of essential hypertension
• Renal sympathetics enhance tubular Na+ reabsorption and stimulate renin release

Endothelial Dysfunction

• Nitric oxide (NO) normally causes vasodilation and inhibits vascular smooth muscle growth
• NO deficiency impairs pressure natriuresis and promotes vasoconstriction
• Endothelin-1 (ET-1) is a potent vasoconstrictor - elevated in salt-sensitive hypertension
• Atrial natriuretic peptide (ANP) enhances pressure natriuresis and lowers BP; its blockade produces salt-sensitive hypertension

Vascular Remodeling

• Chronic elevated BP leads to structural changes: vessel wall thickening, capillary rarefaction
• Long-term mechanisms maintain tissue blood flow via angiogenesis adaptations
• This vascular remodeling becomes self-perpetuating

Immune/Inflammatory Component

• Innate and adaptive immunity contribute to hypertension
• T-cell infiltration in kidneys and vessels promotes sodium retention and oxidative stress

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6. Cardiovascular Risk Factors in Hypertension

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7. Target Organ Damage

• Left ventricular hypertrophy (LVH) - from pressure overload
• Coronary artery disease and myocardial infarction
• Heart failure (HFpEF and HFrEF)
• Atrial fibrillation

• Ischemic stroke (most common)
• Intracerebral hemorrhage (hypertension is the leading cause)
• Lacunar infarcts, white matter changes
• Hypertensive encephalopathy (in emergency: lethargy, seizures, cortical blindness, coma)
• Vascular dementia

• Hypertensive nephrosclerosis (thickening of afferent arterioles, glomerular ischemia)
• CKD progression - BP control is the #1 intervention to slow CKD progression
• Proteinuria (a marker of glomerular damage and cardiovascular risk)

• Arteriolar narrowing (Grade I)
• AV nicking (Grade II)
• Flame hemorrhages and cotton wool spots (Grade III)
• Papilledema (Grade IV - malignant hypertension)

• Aortic aneurysm and dissection
• Peripheral arterial disease
• Accelerated atherosclerosis

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8. Diagnosis and Evaluation

Blood Pressure Measurement

• Must be performed on multiple occasions under unstressful conditions (seated, legs uncrossed, empty bladder, after 5 minutes of rest)
• Do not diagnose hypertension on a single reading unless BP > 180/120 or end-organ damage is present
• Two or more abnormal readings over several weeks before initiating therapy
• Ambulatory BP monitoring (ABPM) is the gold standard for ruling out white coat hypertension and masked hypertension
• Osler sign (Osler maneuver): Palpable artery after cuff inflation suggests pseudohypertension (common in elderly with stiff vessels)

Diagnostic Workup

• Urinalysis (proteinuria, casts)
• Hematocrit
• Fasting glucose, HbA1c
• Serum potassium (hypokalemia → consider primary aldosteronism)
• Serum creatinine/eGFR
• Calcium, uric acid
• Fasting lipid panel

• ECG (LVH, ischemia, arrhythmias)
• Chest X-ray
• Echocardiography (for LVH, structural abnormalities, valvular disease)

• Plasma aldosterone:renin ratio (primary aldosteronism)
• 24-hour urine metanephrines/catecholamines (pheochromocytoma)
• Renal Doppler/CTA (renal artery stenosis)
• TSH (thyroid disease)
• Overnight dexamethasone suppression test (Cushing's)
• Sleep study (OSA)

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9. Treatment

Treatment Goals

• Target BP: < 130/80 mmHg for most patients (ACC/AHA 2017)
• Based on SPRINT trial data, lower targets reduce CVD events
• Older adults (≥ 65): SBP < 130 mmHg as tolerated

Lifestyle Modifications (First Line for All)

When to Start Pharmacotherapy

• Elevated BP (120-129/< 80): Lifestyle only; reassess in 3-6 months
• Stage 1 (130-139/80-89):
  • Low risk (no ASCVD, 10-year CVD risk < 10%): Lifestyle first; reassess 3-6 months
  • High risk (ASCVD or 10-year risk ≥ 10%): Lifestyle + pharmacotherapy; target < 130/80
• Stage 2 (≥ 140/≥ 90): Always start pharmacotherapy + lifestyle; reassess in 1 month

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10. Antihypertensive Drug Classes

Four First-Line Drug Classes

1. Thiazide/Thiazide-Like Diuretics

• Mechanism: Block Na/Cl cotransporter in distal convoluted tubule → ↓ plasma volume
• Agents: Hydrochlorothiazide (HCTZ), Chlorthalidone (preferred - longer acting), Indapamide
• Preferred in: Black patients (often used as initial monotherapy or in combination), elderly, isolated systolic HTN, osteoporosis, calcium nephrolithiasis
• Side effects: Hypokalemia, hypomagnesemia, hyperuricemia, hyperglycemia, hyperlipidemia, hyponatremia, hypercalcemia
• Note: Chlorthalidone has greater risk of hypokalemia and glucose intolerance than HCTZ but is more effective

2. Calcium Channel Blockers (CCBs)

• Mechanism: Block L-type voltage-gated calcium channels → vasodilation (dihydropyridines) or reduce heart rate/contractility (non-dihydropyridines)
• Classes:
  • Dihydropyridines (amlodipine, nifedipine, felodipine) - primarily vascular
  • Non-dihydropyridines: Verapamil (phenylalkylamine) - more cardiac; Diltiazem (benzothiazepine) - intermediate
• Use long-acting agents only - short-acting dihydropyridines increase ischemic cardiac events
• Preferred in: Black patients, angina, isolated systolic HTN, elderly
• Side effects: Peripheral edema (dihydropyridines), bradycardia/AV block (non-dihydropyridines), constipation (verapamil), flushing, gingival hyperplasia

3. ACE Inhibitors (ACEi)

• Mechanism: Block ACE → ↓ Ang II → vasodilation + ↓ aldosterone + efferent arteriolar dilation → ↓ intraglomerular pressure
• Agents: Enalapril, lisinopril, ramipril, perindopril, benazepril
• Compelling indications: Diabetes with proteinuria, CKD with proteinuria, post-MI LV dysfunction, heart failure with reduced EF (HFrEF), high cardiovascular risk
• Special property: Reduce proteinuria independently of BP effect - key for renoprotection
• Side effects: Dry cough (bradykinin accumulation, 10-15%), angioedema (rare but serious), hyperkalemia, acute kidney injury (bilateral renal artery stenosis - contraindicated)
• Contraindicated in: Pregnancy, bilateral renal artery stenosis, prior angioedema with ACEi

4. Angiotensin Receptor Blockers (ARBs)

• Mechanism: Block AT1 receptor directly → similar effects to ACEi without bradykinin accumulation
• Agents: Losartan, valsartan, irbesartan, olmesartan, telmisartan, candesartan
• Same compelling indications as ACEi; preferred when ACEi causes cough
• Side effects: Hyperkalemia, AKI; no cough, angioedema very rare
• Key rule: Never combine ACEi + ARB - dual RAAS blockade increases hyperkalemia and AKI risk without additional cardiovascular benefit

Other Drug Classes

• Mechanism: Block β1 (heart) → ↓ HR, ↓ contractility → ↓ CO; also ↓ renin release
• Selective agents: Atenolol, bisoprolol, metoprolol, nebivolol (also vasodilatory via NO)
• Non-selective: Propranolol, nadolol
• Compelling indications: Post-MI, HFrEF, angina, tachyarrhythmias
• Avoid in: Decompensated HF, severe bradycardia, high-degree AV block, asthma (non-selective)
• Do not stop abruptly (rebound hypertension and angina)

• Spironolactone, eplerenone - competitive aldosterone inhibitors
• Especially useful in resistant hypertension (add-on therapy)
• Finerenone is nonsteroidal MRA approved for HF/CKD but NOT for HTN
• Triamterene/Amiloride - ENaC blockers; often combined with HCTZ
• Side effects: Hyperkalemia; spironolactone causes gynecomastia/breast tenderness (eplerenone does not)

• Furosemide, bumetanide, torsemide, ethacrynic acid
• Block Na/K/2Cl cotransporter in thick ascending limb of loop of Henle
• Preferred when eGFR < 35 mL/min (thiazides lose efficacy in advanced CKD)
• Side effects: Hypokalemia, hypomagnesemia, hypocalcemia, ototoxicity (dose-related, especially IV)

• Prazosin, doxazosin, terazosin - block α1 receptors → peripheral vasodilation
• Useful in resistant hypertension; also treat benign prostatic hypertrophy (BPH)
• Risk of first-dose orthostatic hypotension

• Clonidine, methyldopa
• Reduce central sympathetic outflow → ↓ HR, ↓ TPR
• Methyldopa is drug of choice in pregnancy
• Abrupt discontinuation causes rebound hypertension (especially clonidine)

• Hydralazine (arterial), minoxidil (arterial) - used in refractory hypertension
• Hydralazine: Used IV in hypertensive emergencies of pregnancy
• Minoxidil: Very potent; causes reflex tachycardia, hirsutism, fluid retention

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11. Drug Selection by Clinical Scenario

Combination Therapy

• Most stage 2 hypertensives need ≥ 2 drugs
• Black patients and those with SBP ≥ 150 or DBP ≥ 90 often need 2 drugs initially
• Effective combinations:
  • Thiazide + ACEi/ARB
  • CCB + ACEi/ARB
  • Thiazide + CCB
• Avoid: ACEi + ARB together
• Triple therapy: Thiazide + CCB + ACEi or ARB

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12. Hypertensive Emergency - Management

• Admit to ICU for parenteral therapy
• Reduce MAP by 10-20% in first hour, then a further 5-15% over the next 23 hours
• Avoid overly rapid reduction - causes ischemia (cerebral, coronary, renal)

• Acute ischemic stroke: Permissive hypertension (do not aggressively lower unless > 220/120, or thrombolysis planned)
• Acute aortic dissection: Target SBP < 120 mmHg within minutes (IV beta-blocker + nitroprusside)
• Intracerebral hemorrhage: Controlled BP lowering (target SBP < 140 in first 24 hours)

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13. Secondary Hypertension - Key Clues

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14. Hypertension in Special Populations

• Gestational hypertension: New-onset HTN ≥ 20 weeks without proteinuria
• Pre-eclampsia: HTN ≥ 20 weeks + proteinuria (> 300 mg/24h) or other organ dysfunction
• Eclampsia: Pre-eclampsia + seizures
• Safe agents: Methyldopa, labetalol, nifedipine
• Contraindicated: ACEi, ARBs (teratogenic - fetal renal agenesis, oligohydramnios)

• ACEi or ARB is first-line (reduces proteinuria beyond BP effect)
• Add thiazide-like diuretic as second line; switch to loop diuretic when eGFR < 35
• Target BP < 130/80

• Isolated systolic HTN is common (stiff arteries)
• CCB or thiazide-like diuretic preferred
• Caution with overly aggressive lowering → orthostatic hypotension, falls

• ACEi or ARB is first line (renoprotection)
• Target BP < 130/80 mmHg

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Recent Evidence (PubMed, 2024)

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Quick Reference Summary

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