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Essential Hypertension

Definition

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Pathophysiology

• Fluid volume expansion → increased cardiac output → peripheral vasoconstriction → elevated blood pressure
• A new steady state ("resetting of pressure natriuresis") is reached, but only at the cost of chronically elevated pressure. (Robbins & Cotran Pathologic Basis of Disease)

• Increased sympathetic nerve activity (especially renal) driven by leptin and other adipokines
• Activation of the renin-angiotensin-aldosterone system (RAAS) → raised angiotensin II and aldosterone
• Physical compression of the kidneys by perinephric fat
• Reduced arterial baroreceptor sensitivity (Guyton & Hall Textbook of Medical Physiology)

• Heritability is estimated at ~30%; concordance is higher in monozygotic than dizygotic twins

• 500 genetic variants from genome-wide association studies are linked to blood pressure

• Rare Mendelian forms (Liddle syndrome, Gordon syndrome, apparent mineralocorticoid excess) illustrate how sodium-channel mutations can cause hypertension — highlighting sodium metabolism's central role (Goldman-Cecil Medicine; Robbins & Cotran)

• High dietary sodium (hypertension is rare at < 50 mmol/day sodium intake)
• Physical inactivity
• Heavy alcohol consumption (≥3 drinks/day → sympathetic activation via withdrawal)
• Obstructive sleep apnea → nocturnal sympathetic surges
• Low dietary potassium intake

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Clinical Features

• The vast majority of patients are asymptomatic — hypertension is often detected incidentally
• Some experience sleep disturbance or reduced exercise tolerance
• On physical examination, the earliest sign is typically hypertensive retinopathy
• Secondary hypertension should be excluded, especially in younger patients or those with resistant hypertension

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Vascular Pathology

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Key Points Summary

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Stepwise Drug Selection for Essential Hypertension

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Before Any Drug: Lifestyle Modification (Foundation Step)

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Step 1 — First-Line Monotherapy (or Low-Dose Dual Therapy)

Race consideration (JNC/AHA): In Black patients, thiazide diuretic or CCB is preferred over ACEi/ARB alone as monotherapy (ACEi/ARB less effective as monotherapy in this group).

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Step 2 — Add a Second Drug (If Step 1 Fails After 4–8 Weeks)

• ACEi or ARB + CCB (e.g., Ramipril + Amlodipine) ← most commonly recommended by WHO/ESC
• ACEi or ARB + Thiazide diuretic (e.g., Lisinopril + Chlorthalidone)
• CCB + Thiazide diuretic (for Black patients or when RAAS not tolerated)

⚠️ Avoid: ACEi + ARB together — minimal added BP benefit, high risk of renal impairment and hyperkalemia.

β-blockers are not recommended for initial therapy in uncomplicated hypertension — they are less effective for stroke prevention than first-line drugs.

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Step 3 — Triple Therapy (If Step 2 Fails)

ACEi/ARB + CCB + Thiazide-like diuretic

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Step 4 — Resistant Hypertension (Fails Triple Therapy at Optimal Doses)

1. Confirm adherence and rule out pseudo-resistance (white coat effect)
2. Ensure long-acting thiazide-like diuretic (chlorthalidone or indapamide — not HCTZ alone)
3. Check for secondary causes

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Summary Stepwise Algorithm

STEP 0:  Lifestyle modification (all patients)
          ↓
STEP 1:  One first-line drug (thiazide / ACEi / ARB / CCB)
         [Consider low-dose dual therapy if BP >20/10 above target]
          ↓
STEP 2:  ACEi or ARB  +  CCB  or  Thiazide
          ↓
STEP 3:  ACEi/ARB  +  CCB  +  Thiazide-like diuretic (triple pill)
          ↓
STEP 4:  Add spironolactone ± β-blocker ± α-blocker ± clonidine
         (Resistant HTN — investigate secondary causes)

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Preferred Drug by Compelling Indication

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Corticosteroid Drugs — Detailed Overview

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1. Classification

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2. Mechanism of Action

Genomic (Primary) Mechanism

1. Hsp90 dissociates → GRα undergoes conformational change
2. GRα translocates to the nucleus
3. Binds Glucocorticoid Response Elements (GREs) on DNA → activates anti-inflammatory genes (IL-10, DUSP1, A20)
4. Tethers to AP-1 and NF-κB → represses pro-inflammatory genes (TNF, IL-1, IL-6, IL-12, COX-2, phospholipase A2)

⚠️ Important consequence: Effects have a lag of 30 min to several hours (protein synthesis required). Effects persist long after the drug is cleared due to slow protein turnover.

Non-Genomic Mechanism

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3. Individual Drugs — Comparative Profile

Prednisone and methylprednisolone are the most commonly used clinically due to cost, potency, and half-life.
Prednisone is a prodrug → converted to prednisolone in the liver (use prednisolone directly in severe liver disease).
Dexamethasone is preferred when no mineralocorticoid effect is desired (e.g., cerebral edema, croup, neonatal lung maturation).

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4. Physiological and Pharmacological Effects by System

🔴 Anti-Inflammatory / Immunosuppressive Effects

• Suppress transcription of TNF, IL-1α, IL-1β, IL-6, IL-12 (pro-inflammatory cytokines)
• Inhibit COX-2 → reduce prostaglandins and leukotrienes
• Inhibit phospholipase A2 → reduce arachidonic acid release
• Reduce expression of ICAM, ELAM (cell adhesion molecules) → less leukocyte trafficking
• Promote lymphocyte apoptosis → used in hematologic malignancies
• Favor Th2 over Th1 responses; promote anti-inflammatory macrophage phenotype

🟡 Metabolic Effects

🟠 Cardiovascular Effects

• ↑ Blood pressure (↑ vascular tone, ↑ responsiveness to catecholamines and vasopressin)
• Suppress vasodilators (prostaglandins, nitric oxide)
• ↑ Angiotensin II receptor expression
• High-dose → dyslipidemia (↑ TG, ↑ cholesterol)

🟣 Bone Effects

• ↓ Osteoblast activity → ↓ bone formation
• ↑ Osteoclast activity → ↑ bone resorption
• ↓ Intestinal calcium absorption + ↑ renal calcium excretion → secondary hyperparathyroidism
• Results: Osteoporosis and Osteonecrosis (avascular necrosis — femoral head, humeral head, tibial plateau)

🔵 HPA Axis Suppression

• Exogenous glucocorticoids suppress CRH (hypothalamus) and ACTH (pituitary) via negative feedback
• Adrenal suppression assumed with >20 mg prednisone/day for >3 weeks
• Risk: Adrenal crisis during stress (surgery, infection) if drug is abruptly stopped

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5. Clinical Uses

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6. Adverse Effects

Pneumocystis jirovecii prophylaxis (TMP-SMX) recommended for patients on ≥20 mg prednisone/day for >1 month.

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7. Dose Tapering Protocol

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8. Contraindications and Cautions

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9. Prevention of Glucocorticoid-Induced Osteoporosis

• Calcium 1–1.5 g/day PO
• Vitamin D 1000 IU/day PO
• Bisphosphonate (alendronate, risedronate) — first-line for prophylaxis
• Weight-bearing exercise; avoid alcohol and tobacco

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