Diuretics in Hypertension

Thiazide Diuretics - Pressure Plungers

• Mechanism (MOA): Inhibit Na⁺-Cl⁻ cotransporter (NCC) in early Distal Convoluted Tubule (DCT).
  • Results in ↑ Na⁺, Cl⁻, K⁺, Mg²⁺ excretion.
  • Conversely, ↓ Ca²⁺ excretion (can lead to hypercalcemia).
• Key Drugs:
  • Hydrochlorothiazide (HCTZ): Common, shorter acting.
  • Chlorthalidone: Longer half-life, often preferred for sustained BP control.
  • Indapamide: Vasodilatory properties; less adverse metabolic effects.
• Hypertension Role: First-line therapy, especially for uncomplicated HTN, elderly, and African-American patients. Effective in salt-sensitive hypertension.
  • Added benefit: Slows demineralization in osteoporosis due to ↓ Ca²⁺ excretion.
• Adverse Effects: 📌 "HyperGLUC": HyperGlycemia, HyperLipidemia, HyperUricemia (can precipitate gout), HyperCalcemia.
  • Also: HypoKalemia (⚠️ risk of arrhythmias), Hyponatremia, HypoMagnesemia.
  • Sulfa allergy cross-reactivity.

⭐ Thiazides may lose efficacy when Glomerular Filtration Rate (GFR) falls below 30 mL/min (except Metolazone).

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Loop & K+-Sparing Diuretics - Electrolyte Experts

• Loop Diuretics (e.g., Furosemide, Torsemide):

  • MoA: Inhibit Na+-K+-2Cl- symporter in thick ascending limb (TAL). Potent.
  • HTN Use:
    • Emergencies, fluid overload (HF, CKD).
    • Resistant HTN.
    • Effective if GFR < 30 mL/min.
  • Electrolytes: ↓K+, ↓Mg2+, ↓Ca2+ (chronic); metabolic alkalosis.
  • ADRs: Ototoxicity, hyperuricemia, hypovolemia.

• K+-Sparing Diuretics:

  • Aldosterone Antagonists (e.g., Spironolactone, Eplerenone):
    • MoA: Block aldosterone receptors (late DCT/CD).
    • HTN Use: Resistant HTN (esp. ↑aldosterone), HF.
    • ADRs: Hyperkalemia, gynecomastia (spironolactone).
  • ENaC Inhibitors (e.g., Amiloride, Triamterene):
    • MoA: Block ENaC (late DCT/CD).
    • HTN Use: Combo to prevent ↓K+.
    • ADRs: Hyperkalemia.

⭐ Spironolactone is key for resistant hypertension, especially with suspected hyperaldosteronism.

Clinical Application & Guidelines - Diuretic Strategy

• First-line: Thiazides (e.g., Chlorthalidone, Hydrochlorothiazide) for most uncomplicated hypertension.
  • Chlorthalidone often preferred: longer duration, better 24-hr BP control.
• Specific Conditions:
  • CKD (eGFR < 30 mL/min/1.73$m^2$), Heart Failure: Loop diuretics (e.g., Furosemide).
  • Resistant Hypertension, Primary Aldosteronism: $K^+$-sparing (Spironolactone, Eplerenone).
  • Gout: Avoid thiazides; consider alternatives.
  • Osteoporosis: Thiazides (↓ $Ca^{2+}$ excretion).
• Combination Therapy:
  • Preferred: Diuretic + ACEi/ARB (e.g., "A+D" strategy).
  • Diuretic + CCB.
• Guidelines (JNC8, ACC/AHA, IGH): Emphasize thiazides as initial/adjunctive therapy.

⭐ Chlorthalidone is generally preferred over hydrochlorothiazide for hypertension management due to its longer half-life and superior evidence for cardiovascular risk reduction.

Adverse Effects & Monitoring - Safety Net

• Thiazides (HCTZ, Chlorthalidone):
  • ↓$K^+$, ↓$Na^+$, ↑$Ca^{2+}$, ↑uric acid, ↑glucose, ↑lipids.
  • Sulfa allergy. Ineffective if GFR < 30 mL/min.
• Loop Diuretics (Furosemide):
  • ↓$K^+$, ↓$Na^+$, ↓$Mg^{2+}$, ↓$Ca^{2+}$, ↑uric acid.
  • Ototoxicity (esp. rapid IV). Sulfa allergy.
• $K^+$-Sparing:
  • Spironolactone: ↑$K^+$, gynecomastia.
  • Amiloride: ↑$K^+$.
• Monitoring:
  • BP, electrolytes ($K^+$, $Na^+$), renal function (BUN, Cr).
  • Glucose, uric acid, lipids (for thiazides/loops).
• Interactions:
  • NSAIDs: ↓ diuretic effect.
  • Lithium: ↑ toxicity.
  • Digoxin: ↑ toxicity with ↓$K^+$.
  • ACEi/ARBs + $K^+$-sparing: risk of severe ↑$K^+$.

⭐ Thiazides cause hypercalcemia; Loop diuretics cause hypocalcemia.

High‑Yield Points - ⚡ Biggest Takeaways

• Thiazides (e.g., Chlorthalidone) are first-line for uncomplicated hypertension; act on Na-Cl cotransporter in DCT.
• Chlorthalidone is preferred over HCTZ for longer action and proven CVD risk reduction.
• Key adverse effects: Hypokalemia, hyponatremia, hyperuricemia, hyperglycemia.
• Loop diuretics (e.g., Furosemide) for hypertension with renal insufficiency (GFR < 30) or HF.
• K+-sparing diuretics (e.g., Spironolactone) counter thiazide-induced hypokalemia or for resistant HTN.
• Spironolactone specific risks: gynecomastia, hyperkalemia.