Thiazide and Thiazide-Like Diuretics

Thiazides: Intro & MOA - Salty Water Exiters

• Orally active, moderately potent diuretics.
• Types:
  • Thiazides: Hydrochlorothiazide (HCTZ), Bendroflumethiazide.
  • Thiazide-like: Chlorthalidone, Indapamide, Metolazone.
• Most are sulfonamides (⚠️ sulfa allergy risk).
• Site: Early Distal Convoluted Tubule (DCT).
• MOA:
  • Block Na+/Cl- cotransporter (NCC) on luminal side.
  • ↓ NaCl reabsorption → ↑ excretion of Na+, Cl-, $H_2O$.
  • Also ↑ K+, $Mg^{2+}$ loss; ↓ $Ca^{2+}$ excretion (leading to hypercalcemia). 📌 Mnemonic: "Thia-ZIDE blocks Na/Cl in DI-stal C-T".

⭐ Thiazides are first-line for uncomplicated hypertension and help prevent calcium kidney stones.

Thiazides: Types & PK - The Diuretic Lineup

• Classification:
  • Thiazides: e.g., Hydrochlorothiazide (HCTZ), Chlorthalidone. Generally shorter duration.
  • Thiazide-like: e.g., Indapamide, Metolazone. Often longer duration; Indapamide also has direct vasodilatory effects.
• Key Pharmacokinetics (PK):
  • Route: Oral. Onset: 1-2 hrs. Peak effect: 4-6 hrs.
  • Duration: HCTZ (6-12h), Chlorthalidone (24-72h), Indapamide (up to 36h).
  • Elimination: Renal secretion via OATs (competes with uric acid). HCTZ largely unchanged.

⭐ Chlorthalidone demonstrates superior BP control and cardiovascular risk reduction over HCTZ in many studies, attributed to its longer half-life (~40-60h).

Thiazides: Clinical Uses - Pressure & Stone Relief

• Hypertension (Pressure Relief):
  • First-line therapy, especially for salt-sensitive, elderly, African-American populations.
  • Initial effect: ↓ blood volume. Chronic effect: ↓ peripheral vascular resistance.
  • Effective as monotherapy or in combination.
• Recurrent Calcium Stones (Stone Relief):
  • Key for idiopathic hypercalciuria; ↓ urinary Ca²⁺ excretion.
  • Mechanism: Enhances Ca²⁺ reabsorption in the Distal Convoluted Tubule (DCT).
• Other Important Uses:
  • Edema (mild heart failure, cirrhosis).
  • Nephrogenic Diabetes Insipidus (paradoxical reduction in polyuria).

⭐ Thiazides significantly reduce urinary calcium, making them a primary choice for preventing recurrent calcium oxalate kidney stones.

Thiazides: Side Effects & CIs - The Downside Drips

• Side Effects (SEs): 📌 "HyperGLUC + HypoNaKMg"
  • Hyperglycemia (impaired insulin release)
  • Hyperlipidemia (↑LDL, ↑Total Cholesterol)
  • Hyperuricemia (may precipitate gout attacks)
  • Hypercalcemia (due to ↓urinary Ca²⁺ excretion)
  • Hypokalemia (arrhythmia risk), Hyponatremia (esp. in elderly), Hypomagnesemia
  • Metabolic alkalosis
  • Others: Photosensitivity, sexual dysfunction, pancreatitis (rare)
• Contraindications (CIs):
  • Anuria or severe renal failure (GFR < 30 mL/min)
  • Hypersensitivity to thiazides or sulfonamide-derived drugs
  • Significant pre-existing hypokalemia or hyponatremia
  • Caution: Gout, diabetes mellitus, severe liver disease (hepatic encephalopathy risk)

⭐ Thiazides are generally ineffective when Glomerular Filtration Rate (GFR) is < 30 mL/min; metolazone is a notable exception.

Thiazides: Interactions & Pearls - Cautionary Cocktails

• Drug Interactions:
  • NSAIDs: ↓ diuretic effect.
  • Digoxin: ↑ toxicity (hypokalemia).
  • Lithium: ↑ toxicity (↓ renal clearance).
  • Corticosteroids/Loop diuretics: Additive hypokalemia.
  • Dofetilide: ↑ QTc risk (hypokalemia).
• Pearls & Cautions:
  • Ineffective if GFR < 30 mL/min (metolazone exception).
  • 📌 HyperGLUC: HyperGlycemia, Lipidemia, Uricemia, Calcemia.
  • Hypo-NaK-Mg: Hyponatremia, kalemia, magnesemia.
  • Sulfa allergy: Use with caution.

  ⭐ Thiazides may precipitate gout attacks due to hyperuricemia.

High‑Yield Points - ⚡ Biggest Takeaways

• Thiazides inhibit the Na+/Cl- cotransporter in the Distal Convoluted Tubule (DCT).
• Key indications include hypertension, nephrogenic diabetes insipidus, and idiopathic hypercalciuria.
• Cause hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, but hypercalcemia.
• Chlorthalidone and Indapamide are longer-acting thiazide-like diuretics.
• Generally ineffective if GFR < 30 mL/min (exception: Metolazone).
• Risk of sulfa allergy; can precipitate gout due to hyperuricemia.
• Increase lithium toxicity by reducing its renal clearance.