Hydrochlorothiazide
Hydrochlorothiazide (HCTZ)
Generic Name
Hydrochlorothiazide (HCTZ)
Mechanism
- Inhibits the sodium‑chloride symporter (NCC) in the distal convoluted tubule, decreasing Na⁺ reabsorption and increasing delivery of fluid to the collecting duct.
- Promotes downstream water excretion and modest increases in K⁺, Mg²⁺, and Ca²⁺ excretion.
- The diuretic effect peaks within 2–4 h and lasts 6–8 h, allowing once‑daily dosing for most indications.
Pharmacokinetics
| Parameter | Typical Value (oral, 25 mg) |
| Absorption | ~60–100 % bioavailability, peak plasma concentration at 1–2 h. |
| Distribution | Volume of distribution 0.25–0.5 L/kg; protein binding ~30 %. |
| Metabolism | Primarily hepatic; glucuronidation is negligible. |
| Elimination | Renal excretion of unchanged drug (≈ 85 %); half‑life 6–8 h. |
| Drug interactions | Potentiated by ACE inhibitors or NSAIDs; may reduce C₂₃‑levels of metformin. |
> Key point: HCTZ is safe in patients with mild to moderate renal impairment but dose adjustment is advised in severe CKD (CrCl < 30 mL/min).
Indications
- Hypertension (alone or with other antihypertensives).
- Generalized edema secondary to heart failure, cirrhosis, or nephrotic syndrome.
- Glomerulonephritis with nephrotic-range proteinuria (together with RAAS blockade).
- Hypercalciuria‑associated nephrolithiasis prophylaxis (less commonly used now).
Contraindications
- Absolute: Known hypersensitivity to sulfa drugs or HCTZ.
- Relative: Severe renal failure (CrCl < 30 mL/min), uncontrolled hyperkalemia, significant hepatic dysfunction.
- Cautions:
- Use with caution in patients with hypermagnesemia or hypomagnesemia.
- Avoid in gouty arthritis; chronic use can precipitate uric acid crystals.
- Pregnant women: Category C; avoid in lactation due to potential diuretic effect on milk production.
Dosing
| Condition | Typical Dose | Notes |
| Hypertension | 12.5–25 mg daily (max 50 mg) | Start low; titrate to goal BP. |
| Edema | 50 mg daily | May add 25 mg for refractory edema. |
| Nephrolithiasis prophylaxis | 12.5–25 mg daily | Oral; ensure adequate hydration. |
| Injectable | 15 mg/5 mL IV/IM | Use in acute settings; slow infusion to prevent burns if IV. |
• Administer morning to prevent nocturia.
• Do not co‑administer high‑dose NSAIDs unless a reversible kidney injury is suspected; consider supplemental potassium.
> Tip: For patients on calcium supplements, schedule calcium intake 1 h before or after HCTZ to mitigate hypocalcemia risk.
Adverse Effects
| Class | Examples | Frequency |
| Electrolyte disturbances | Hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia | 10–20 % |
| Metabolic | Hyperglycemia, hyperuricemia, hyperlipidemia, hypoglycemia (rare) | 5–15 % |
| Renal | Oliguria, nephrolithiasis (due to hypercalciuria) | Serious: Hyperkalemia in setting of ACEI/ARB therapy; require immediate discontinuation.
Monitoring
- Baselines: Serum electrolytes (Na⁺, K⁺, Mg²⁺, Ca²⁺, phosphate), creatinine & CrCl, fasting glucose & lipid profile.
- During therapy:
- K⁺ and Mg²⁺: every 1–2 weeks first month, then quarterly.
- Creatinine: 2–4 weeks after initiation, then every 3 months.
- Blood pressure: at each visit or self‑monitoring.
- Urinalysis: for proteinuria or hematuria when indicated.
> When to stop: K⁺ 10.5 mg/dL, severe hyperkalemia or hypomania.
Clinical Pearls
- Dual diuretic blanch: Add a loop diuretic to overcome HCTZ resistance when K⁺ levels remain high.
- Gout & HCTZ: In gout patients, prescribe a potassium‑sparing diuretic or Mg²⁺ supplement to offset hyperuricemia risk.
- Drug metabolism: HCTZ is not metabolized by CYP450, reducing potential for significant drug-drug interactions with hepatically cleared agents.
- Pulmonary edema: While not first choice, HCTZ can be used as an adjunct to diuretic therapy for chronic heart failure, but not as an acute relief agent.
- Kidney stone prophylaxis: HCTZ increases urinary Ca²⁺; advise dietary moderation of oxalate and adequate fluid intake in susceptible patients.
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• References
1. Katzung & Trevor’s *Basic & Clinical Pharmacology* (15th ed.).
2. UpToDate: “Hydrochlorothiazide: dosing, efficacy, and safety.”
3. U.S. FDA Summary of Product Characteristics for HCTZ.
These concise, high‑yield facts will assist medical students and clinicians in applying hydrochlorothiazide effectively while minimizing adverse outcomes.