Hydrochlorothiazide - Drug Monograph

Introduction

Hydrochlorothiazide is a thiazide diuretic medication that has been widely used in clinical practice since its approval in 1959. As one of the most commonly prescribed antihypertensive agents, it plays a crucial role in managing hypertension, edema, and other conditions. This monograph provides comprehensive information about hydrochlorothiazide's pharmacology, clinical applications, and safety profile.

Mechanism of Action

Hydrochlorothiazide acts primarily on the distal convoluted tubule of the nephron, where it inhibits the sodium-chloride symporter (NCC). This inhibition reduces sodium and chloride reabsorption, leading to increased excretion of sodium, chloride, and water. The resulting natriuresis and diuresis reduce plasma volume and extracellular fluid volume, contributing to its antihypertensive effects. Additionally, thiazides produce vasodilation through mechanisms that may involve opening calcium-activated potassium channels and reducing vascular smooth muscle contractility.

Indications

FDA-approved indications:

• Hypertension (as monotherapy or in combination with other antihypertensive agents)
• Edema associated with congestive heart failure, cirrhosis, and corticosteroid/estrogen therapy
• Edema due to renal dysfunction (nephrotic syndrome, acute glomerulonephritis, chronic renal failure)

Off-label uses:

• Prevention of calcium-containing kidney stones
• Diabetes insipidus
• Osteoporosis (as adjunct therapy)

Dosage and Administration

• Initial dose: 12.5-25 mg orally once daily
• Maintenance dose: 12.5-50 mg daily
• Maximum dose: 50 mg daily (higher doses provide little additional blood pressure reduction but significantly increase adverse effects)

• Initial dose: 25-100 mg orally once daily or divided doses
• Maintenance dose: 25-100 mg daily
• Intermittent therapy often preferred for chronic management

• Geriatric patients: Start with 12.5 mg daily
• Renal impairment: Use with caution; contraindicated in anuria
• Hepatic impairment: Monitor for fluid and electrolyte imbalances
• Pediatric use: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Anuria
• History of hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs
• Concomitant use with dofetilide
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Refractory hypokalemia, hyponatremia, or hypercalcemia

Warnings and Precautions

• Electrolyte imbalances (hypokalemia, hyponatremia, hypochloremia, hypomagnesemia, hypercalcemia)
• Hyperuricemia and gout exacerbation
• Glucose intolerance and worsening of diabetes mellitus
• Systemic lupus erythematosus exacerbation
• Photosensitivity reactions
• Orthostatic hypotension
• Renal impairment and acute interstitial nephritis
• Pancreatitis
• Hepatic encephalopathy in predisposed patients

Drug Interactions

• Lithium: Increased lithium levels and toxicity risk
• Digoxin: Hypokalemia may potentiate digoxin toxicity
• NSAIDs: Reduced antihypertensive and diuretic effects
• Cholestyramine/Colestipol: Reduced absorption of hydrochlorothiazide
• Other antihypertensives: Additive hypotensive effects
• Corticosteroids: Enhanced potassium wasting
• Amphotericin B: Increased risk of hypokalemia
• Dofetilide: Contraindicated due to risk of torsades de pointes

Adverse Effects

• Hypokalemia (28-50%)
• Hyperuricemia (20-40%)
• Hyperglycemia (10-15%)
• Dizziness/lightheadedness (10-15%)

• Orthostatic hypotension
• Photosensitivity
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Impotence
• Headache
• Paresthesias

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Acute interstitial nephritis
• Pancreatitis
• Aplastic anemia
• Agranulocytosis
• Hepatic toxicity
• Anaphylactic reactions

Monitoring Parameters

• Complete blood count
• Comprehensive metabolic panel (electrolytes, renal function)
• Uric acid levels
• Glucose and HbA1c (in diabetic patients)
• Blood pressure measurement

• Serum electrolytes (especially potassium, sodium) within 1-2 weeks of initiation and periodically thereafter
• Renal function periodically
• Blood pressure at appropriate intervals
• Body weight in patients with edema
• Signs and symptoms of fluid/electrolyte imbalance
• Glucose monitoring in diabetic patients

Patient Education

• Take medication in the morning to avoid nighttime diuresis
• Report signs of electrolyte imbalance (muscle weakness, cramps, fatigue, thirst)
• Monitor weight regularly if prescribed for edema
• Rise slowly from sitting/lying position to prevent dizziness
• Maintain adequate fluid intake unless otherwise directed
• Use sun protection due to photosensitivity risk
• Report unusual skin reactions, sore throat, fever, or jaundice
• Do not stop medication abruptly without medical advice
• Inform all healthcare providers about hydrochlorothiazide use
• Dietary considerations: Maintain consistent potassium intake; avoid excessive salt substitutes containing potassium

• Elderly patients: Increased risk of side effects; monitor closely
• Pregnancy: Category B; use only if clearly needed
• Lactation: Excreted in breast milk; consider alternative feeding options

References

1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Am Coll Cardiol. 2018;71(19):e127-e248.

2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.

3. Ellison DH, Loffing J. Thiazide effects and adverse effects: insights from molecular genetics. Hypertension. 2009;54(2):196-202.

4. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43(1):4-9.

5. FDA Prescribing Information for Hydrochlorothiazide. Accessed January 2024.

6. Sica DA, Carter B, Cushman W, Hamm L. Thiazide and loop diuretics. J Clin Hypertens (Greenwich). 2011;13(9):639-643.

7. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361(22):2153-2164.

8. Roush GC, Ernst ME, Kostis JB, et al. Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. Hypertension. 2015;65(5):1041-1046.