Introduction
Chlorthalidone is a long-acting thiazide-like diuretic that has been used clinically for over six decades. It remains a cornerstone therapy in hypertension management and is increasingly recognized as one of the most effective diuretics for cardiovascular risk reduction. Unlike shorter-acting thiazides, chlorthalidone's extended duration of action provides sustained blood pressure control with once-daily dosing.
Mechanism of Action
Chlorthalidone exerts its primary therapeutic effects by inhibiting sodium-chloride symporters in the distal convoluted tubule of the nephron. This inhibition reduces sodium reabsorption, leading to increased excretion of sodium, chloride, and water. The resulting reduction in plasma volume and extracellular fluid decreases cardiac output and blood pressure. With chronic administration, chlorthalidone produces peripheral vasodilation through direct vascular effects and reduction of vascular responsiveness to norepinephrine and angiotensin II.
Indications
- Hypertension: First-line therapy for uncomplicated hypertension, either as monotherapy or in combination with other antihypertensive agents
- Edema: Management of edema associated with congestive heart failure, hepatic cirrhosis, and nephrotic syndrome
- Calcium nephrolithiasis: Prevention of recurrent calcium oxalate stones in hypercalciuric patients (off-label)
Dosage and Administration
Hypertension:- Initial dose: 12.5-25 mg orally once daily
- Maintenance dose: 12.5-50 mg daily (maximum 100 mg/day)
- Elderly patients: Start with 12.5 mg daily
- Initial dose: 50-100 mg daily or 100 mg on alternate days
- Maintenance dose: 25-200 mg daily based on response
- Renal impairment: Use with caution; not recommended if eGFR <30 mL/min
- Hepatic impairment: Use with caution due to risk of electrolyte imbalance
- Geriatric patients: Lower initial doses recommended (12.5 mg daily)
Pharmacokinetics
Absorption: Incomplete and variable oral absorption (approximately 65%) Distribution: Extensive plasma protein binding (75%), crosses placental barrier Metabolism: Minimal hepatic metabolism Elimination: Primarily renal excretion (50-60%), with significant enterohepatic recirculation Half-life: 40-60 hours (significantly longer than hydrochlorothiazide) Onset of action: 2-3 hours Peak effect: 2-6 hours Duration: 24-72 hoursContraindications
- Hypersensitivity to chlorthalidone or sulfonamide-derived drugs
- Anuria
- Severe renal impairment (eGFR <30 mL/min)
- Refractory hypokalemia
- Addison's disease
- Concomitant use with dofetilide
Warnings and Precautions
Electrolyte Imbalance: Risk of hypokalemia, hyponatremia, hypochloremia, hypomagnesemia, and hypercalcemia Metabolic Effects: May cause hyperglycemia, hyperuricemia, and hyperlipidemia Renal Effects: May precipitate azotemia in renal impairment Hepatic Effects: Can cause hepatic encephalopathy in patients with severe liver disease Photosensitivity: Increased risk of sunburn Pregnancy: Category B - use only if clearly needed Lactation: Excreted in breast milk; use with cautionDrug Interactions
Potassium-Depleting Drugs: Enhanced risk of hypokalemia with corticosteroids, amphotericin B Lithium: Reduced renal clearance leading to lithium toxicity Digoxin: Hypokalemia may potentiate digoxin toxicity Antidiabetic Agents: May decrease effectiveness of insulin and oral hypoglycemics NSAIDs: May reduce diuretic and antihypertensive effects Cholestyramine/Colestipol: Reduced absorption of chlorthalidone Other Antihypertensives: Additive hypotensive effectsAdverse Effects
Common (≥5%):- Hypokalemia (dose-dependent)
- Dizziness, lightheadedness
- Headache
- Hyperuricemia
- Glucose intolerance
- Impotence
- Severe electrolyte disturbances
- Pancreatitis
- Aplastic anemia
- Stevens-Johnson syndrome
- Hepatic encephalopathy
- Anaphylactic reactions
- Acute interstitial nephritis
Monitoring Parameters
Baseline:- Complete blood count
- Comprehensive metabolic panel (electrolytes, renal function)
- Uric acid levels
- Fasting glucose
- Lipid profile
- Blood pressure measurements
- Serum electrolytes (particularly potassium) at 1-4 week intervals initially, then every 3-6 months
- Renal function periodically
- Blood glucose in diabetic patients
- Body weight for edema management
Patient Education
- Take in morning to avoid nocturnal diuresis
- Report signs of electrolyte imbalance: muscle weakness, cramps, fatigue, thirst
- Regular blood pressure monitoring is essential
- Maintain adequate hydration unless contraindicated
- Dietary potassium-rich foods may be recommended
- Avoid excessive sun exposure and use sunscreen
- Rise slowly from sitting/lying position to prevent dizziness
- Do not discontinue abruptly without medical supervision
- Inform all healthcare providers about chlorthalidone use
- Report any unusual bruising, bleeding, or signs of infection
References
1. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361(22):2153-2164. 2. 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. 3. Chlorthalidone [package insert]. U.S. Food and Drug Administration; 2021. 4. ALLHAT Officers and Coordinators. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. 5. Sica DA, Carter B, Cushman W, et al. Thiazide and loop diuretics. J Clin Hypertens (Greenwich). 2011;13(9):639-643. 6. Wright JM, Musini VM, Gill R. First-line drugs for hypertension. Cochrane Database Syst Rev. 2018;4(4):CD001841.