Chlorothiazide - Drug Monograph

Introduction

Chlorothiazide is a thiazide diuretic medication that was first introduced in 1958. It remains an important therapeutic agent in modern clinical practice, primarily used for its antihypertensive and diuretic properties. As a prototype of the thiazide class, chlorothiazide has served as the reference standard for subsequent thiazide diuretics.

Mechanism of Action

Chlorothiazide exerts its pharmacological effects by inhibiting the sodium-chloride symporter in the distal convoluted tubule of the nephron. This inhibition reduces sodium reabsorption, leading to increased excretion of sodium, chloride, and water. The resulting natriuresis and diuresis reduce plasma volume and extracellular fluid volume. Additionally, chlorothiazide produces vasodilatory effects through mechanisms that may involve opening calcium-activated potassium channels and reducing vascular responsiveness to catecholamines.

Indications

• Hypertension (as monotherapy or in combination with other antihypertensive agents)
• Edema associated with congestive heart failure
• Edema associated with hepatic cirrhosis
• Edema associated with renal dysfunction, including nephrotic syndrome
• Idiopathic edema
• Diabetes insipidus (particularly nephrogenic diabetes insipidus)

Dosage and Administration

• Hypertension: 500 mg to 2 g daily in single or divided doses
• Edema: 500 mg to 2 g daily in single or divided doses
• Maximum daily dose: 2 g

• Reserved for patients unable to take oral medication
• Usual dose: 500 mg to 1 g once or twice daily
• Administer slowly over 30 minutes

• Geriatric patients: Initiate with lower doses due to increased sensitivity
• Renal impairment: Use with caution; may be ineffective when GFR <30 mL/min
• Hepatic impairment: Use with caution due to risk of precipitating hepatic encephalopathy

Pharmacokinetics

Contraindications

• Anuria
• History of hypersensitivity to chlorothiazide or other sulfonamide-derived drugs
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Refractory hypokalemia
• Hyponatremia
• Hepatic coma or precoma

Warnings and Precautions

• Electrolyte imbalances: Monitor for hypokalemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, and hypercalcemia
• Hyperuricemia and gout: May occur due to reduced renal excretion of uric acid
• Glucose intolerance: May alter glucose tolerance and precipitate diabetes mellitus
• Hyperlipidemia: May increase LDL and total cholesterol levels
• Renal impairment: May precipitate azotemia in patients with renal disease
• Hepatic impairment: May precipitate hepatic encephalopathy in cirrhotic patients
• Systemic lupus erythematosus: May exacerbate or activate SLE
• Photosensitivity: May cause photosensitivity reactions

Drug Interactions

• Lithium: Reduced renal clearance of lithium, increasing risk of lithium toxicity
• Digoxin: Hypokalemia may potentiate digoxin toxicity
• Other antihypertensives: Additive hypotensive effects
• NSAIDs: May reduce diuretic and antihypertensive effects
• Corticosteroids, ACTH: Enhanced potassium loss
• Cholestyramine, colestipol: Reduced absorption of chlorothiazide
• Diabetes medications: May alter glycemic control requiring dosage adjustments
• Neuromuscular blocking agents: Prolonged neuromuscular blockade

Adverse Effects

• Hypokalemia
• Hyponatremia
• Hyperuricemia
• Dizziness
• Headache
• Orthostatic hypotension
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)

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

Monitoring Parameters

• Blood pressure (sitting and standing)
• Serum electrolytes (sodium, potassium, chloride, bicarbonate) at baseline and periodically
• Renal function (BUN, creatinine)
• Uric acid levels
• Blood glucose levels
• Lipid profile
• Body weight
• Signs of fluid overload or dehydration
• Clinical signs of hypokalemia (muscle weakness, cramps)

Patient Education

• Take medication in the morning to avoid nighttime diuresis
• Report signs of electrolyte imbalance: muscle cramps, weakness, dizziness, excessive thirst
• Maintain adequate fluid intake unless otherwise directed
• Consume potassium-rich foods if recommended by healthcare provider
• Avoid excessive alcohol consumption
• Use sun protection due to photosensitivity risk
• Rise slowly from sitting or lying position to prevent dizziness
• Do not stop medication abruptly without medical advice
• Inform all healthcare providers about chlorothiazide use
• Monitor weight regularly and report sudden changes
• Be aware that chlorothiazide may affect blood glucose levels

References

1. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill Education; 2017. 2. Chlorothiazide [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2021. 3. 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. 4. Ellison DH, Loffing J. Thiazide effects and side effects: insights from molecular genetics. Hypertension. 2009;54(2):196-202. 5. Sica DA, Carter B, Cushman W, Hamm L. Thiazide and loop diuretics. J Clin Hypertens (Greenwich). 2011;13(9):639-643. 6. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361(22):2153-2164. 7. National Kidney Foundation. KDOQI Clinical Practice Guideline for Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 2004;43(5 Suppl 1):S1-S290.