What is the mechanism of action of Chlorthalidone (diuretic) in treating hypertension?

Mechanism of Action of Chlorthalidone in Hypertension

Chlorthalidone lowers blood pressure primarily by inhibiting sodium and chloride reabsorption in the cortical diluting segment of the ascending limb of Henle's loop, producing copious diuresis with greatly increased excretion of sodium and chloride, which reduces intravascular volume and subsequently decreases blood pressure. 1

Primary Mechanism: Renal Sodium and Chloride Excretion

• The site of action is specifically the cortical diluting segment of the ascending limb of Henle's loop of the nephron, where chlorthalidone blocks sodium-chloride cotransport 1
• This blockade produces copious diuresis with greatly increased excretion of sodium and chloride, leading to volume depletion 1
• At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics 1

Pharmacokinetic Properties Contributing to Antihypertensive Effect

• Chlorthalidone has a prolonged duration of action lasting 48-72 hours, which provides sustained blood pressure control 1
• The diuretic effect begins in approximately 2.6 hours and continues for up to 72 hours 1
• The mean elimination half-life is 40-60 hours (53 hours following 50 mg dose, 60 hours following 100 mg dose), which is substantially longer than hydrochlorothiazide 1
• Approximately 75% of the drug is bound to plasma proteins, with 58% bound to albumin 1
• The major portion of the drug is excreted unchanged by the kidneys 1

Volume-Mediated Blood Pressure Reduction

• Patients with resistant hypertension frequently have occult volume expansion underlying their treatment resistance, which chlorthalidone effectively addresses through enhanced diuresis 2
• Studies at Mayo Clinic found that after measuring cardiac output, vascular resistance, and intravascular volume, blood pressure control was improved primarily through the use of increased doses of diuretics to counteract volume expansion 2
• The long-acting nature of chlorthalidone provides superior 24-hour blood pressure reduction compared to shorter-acting thiazides, with the largest difference occurring overnight 2, 3

Clinical Superiority Over Hydrochlorothiazide

• In a blinded comparison, chlorthalidone 25 mg daily provided greater 24-hour ambulatory blood pressure reduction than hydrochlorothiazide 50 mg daily, with nighttime systolic BP reduction of -13.5 mm Hg versus -6.4 mm Hg (p=0.009) 3
• Even at the low dose of 6.25 mg daily, chlorthalidone significantly reduced mean 24-hour ambulatory BP as well as daytime and nighttime BP, whereas hydrochlorothiazide 12.5 mg daily showed no significant 24-hour ABP reduction 4
• Given the outcome benefit demonstrated with chlorthalidone and its superior efficacy compared with hydrochlorothiazide, chlorthalidone should be preferentially used in patients with resistant hypertension 2

Common Pitfalls and Monitoring Requirements

• Chlorthalidone carries a significantly higher risk of hypokalemia (HR 2.72) and hyponatremia (HR 1.31) compared to hydrochlorothiazide, requiring vigilant electrolyte monitoring 5
• Monitor electrolytes, particularly potassium and magnesium, within 2-4 weeks of initiation or dose escalation 6
• The risk of acute renal failure (HR 1.37) and chronic kidney disease (HR 1.24) is also elevated with chlorthalidone 5
• Despite these metabolic effects, chlorthalidone doses of 25 mg daily have been shown to reduce cardiovascular morbidity and mortality in multiple landmark trials 2