What is the mechanism of action of chlorthalidone?

Mechanism of Action of Chlorthalidone

Chlorthalidone inhibits sodium and chloride reabsorption in the cortical diluting segment of the ascending limb of Henle's loop in the nephron, producing copious diuresis with greatly increased excretion of sodium and chloride. 1

Primary Mechanism

• The site of action is specifically the cortical diluting segment of the ascending limb of Henle's loop, where chlorthalidone blocks the sodium-chloride cotransporter 1
• This inhibition leads to increased delivery of sodium to the distal tubule, which triggers increased potassium excretion and subsequent risk of hypokalemia 2
• The drug produces more sustained diuresis and renin-angiotensin-aldosterone system (RAAS) activation compared to other thiazide diuretics 2

Pharmacokinetic Properties That Enhance Its Mechanism

• Chlorthalidone has an extremely long half-life of 40-60 hours following a 50-200 mg dose, with prolonged action lasting 48-72 hours 1, 3
• The elimination half-life is 53 hours following a 50 mg dose and 60 hours following a 100 mg dose 1
• Approximately 75% of the drug is bound to plasma proteins, with 58% bound to albumin 1
• The drug has a large volume of distribution with gradual elimination from the plasma compartment by tubular secretion 3

Unique Absorption and Distribution

• Absorption from the gastrointestinal tract is slow due to low solubility, contributing to its prolonged effect 1
• After hepatic passage, some drug enters general circulation while some is excreted in bile and later reabsorbed, creating an enterohepatic circulation 1
• The drug is distributed widely to tissues but achieves highest concentrations in the kidneys, where it can be detected 72 hours after ingestion 1
• The drug is excreted unchanged in the urine, with the major portion eliminated unchanged by the kidneys 1

Additional Pleiotropic Effects Beyond Diuresis

• Chlorthalidone potently inhibits carbonic anhydrase in platelets, which reduces catecholamine-induced platelet aggregation more effectively than other thiazide diuretics 4
• The drug increases the amount of epinephrine needed to induce platelet aggregation, providing antiplatelet effects 4
• Chlorthalidone induces changes in gene transcripts for vascular endothelial growth factor C and transforming growth factor-beta3, proteins that mediate angiogenesis and vascular permeability 4
• The drug reduces vascular permeability to albumin and promotes angiogenesis, effects that may contribute to cardiovascular protection beyond blood pressure reduction 4

Clinical Implications of the Mechanism

• The diuretic effect begins in approximately 2.6 hours and continues for up to 72 hours, allowing once-daily dosing 1
• At maximal therapeutic dosage, chlorthalidone is approximately equal in diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics 1
• The prolonged duration of action provides superior 24-hour blood pressure control, particularly overnight blood pressure reduction compared to shorter-acting thiazides 5, 3
• The sustained RAAS activation from prolonged diuresis increases the risk of hypokalemia 3-fold compared to hydrochlorothiazide 2