From the Guidelines
Chlorthalidone is a long-acting thiazide-like diuretic with a half-life of 40-60 hours, allowing for once-daily dosing and consistent blood pressure control over 24 hours. The pharmacokinetics of chlorthalidone are characterized by approximately 65% bioavailability after oral administration, with peak plasma concentrations reached within 2-6 hours 1. The drug distributes extensively into red blood cells, which serve as a reservoir and contribute to its prolonged duration of action. Chlorthalidone is minimally metabolized, with about 50-60% excreted unchanged in urine and the remainder eliminated through biliary excretion.
Key Pharmacokinetic Properties
- Half-life: 40-60 hours
- Bioavailability: approximately 65%
- Peak plasma concentrations: reached within 2-6 hours
- Protein binding: approximately 75%
- Metabolism: minimal, with about 50-60% excreted unchanged in urine
Clinical Implications
The pharmacokinetic profile of chlorthalidone is relatively unaffected by renal impairment until severe dysfunction occurs, though dose adjustments may be needed in patients with significant kidney disease 1. These pharmacokinetic characteristics explain why chlorthalidone provides more consistent and sustained blood pressure control compared to shorter-acting diuretics like hydrochlorothiazide, often making it a preferred choice for hypertension management 1.
Dosage and Administration
The usual dose of chlorthalidone ranges from 12.5-25 mg/day, with a frequency of once daily, as recommended by the 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 1.
From the FDA Drug Label
CLINICAL PHARMACOLOGY Chlorthalidone is an oral diuretic with prolonged action (48-72 hours) and low toxicity. The major portion of the drug is excreted unchanged by the kidneys. The diuretic effect of the drug occurs in approximately 2. 6 hours and continues for up to 72 hours. The mean half-life following a 50 to 200 mg dose is 40 hours. In the first order of absorption, the elimination half-life is 53 hours following a 50 mg dose, and 60 hours following a 100 mg dose. Approximately 75 percent of the drug is bound to plasma proteins, 58 percent of the drug being bound to albumin The pharmacokinetics of Chlorthalidone are characterized by:
- Prolonged action: 48-72 hours
- Half-life:
- Mean half-life: 40 hours (following a 50 to 200 mg dose)
- Elimination half-life:
- 53 hours (following a 50 mg dose)
- 60 hours (following a 100 mg dose)
- Protein binding: Approximately 75% bound to plasma proteins, with 58% bound to albumin
- Excretion: Major portion of the drug is excreted unchanged by the kidneys 2
From the Research
Pharmacokinetics of Chlorthalidone
- Chlorthalidone has a longer half-life for effect and a wider volume of distribution compared to hydrochlorothiazide, with heavy partitioning in red blood cells 3
- The pharmacokinetic features of chlorthalidone afford it a unique advantage in its capacity to act as an effective diuretic and blood-pressure-lowering agent 3
- Chlorthalidone is more effective in lowering systolic blood pressures than hydrochlorothiazide, as evidenced by 24-hour ambulatory blood pressures 4
Dosing and Efficacy
- A dose of 25 mg daily of chlorthalidone was found to be at least as effective as 50 and 75 mg daily in lowering blood pressure, with less perturbation of potassium levels 5
- Chlorthalidone was associated with a significantly higher risk of hypokalemia, hyponatremia, acute renal failure, chronic kidney disease, and type 2 diabetes mellitus compared to hydrochlorothiazide 6
- Chlorthalidone was not associated with significant cardiovascular benefits when compared to hydrochlorothiazide, but was associated with a greater risk of renal and electrolyte abnormalities 6
Comparison to Hydrochlorothiazide
- Chlorthalidone and hydrochlorothiazide have similar antihypertensive effects at lower doses, but chlorthalidone may be more effective in lowering systolic blood pressures 4
- Chlorthalidone was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia, compared to hydrochlorothiazide 7
- The results of studies comparing the effectiveness and safety of chlorthalidone and hydrochlorothiazide are inconsistent, with some studies finding no significant difference in cardiovascular outcomes 7 and others finding a greater risk of renal and electrolyte abnormalities with chlorthalidone 6