Is chlorthalidone (Chlorthalidone) more potent than Hydrochlorothiazide (HCTZ)?

From the Guidelines

Yes, chlorthalidone is more potent than hydrochlorothiazide (HCTZ). Chlorthalidone is approximately 1.5 to 2 times more potent than HCTZ on a milligram-per-milligram basis, meaning that 12.5-25 mg of chlorthalidone is roughly equivalent to 25-50 mg of HCTZ in terms of blood pressure lowering effects, as indicated in the 2018 guideline for the prevention, detection, evaluation, and management of high blood pressure in adults 1.

Key Differences Between Chlorthalidone and HCTZ

• Chlorthalidone has a significantly longer half-life (40-60 hours) compared to HCTZ (8-15 hours), which provides more consistent 24-hour blood pressure control and allows for once-daily dosing.
• This extended duration of action means chlorthalidone maintains more stable blood pressure control, particularly during nighttime and early morning hours when cardiovascular events are more common.
• When switching from HCTZ to chlorthalidone, patients typically start with half the HCTZ dose.

Clinical Implications

• Chlorthalidone's greater potency and longer duration of action may explain why some clinical trials have shown it to be more effective than HCTZ in reducing cardiovascular events, particularly stroke and heart failure, despite both being thiazide-type diuretics that work by inhibiting sodium reabsorption in the distal convoluted tubule of the kidney.
• A meta-analysis of 25 RCTs involving chlorthalidone and hydrochlorothiazide found dose-dependent reductions in serum potassium with increasing dosage; one important takeaway from this study was that chlorthalidone has a higher potency than hydrochlorothiazide, which may influence the dosage of drug provided to meet target goals and lead to differences in adverse effects 1.
• The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) compared the effectiveness of an ACE inhibitor (lisinopril) versus a calcium-channel blocker (amlodipine) versus a thiazide diuretic (chlorthalidone) as first-line therapy for mild to moderate hypertension, and the results showed no differences between treatments in primary outcome or all-cause mortality, but the amlodipine group had a higher risk for heart failure than the chlorthalidone group 1.

Recommendations

• Chlorthalidone is preferred over HCTZ due to its prolonged half-life and proven trial reduction of cardiovascular disease, as stated in the 2018 guideline for the prevention, detection, evaluation, and management of high blood pressure in adults 1.
• Patients should be monitored for hyponatremia, hypokalemia, uric acid, and calcium levels when taking chlorthalidone.
• The choice between chlorthalidone and HCTZ should be based on individual patient characteristics and medical history.

From the FDA Drug Label

At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The diuretic effect of chlorthalidone is approximately equal to that of benzothiadiazine diuretics, such as HCTZ, at maximal therapeutic doses.

• The potency of chlorthalidone and HCTZ is similar at maximal therapeutic doses. 2

From the Research

Comparison of Chlorthalidone and Hydrochlorothiazide

• Chlorthalidone has been shown to be more potent than Hydrochlorothiazide (HCTZ) in several studies 3, 4, 5, 6.
• A study published in the Journal of the American College of Cardiology found that chlorthalidone, 6.25 mg daily, significantly reduced mean 24-h ambulatory blood pressure (ABP) as well as daytime and nighttime BP, whereas HCTZ, 12.5 mg daily, did not show a significant 24-h ABP reduction 3.
• Another study published in Hypertension found that chlorthalidone is more effective in lowering systolic BPs than HCTZ, as evidenced by 24-hour ambulatory BPs 5.
• A review published in Current opinion in cardiology found that HCTZ is less potent in lowering blood pressure than other thiazide diuretics, including chlorthalidone, and is associated with higher adverse cardiovascular events 6.
• However, a more recent study published in Cureus found that there is no significant difference in the results of patients treated with HCTZ versus those treated with chlorthalidone, and that chlorthalidone has worse outcomes regarding side effects when compared to HCTZ 7.

Key Findings

• Chlorthalidone has a more sustained antihypertensive effect than HCTZ, probably due to its very long half-life 4.
• Chlorthalidone is more effective in lowering systolic BPs than HCTZ, as evidenced by 24-hour ambulatory BPs 5.
• HCTZ is less potent in lowering blood pressure than other thiazide diuretics, including chlorthalidone 6.
• The choice between chlorthalidone and HCTZ should be based on individual patient characteristics and the potential for side effects 7.