What is the information about Chlorthalidone (Thiazide-like Diuretic)?

From the Guidelines

Chlorthalidone is a thiazide-like diuretic medication that should be used as a first-line treatment for hypertension due to its proven efficacy in reducing cardiovascular events and its longer duration of action compared to hydrochlorothiazide, with a typical starting dose of 12.5 mg once daily, which can be increased to 25 mg daily if needed, as recommended by the 2017 ACC/AHA guideline 1.

Key Points

• Chlorthalidone works by increasing urine output, which reduces blood volume and lowers blood pressure.
• Common side effects include increased urination, electrolyte imbalances (particularly low potassium), increased blood sugar, elevated uric acid levels, and rarely, allergic reactions.
• Patients taking chlorthalidone should have their electrolytes monitored periodically, especially potassium levels, as it can cause hypokalemia, with a higher risk compared to hydrochlorothiazide, as shown in a meta-analysis of 25 RCTs 1.
• The medication should be taken in the morning to avoid nighttime urination disrupting sleep.
• Chlorthalidone is particularly effective for patients with resistant hypertension and has shown benefits in reducing cardiovascular events in long-term studies, as demonstrated in the SPRINT trial, where chlorthalidone was the primary diuretic used 1.
• It's contraindicated in patients with sulfa allergies and should be used cautiously in those with gout, diabetes, or kidney dysfunction.
• For optimal effectiveness, patients should maintain adequate hydration while taking this medication but avoid excessive salt intake.

Dosage and Administration

• The usual dose of chlorthalidone is 12.5-25 mg once daily, with a maximum dose of 50 mg daily, as recommended by the 2017 ACC/AHA guideline 1.
• The dose should be adjusted based on the patient's response to the medication and their kidney function.

Monitoring and Precautions

• Patients taking chlorthalidone should have their electrolytes, particularly potassium levels, monitored periodically.
• They should also be monitored for signs of hypokalemia, such as muscle weakness, fatigue, and arrhythmias.
• Chlorthalidone should be used with caution in patients with kidney dysfunction, as it can worsen kidney function, and in patients with gout, as it can increase uric acid levels.

From the FDA Drug Label

Chlorthalidone is an oral antihypertensive/diuretic. It is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double-ring system is incorporated in its structure. It is 2-chloro-5(1- hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide with the following structural formula: Molecular Formula: C14H11ClN2O4S Molecular weight: 338. 76 Chlorthalidone, USP is practically insoluble in water, in ether, and in chloroform; soluble in methanol; slightly soluble in ethanol. Chlorthalidone tablets are available containing either 25 mg or 50 mg of chlorthalidone USP and the following inactive ingredients: Colloidal silicon dioxide, D & C Yellow No. 10 Aluminum Lake, Microcrystalline cellulose, Pregelatinized starch (maize), Sodium starch glycolate (Type A), Stearic acid. The 50 mg tablets also contain FD&C Blue No.1.

• Drug Name: Clorthalidone
• Classification: Oral antihypertensive/diuretic
• Chemical Structure: Monosulfamyl diuretic with a double-ring system
• Molecular Formula: C14H11ClN2O4S
• Molecular Weight: 338.76
• Solubility: Practically insoluble in water, ether, and chloroform; soluble in methanol; slightly soluble in ethanol
• Available Dosages: 25 mg or 50 mg tablets
• Inactive Ingredients: Colloidal silicon dioxide, D & C Yellow No. 10 Aluminum Lake, Microcrystalline cellulose, Pregelatinized starch (maize), Sodium starch glycolate (Type A), Stearic acid, and FD&C Blue No.1 (in 50 mg tablets) 2

From the Research

Overview of Chlorthalidone

• Chlorthalidone is a thiazide diuretic used to treat hypertension, as studied in 3 and 4.
• It is currently recommended as the preferred thiazide diuretic to treat hypertension, but its use has been associated with greater risk of renal and electrolyte abnormalities, as found in 3.

Comparison with Hydrochlorothiazide

• A study comparing chlorthalidone and hydrochlorothiazide found no significant difference in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, as reported in 3.
• However, chlorthalidone was associated with a significantly higher risk of hypokalemia, hyponatremia, acute renal failure, chronic kidney disease, and type 2 diabetes mellitus, as noted in 3.

Use in Advanced Chronic Kidney Disease

• Chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo in patients with advanced chronic kidney disease and poorly controlled hypertension, as demonstrated in 4.
• However, chlorthalidone was associated with more frequent hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia, as reported in 4.

Mechanism of Action

• The exact mechanism of chlorthalidone's antihypertensive effects is not clearly understood, but it is thought to be related to decreases in circulating plasma volume and increases in the renin-angiotensin-aldosterone system, as discussed in 5.
• Chlorthalidone has been shown to decrease platelet aggregation and vascular permeability and promote angiogenesis in vitro, as noted in 5.

Interaction with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• NSAIDs are associated with a number of serious adverse effects, including hypertension, cardiovascular disease, kidney injury, and GI complications, as reported in 6 and 7.
• The use of NSAIDs, including tNSAIDs and coxibs, is associated with an increased risk of adverse CV events, myocardial infarction, heart failure, and cerebrovascular events, as found in 7.