First-Line Diuretic for Uncomplicated Hypertension
Chlorthalidone 12.5–25 mg once daily is the optimal first-line diuretic for adults with uncomplicated hypertension, based on superior cardiovascular outcome data from the ALLHAT trial and its longer duration of action providing 24-hour blood pressure control. 1, 2, 3
Why Chlorthalidone Over Hydrochlorothiazide
Chlorthalidone is pharmacologically superior because of its 40–60 hour half-life and large volume of distribution, providing sustained overnight blood pressure reduction that hydrochlorothiazide cannot match. 4 At 25 mg, chlorthalidone is more potent than 50 mg of hydrochlorothiazide, particularly for nocturnal blood pressure control. 4
The evidence base strongly favors chlorthalidone:
- In the ALLHAT trial of >50,000 participants, chlorthalidone reduced heart failure incidence by 38% compared with amlodipine and stroke incidence by 15% compared with lisinopril. 1, 2, 4, 3
- Chlorthalidone demonstrated superior prevention of stroke, heart failure, and combined cardiovascular disease compared with ACE inhibitors and calcium-channel blockers in head-to-head trials. 2, 3
- The ACC/AHA guideline explicitly states a preference for chlorthalidone over other diuretics because it was the agent used in landmark event-based randomized trials. 1
Starting Dose and Titration
Begin with chlorthalidone 12.5 mg once daily to minimize metabolic side effects while achieving effective blood pressure reduction. 1, 5 This low dose provides optimal antihypertensive effect with the smallest occurrence of hypokalemia, hyperglycemia, and lipid abnormalities. 6
Titrate to 25 mg once daily if needed after 4 weeks to reach the target blood pressure of <130/80 mmHg. 1, 5 Doses above 25 mg are not recommended because they increase metabolic adverse effects without proportional blood pressure benefit. 6
When Chlorthalidone Is Unavailable
If chlorthalidone is not available, use hydrochlorothiazide 25 mg once daily as the alternative thiazide diuretic. 3 However, recognize that hydrochlorothiazide doses <25 mg daily as monotherapy are unproven and less effective in outcome trials. 7
The FDA-approved dosing for hydrochlorothiazide is 12.5–50 mg once daily, with total daily doses >50 mg not recommended. 8 For hypertension, start at 25 mg once daily. 8
Alternative First-Line Diuretic: Indapamide
Indapamide is a thiazide-like diuretic with cardiovascular outcome data, though the evidence is less robust than for chlorthalidone. 1 The AHA Scientific Statement on Resistant Hypertension recommends thiazide-like diuretics (chlorthalidone or indapamide) as preferred over hydrochlorothiazide. 1
Population-Specific Considerations
For Black patients without heart failure or chronic kidney disease, thiazide diuretics (chlorthalidone preferred) or calcium-channel blockers are the recommended first-line agents because ACE inhibitors and ARBs are 30–36% less effective for stroke prevention in this population. 1, 2, 5
For non-Black patients with uncomplicated hypertension, chlorthalidone remains the optimal first-line choice among the four acceptable drug classes (thiazides, ACE inhibitors, ARBs, calcium-channel blockers). 2, 5
Monitoring Requirements
Obtain baseline labs before starting: serum creatinine, estimated GFR, potassium, sodium, fasting glucose, and uric acid. 1, 5
Repeat labs 1–2 weeks after initiation to check for hyponatremia, hypokalemia, and changes in renal function. 1, 5 Monitor uric acid levels, especially in patients with a history of gout. 1
Follow up monthly after starting therapy until blood pressure target (<130/80 mmHg) is achieved, then every 3–5 months for maintenance. 1, 5
Critical Pitfalls to Avoid
Do not use loop diuretics (furosemide, bumetanide, torsemide) as first-line therapy for uncomplicated hypertension because there are no outcome data supporting their use; reserve them for heart failure or advanced chronic kidney disease (eGFR <30 mL/min). 1, 4
Avoid hydrochlorothiazide doses <25 mg as monotherapy because such low doses are unproven in outcome trials. 7 The ACCOMPLISH trial used only 12.5–25 mg hydrochlorothiazide, which was lower than doses used in placebo-controlled trials. 4
Use thiazides cautiously in patients with acute gout unless the patient is on uric acid-lowering therapy (e.g., allopurinol). 1 Thiazide-induced hyperuricemia results from volume contraction and competition with uric acid for renal tubular secretion. 4
Monitor for thiazide-induced hypokalemia, which is associated with increased blood glucose and may precipitate diabetes. 4 Treatment of hypokalemia may reverse glucose intolerance. 4
Recognize that nonsteroidal anti-inflammatory drugs (NSAIDs) blunt thiazide effects and should be avoided or used cautiously in hypertensive patients on diuretics. 4
When to Add a Second Agent
If blood pressure remains ≥130/80 mmHg after 4 weeks on chlorthalidone 25 mg, add an ACE inhibitor, ARB, or calcium-channel blocker rather than increasing the diuretic dose further. 5, 7 Preferred two-drug combinations include chlorthalidone + ACE inhibitor/ARB or chlorthalidone + calcium-channel blocker. 1, 5
For Stage 2 hypertension (≥140/90 mmHg or >20/10 mmHg above goal), initiate combination therapy with two agents from different classes immediately, preferably as a single-pill formulation. 1, 5