Thiazide and thiazide-like diuretics remain foundational therapies in hypertension management. Two of the most commonly discussed agents are hydrochlorothiazide (HCTZ) and chlorthalidone. While they are often used interchangeably in practice, important pharmacologic and clinical differences exist that can influence drug selection. In this blog post, we will compare hydrochlorothiazide versus chlorthalidone.
Potency and Duration
One of the biggest differences is the duration of action. Chlorthalidone has a much longer half-life, approximately 40 to 60 hours, compared to hydrochlorothiazide, which has a half-life closer to 6 to 15 hours. This longer duration can translate into more consistent 24-hour blood pressure control. Milligram for milligram, chlorthalidone is also more potent. This longer half-life may also lead to urinary frequency later in the day, even if taken in the morning. This is something I look out for when I see orders for chlorthalidone. If the frequency is problematic, one might consider trying hydrochlorothiazide with its shorter half-life.
Mechanism of Action
Both hydrochlorothiazide and chlorthalidone inhibit sodium reabsorption in the distal convoluted tubule. This promotes natriuresis and mild diuresis, ultimately lowering blood pressure. Chlorthalidone is technically a thiazide-like diuretic, but functionally it works very similarly to hydrochlorothiazide.
Evidence and Outcomes
Chlorthalidone has more robust outcome data supporting cardiovascular risk reduction, including a large hypertension trial. The major landmark trial, ALLHAT, used chlorthalidone as the chosen thiazide-type diuretic (excellent board exam nugget). Some guidelines and experts have historically preferred chlorthalidone for this reason. More recently, the Diuretic Comparison Project looked at HCTZ versus chlorthalidone and found there was no cardiovascular difference between these agents. Hydrochlorothiazide remains widely used, especially in fixed-dose combination products. In practice, I see significantly more use of hydrochlorothiazide than chlorthalidone.
Adverse Effects and Monitoring
Both medications can cause hypokalemia, hyponatremia, hyperuricemia, and increases in blood glucose. Because chlorthalidone is more potent and longer acting, electrolyte disturbances may be more pronounced. Close monitoring of potassium, sodium, and renal function is essential, particularly after initiation or dose increases.
Practical Pearls
Hydrochlorothiazide may be preferred when flexibility, lower potency, or combination product availability is desired. Chlorthalidone may be preferred when stronger and longer blood pressure control is needed, especially in patients at high cardiovascular risk. At the end of the day, both agents are effective. The key is understanding their pharmacokinetic differences, monitoring closely for adverse effects, and individualizing therapy based on patient risk factors, clinical response, and blood pressure goals.
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