How does Hydrochlorothiazide (HCTZ) work as an antihypertensive medication?

From the Guidelines

Hydrochlorothiazide (HCTZ) works as an antihypertensive medication by acting as a thiazide diuretic that reduces blood pressure through several mechanisms, primarily inhibiting sodium and chloride reabsorption in the distal convoluted tubule of the kidney, causing increased excretion of sodium, chloride, and water through urine, as supported by the most recent guideline-driven management of hypertension update 1.

Mechanism of Action

HCTZ decreases blood volume and cardiac output, leading to lower blood pressure.

• It is typically prescribed at doses of 12.5 to 50 mg once daily, with most patients responding well to 25 mg daily.
• The blood pressure-lowering effect begins within 3-4 days but may take up to 3-4 weeks for maximum effect.

Clinical Use

Beyond its diuretic action, HCTZ also causes direct vasodilation of blood vessels after several weeks of use, which contributes to its long-term antihypertensive effect.

• Patients taking HCTZ should maintain adequate hydration but avoid excessive salt intake, monitor for side effects like electrolyte imbalances (particularly potassium depletion), and have periodic blood tests to check electrolytes and kidney function.
• HCTZ is often combined with other antihypertensive medications like ACE inhibitors or angiotensin receptor blockers for enhanced blood pressure control, as recommended by the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure 1 and the nhlbi releases new high blood pressure guidelines 1.

Recommendations

The most recent evidence suggests that thiazide or thiazide-type diuretics, such as HCTZ, are recommended as initial drug choices for the management of hypertension, along with calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers 1.

• However, chlorthalidone and indapamide, thiazide-like diuretics, have a longer duration of action compared to thiazide diuretics and are the preferred diuretics for management of hypertension, as shown in network meta-analyses 1.
• The choice of antihypertensive medication should be based on individual patient characteristics, such as comorbidities and potential side effects, as well as the latest clinical guidelines and evidence-based recommendations 1.

From the FDA Drug Label

Hydrochlorothiazide blocks the reabsorption of sodium and chloride ions, and it thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. Acute antihypertensive effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased

The mechanism of action of hydrochlorothiazide as an anti-hypertension medication is through:

• Blocking the reabsorption of sodium and chloride ions
• Increasing the quantity of sodium traversing the distal tubule and the volume of water excreted
• Reducing blood volume and cardiac output secondary to a natriuretic effect
• Possibly a direct vasodilatory mechanism With chronic administration, peripheral vascular resistance is decreased 2

From the Research

Mechanism of Action

• Hydrochlorothiazide (HCTZ) is a thiazide diuretic that works by inhibiting the reabsorption of sodium and chloride in the distal tubule of the kidney, leading to increased excretion of sodium and water in the urine 3.
• This mechanism of action helps to reduce blood volume and cardiac output, which in turn lowers blood pressure 4.

Efficacy in Hypertension

• HCTZ is effective in reducing blood pressure in patients with hypertension, although its potency may be lower compared to other antihypertensive agents such as chlorthalidone, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers 3.
• The use of HCTZ as an add-on therapy to a renin-angiotensin system blocker has been shown to be effective in treating hypertension in patients with renal disease 5.

Metabolic Effects

• HCTZ may cause metabolic abnormalities, including hypokalaemia, which is a well-recognized adverse effect of thiazide diuretics 6, 7.
• The risk of hypokalaemia is higher in certain populations, such as women, non-Hispanic blacks, underweight individuals, and those taking HCTZ for an extended period 7.

Clinical Use

• HCTZ is a commonly used antihypertensive medication, and its use is recommended in major domestic and international hypertension guidelines 4.
• However, the use of HCTZ should be carefully monitored, particularly in patients at risk of hypokalaemia, and combination with potassium-sparing drugs may be necessary to minimize this risk 7.