From the Guidelines
Thiazide diuretics increase sodium and water excretion by inhibiting the sodium-chloride cotransporter (NCC) in the distal convoluted tubule of the nephron, leading to the excretion of about 5-10% of filtered sodium, as noted in the 2009 guidelines 1. When medications like hydrochlorothiazide, chlorthalidone, or indapamide block this transporter, they prevent the reabsorption of sodium and chloride ions that would normally occur at this site. This leads to increased sodium and chloride excretion in the urine, which pulls water along with it through osmosis, resulting in increased urine output. The mechanism of action of thiazide diuretics is further supported by the 2007 statement from the American Heart Association 1, which highlights their effectiveness in preventing heart failure in hypertensive patients and their role in treating mild heart failure due to their sustained natriuretic and diuretic action. Some key points to consider when using thiazide diuretics include:
- Their effectiveness in patients with relatively normal kidney function, with a loss of efficacy when glomerular filtration rate falls below 30-40 mL/min, as mentioned in the 2009 guidelines 1.
- The potential side effects, such as hypokalemia and metabolic alkalosis, due to the increased delivery of sodium to the distal tubule, which promotes potassium and hydrogen ion secretion.
- The ceiling dose effect, beyond which higher doses primarily increase side effects without enhancing diuresis, making them effective treatments for hypertension, heart failure, and edematous conditions, as noted in the 2007 statement 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. Thiazide diuretics, such as hydrochlorothiazide, increase sodium and water excretion by:
- Blocking the reabsorption of sodium and chloride ions in the distal tubule
- Increasing the quantity of sodium traversing the distal tubule
- Increasing the volume of water excreted as a result of the increased sodium load in the distal tubule 2
From the Research
Mechanism of Thiazide Diuretics
Thiazide diuretics increase sodium and water excretion primarily by inhibiting mechanisms for electroneutral sodium and chloride transport by distal convoluted tubule cells 3. This is achieved by inhibiting the electroneutral Na(+)-Cl(-) cotransporter located on the apical membrane of the early segment of the distal convoluted tubule 4, 5.
Effects on Ion Transport
The inhibition of sodium and chloride absorption by thiazide diuretics leads to:
- Stimulation of potassium secretion, likely due to the increase in distal tubule fluid flow rate 3
- Stimulation of calcium absorption, possibly via a decrease in distal convoluted tubule cell sodium activity and an increase in basolateral sodium/calcium exchange 3
Additional Effects
Thiazide diuretics also:
- Inhibit carbonic anhydrase to a varying degree, which can contribute to diuresis but is largely buffered by the reserve transport capacity of the loop of Henle 3
- Activate tubuloglomerular feedback, leading to a reduction in glomerular filtration rate 3
Clinical Implications
The use of thiazide diuretics is effective in reducing blood pressure and is often prescribed for the treatment of hypertension 4, 6, 7. However, the mechanisms by which they chronically lower blood pressure remain unknown 4. Thiazide diuretics have a flat dose-response curve, and their use at high doses can lead to adverse effects such as electrolyte changes and metabolic abnormalities 4.
Comparison of Thiazide Diuretics
Different thiazide diuretics have similar maximal blood pressure-lowering effects, but may vary in their potency and adverse effects 6, 7. For example: