Pharmacology and mechanism of action
Indapamide acts on the nephron (the smallest functional unit of the kidney), specifically in the proximal segment of the distal tubule. There it inhibits the Na+/Cl-cotransporter, resulting in decreased sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron and excreted in the urine. Subsequent effects include decreased plasma volume, decreased venous return, decreased cardiac output, and ultimately low blood pressure.
It is likely that thiazide-like diuretics such as indapamide have additional blood pressure-lowering mechanisms unrelated to diuresis. The exact mechnism behind this additional mechanism of action is not clear. Some studies suggest that indapamide reduces responsiveness to pressor agents (substances that can increase blood pressure). Other studies suggest that indapamide may decrease peripheral resistance by an unexplained mechanism.
The bioavailability of indapamide is virtually complete after an oral dose and is not affected by food or antacids. Indapamide is highly lipophilic due to its indoline moiety. This property probably explains why the renal clearance of indapamide is less than 10% of the total systemic clearance. The maximum plasma concentration is reached after approximately 2 to 3 hours. Approximately 75-80% of indapamide is present in protein-bound form. Indapamide binds primarily to acid alpha-1-glycoprotein and less strongly to serum albumin. In blood, indapamide is additionally strongly bound to erythrocytes. As a result of extensive metabolism in the liver, most of the given dose is metabolized. Only about 7% remains unchanged. There are several metabolic pathways by which indapamide can be metabolized. The major enzyme that metabolizes indapamide is the liver enzyme CYP3A4. Indapamide is excreted approximately 60-70% in urine and 15-25% in feces. The elimination half-life is usually between 14 and 18 hours.
When indapamide is combined with lithium and drugs that may cause prolonged QT interval or arrhythmias.
Substances that may cause interaction with indapamide include:
- Amiodarone and other antiarrhythmic agents.
- Digitoxin and related substances
- Erythromycin and related substances