Indapamide

Absorption

The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively.

Toxicity

Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances.

Description

Indapamide is a derivative of benzolsulfonamide and its mechanism of action is analogous to that of thiazides. It is intended for lowering arterial blood pressure and as an adjuvant drug for treating edema caused by cardiac insufficiency.

The Uses of Indapamide

Used as an antihypertensive. Diuretic

Background

The most significant modifiable risk factor for cardiovascular disease and the most prominent contributor to all-cause mortality is hypertension. Characterized by an office blood pressure of ≥140/90, hypertension is pervasive and impacts an estimated 25% of adults globally. Treatment for hypertension should include a number of lifestyle changes (ie. reduced sodium intake) along with pharmacotherapy - it should be noted that treatment with several antihypertensive agents may be required in order to achieve blood pressure targets.
Thiazide-like diuretics such as indapamide are a valuable tool for the treatment of hypertension and continue to grow in popularity, falling behind only ACE inhibitors in terms of prescription frequency. When compared to hydrochlorothiazide (another commonly prescribed diuretic), indapamide has been shown to be superior at lowering systolic blood pressure, reducing left ventricular mass index, lowering oxidative stress, inhibiting platelet aggregation, and reducing microalbuminuria associated with diabetes. Interestingly, unlike thiazide diuretics, several sources suggest that indapamide is not associated with glucose or lipid disturbances.
Indapamide is characterized by both a methylindoline and a sulfamoyl chlorobenzamide functional group, with the former being largely responsible for the molecule’s lipid solubility.

Indications

Indapamide is a diuretic indicated for use as monotherapy or in combination with other blood pressure-lowering agents to treat hypertension. It may also be used to treat fluid and salt retention associated with congestive heart failure.

What are the applications of Application

Indapamide is an NCCT inhibitor

Pharmacokinetics

Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium.
Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients.

Metabolism

As a result of extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged. In humans, as many as 19 distinct indapamide metabolites may be produced, although not all have been identified.
There are several metabolic routes through which indapamide may be metabolized, and CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions.
Indapamide can undergo dehydrogenation to form M5, then oxidation to form M4, then further hydroxylation at the indole moiety to form M2. These reactions are facilitated by CYP3A4.
Another route of metabolism occurs when indapamide is first hydroxylated to M1 by CYP3A4. M1 then undergoes dehydrogenation to form M3 and is further oxidized to form M2. Hydroxylation of indapamide’s indole moiety is thought to form the major metabolite (M1), which is less pharmacologically active compared to its parent compound according to animal studies.
Indapamide may also undergo epoxidation via CYP3A4 to form a reactive epoxide intermediate. The unstable epoxide intermediate may then undergo dihydroxylation via microsomal epoxide hydrolase to form M6, or glutathione conjugation to form M7.