NATRILIX Tablet Ref.[107804] Active ingredients:

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2021  Publisher: Servier Laboratories Limited, Sefton House, Sefton Park, Bells Hill, Stoke Poges, Slough, SL2 4JS

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Sulfonamides, plain
ATC code: C03BA11

Mechanism of action

Natrilix (indapamide) is a non-thiazide sulfonamide with an indole ring, belonging to the diuretic family. At the dose of 2.5 mg per day Natrilix exerts a prolonged antihypertensive activity in hypertensive human subjects.

Pharmacodynamic effects

Dose-effect studies have demonstrated that, at the dose of 2.5 mg per day, the antihypertensive effect is maximal and the diuretic effect is sub-clinical.

At this antihypertensive dose of 2.5 mg per day, Natrilix reduces vascular hyperreactivity to noradrenaline in hypertensive patients and decreases total peripheral resistance and arteriolar resistance.

The vascular mechanism of action of Natrilix involves:

  • a reduction in the contractility of vascular smooth muscle due to a modification of transmembrane ion exchanges, essentially calcium;
  • vasodilatation due to stimulation of the synthesis of prostaglandin PGE2 and the vasodilator and platelet antiaggregant prostacyclin PGI2;
  • potentiation of the vasodilator action of bradykinin.

It has also been demonstrated that in the short-, medium- and long-term, in hypertensive patients, Natrilix:

  • reduces left ventricular hypertrophy;
  • does not appear to alter lipid metabolism: triglycerides, LDL-cholesterol and HDL-cholesterol;
  • does not appear to alter glucose metabolism, even in diabetic hypertensive patients. Normalisation of blood pressure and a significant reduction in microalbuminuria have been observed after prolonged administration of Natrilix in diabetic hypertensive subjects.

Lastly, the co-prescription of Natrilix with other antihypertensives (beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors) results in an improved control of hypertension with an increased percentage of responders compared to that observed with single-agent therapy.

5.2. Pharmacokinetic properties

Absorption

Indapamide is rapidly and completely absorbed after oral administration. Peak blood levels are obtained after 1 to 2 hours.

Distribution

Indapamide is concentrated in the erythrocytes and is 79% bound to plasma protein and to erythrocytes. It is taken up by the vascular wall in smooth vascular muscle according to its high lipid solubility.

Metabolism

70% of a single oral dose is eliminated by the kidneys and 23% by the gastrointestinal tract. Indapamide is metabolised to a marked degree with 7% of the unchanged product found in the urine during the 48 hours following administration. Elimination half-life (β phase) of indapamide is approximately 15-18 hours.

5.3. Preclinical safety data

Indapamide has been tested negative concerning mutagenic and carcinogenic properties.

The highest doses administered orally to different animal species (40 to 8000 times the therapeutic dose) have shown an exacerbation of the diuretic properties of indapamide. The major symptoms of poisoning during acute toxicity studies with indapamide administered intravenously or intraperitoneally were related to the pharmacological action of indapamide, i.e. bradypnoea and peripheral vasodilation.

Reproductive toxicity studies have not shown embryotoxicity and teratogenicity.

Fertility was not impaired either in male or in female rats.

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