Irbesartan + Hydrochlorothiazide

Irbesartan: Angiotensin II is a potent vasoconstrictor. It forms from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). It is the principal pressor agent of the RAS, and it also stimulates aldosterone synthesis and secretion by the adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by binding selectively to the AT1 angiotensin II receptor. Many tissues also have an AT2 receptor, but it is not involved in cardiovascular homeostasis.

Irbesartan is a specific competitive antagonist of the AT1 receptor and has no agonist activity. Its affinity for the AT1 receptor is much greater than for the AT2 receptor (more than 8500-fold). Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion. Plasma renin activity and circulating angiotensin II then rise, but this does not overcome the effects of irbesartan on blood pressure.

Irbesartan does not inhibit ACE or renin, and it does not affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because it does not inhibit ACE, it does not affect the response to bradykinin (whether this has clinical relevance is not known).

Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. Thiazides act on the renal tubular mechanisms of electrolyte reabsorption and directly increase the excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume. This brings increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so giving an angiotensin II receptor antagonist together with the diuretic tends to reverse the potassium loss associated with these diuretics.