Combizar Mechanism of Action

Pharmacology: Pharmacodynamics: The blood pressure lowering effect of losartan is additive with that of hydrochlorothiazide (HCTZ), decreasing blood pressure to a greater degree than either component alone.
Losartan potassium: Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex.
Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the angiotensin II subtype 1 (AT₁) receptor found in many tissues such as vascular smooth muscles, adrenal gland, kidneys, and the heart. A second angiotensin II receptor has been identified as the AT₂ receptor subtype found in many tissues but is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT₁ receptor and have much greater affinity (about 1000-fold) for the AT₁ receptor than that for the AT₂ receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT₁ receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT₁ receptor.
Losartan does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin). Angiotensin II receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
Hydrochlorothiazide: Hydrochlorothiazide (HCTZ), a thiazide diuretic, increases the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The natriuretic effects are accompanied by a secondary loss of potassium and bicarbonate which can cause a mild hypokalemic, hypochloremic, metabolic alkalosis. Thiazides also decrease the elimination of calcium and uric acid. Thiazide diuretics usually do not affect normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known, however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction.
Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion, urinary potassium loss, and decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, therefore coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with HCTZ.
Diuresis begins with 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours after oral administration of HCTZ.
Pharmacokinetics: Losartan potassium: Losartan is well absorbed after oral administration. It undergoes presystemic metabolism, forming an active metabolite (E-3174) and other inactive metabolites. Systemic bioavailability of losartan tablets is about 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. There is no clinically significant effect on the plasma concentration profile of losartan when the drug is administered with a meal.
Both losartan and its metabolite are highly bound (≥99%) to plasma proteins, primarily albumin. Losartan's volume of distribution is 34 L.
Plasma concentrations of the active metabolite are higher than those of losartan at all doses, C_max and AUC for E-3174 are about 2 and 5 to 8 times greater than the corresponding values for losartan itself.
After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with terminal half-lives of about 2 hours (1.5 to 2.5 hours) and 6 to 9 hours, respectively. As anticipated from their short half-lives, neither losartan nor its active metabolite accumulates significantly in plasma during once-daily dosing with 100 mg.
The plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. Losartan is extensively metabolized in the liver. Approximately 35% of an oral losartan dose is excreted in urine as unchanged compound and metabolites. Only 4% of the dose is eliminated unchanged via the kidneys. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. Losartan and its metabolites are also eliminated by biliary excretion, with 58% of an oral dose recovered in the feces.
Hydrochlorothiazide: HCTZ is well absorbed from the gastrointestinal tract. Oral bioavailability is approximately 65 to 75%. After oral administration of HCTZ at doses of 12.5 to 100 mg, peak plasma concentrations of 70 to 490 ng/mL are observed within 1 to 5 hours of dosing.
Approximately 40 to 60% of the drug is bound to plasma proteins. HCTZ crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. It appears to be preferentially bound to red blood cells.
HCTZ is not metabolized but is eliminated rapidly as unchanged drug in the urine. HCTZ's plasma half-life ranged from 5.6 to 15 hours when plasma levels were followed for at least 24 hours. At least 61% of an oral dose is eliminated unchanged within 24 hours.
Special Populations: Renal Impairment: Plasma concentrations and AUCs of losartan and its active metabolite are increased by 50 to 90% in patients with mild (creatinine clearance 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment. Renal clearance was reduced by 55 to 85% for both losartan and its active metabolite in these patients.
In patients with renal impairment (mean creatinine clearance of 19 mL/min), the elimination half-life of HCTZ was prolonged to 20.7 hours.
Hepatic Impairment: In patients with mild to moderate alcohol-induced hepatic cirrhosis, the plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher than in healthy subjects, respectively. Losartan has not been studied in patients with severe hepatic impairment.
Monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.