indication

May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Losartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.

pharmacology

Losartan is the first of a class of antihypertensive agents called angiotensin II receptor blockers (ARBs). Losartan and its longer acting active metabolite, E-3174, are specific and selective type-1 angiotensin II receptor (AT1) antagonists which block the blood pressure increasing effects angiotensin II via the renin-angiotensin-aldosterone system (RAAS). RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: AT1 and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure.

mechanism of action

Losartan competitively inhibits the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. Losartan is metabolized to its active metabolite, E-3174, which is 10 to 40 times more potent than losartan and acts as a non-competitive AT1 antagonist. Inhibition of angiotensin II binding to AT1 inhibits its AT1-mediated vasoconstrictive and aldosterone-secreting effects and results in decreased vascular resistance and blood pressure. Losartan is 1,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. Losartan is effective for reducing blood pressure and may be used to treat essential hypertension, left ventricular hypertrophy and diabetic nephropathy.

toxicity

Hypotension and tachycardia; Bradycardia could occur from parasympathetic (vagal) stimulation, LD₅₀= 1000 mg/kg (orally in rat)

biotransformation

Hepatic. Losartan is metabolized to a 5-carboxylic acid derivative (E-3174) via an aldehyde intermediate (E-3179) primarily by cytochrome P450 (CYP) 2C9 and CYP3A4. E-3174 is an active metabolite with 10- to 40-fold higher potency than its parent compound, losartan. Approxiamtely 14% of losartan is converted to E-3174; however, the AUC of E-3174 was found to be 4- to 8-fold higher than losartan and E-3174 is considered the main contributor to the pharmacologic effects of this medication.

absorption

Well absorbed, the systemic bioavailability of losartan is approximately 33%

half life

The terminal t_1/2 of losartan is 2 hours and that of E-3174 is 6-9 hours.

route of elimination

After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites.

drug interactions

Amiloride: Increased risk of hyperkalemia

Drospirenone: Increased risk of hyperkalemia

Indomethacin: Indomethacin decreases the effect of losartan

Lithium: Losartan increases serum levels of lithium

Potassium: Increased risk of hyperkalemia

Quinupristin: This combination presents an increased risk of toxicity

Rifampin: Rifampin decreases the effect of losartan

Spironolactone: Increased risk of hyperkalemia

Tobramycin: Increased risk of nephrotoxicity

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Losartan. Consider alternate therapy or monitor for changes in Losartan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Trandolapril: The angiotensin II receptor blocker, Losartan, may increase the adverse effects of Trandolapril.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Tretinoin: The moderate CYP2C8 inhibitor, Losartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Losartan is initiated, discontinued to dose changed.

Triamterene: Increased risk of hyperkalemia