| 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. |
| Pharmacodynamics |
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. |
| Absorption |
Well absorbed, the systemic bioavailability of losartan is approximately 33% |
| Volume of distribution |
- 34 L [losartan]
- 12 L [active metabolite]
|
| Protein binding |
99.7%, primarily to albumin |
| Metabolism |
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. |
| 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. |
| Half life |
The terminal t1/2 of losartan is 2 hours and that of E-3174 is 6-9 hours. |
| Clearance |
- 600 mL/min [Healthy volunteers after IV administration]
- Renal cl=56 +/- 23 mL/min [Hypertensive adults given 50 mg once daily for 7 days]
- Renal cl=53 +/- 33 mL/min [Hypertensive children (6-16 years old) given 0.7 mg/kg once daily for 7 days]
|
| Toxicity |
Hypotension and tachycardia; Bradycardia could occur from parasympathetic (vagal) stimulation, LD50= 1000 mg/kg (orally in rat) |
