| 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 |
Valsartan belongs to a class of antihypertensive agents called
angiotensin II receptor blockers (ARBs). Valsartan is a specific and
selective type-1 angiotensin II receptor (AT1) antagonist which blocks
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 |
Valsartan is an ARB that selectively inhibits the binding of
angiotensin II to AT1, which is found in many tissues such as vascular
smooth muscle and the adrenal glands. This effectively inhibits the
AT1-mediated vasoconstrictive and aldosterone-secreting effects of
angiotensin II and results in a decrease in vascular resistance and
blood pressure. Valsartan is selective for AT1 and has virtually no
affinity for AT2. Inhibition of aldosterone secretion may inhibit sodium
and water reabsorption in the kidneys while decreasing potassium
excretion. The primary metabolite of valsartan, valeryl 4-hydroxy
valsartan, has no pharmacological activity. |
| Absorption |
Absolute bioavailability = 23% with high variability |
| Volume of distribution |
- 17 L (low tissue distribution)
|
| Protein binding |
94 - 97% bound to serum proteins, primarily serum albumin |
| Metabolism |
Valsartan is excreted largely as unchanged drug (80%) and is
minimally metabolized in humans. The primary circulating metabolite,
4-OH-valsartan, is pharmacologically inactive and produced CYP2C9.
4-OH-valsartan accounts for approximately 9% of the circulating dose of
valsartan. Although valsartan is metabolized by CYP2C9, CYP-mediated
drug-drug interactions between valsartan and other drugs is unlikely. |
| Route of elimination |
83% of absorbed valsartan is excreted in feces and 13% is excreted in urine, primarily as unchanged drug |
| Half life |
The initial phase t1/2 α is < 1 hour while the terminal phase t1/2 β is 5-9 hours. |
| Clearance |
- 2 L/h [IV administration]
- 4.5 L/h [heart Failure patients receiving oral administration 40 to 160 mg twice a day]
|
| Toxicity |
Not Available |
