Structural Biochemistry/Valsartan

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Valsartan/Diovan


Description

Valsartan, marketed as Diovan in the US, UK, and Australia [1], is chemically described as N-(1-oxopentyl)-N-[[2’-(1H-tetrazol-5-yl) [1,1’-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C24H29N5O3, and its molecular weight is 435.5 grams per mole [2].

Physically, Valsartan is a fine white powder that is soluble in ethanol and methanol and slightly soluble in water. Diovan is available as tablets for oral administration, containing 40 mg, 80 mg, 160 mg or 320 mg of valsartan. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides (yellow, black and/or red), magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, and titanium dioxide [2].

The structural formula for Valsartan is


Mechanism

Valsartan is an angiotensin II receptor antagonist, or more commonly, an angiotensin receptor blocker (ARB) of the type I (AT1) angiotensin receptor [1]. Blocking the activation of angiotensin II AT1 receptors widens blood vessels by relaxing the smooth muscle cells within the vessel walls [3, 4]. This mechanism also reduces the production and excretion of vasopressin and aldosterone, which are two hormones that increase water retention in the kidneys and subsequently increase blood pressure [5, 6].

Pharmacokinetics

Valsartan reaches a peak concentration 2-4 hours after dosage administration, and has a half-life of approximately 6 hours. However, if taken with food, Valsartan exposure decreases by 40% and the peak concentration decreases by about 50% [2].

Metabolism and Elimination

When recovering the drug, most of it is the drug unchanged, but about 20% is recovered as metabolites. Nine percent of the recovered metabolites were found to be valeryl 4-hydroxy valsartan. From in vitro metabolism studies, the CYP 2C9 isoenzyme was found to be the enzyme responsible for forming valeryl 4-hydroxy valsartan. When taken orally, about 83% of the dosage is eliminated in feces and about 13% of the dosage is eliminated in urine [2].

Role in Blood Pressure (Hypertension)

As the heart beats, blood pumps through the blood vessels and produces a force inside the blood vessels, which is known as blood pressure. When the blood pressure is high, the heart has to work harder to pump blood through the blood vessels, which causes damage to the blood vessels and may lead to stroke, heart attack, heart failure, kidney failure, and vision problems [7].

One cause of high blood pressure is angiotensin II, which narrows blood vessels, thus decreasing the blood flow and increasing the blood pressure within the blood vessel [8]. Therefore, by blocking the activation of angiotensin II AT1 receptors, Valsartan lowers high blood pressure (hypertension) by relaxing and widening the blood vessels, thus decreasing the flow resistance [8]. Valsartan is also used in treating congestive heart failure (CHF), or post-myocardial infarction (MI) [1].

Side Effects of Diovan [7]

Common side effects of Diovan for high blood pressure patients: headache, dizziness, flu symptoms, tiredness, abdominal pain.

Common side effects of Diovan for heart failure patients: dizziness, low blood pressure diarrhea, joint and back pain, tiredness, high blood potassium

Common side effects of Diovan for heart attack patients: low blood pressure, cough, (high blood creatinine), decreased kidney function, rash.

Drugs that Affect Diovan [9]

Cyclosporine (Gengraf, Neoral, Sandimmune) A diuretic (water pill) Rifampin (Rifadin, Rifater, Rifamate) Ritonavir (Norvir, Kaletra) A nonsteroidal anti-inflammatory drug (NSAID) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.


[1] http://en.wikipedia.org/wiki/Valsartan#Myocardial_infarction_controversy

[2] http://www.pharma.us.novartis.com/product/pi/pdf/diovan.pdf

[3] http://en.wikipedia.org/wiki/Angiotensin_receptor_blocker

[4] http://en.wikipedia.org/wiki/Vasodilation

[5] http://en.wikipedia.org/wiki/Vasopressin

[6] http://en.wikipedia.org/wiki/Aldosterone

[7] http://www.pharma.us.novartis.com/product/pi/pdf/diovan_ppi.pdf

[8] http://www.diovan.com/info/about-diovan/what-is-diovan-and-how-it-works.jsp

[9] http://www.drugs.com/diovan.html