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Valsartan; Uses, Dosage, Side Effects, Interactions, Pregnancy

Valsartan is an orally active nonpeptide triazole-derived antagonist of angiotensin (AT) II with antihypertensive properties. Valsartan selectively and competitively blocks the binding of angiotensin II to the AT1 subtype receptor in vascular smooth muscle and the adrenal gland, preventing AT II-mediated vasoconstriction, aldosterone synthesis and secretion, and renal reabsorption of sodium, and resulting in vasodilation, increased excretion of sodium and water, a reduction in plasma volume, and a reduction in blood pressure.

Valsartan is mainly used for treatment of high blood pressure, congestive heart failure, and to increase the chances of living longer after a heart attack. It is an angiotensin II receptor antagonist (commonly called an ARB, or angiotensin receptor blocker), that is selective for the type I (AT₁) angiotensin receptor.Valsartan is an angiotensin-receptor blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Valsartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II.

Mechanism of Action of Valsartan

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.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.

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Diovan (valsartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.

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Indications of Valsartan

High Blood Pressure
Diabetic Kidney Disease
Hypertension and microalbuminuria (>30 mg/24 h) or proteinuria (>900 mg/24 h).
High Blood Pressure (Hypertension)
Congestive heart failure,
Systolic dysfunction,
Myocardial infarction
Diabetic nephropathies
High blood pressure (hypertension)
Chronic heart failure with reduced ejection fraction (NYHA Class II)
Chronic heart failure with reduced ejection fraction (NYHA Class III)
Chronic heart failure with reduced ejection fraction (NYHA Class IV)
Symptomatic left ventricular ejection fraction ≤ 35% Chronic heart failure
Treatment of uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy.
Coronary artery disease in those intolerant of ACE inhibitors.
Pediatric hypertension 6 to 16 years of age.
Post-myocardial infarction.
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.

Therapeutic indications

Treatment of essential hypertension, of recent myocardial infarction and of heart failure.
Treatment of essential hypertension. Exforge is indicated in adults whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy.
Hypertension – Treatment of hypertension in adults.
Recent myocardial infarction – Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours-10 days) myocardial infarction (all except 320 mg film-coated tablets)
Heart failure , Treatment of symptomatic heart failure in adult patients when angiotensin converting enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when beta-blockers cannot be used. (all except 320 mg film-coated tablets)
Valsartan is an angiotensin II receptor blocker (ARB) indicated for: treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
Valsartan is an angiotensin II receptor blocker (ARB) indicated for: reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Valsartan is an angiotensin II receptor blocker (ARB) indicated for: treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure.
Both angiotensin II receptor antagonists (e.g., valsartan) and ACE inhibitors have been shown to slow the rate of progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy, and use of a drug from either class is recommended in such patients.

Contra Indications of Valsartan

The packaging for valsartan includes a warning stating the drug should not be used with the renin inhibitor aliskiren in people with diabetes mellitus. It also states the drug should not be used in people with kidney disease.

Low amount of sodium in the blood
High amount of potassium in the blood
Decreased neutrophils a type of white blood cell
Renal Artery Stenosis
Abnormally low blood pressure
Liver problems
Severe renal impairment
Pregnancy
Decreased blood volume
Hypersensitivity to the active substance, soya oil, peanut oil or to any of the excipients
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Second and third trimester of pregnancy
The concomitant use of valsartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²)

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Dosage of Valsartan

Strengths: 40mg ,80 mg; 160 mg; 320 mg;

Oral solution : 4mg/mL

Hypertension

Initial dose: 80 to 160 mg orally once a day.
Maintenance dose: 80 to 320 mg orally once a day

Heart failure

Adults—At first, 40 milligrams (mg) two times a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 320 mg per day.
Children—Use and dose must be determined by your doctor.

High Blood Pressure

Adults—At first, 80 or 160 milligrams (mg) once a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 320 mg per day.
Children 6 to 16 years of age—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 1.3 milligrams (mg) per kilogram (kg) of body weight per day given as a single dose. Your doctor may adjust the dose as needed. However, the dose is usually not more than 2.7 mg per kg of body weight or 160 mg per day.
Children younger than 6 years of age—Use is not recommended.

Left Ventricular Failure after a heart attack

Adults—At first, 20 milligrams (mg) two times a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 320 mg per day.
Children—Use and dose must be determined by your doctor.

Side Effects of Valsartan

Common

chills or fever
headache, severe and throbbing
joint or back pain
muscle aching or cramping
muscle pains or stiffness
chest pressure or squeezing pain in chest
excessive sweating
sudden drowsiness or need to sleep
coughing up blood
liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
decreased amount of urine

Rare

Anxiety
change in vision
chest pain or tightness
confusion
cough
Agitation
arm, back, or jaw pain
blurred vision
chest pain or discomfort
convulsions
extra heartbeats
hallucinations
headache
irritability
lightheadedness
cold and clammy skin
fast and shallow breathing
swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
fast or abnormal heart rate or palpitations
loss of appetite
lower back, side, or stomach pain
mental depression
muscle pain or cramps
Swelling of your feet or ankles
Shortness of breath
Nausea, fever, dark urine, loss of appetite
Depression

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Drug Interactions of Valsartan

Valsartan may interact with following drugs, supplyments, & may change the efficacy of drugs

angiotensin converting enzyme inhibitors (ACEIs; captopril, enalapril, ramipril)
benzodiazepines (e.g., clonazepam, diazepam, lorazepam)
beta-blockers (e.g., atenolol, metoprolol, propranolol)
carbamazepine
cimetidine
cyclosporine
dasatinib
dexamethasone
duloxetine
asthma medications (e.g., theophylline)
nonsteroidal anti-inflammatory medications (NSAIDs; e.g., indomethacin, naproxen)
oral diabetes medications (e.g., metformin, pioglitazone)
pentoxyifylline
monoamine oxidase (MAO) inhibitors (e.g., phenelzine, selegiline, )
other beta-blockers (e.g., propranolol, metoprolol)
oxtriphylline
verapamil
imatinib
imipramine
macrolide antibiotics (e.g., clarithromycin, erythromycin)
monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, rasagiline, selegiline, )
pentoxifylline
phenytoin
phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
quetiapine
sertraline
tetracycline
theophylline
tocilizumab
warfarin

Pregnancy & Lactation of Valsartan

FDA pregnancy category D

Pregnancy

Valsartan falls in FDA pregnancy category D and includes a black box warning for fetal toxicity. Discontinuation of these agents is recommended immediately after detection of pregnancy and an alternative medication should be started. The US labeling makes no recommendation regarding continuation or discontinuation of valsartan for breastfeeding mothers. The Canadian labeling does not recommend use by nursing women.

Lactation

Because no information is available regarding the use of valsartan during breastfeeding, Valsartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on an mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).