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.
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.
- 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
- 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)
Dosage of Valsartan
Strengths: 40mg ,80 mg; 160 mg; 320 mg;
Oral solution : 4mg/mL
- Initial dose: 80 to 160 mg orally once a day.
- Maintenance dose: 80 to 320 mg orally once a day
- 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
- cold symptoms such as stuffy nose, sore throat, cough
- Dry cough
- Dizziness and light-headedness due to low blood pressure
- Fatigue, especially in the early stages
- Mouth dryness in the early stages
- The most commonrn (a burning feeling in the chest, behind the breastbone or gullet)
- Abdominal or stomach pain
- Nausea ,vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- dull, aching pain in the hip, groin, or thigh
- stomach pain,
- reversible hair loss or thinning, and
- 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
- change in vision
- chest pain or tightness
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- extra heartbeats
- 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
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)
- asthma medications (e.g., theophylline)
- nonsteroidal anti-inflammatory medications (NSAIDs; e.g., indomethacin, naproxen)
- oral diabetes medications (e.g., metformin, pioglitazone)
- monoamine oxidase (MAO) inhibitors (e.g., phenelzine, selegiline, )
- other beta-blockers (e.g., propranolol, metoprolol)
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, rasagiline, selegiline, )
- phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
Pregnancy & Lactation of Valsartan
FDA pregnancy category D
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.
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).