Valsartan

Valsartan is an antihypertensive agent belonging to the Angiotensin II receptor blocker class. Valsartan is approved for the treatment of Hypertension and also for heart failure, and to prevent heart attack, alone or with other antihypertensive agents. Valsartan relaxes the blood vessel and lower blood pressure. Lower blood pressure will gain the supply of blood and oxygen to the heart.

After one oral dose, the antihypertensive activity of Valsartan begins within approximately 2 hour and peaks within 4hours to 6 hours in most patients. AUC and Cmax value of Valsartan generally gain linearly with increasing dose over the therapeutic dose range. The steady state volume of distribution of Valsartan after intravenous administration is small (17 L), indicating that Valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum Valsartan is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The enzyme responsible for Valsartan metabolism have not been identified but does not seem to be CYP 450 isozymes.

The common side effects associated with Valsartan include Stomach pain, Chills, Difficult or painful urination, Fast heartbeat, Back pain, etc.

Valsartan is available in the form of tablets.

Valsartan is available in India, US and UK.

Valsartan, belonging to the Angiotensin II Receptor Blocker, acts as an antihypertensive agent. Valsartan works by relaxing blood vessels so blood can flow more easily.

Valsartan block 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 the adrenal gland and the vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 receptor is not known to be associated with cardiovascular homeostasis. Valsartan has more greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor.

The onset of action of Valsartan occurs within 2 hours of its administration.

The Duration of Action for Valsartan in the body is approximately 24 hours.

The Tmax was found within 2-4 hours following the administration of Valsartan, and the Cmax was about 4314 ± 1522.6 ng/mL.

Valsartan is available in the form of Tablet.

Valsartan tablet is taken as directed by physician, and the regular tablet is often taken once a day, swallowed with plenty of water, with or without Food.

Valsartan is approved for the treatment of Hypertension and also for heart failure, and to prevent death after a heart attack. Valsartan may be used alone or with other medications.

Valsartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker which blocks the vasoconstrictor and aldosterone secreting effect of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor. Hence relaxation of blood vessels, so blood flows more efficiently to treat Hypertension.

Valsartan is approved for use in the following clinical indications:

• Hypertension

Valsartan is indicated for the treatment of Hypertension, to lower blood pressure in adults and pediatric patients six years of age and older. Lowering of blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which Valsartan principally belongs. There are no controlled trials in hypertensive patients demonstrating risk reduction with Valsartan. Valsartan may be used alone or in combination with other antihypertensive agents.

• Heart Failure

Valsartan is indicated to lower the risk of hospitalization for heart failure in a patient with (NYHA class II-IV) heart failure. There is no evidence that Valsartan provides added benefits when it is used with an adequate dose of an ACE inhibitor.

• Post-Myocardial Infarction

In clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, Valsartan is indicated to lower the risk of cardiovascular mortality.

• Adult Hypertension

The recommended initial dose of Valsartan is 80 mg or 160 mg once daily when used as monotherapy in a patient who is not volume-depleted. A patient requiring greater reduction may be started at a higher dose. Valsartan may be used dose range of 80 mg to 320 mg daily, administered once a day. The antihypertensive effect is substantially present within two weeks, and maximal reduction is generally attained after four weeks. If the additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg, or a diuretic may be added. Increases in dose above 80 mg have less of an impact than the addition of a diuretic. Patients who are elderly, have mild or moderate renal impairment, or have mild or moderate hepatic insufficiency don't need to have their initial dosage adjusted. Valsartan dosage should be used with caution to individuals who have significant renal or hepatic impairment. Other antihypertensive drugs may be used along with Valsartan. It may be administered with or without Food.

• Pediatric Hypertension

The usual recommended initial starting dose for children who can swallow tablets is (up to 40 mg total) 1.3 mg/kg once daily . Dosage should be adjusted based on blood pressure response.Pediatric patients between the ages of 6 and 16 have not been studied at doses greater than (up to 160 mg) 2.7 mg/kg once daily.

• Heart Failure

Valsartan can be taken at a starting dose of 40 mg twice daily. The largest dose that the patient can tolerate should be increased by titration to 80 mg and 160 mg twice daily. The dose of concurrent diuretics should be taken into consideration. 320 mg in divided doses is the daily maximum dosage used in clinical trials.

• Post-Myocardial Infarction

In the first 12 hours following a myocardial infarction, Valsartan can be started. Valsartan should be taken at a starting dose of 20 mg twice a daily. Patients may be up titrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consideration should be given to a dosage reduction. Valsartan may be given with other standard post-myocardial infarction treatments, including thrombolytics, aspirin, beta-blockers, and statins.

Valsartan is available in dosage strengths of 40mg, 80mg, 160mg and 320mg.

Valsartan is available in the dosage form of Tablets.

Salt substitutes containing potassium are avoided, and low salt or low sodium diet is maintained systematically.

The dietary restriction should be individualized as per patient requirements.

Valsartan may be contraindicated in the following:

• Hypersensitivity
• Do not co-administer aliskiren with Valsartan in a patient with diabetes.
• Pregnancy (especially second/third trimester)

• Fetal Toxicity

Valsartan may cause fetal harm when administered to a pregnant woman. The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. The resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Valsartan as soon as possible.

• Hypotension volume- and/or salt-depleted patients

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to the administration of Valsartan, or the treatment should start under close medical supervision.

• Heart failure or post-myocardial infarction patient

Patients with heart failure or post-myocardial infarction patients given Valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. If excessive hypotension occurs, place the patient in the supine position and, if necessary, give normal intravenous saline. Transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

• Impaired Renal Function

Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Valsartan.

• Hyperkalemia

Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of Valsartan may be required.

Consumption of alcohol with Valsartan can cause drowsiness, dizziness, light-headedness, or fainting; therefore, it is better to avoid alcohol while taking Valsartan.

Whether Valsartan is secreted in human milk is unknown. Valsartan was secreted in the milk of nursing rats, however medication levels in animal breast milk might not be actually indicative of human breast milk levels. Because many medications are secreted in human milk and because Valsartan may produce negative effects in nursing infants, a choice should be taken on whether to stop breastfeeding or stop the medication, taking into account the significance of the medication to the mother.

Valsartan is an angiotensin II receptor blocker that should not be initiated during pregnancy as it can lead to fetal harm when administered to pregnant women. Valsartan can reduce fetal renal function and result in oligohydramnios related to skeletal deformities. Patients planning pregnancy should be considered alternative antihypertensive treatments with an established safety profile for use in pregnancy.

Valsartan is used with caution with Food rich in potassium, such as bananas, nuts, and sweet potatoes, as it can lead to hyperkalemia.

The adverse reactions related to Valsartan can be categorized as

Common Adverse effects

• Diarrhea

• Dry cough

• Dizziness

• Fatigue

Less Common Adverse effects

• Nausea

• Muscle spasm

• Blurred vision

• Asthenia

Rare adverse effects

• Skin rash
• Pruritus
• Angio edema

• Agents Increasing Serum Potassium

Concomitant use of Valsartan with another agent that blocks the renin-angiotensin system, potassium supplements, potassium-sparing diuretics, salt substitutes that contain potassium or other drugs that may gain potassium level may lead to an increase in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring the serum potassium is advisable.

• Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those receiving diuretic therapy), or who have compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Valsartan, may worsen renal function and increase the risk of acute renal failure. Usually, these effects are reversible. When Valsartan and NSAID medication is being used, patients' renal function should be routinely monitored. NSAIDs, such as selective COX-2 inhibitors, may reduce the antihypertensive action of angiotensin II receptor antagonists, such as Valsartan.

• Dual Blockade of The Renin-Angiotensin System (RAS)

As compared to monotherapy, dual blockage of the RAS with ACE inhibitors, aliskiren, or angiotensin receptor blockers increases the risk of hypotension, hyperkalemia, and abnormalities in renal function (including acute renal failure). Most patients who receive two RAS inhibitors in combination do not benefit any more than they would with monotherapy. In general, avoid the combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Valsartan and other agents that affect the RAS. Do not coadminister aliskiren with Valsartan in patients with diabetes. When combined Valsartan with aliskiren should not be taken by patients with renal impairment (GFR 60 mL/min).

• Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during the concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

The common side of Valsartan includes the following

Major side effects

• Stomach pain
• Chills
• Difficult or painful urination
• Fast heartbeat
• Back pain
• Nasal congestion
• Heartburn
• Sore throat

Minor side effects

• Chest tightness
• Dizziness
• Weakness in arms, hands, legs or feet

The use of Valsartan should be prudent in the following group of special populations.

Pregnancy

Pregnancy Category D

When used during the second or third trimester of pregnancy, Valsartan, like other drugs that affect the renin-angiotensin system, can result in morbidity and death for the foetus and the newborn. When given to a pregnant woman, Valsartan has the potential to harm the foetus. If Valsartan is used during pregnancy, or if a patient becomes pregnant while taking this drug Valsartan, the potential risk to the foetus should be explained to the patient. Similar effects on the renin-angiotensin system are produced by angiotensin II receptor antagonists like Valsartan and angiotensin converting enzyme inhibitors. ACE inhibitor use throughout the second and third trimesters of pregnancy has been linked to foetal and newborn harm in several dozen published cases. These injuries include hypotension, infant skull hypoplasia, anuria, reversible or permanent renal failure, and death. Additionally, oligohydramnios was identified, most likely due to impaired foetal renal function. In this situation, oligohydramnios was linked to the development of hypoplastic lungs, craniofacial abnormalities, and foetal limb contractures. Additionally documented conditions included prematurity, intrauterine growth retardation, and patent ductus arteriosus, though it is unclear if these conditions were brought on by drug exposure. The first trimester usage of ACE inhibitors, a particular class of medications that affects the renin-angiotensin system, was linked to a potential risk of birth abnormalities in a retrospective research. When a patient using Valsartan becomes pregnant, the doctor must stop prescribing the medication as soon as possible. Based on the patient's exposure to Valsartan during pregnancy, the doctor needs to explain any possible hazards to the foetus (first trimester only or later). An ultrasound check needs to be done if exposure occurs beyond the first trimester. Serial ultrasonography exams should be carried out to evaluate the intraamniotic environment in rare circumstances where another antihypertensive drug cannot be administered to treat the pregnant patient. Based on the stage of pregnancy and accepted standards of care in the community, routine foetal testing using non-stress tests, biophysical profiles, and/or contraction stress tests may be necessary. The patient, the doctor, and a specialist in the management of high-risk pregnancies should individually decide whether to continue or stop Valsartan treatment if oligohydramnios develops in these circumstances. Patients and physicians should be aware that oligohydramnios might not become evident until the foetus has already undergone irreparable harm. Valsartan exposure during pregnancy should be closely monitored for hypotension, oliguria, and hyperkalemia in infants. These infants may need blood pressure and renal perfusion assistance if oliguria develops. Dialysis or exchange transfusion may be necessary to sustain impaired renal function or to restore hypotension. The hazards of these medications during pregnancy should be discussed with women of reproductive potential by healthcare practitioners who prescribe medications that directly affect the renin-angiotensin system.

Nursing Mothers

Whether Valsartan is secreted in human milk is unknown. Valsartan was secreted in the milk of nursing rats, however medication levels in animal breast milk might not be actually indicative of human breast milk levels. Because many medications are secreted in human milk and because Valsartan may produce negative effects in nursing infants, a choice should be taken on whether to stop breastfeeding or stop the medication, taking into account the significance of the medication to the mother.

Pediatric Use

The antihypertensive effects of Valsartan have been evaluated in two randomized, double-blind clinical studies in pediatric patients from 1-5 and 6-16 years of age. The pharmacokinetics of Valsartan have been evaluated in pediatric patients 1 to 16 years of age. Valsartan was generally well tolerated in children 6-16 years, and the adverse experience profile was similar to that described for adults. Due to safety results for which a causation to therapy could not be established out, Valsartan is not advised for paediatric patients younger than 6 years. Due to a lack of data, Valsartan is not advised for the treatment of children whose glomerular filtration rate is below 30 mL/min/1.73 m2.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted. Valsartan is not removed from the plasma by hemodialysis. Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmoset rats, except for salivation and diarrhea in the rat and vomiting in the marmoset rats at the highest dose (60 and 31 times, respectively, the maximum recommended human dose on an mg/m2 basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Pharmacodynamics

Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak, with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of Valsartan; very little effect on serum potassium was observed. In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular Hypertension, Valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow. In multiple-dose studies in hypertensive patients, Valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.

Pharmacokinetics

• Absorption

After a single oral dose, Valsartan's antihypertensive action starts to take effect in about two hours and typically reaches its peak within four to six hours in most patients. Food reduces the exposure to Valsartan taken orally by about 40% and the peak plasma concentration by about 50%. Over the therapeutic dose range, Valsartan's AUC and Cmax values usually increase with increasing doses. Valsartan does not significantly accumulate in plasma after repeated administration.

• Distribution

The steady-state volume of distribution of Valsartan after intravenous administration is small (17 L), indicating that Valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

• Metabolism and Elimination

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as an unchanged drug, with only about 20% of the dose recovered as metabolites. Valeryl 4-hydroxy Valsartan, which consists about 9% of the dosage, is the main metabolite. The enzyme(s) responsible for Valsartan metabolism has not been identified but do not seem to be CYP 450 isozymes. Following intravenous administration, plasma clearance of Valsartan is about 2 L/h, and its renal clearance is 0.62 L/h (about 30% of total clearance).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021283s033lbl.pdf

• https://www.rxlist.com/diovan-drug.htm#dosage

• https://www.practo.com/medicine-info/Valsartan-579-api

• https://go.drugbank.com/drugs/DB00177

• https://www.drugs.com/dosage/Valsartan.html