Valsartan+ Hydrochlorothiazide

Valsartan+ Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class and Thiazide Diuretics.

Valsartan+ Hydrochlorothiazide is approved for treating hypertension (high blood pressure)in adults. It combines valsartan (an angiotensin II receptor blocker) and Hydrochlorothiazide (a diuretic) to reduce blood pressure and more effectively treat hypertension.

Valsartan has a 25% bioavailability and is effectively absorbed from the gastrointestinal system. Similarly, Hydrochlorothiazide is readily absorbed. Within two to four hours of oral dosing, both medications reach peak plasma concentrations. Hydrochlorothiazide is excreted mainly through the kidneys, whereas valsartan is primarily eliminated in the faeces.

The common side effects of Valsartan+ Hydrochlorothiazide include oedema (swelling), headache, dizziness and tiredness.

Valsartan+ Hydrochlorothiazide is available as a tablet for convenient administration.

Valsartan+ Hydrochlorothiazide is available in the United States, Canada, the United Kingdom, India and Australia.

Valsartan+ Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class and Thiazide Diuretics.

Valsartan: Valsartan explicitly prevents angiotensin II from binding to the AT1 receptor in several tissues, including the adrenal gland and vascular smooth muscle. Valsartan inhibits the vasoconstrictor and aldosterone-secreting effects of high blood pressure. Its activity is, therefore, independent of the angiotensin II synthesis pathways. Although the AT2 receptor is present in numerous organs, it is not known to be associated with cardiovascular homeostasis. Valsartan has a 20,000-fold higher affinity for the AT1 receptor than 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.

Protein-bound: 94-95%

Clearance: 0.62 L/hr

Vd: 17 L

Half-life: 6-9 hr

Hydrochlorothiazide: Thiazide diuretic lowers blood pressure and reduces oedema by inhibiting Na reabsorption in distal renal tubules, increasing Na and water excretion.

The Onset of action of Hydrochlorothiazide occurs within 2 hours of its administration.

The Duration of Action for Hydrochlorothiazide in the body is approximately 6-12 hours.

The Tmax was found within 1-5 hours, and Cmax 70 to 490 ng/mL following the administration of Hydrochlorothiazide.

Protein Bound: 68%

Clearance: 335 mL/min

Vd: 3.6-7.8 L/kg

Half-Life: 6-15 hr

Synergistic Benefits: Valsartan+ Hydrochlorothiazide provides a synergistic approach to managing hypertension. Angiotensin II receptor blocker (ARB) Valsartan relaxes blood arteries. Diuretics like Hydrochlorothiazide help the body flush out extra water and salt. They exert more overall control by lowering blood pressure through various mechanisms. An efficient and comprehensive strategy for managing hypertension is provided by this combination, which reduces the risk of cardiovascular events, including strokes and heart attacks, while also minimizing fluid retention.

When one medication fails to regulate your blood pressure, these medications are combined. Thus, they work synergistically to help lower blood pressure and manage hypertension effectively.

Data Onset of action of Valsartan is shown within a few hours, while Hydrochlorothiazide's diuretic effect may take a few hours post-administration

Data duration of action of Valsartan+ Hydrochlorothiazide effects can last up to 24 hours—following oral administration.

The Data of Tmax and Cmax of Valsartan+ Hydrochlorothiazide needs to be established.

Valsartan+ Hydrochlorothiazide is available in tablets.

Tablets: To be swallowed whole with water/liquid.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

• Valsartan is approved to treat hypertension and heart failure and prevent the death that follows a heart attack. Valsartan can be used either on its own or in combination with other drugs.

• Hydrochlorothiazide may also be used to treat patients with diabetes insipidus and prevent kidney stones in those patients with high calcium levels in their blood.

• Valsartan+Hydrochlorothiazide combination is used to treat hypertension or high blood pressure. Strokes, heart attacks, and renal issues can all be prevented by lowering excessive blood pressure.

• This combination may also reduce the risk of cardiovascular events such as strokes and heart attacks in patients with hypertension and other risk factors.

Valsartan+ Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class and Thiazide Diuretics.

Valsartan: Angiotensin II Receptor Blocker Valsartan is an antihypertensive medication that inhibits angiotensin II from binding to the AT1 receptor, hence suppressing the angiotensin II's vasoconstrictor and aldosterone-secreting effects. Thus, blood arteries relax, enabling greater blood flow to treat hypertension.

Hydrochlorothiazide: People with congestive heart failure, liver cirrhosis, renal problems, or oedema brought on by using steroids or oestrogen and hypertension are treated with Hydrochlorothiazide.

The Valsartan + Hydrochlorothiazide combination benefits hypertension by effectively lowering blood pressure and related conditions through distinct mechanisms of action. Valsartan blocks the action of angiotensin II, relaxing blood vessels. Hydrochlorothiazide is a diuretic that reduces fluid retention. Together, they provide comprehensive blood pressure control, reduce the risk of cardiovascular events, and offer convenience with a single-pill regimen, promoting medication adherence and patient well-being.

Valsartan+ Hydrochlorothiazide is approved for use in the following clinical indications:

• Patients who have already been titrated on the individual components, Hydrochlorothiazide and valsartan, are indicated for therapy of hypertension.

• This combination therapy might help to lower the risk of cardiovascular events, including heart attacks and strokes, in patients with hypertension and other cardiovascular risk factors.

• It is indicated to be used in individuals who would benefit from combination therapy or as the first line of treatment for patients likely to require many medications to achieve their blood pressure goals.

• To prevent accumulation of excess fluid in the body's tissues. People who endure fluid retention due to several ailments will find this effect very beneficial.

Orally: Valsartan+ Hydrochlorothiazide is available as a tablet that can be taken orally. Valsartan+ Hydrochlorothiazide should be taken on an empty stomach or with food. It is best to take this medication at least 4 hours before your bedtime, and advised to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Valsartan+ Hydrochlorothiazide has various strengths, such as

80mg+ 12.5mg, 160mg+12.5mg, 320mg+ 12.5mg, 160mg+25mg or 320mg +25mg

Dosage Adjustment for Adult Patients

Hypertension

One tablet, used orally once a day, containing 80–160 mg of valsartan and 12.5–25 mg of Hydrochlorothiazide, with a maximum daily dose of 320 mg of valsartan and 25 mg of Hydrochlorothiazide.

Valsartan+ Hydrochlorothiazide is available in the form of Oral tablets.

Valsartan+ Hydrochlorothiazide should be used in treating hypertension, along with appropriate dietary restrictions.

Avoid consumption of a high-salt or high-sodium diet while taking Hydrochlorothiazide.

High caffeine intake may affect blood pressure. Consider moderating caffeine consumption.

Avoid excessive consumption of alcohol, grapefruit or grapefruit juice while taking valsartan, as it may interact with the medication.

Hydrochlorothiazide can lead to potassium loss. To prevent low potassium levels, consider including potassium-rich foods like bananas, oranges, potatoes, and spinach.

While taking this combination, it is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins.

The dietary restriction should be individualized as per patient requirements.

Valsartan+ Hydrochlorothiazide may be contraindicated in patients with the following conditions:-

• Hypersensitivity (drug component such as valsartan, hydrochlorothiazide or sulfonamide-derived substance)

• Anuria

• Pregnancy: Significant risk of fetal/neonatal morbidity and death during the second and third trimesters of pregnancy

• Co-administer aliskiren in patients with diabetes mellitus

• Severe Renal impairment (<30 mL/min)

• History of Angioedema

• Hypotension

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• It might result in hypotension, especially if the volume or salt levels are low (fix before starting)

• Syncope or symptomatic hypotension may happen.

• Patients who have significant renal or hepatic impairment should be titrated cautiously.

• Patients with diabetes, autonomic dysfunction, and geriatric patients should start combination treatment with two antihypertensive medications cautiously to reduce the risk of orthostatic hypotension.

• The medication's antihypertensive effects may be increased in post-sympathectomy patients.

• Photosensitivity could happen; advise patients to use sunblock and get frequent skin cancer screenings

• Use thiazides cautiously if individuals have mild to moderate liver damage or progressing liver disease.

• Maintain fluid and electrolyte imbalance

• Monitor for deteriorating heart failure, which might cause oliguria or progressive azotemia.

• When treating individuals with hypercalcemia, Hydrochlorothiazide may cause blood calcium levels to rise and reduce urine calcium excretion.

• Compared to monotherapy, dual blockade of the renin-angiotensin system with ARBs, ACE inhibitors, or aliskiren increases the risk of hypotension, Hyperkalemia, and impaired renal function (including acute renal failure).

• Hydrochlorothiazide may impair glucose tolerance, elevated blood uric acid levels, raise cholesterol and triglyceride levels, and aggravate hyperuricemia and gout in hypersensitive individuals.

• Monitor acute hyperkalemia. Hyperkalemia, especially when combined with potassium-sparing diuretics, potassium supplements, or salt replacements, concomitant hydrochlorothiazide medication may lessen the incidence of this effect.

• Systemic lupus erythematosus has been seen to be aggravated or exacerbated by thiazide diuretics.

• When giving patients Hydrochlorothiazide, be extra cautious if they have a history of allergies or bronchial asthma since these patients are more likely to experience hypersensitivity responses, which can happen to any individual. However, they are more probable in these patients.

It is unsafe to consume alcohol with Valsartan+ Hydrochlorothiazide

Avoid use during breastfeeding.

Avoid or minimize the consumption of grapefruit or grapefruit juice. Caution should be taken while consuming caffeine, potassium or sodium-rich foods, and alcohol, as it may interact with the medication.

The adverse reactions related to Valsartan+ Hydrochlorothiazide can be categorized as

• Common: Dizziness, hypotension, swelling of the ankles, fatigue and Hyperkalemia
• Less Common: Muscle cramps, blurred vision, altered kidney function and abnormal liver function tests.
• Rare: Allergic reactions, Angio oedema and thrombocytopenia.

Reports on Post-marketing

Hypersensitivity: Rare urticaria and angioedema

Digestive: Hepatitis (rare), elevated liver enzymes

Renal dysfunction and renal failure

Clinical laboratory testing: Hyperkalemia

Alopecia, bullous dermatitis: Dermatologic

Blood and lymphatic system: Rare thrombocytopenia

Vascular: Vasculitis

Musculoskeletal system: rhabdomyolysis

Hydrochlorothiazide: melanoma-free skin cancer

The clinically relevant drug interactions of Valsartan+ Hydrochlorothiazide are briefly summarized here.

• Lithium: Lithium toxicity and blood lithium concentration increase when angiotensin II receptor antagonists, such as Valsartan, are used concurrently with lithium. When using lithium concurrently, maintain a close watch on the blood levels.
• Agents Increasing Serum Potassium: Valsartan may cause increases in serum potassium when used concurrently with other renin-angiotensin system blockers, potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes, or other medications that may raise potassium levels (such as heparin). It is advised to monitor serum potassium levels if co-medication is essential.
• Antidiabetic drugs (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.
• Cholestyramine and colestipol resins: Cholestyramine and colestipol resins bind Hydrochlorothiazide and reduce it by up to 85% and 43%, respectively, in the gastrointestinal system.
• Non-steroidal anti-inflammatory drugs: Non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the intended benefits of diuretics like Hydrochlorothiazide when used concurrently. A thorough observation is recommended to determine how effective a diuretic is in this combination. Combining NSAIDs with angiotensin II receptor antagonists, such as valsartan, may cause renal problems in older individuals, those with low fluid volume, or patients with impaired kidney function. These problems, however, may be treatable. When taking valsartan plus NSAIDs, such as selective COX-2 inhibitors, it is advisable to have regular renal function tests since NSAIDs might decrease valsartan's antihypertensive impact.

• Nausea
• Taste change
• Diarrhea
• Upset stomach
• Dizziness
• Decreased blood pressure
• Headache
• Fatigue
• Increased blood lipid level
• Electrolyte imbalance
• Increased blood uric acid
• Glucose intolerance

Valsartan+ Hydrochlorothiazide should be prudent in the following group of special populations.

• Pregnancy

Valsartan: Pregnancy Category D; Use in LIFE-THREATENING situations when no better alternatives are available.

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. A patient should be warned of the potential risk to the baby if Valsartan is used during pregnancy or if she gets pregnant while taking the medication. Angiotensin II receptor antagonists like Valsartan and angiotensin-converting enzyme inhibitors produce similar effects on the renin-angiotensin system. ACE inhibitor use throughout pregnancy's second and third trimesters 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. When a patient using Valsartan becomes pregnant, the doctor must stop prescribing the medication immediately. Based on the patient's exposure to Valsartan during pregnancy, the doctor must explain any possible hazards to the foetus (first trimester only or later). It is necessary to perform an ultrasound check if exposure happens beyond the first trimester. Serial ultrasonography exams should be conducted 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.

Hydrochlorothiazide: Pregnancy Category B; Could be acceptable. Either no danger has been shown by animal research, but human studies have not been conducted, or some risk has been shown by animal studies but not by human studies.

Teratogenic Effects

Thiazides can cross the placenta, and the quantities in the umbilical vein are similar to those in maternal plasma. Like other diuretics, hydrochlorothiazide can result in placental hypoperfusion. With observed amounts up to 19 times higher than in umbilical vein plasma, it accumulates in the amniotic fluid. Pregnancy-related thiazide use has been linked to an increased risk of thrombocytopenia or jaundice in the foetus or newborn. These medications shouldn't be used to treat hypertension in pregnant women since they don't stop or change the progression of EPH (Oedema, Proteinuria, Hypertension) or Gestosis (pre-eclampsia). It is recommended to avoid using Hydrochlorothiazide during pregnancy for any other conditions, such as heart disease.

Due to the high potential risk to the foetus, avoid the Valsartan + Hydrochlorothiazide combination when pregnant. If pregnancy is detected, stop immediately according to pregnancy recommendations. High blood pressure during pregnancy raises the chances of complications for both the mother and the baby, including conditions like pre-eclampsia and premature birth. Close monitoring and proper management are essential.

When using this drug while expecting or planning a pregnancy, use caution and consult a physician.

• Lactating Mothers

Valsartan: It's uncertain if human milk contains Valsartan secretions. Valsartan was found in nursing rats' milk, although it's possible that the drug concentrations aren't necessarily representative of those seen in human breast milk. A choice should be made on whether to discontinue breastfeeding or the medicine since numerous medications are secreted in human milk and because Valsartan may have adverse effects on nursing infants, taking into account the relevance of the drug to the mother.

Hydrochlorothiazide: Breast milk contains thiazide excretion. Considering the significance of the medication to the mother, a choice should be taken on whether to stop nursing or to stop taking Hydrochlorothiazide due to potential significant adverse effects in nursing infants.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

Neonates with a history of in-utero utero exposure to drugs should be closely monitored for hypotension, oliguria, and Hyperkalemia. If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be necessary to treat hypotension and/or the replacement of impaired renal function.

• Geriatric Use

Geriatric people should have their use of Valsartan+ Hydrochlorothiazide closely monitored. Elderly people may be more vulnerable to adverse drug reactions and drug interactions. It is essential to closely monitor liver and kidney function and any possible medication interactions. Depending on the individual's medical situation and drug regimen, dosage modifications may be required. It's crucial to monitor patients and consult with medical professionals regularly.

Dosage Adjustment in Kidney Impairment Patient

CrCl >30 mL/min: No dosage adjustment is necessary for mild to moderate

CrCl 30 mL/min or less: Avoid usage. With severe renal impairment, loop diuretics are recommended over thiazides because they are less likely to cause azotemia.

This combination should be used cautiously in severe cases, and alternative treatments may be considered.

Dosage Adjustment in Hepatic Impairment Patient

Moderate to mild impairment: Specific dosage adjustments may not be necessary.

Severe hepatic impairment: Caution is advised, and regular monitoring of liver function is recommended.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Valsartan+ Hydrochlorothiazide. Overconsumption of this combination could lead to symptoms such as severe hypotension (low blood pressure) and electrolyte imbalances.

There is no specific antidote or treatment for excessive intake of Valsartan+ Hydrochlorothiazide. However, immediate medical attention is essential.

Valsartan+ Hydrochlorothiazide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should be given, addressing any symptoms that persist or worsen. Activated charcoal may also be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring the patient's vital signs and correcting any electrolyte imbalances, especially Hyperkalemia (high potassium levels), is crucial. Physical treatment might be added if necessary.

Pharmacodynamic of Valsartan + Hydrochlorothiazide

Valsartan: Valsartan inhibits angiotensin II infusions from having a pressure effect. An oral dosage of 80 mg hampers the pressor development to a peak of around 80%, with about 30% of the inhibition remaining for 24 hours. The impact of higher dosages is not currently known. Patients with hypertension have a 2- to 3-fold increase in plasma renin and a subsequent increase in the plasma levels of angiotensin II when the negative feedback of angiotensin II is removed. After the treatment of Valsartan, there were very slight drops in plasma aldosterone and almost no changes in serum potassium. Valsartan demonstrated no clinically meaningful effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow in trials including repeated doses of hypertensive individuals with stable renal insufficiency and patients with renovascular hypertension. Valsartan did not significantly alter total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid in investigations with hypertensive individuals that involved several doses.

Hydrochlorothiazide: Thiazides have been shown to have acute antihypertensive effects secondary to a natriuretic impact on blood volume and cardiac output; however, a direct vasodilatory mechanism has also been hypothesized. Plasma volume returns to normal after prolonged dosing, although peripheral vascular resistance is reduced. Hydrochlorothiazide has an antihypertensive impact. However, the specific mechanism is unknown. Normal blood pressure is unaffected by thiazides. Within two hours of the dose, the effects start to manifest, reaching their peak at around four hours and lasting up to 24 hours.

Pharmacokinetics of Valsartan+ Hydrochlorothiazide

Absorption

Valsartan: Following a single oral dosage, the antihypertensive activity of valsartan begins to work in approximately two hours and typically peaks in most patients between four and six hours later. Consuming food lowers the peak plasma concentration and exposure to oral valsartan by around 50% and 40%, respectively. After repeated dosing, plasma valsartan does not appreciably accumulate.

Hydrochlorothiazide: Hydrochlorothiazide is well absorbed (65% to 75%) after oral administration. Absorption of Hydrochlorothiazide is lower in patients with congestive heart failure.

Distribution

Valsartan: Valsartan is not distributed widely into tissues, as evidenced by the fact that its steady-state volume of distribution is limited (17 L) following administration. Ninety-five per cent of the blood proteins, mainly serum albumin, are bound to valsartan.

Hydrochlorothiazide: The given dosage has a linear relationship with plasma concentrations. Compared to plasma, whole blood has hydrochlorothiazide concentrations of 1.6–1.8 times greater. Serum protein binding has been estimated to range from 40% to 68%. According to reports, the plasma elimination half-life is between 6 and 15 hours.

Metabolism

Valsartan: It is Minimally metabolized in the liver. The primary metabolite of valsartan is valeryl 4-hydroxy valsartan, which makes up around 9% of the dose. Although the enzyme(s) involved in the metabolism of valsartan have not been discovered, they do not appear to be CYP 450 isozymes.

Hydrochlorothiazide: Hydrochlorothiazide is eliminated primarily by renal pathways.

Excretion

Valsartan: When given orally, most of the valsartan doses are excreted in the faeces (83% of the amount) and urine (13%). Only approximately 20% of the dosage is retrieved as metabolites; most drug remains unaltered.

Hydrochlorothiazide: More than 95% of the absorbed dosage is excreted in urine as an unaltered substance at oral doses of 12.5 to 100 mg, with 55% to 77% of the given amount appearing in the urine.

Therapeutic benefits of a combination of Valsartan + Hydrochlorothiazide

• Valsartan + Hydrochlorothiazide is primarily prescribed to treat hypertension (high blood pressure) as it provides a potent antihypertensive effect. Valsartan is an angiotensin II receptor blocker (ARB), which relaxes blood vessels, and Hydrochlorothiazide is a diuretic that helps the body remove excess sodium and water. They efficiently decrease blood pressure by reducing peripheral vascular resistance and blood volume.
• This medicine combination lowers blood pressure, which reduces the risk of cardiovascular events, including heart attacks and strokes. It protects the heart and blood arteries from the adverse effects of persistent hypertension by maintaining optimal blood pressure levels.
• Edoema, the buildup of extra fluid in the body's tissues, is another condition for which Valsartan + Hydrochlorothiazide is recommended. Hydrochlorothiazide's diuretic effect helps to reduce fluid retention, alleviating the oedema caused by several medical disorders.

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