Candesartan+ Hydrochlorothiazide

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

Candesartan+ Hydrochlorothiazide is approved for treating adults' hypertension (high blood pressure). It combines Candesartan (an angiotensin II receptor blocker) with Hydrochlorothiazide (a diuretic) to lower blood pressure by relaxing blood vessels and decreasing fluid retention, helping to manage and control hypertension.

Candesartan has a 15% absolute bioavailability and is absorbed slowly, with peak levels reached in 3-4 hours from the gastrointestinal system, while Hydrochlorothiazide is absorbed rapidly, with peak levels in 2 hours. Candesartan+ Hydrochlorothiazide is metabolized in the liver and excreted mainly through the kidneys via urine.

The common side effect of Candesartan+ Hydrochlorothiazide is dizziness. Other side effects include tiredness, nausea, diarrhoea, headache, and low blood pressure.

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

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

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

Candesartan: Candesartan inhibits angiotensin II's vasoconstrictor and aldosterone-secreting activities by blocking angiotensin II binding to the AT1 receptor in various tissues, including vascular smooth muscle and the adrenal gland. Its action is thus independent of the angiotensin II production routes. AT2 receptors are also found in numerous organs, although they are not linked to cardiovascular homeostasis. Candesartan has a substantially higher affinity for the AT1 receptor (>10,000-fold) than the AT2 receptor.

The Onset of action of Candesartan occurs within 2 hours of being administered.

Candesartan's duration of action in the body is approximately 24 hours.

The Tmax was found 4 hours after Candesartan administration, and the Cmax was approximately 872 ng/mL.

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: Candesartan + Hydrochlorothiazide provides a synergistic approach to managing hypertension.

Candesartan works by relaxing and expanding blood arteries, allowing the blood to flow freely through the blood vessels. This will cause the heart rate to fall. Hydrochlorothiazide is a diuretic (water pill) that increases urine production and lowers blood pressure. This combination reduces fluid retention, lowers heart strain, and improves blood pressure control. It is an effective medication for lowering the risk of heart disease, stroke, and other hypertensive complications.

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 Candesartan + Hydrochlorothiazide effects is shown within a few hours post-administration

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

The Data of Tmax of Candesartan+ Hydrochlorothiazide is about 3-4 hours after administration.

The Data of Cmax of Candesartan+ Hydrochlorothiazide is typically about 3-4 hours after administration.

Candesartan+ 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.

• To treat high blood pressure in adults and children over one year, Candesartan may be used alone or with other medications. Additionally, it is used to treat congestive heart failure, a disease when the heart cannot adequately pump blood to other body areas.

• Patients with diabetes insipidus and those with excessive blood calcium levels may benefit from hydrochlorothiazide treatment and the prevention of kidney stones.

• Candesartan+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.

• In individuals with hypertension and other health risk factors, this combination may also lower the risk of cardiovascular events such as heart attacks and strokes.

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

Candesartan: Candesartan is an antihypertensive medication that belongs to the Angiotensin II Receptor Blocker class. Candesartan inhibits angiotensin II's vasoconstrictor and aldosterone-secreting actions by specifically inhibiting angiotensin II binding to the AT1 receptor in various tissues. Candesartan is an antihypertensive medication used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy, and diabetic nephropathy.

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 Candesartan + Hydrochlorothiazide combination benefits hypertension by effectively lowering blood pressure and related conditions through distinct mechanisms of action. Candesartan 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.

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

• It is indicated to lower blood pressure and treat hypertension. Lowering blood pressure may help reduce the risk of fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions.
• This combination therapy might help to reduce the risk of cardiovascular events, including strokes and heart attacks, 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.

Orally: Candesartan+ Hydrochlorothiazide is available as a tablet that can be taken orally. Candesartan+ 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.

This combination may also be administered with other antihypertensive agents.

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

Candesartan+ Hydrochlorothiazide has various strengths, such as 16mg+12.5mg, 32mg+12.5mg, 32mg+25mg

Dosage Adjustment for Adult Patients

Hypertension

One tablet, used orally once a day, containing 16-32 mg of Candesartan and 12.5–25 mg of Hydrochlorothiazide, optimum therapeutic effect expected within four weeks.

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

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

While taking Hydrochlorothiazide, avoid consumption of a high-salt or high-sodium in the diet and be cautious of high-sodium processed foods.

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

Avoid excessive consumption of alcohol, grapefruit or grapefruit juice while taking Candesartan, as it may interact with the effectiveness of these medications.

Hydrochlorothiazide can increase potassium levels in the blood, so it's advisable to maintain a balanced intake of potassium-rich foods like bananas, oranges, and potatoes.

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.

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

• Hypersensitivity (drug components such as Candesartan, 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
• Gout
• Hypercalcemia Refractory
• Hypokalemia
• Severe hepatic dysfunction and/or cholestasis
• As an initial treatment

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, elevate 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.

Avoid use during breastfeeding.

Unsafe to use during pregnancy.

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 Candesartan+ Hydrochlorothiazide can be categorized as

• Common: Dizziness, hypotension, swelling of the ankles, fatigue and Hyperkalemia
• Less Common: Muscle cramps, hyperuricemia and altered kidney function
• Rare: Allergic reactions, hyponatremia and Severe skin reactions, such as Stevens-Johnson syndrome (very rare)

Reports on Post-marketing

Hydrochlorothiazide: melanoma-free skin cancer

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

• Lithium: Lithium toxicity and blood lithium concentration increase when angiotensin II receptor antagonists, such as Candesartan, are used concurrently with lithium. When using lithium concurrently, maintain a close watch on the blood levels.
• Renin-Angiotensin System (RAS) Combination Blockade: Dual RAS inhibition with ACE inhibitors, aliskiren, or angiotensin receptor blockers is linked with a higher risk of hyperkalemia, hypotension, and changes in renal function, including acute renal failure, compared to monotherapy. In most cases, candesartan combined with an ACE inhibitor and a mineralocorticoid receptor antagonist is not indicated. Patients taking Candesartan or other RAS inhibitors should closely monitor their blood pressure, renal function, and electrolytes.
• Agents Increasing Serum Potassium: Candesartan used with potassium-sparing diuretics, potassium supplements, potassium-containing salt replacements, or other medicines that boost serum potassium levels may result in Hyperkalemia. In such situations, serum potassium levels should be monitored.
• 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. In elderly patients, volume-depleted (including those on diuretic therapy), or have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Candesartan, may lead to a deterioration in renal function, including potential acute renal failure. These effects are generally reversible. Patients receiving Candesartan and NSAIDs should have their renal function checked regularly. NSAIDs, particularly selective COX-2 inhibitors, may reduce the antihypertensive action of angiotensin II receptor antagonists such as Candesartan.

• Dizziness
• Infection of the upper respiratory tract
• Backache
• Flu-like symptoms

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

• Pregnancy:

Candesartan: Pregnancy Category: C (1st trimester); D (2nd and 3rd trimesters)

When used during the second or third trimester of pregnancy, Candesartan, 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, Candesartan has the potential to harm the foetus.

Hydrochlorothiazide: Pregnancy Category B

Studies in which pregnant mice and rats received dosages of up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, orally during their respective periods of major organogenesis did not show any signs of harm to the foetus.

Thiazides can penetrate the placenta and result in placental hypoperfusion. They accumulate in the amniotic fluid and can cause thrombocytopenia or foetal or neonatal jaundice. Avoid use

Certain medications affecting the renin-angiotensin system, used by pregnant women in the later stages of pregnancy, can lead to low amniotic fluid levels. This may cause issues like reduced fetal kidney function, lung problems, skeletal deformities, low blood pressure, and even death.

Due to the high potential risk to the foetus, avoid the Candesartan + 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

Minimal is known about the prevalence of these medicines in human milk and how they affect newborns. Hydrochlorothiazide and Candesartan can be detected in animal and human milk, respectively. It is not advised to breastfeed while taking this medication combination since there might be severe side effects in breastfed infants, considering the importance of the drug to the mother.

• 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.

• Geriatric Use

Geriatric people should have their use of Candesartan+ 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

Mild to Moderate Kidney Impairment (eGFR 30-89 mL/min/1.73 m²): There is no requirement to change the dose.

Severe Kidney Impairment (eGFR less than 30 mL/min/1.73 m²): Avoid usage. Alternative treatments should be considered.

End-Stage Renal Disease (ESRD) or Hemodialysis: Avoid usage. Alternative treatments should 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 with lower doses of Candesartan + Hydrochlorothiazide may be required. Regular monitoring of liver function is recommended.

End-Stage Liver Disease: This combination of medications may not be recommended.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Candesartan+ Hydrochlorothiazide. Overconsumption of this combination could lead to symptoms such as fast heartbeat, severe dizziness and fainting.

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

Candesartan+ 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), by administrating Intravenous (IV) fluids. Physical treatment might be added if necessary.

Pharmacodynamic of Candesartan + Hydrochlorothiazide

Candesartan: Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After one week of once-daily dosage with 8 mg of Candesartan, the pressor effect was decreased by roughly 90% at peak, with approximately 50% suppression remaining for 24 hours. After single and repeated administrations of Candesartan to healthy people, hypertension patients, and heart failure patients, plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increased dose-dependent. In healthy patients, repeated Candesartan treatment did not affect ACE activity. The once-daily treatment of up to 16 mg of Candesartan in healthy participants did not affect plasma aldosterone concentrations. In contrast, hypertensive patients had a significant decrease in plasma aldosterone concentrations when 32 mg of Candesartan was provided. Despite its influence on aldosterone secretion, Candesartan had minimal effect on serum potassium.

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 Candesartan+ Hydrochlorothiazide

Absorption

Candesartan: The absolute bioavailability of Candesartan after ingestion of the Candesartan cilexetil prodrug was estimated to be 15%. Peak plasma concentrations (Cmax) of Candesartan are attained 3 to 4 hours post oral administration of Candesartan cilexetil. Food containing a high fat content does not influence the bioavailability of Candesartan cilexetil.

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

Distribution

Candesartan: Candesartan has a volume distribution of 0.13 L/kg. Candesartan is well attached to plasma proteins (>99%) and does not cross the blood-brain barrier. Protein binding continues at Candesartan plasma values considerably above the therapeutic dosing range.

Hydrochlorothiazide: The given dosage has a linear relationship with plasma concentrations. Whole blood has hydrochlorothiazide concentrations of 1.6–1.8 times more significant than plasma. 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

Candesartan: Oral Candesartan undergoes minimal hepatic metabolism. Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg.

Hydrochlorothiazide: Hydrochlorothiazide is eliminated primarily by renal pathways.

Excretion

Candesartan: When candesartan is taken orally, around 26% of the dosage is eliminated in urine unaltered. Urine and faeces recover around 33% and 67% of the radioactivity after an oral dosage of 14C-labeled Candesartan cilexetil, respectively. Candesartan is eliminated partially by biliary excretion.

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 Candesartan + Hydrochlorothiazide

• Candesartan + Hydrochlorothiazide is primarily prescribed to treat hypertension (high blood pressure) as it provides a potent antihypertensive effect. Candesartan is an angiotensin II receptor blocker, 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 combination improves blood pressure regulation, making it an effective hypertension treatment.
• Blood pressure control is essential in lowering the risk of cardiovascular events such as heart attacks, strokes, and heart failure. Candesartan + Hydrochlorothiazide decreases the strain on the heart and reduces the risk of hypertension problems, thereby improving overall cardiovascular health.
• Hydrochlorothiazide's diuretic activity helps eliminate excess fluid and sodium in the body, which is especially advantageous for people prone to oedema (swelling) owing to fluid retention. This impact reduces swelling and pain caused by illnesses such as congestive heart failure.

• Bönner G, Landers B, Bramlage P. Candesartan cilexetil/hydrochlorothiazide combination treatment versus high-dose candesartan cilexetil monotherapy in patients with mild to moderate cardiovascular risk (CHILI Triple T). Vasc Health Risk Manag. 2011;7:85-95. doi: 10.2147/VHRM.S17004. Epub 2011 Feb 17. PMID: 21415922; PMCID: PMC3049544.
• Baumgart P, Naudts I, Kiel G. Introducing Candesartan 32 mg plus hydrochlorothiazide 25 mg in previously untreated patients with severe essential hypertension. Pragmat Obs Res. 2011 Apr 29;2:5-12. Doi: 10.2147/POR.S18303. PMID: 27774009; PMCID: PMC5045001.
• Karlson BW, Zetterstrand S, et al. A dose-response analysis of candesartan-hydrochlorothiazide combination therapy in patients with hypertension. Blood Press. 2009;18(3):149-56. doi: 10.1080/08037050902975155. PMID: 19462314

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