Candesartan

Candesartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker.

Candesartan is approved for the treatment of Hypertension. It is also used to treat congestive heart failure.

The absolute bioavailability of Candesartan was estimated to be 15%. After the oral administration of Candesartan cilexetil, peak plasma concentrations (Cmax) of Candesartan are reached within 3 to 4 hours.The volume of distribution of Candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. Total plasma clearance of Candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When Candesartan is administered orally, about 26% of the dose is excreted unchanged in urine.

Candesartan shows common side effects like arm, back, or jaw pain, chest pain or discomfort, chest tightness or heaviness, cough or hoarseness, fast or irregular heartbeat, joint pain etc

Candesartan is available in the form of Tablet.

Candesartan is available in India, Europe, US, Mexico, Canada, Australia, South Africa and Japan.

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

Candesartan 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. Candesartan has much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor.

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

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

The Tmax was found within 4 hours following the administration of Candesartan and the Cmax was about 87±26 ng/mL.

Candesartan is available in the form of tablets.

Tablets to be swallowed whole with water. Candesartan comes as a tablet to be taken by mouth everyday or every 12 hours.

Candesartan is approved for the treatment of Hypertension. Candesartan is used alone or in combination with other medicines for the treatment of high blood pressure in adults and children above the age of 1 year. It is also used to treat congestive heart failure, a condition in which the heart is unable to pump enough blood to other parts of the body.

Candesartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker. Candesartan 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. Candesartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy.

Candesartan is approved for use in the following clinical indications

• Hypertension

Candesartan is indicated for the treatment of hypertension in adults and as well as for children above 1 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Candesartan may be used alone or in combination with other antihypertensive agents.

• Heart Failure

Candesartan is indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. CANDESARTAN also has an added effect on these outcomes when used with an ACE inhibitor

Although not approved, there have been certain off-label indications. These include:

• Cerebrovascular accident or stroke

Long-term treatment with inhibitors of the renin–angiotensin system, Candesartan has been shown to reduce the risks of cognitive impairment and low quality of life after stroke.

• Diabetic nephropathy

The optimal dose of Candesartan is 16 mg daily for renoprotection, as reflected by short-term reduction in albuminuria, in hypertensive type 2 diabetic patients with nephropathy.

• Left ventricular hypertrophy

Candesartan use was associated with significant regression of LV hypertrophy, and improvement of LV function, symptoms and exercise tolerance.

• Migraine

The mechanism of action of Candesartan as a migraine prophylaxis is not yet known. Candesartan reduces the effects of angiotensin II, which has several effects that may be relevant to migraine, such as direct vasoconstriction, increased sympathetic discharge, and adrenal medullary catecholamine release.

Candesartan is available in the form of tablets.

• Adult Hypertension

Adults and geriatric patients should receive an initial dose of 16 mg once daily. If the patient is volume-depleted, the initial dose should be lowered to 8 mg once daily. The usual dose ranges from 8 to 32 mg/day.

• Paediatric Hypertension

Children above 1 year of age: Candesartan may be administered once daily or divided into two equal doses. Adjust the dosage according to blood pressure response. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Candesartan under close medical supervision and consider administration of a lower dose.

Children 1 To < 6 years of age: The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.20 mg/kg (oral suspension).

Children 6 and above years of age: For those less than 50 kg, the dose range is 2 to 16 mg per day. The recommended starting dose is 4 to 8 mg. For those greater than 50 kg, the dose range is 4 to 32 mg per day. The recommended starting dose is 8 to 16 mg. Doses above 0.4 mg/kg (1 to < 6-year-olds) or 32 mg (6 to < 17-year-olds) have not been studied in pediatric patients. An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with Candesartan.

Children < 1 year of age: must not receive Candesartan for hypertension.

• Adult Heart Failure

The recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.

• Diabetic nephropathy

The optimal dose of Candesartan is 16 mg daily for renoprotection, as reflected by short-term reduction in albuminuria, in hypertensive type 2 diabetic patients with nephropathy.

• Left ventricular hypertrophy

Hypertensive patients treated with Candesartan 16 mg once-daily for 24 weeks demonstrated a significant regression of LVMI, and significant improvements in left ventricular diastolic function were detected in parallel.

• Migraine

Adults should receive 16 mg dose of Candesartan once daily.

Candesartan is available in various strengths as 4mg, 8mg,16mg and 32mg

Candesartan is available in the form of tablets.

Hypertension:

• Potassium Rich Foods: Candesartan may cause high blood potassium levels. Hence, avoid potassium-rich Food while taking this medication.

The dietary restriction should be individualized as per patient requirements.

Candesartan is contraindicated in patients with

• Hypersensitivity
• Severe hepatic impairment
• Do not coadminister with aliskiren in patients has diabetes
• Pregnancy

• Fetal Toxicity

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. 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 Candesartan as soon as possible.

• Morbidity in Infants

Children < 1 year of age must not receive Candesartan for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys.

• Hypotension

Candesartan can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with symptomatic hypotension may require temporarily reducing the dose of Candesartan, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with Candesartan.

• Major Surgery/Anaesthesia

Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including Candesartan, due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

• Impaired Renal Function

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

• Hyperkalemia

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Concomitant use of Candesartan with drugs that increase potassium levels may increase the risk of hyperkalemia. Monitor serum potassium periodically.

Consumption of alcohol with Candesartan can lower blood pressure resulting in drowsiness, dizziness or fainting; therefore, is better to avoid alcohol while taking Candesartan.

It is not known whether Candesartan is excreted in human milk, but Candesartan has been shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue Candesartan, taking into account the importance of the drug to the mother.

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

Avoid use in pregnancy. When pregnancy is detected, discontinue the use of Candesartan as soon as possible. It acts directly on the renin-angiotensin system and can cause injury and death to the developing fetus.

The food warning while consuming Candesartan is that it should be taken in concentrations during its consumption

Potassium Rich Foods: Candesartan may cause high blood potassium levels. Hence, avoid potassium-rich Food while taking this medicine

The adverse reactions related to Candesartan can be categorized as

Common Adverse effects

• Dizziness
• Diarrhea
• Fatigue
• Abdominal pain

Less Common Adverse effects

• Nausea
• Coughing
• Back pain

Rare adverse effects

• Peripheral edema
• Arthralgia
• Pruritus
• Skin rash
• Urticaria

• Agents Increasing Serum Potassium

Co-administration of Candesartan with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

• Lithium

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

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

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Candesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Candesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including Candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

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

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Triple combination of Candesartan with an ACE-inhibitor and a mineralocorticoid receptor antagonist is generally not recommended. Closely monitor blood pressure, renal function and electrolytes in patients on Candesartan and other agents that affect the RAS.

The common side effect of Candesartan includes the following

Major side effect

• Trouble sleeping
• Back pain
• Irregular heartbeat
• Hypotension
• Headache

Minor side effect

• Hypersensitivity
• Decrease in blood cell count
• Kidney Impairment
• Shortness of breath

Pregnancy

• Pregnancy Category D

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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Candesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Candesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Candesartan for hypotension, oliguria, and hyperkalemia.

• Nursing Mothers

It is not known whether Candesartan is excreted in human milk, but Candesartan has been shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue Candesartan, taking into account the importance of the drug to the mother.

• Pediatric Use

Neonates with a history of in utero exposure to Candesartan: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. The antihypertensive effects of Candesartan were evaluated in hypertensive children above year of age in randomized, double-blind clinical studies. The pharmacokinetics of Candesartan have been evaluated in pediatric patients above 1 year of Children < 1 year of age must not receive Candesartan for hypertension

No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of Candesartan cilexetil. In mice given single oral doses of the primary metabolite, Candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.

The most likely manifestation of overdosage with Candesartan would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Candesartan cannot be removed by hemodialysis.

Pharmacodynamics:

Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once daily dosing with 8 mg of Candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours. Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of Candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. ACE activity was not altered in healthy subjects after repeated Candesartan cilexetil administration. The oncedaily administration of up to 16 mg of Candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of Candesartan cilexetil was administered to hypertensive patients. In spite of the effect of Candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed.

• Hypertension Adults

In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA1c.

• Heart Failure

In heart failure patients, Candesartan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.

Pharmacokinetics:

• Absorption

Following administration of the Candesartan cilexetil prodrug, the absolute bioavailability of Candesartan was estimated to be 15%. After the oral administration of Candesartan cilexetil, peak plasma concentrations (Cmax) of Candesartan are reached within 3 to 4 hours. Food with a high fat content has no effect on the bioavailability of Candesartan from Candesartan cilexetil.

• Distribution

The volume of distribution of Candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at Candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that Candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that Candesartan passes across the placental barrier and is distributed in the fetus.

• Metabolism and Excretion

Total plasma clearance of Candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When Candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of 14C-labeled Candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of 14C-labeled Candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of Candesartan.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020838s036lbl.pdf

• https://www.ncbi.nlm.nih.gov/books/NBK519501/#article-18808.s4

• https://www.rxlist.com/atacand-drug.htm#side_effects

• https://go.drugbank.com/drugs/DB00796

• https://www.drugs.com/atacand.html

• https://www.practo.com/medicine-info/candesartan-582-api