Candesartan

Pharmacological properties

Angiotensin ii, the primary vasoactive hormone of the renin-angiotensin-aldosterone system, plays a role in the pathophysiology of arterial hypertension, heart failure, and other cardiovascular disorders. the main physiological effects of angiotensin ii, such as narrowing of blood vessels, stimulation of aldosterone secretion, regulation of salt and water homeostasis, and stimulation of cell growth, are mediated through the receptor type 1 (at1).

Candesartan Cilexetil is a prodrug suitable for oral use. Candesartan is rapidly converted to the active substance by ester hydrolysis during absorption in the digestive tract. Candesartan is an angiotensin II receptor antagonist selective for AT receptors₁, with strong binding to the receptor and slow dissociation with it. Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and destroys bradykinin. There is no effect on ACE and potentiation of bradykinin or substance P. In controlled clinical trials, in which candesartan was compared with ACE inhibitors, the incidence of coughing was lower in patients receiving candesartan cilexetil. Candesartan does not bind or block other hormone receptors or ion channels, which play an important role in cardiovascular regulation. Angiotensin II (AT) receptor antagonism₁) leads to a dose-dependent increase in the level of plasma renin, angiotensin I and II, as well as to a decrease in the concentration of aldosterone in blood plasma.

Arterial hypertension

In hypertension, candesartan leads to a dose-dependent long-term decrease in blood pressure. Antihypertensive activity is due to a decrease in systemic peripheral resistance, which is not accompanied by a reflex increase in heart rate. Nothing indicates serious or increased hypotension after taking the first dose or a reactive effect after discontinuation of treatment.

After taking a single dose of candesartan cilexetil, the onset of the antihypertensive effect occurs within 2 hours. With continuous therapy, the maximum decrease in blood pressure with any dose is achieved for 4 weeks and is maintained with prolonged treatment. According to meta-analysis, the average additional effect of increasing the dose from 16 to 32 mg once a day was negligible. Given the interindividual variability in some patients, a higher than average effect is possible. When candesartan cilexetil is used once a day, an effective and uniform decrease in blood pressure is achieved within 24 hours with a slight difference between the effects of the maximum and minimum doses.

Candesartan increases renal blood flow and / or does not affect the glomerular filtration rate, or increases it, while vascular resistance and filtration fraction are reduced. In patients with hypertension and type II diabetes mellitus, 8-16 mg candesartan cilexetil therapy for 12 weeks did not cause a side effect regarding blood glucose or lipid profile.

Heart failure

Treatment with candesartan cilexetil reduces mortality and hospitalization due to heart failure and eliminates symptoms in patients with impaired systolic function of the left ventricle.

The positive effect of candesartan on reducing mortality due to cardiovascular disease or the frequency of first hospitalization due to chronic heart failure (CHF) was unchanged regardless of age, gender and concomitant treatment. Candesartan was also effective in patients who simultaneously took both β-adrenergic blockers and ACE inhibitors, a positive effect was achieved regardless of whether the patient took ACE inhibitors at the recommended dose.

In patients with heart failure and impaired systolic function of the left ventricle (left ventricular ejection fraction ≤40%), candesartan reduces systemic vascular resistance and pulmonary capillary pressure, increases renin activity and the concentration of angiotensin II in blood plasma, and also reduces aldosterone levels.

Absorption and distribution

After oral administration, candesartan cilexetil is converted into the active substance candesartan. Absolute bioavailability is 40%. Middle C_max in blood serum is achieved 3-4 hours after taking the drug, increasing linearly with increasing doses within the therapeutic dose. Differences in pharmacokinetics associated with sexual differences were not noted. Eating does not have a significant effect on an indicator of candesartan such as AUC. Candesartan is largely (99%) bound to plasma proteins. The apparent volume of distribution is 0.1 l / kg body weight.

Metabolism and excretion

It is excreted unchanged in urine and bile and only in small quantities by hepatic metabolism. Final t_½ - about 9 hours. After repeated intake of accumulation is not observed.

The total clearance of blood plasma is about 0.37 ml / min / kg, and the renal clearance is approximately 0.19 ml / min / kg. Candesartan is excreted by the kidneys both by glomerular filtration and by active tubular secretion. After oral administration in a dose ¹⁴With C-labeled candesartan cilexetil, about 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, although about 56% of the dose is excreted in the form of candesartan and 10% as an inactive metabolite.

In elderly people (65 years old)_max and candesartan AUC increased by approximately 50 and 80%, respectively, compared with young patients. However, the blood pressure reaction and the incidence of side effects are the same after taking the drug in the prescribed dose in patients of young and old age.

In patients with mild to moderate renal failure compared with patients with normal renal function C_max and AUC of candesartan increased during repeated administration by approximately 50 and 70%, respectively, however, T_½ remained unchanged. The corresponding changes in patients with severe renal failure were about 50 and 110%, respectively. Final t_½ candesartan was approximately doubled in patients with severe renal failure. AUC in patients on hemodialysis was similar to that in patients with severe renal failure.

Patients with mild to moderate hepatic insufficiency showed an increase in AUC by 23%.

Indications

Essential hypertension. heart failure and impaired systolic function of the left ventricle (left ventricular ejection fraction ≤40%) as an additional therapy for treatment with APF inhibitors or in case of intolerance to them.

Application

Ag

The recommended starting and usual maintenance dose is 8 mg once daily. The dose can be increased to 16 mg once a day. If sufficient control of blood pressure is not achieved after 4 weeks of treatment with a dose of 16 mg once a day, then it can be increased to a maximum of 32 mg once a day. If blood pressure control is not achieved by using the drug at this dose, the appropriateness of alternative treatments should be considered.

Therapy must be adjusted for blood pressure. The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment.

Elderly people

The initial dose does not require correction.

Patients with reduced bcc

For patients at risk of developing arterial hypotension, for example, for patients with a possible decrease in BCC, an initial dose of 4 mg should be considered.

Renal failure

In patients with renal failure, including those on hemodialysis, the initial dose is 4 mg. The dose must be corrected taking into account blood pressure. The experience of use in patients with severe renal failure or end-stage renal failure (creatinine clearance of 15 ml / min) is limited.

Liver failure

For patients with mild to moderate hepatic insufficiency, an initial dose of 2 mg once a day is recommended. The dose can be corrected taking into account blood pressure. There is no experience with patients with severe liver failure.

Concomitant therapy

It was found that the additional use of hydrochlorothiazide in combination with Atacand causes an additive antihypertensive effect.

Negro Patients

The antihypertensive effect of candesartan is less pronounced than in patients of the Caucasian race. Upward titration of the Atacand and concomitant therapy to control blood pressure are more often needed in patients of the Negroid race than in those of the Caucasian race.

Heart failure

The recommended starting dose of Atacand is 4 mg 1 time per day. Titration upward to the target dose of 32 mg 1 time per day or the maximum tolerated dose is carried out by doubling the dose after a period of at least 2 weeks.

Special categories of patients

For elderly patients or with a decrease in bcc, renal or hepatic insufficiency, mild to moderate initial dose adjustment is not required.

Concomitant therapy

Atacand can be prescribed in combination with other drugs for the treatment of heart failure, including ACE inhibitors, β-adrenergic receptor blockers, diuretics and digitalis drugs, or a combination of these drugs.

Application. Atacand is taken 1 time per day with or without food.

Children and teens

Safety and effectiveness of Atacand for children and adolescents (under 18 years of age) have not been established.

Contraindications

Hypersensitivity to candesartan cilexetil or any excipient; During pregnancy and breastfeeding; severe liver failure and / or stagnation of bile (cholestasis).

Side effects

In the treatment of ag

During controlled clinical trials, side effects were mild, temporary, and comparable to placebo. The overall incidence of side effects did not indicate a dose or age dependence. The frequency of refusal due to adverse reactions was similar in candesartan cilexetil (3.1%) and placebo (3.2%).

The following common (1/100) adverse reactions have been reported (incidence of adverse effects that are at least 1% higher than the incidence of such effects with placebo):

from the nervous system: dizziness, headache;

infections and infestations: respiratory tract infections.

Laboratory Results

There was no clinically significant effect of Atacand on laboratory parameters. When using other inhibitors of the renin-angiotensin-aldosterone system, a slight decrease in hemoglobin was detected. Creatinine, urea, or potassium levels increased and sodium levels decreased. The increase in ALAT, which was regarded as a side effect, was not much more often reported with Atacand than with placebo (1.3 versus 0.5%). For patients receiving Atacand, ongoing monitoring of laboratory parameters is not necessary. However, patients with renal failure are advised to periodically monitor serum potassium and creatinine levels.

In heart failure: the side effect profile of Atacand in patients with heart failure corresponds to the pharmacological properties of this drug and the health status of patients.Common adverse reactions (≥1 / 100, 1/10) identified during clinical trials included:

From the cardiovascular system: arterial hypotension.

Metabolic and nutritional disorders: hyperkalemia.

From the urinary system: renal failure.

Laboratory tests: increased creatinine, urea, and potassium. Periodic monitoring of serum creatinine and potassium levels is recommended.

Post-marketing study: the following adverse events were reported very rarely (1/10 000):

from the blood system: leukopenia, neutropenia and agranulocytosis;

metabolic and nutritional disorders: hyperkalemia, hyponatremia;

from the nervous system: dizziness, headache;

from the gastrointestinal tract: nausea;

from the hepatobiliary system: an increase in the level of liver enzymes, an abnormality of the liver function or hepatitis;

on the part of the skin and subcutaneous tissue: angioedema, rash, urticaria, itching;

from the musculoskeletal system, connective tissue: back pain, arthralgia, myalgia;

from the urinary system: impaired renal function, including renal failure in susceptible patients.

special instructions

Renal failure

As with other drugs that inhibit the renin-angiotensin-aldosterone system, changes in renal function in predisposed patients taking Atacand can be expected.

When using Atacand in patients with hypertension and renal failure, periodic monitoring of serum potassium and creatinine levels is recommended. The experience of use in patients with severe renal failure or end-stage renal failure (creatinine clearance of 15 ml / min) is limited. In these patients, Atacand should be titrated in combination with blood pressure monitoring.

Assessment of the condition of patients with heart failure should include a periodic assessment of renal function, especially in the elderly over 75 years old and in patients with renal failure. During titration of Atacand dose, monitoring of serum creatinine and potassium levels is recommended. Clinical trials in patients with heart failure did not include individuals with a serum creatinine level of 265 mmol / L (3 mg / dL).

Concomitant therapy with an ACE inhibitor in heart failure

The risk of side effects, especially with insufficient renal function and hyperkalemia, may increase with the use of candesartan in combination with an ACE inhibitor. These patients require regular and careful monitoring.

Hemodialysis

During dialysis, blood pressure can be especially sensitive to blockade of the AT receptor.₁ due to a decrease in blood plasma volume and activation of the renin-angiotensin-aldosterone system. For patients on hemodialysis, it is necessary to carefully titrate Atacand and carefully monitor blood pressure.

Renal artery stenosis

Other drugs that affect the renin-angiotensin-aldosterone system, such as ACE inhibitors, can increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or artery stenosis leading to one kidney. A similar effect can be expected with angiotensin II receptor antagonists.

Kidney transplant

There is no experience with Atacand in patients who have recently undergone kidney transplantation.

Arterial hypotension

During the use of Atacand in patients with heart failure, hypotension may occur. As described for other drugs that affect the renin-angiotensin-aldosterone system, hypotension can also occur in patients with hypertension and reduced BCC, such as those taking high-dose diuretics.At the beginning of therapy, care should be taken and try to correct hypovolemia.

Anesthesia and surgery

In patients receiving treatment with angiotensin II receptor antagonists, hypotension may develop during anesthesia and surgery due to blockade of the renin-angiotensin-aldosterone system. In very rare cases, hypotension can be so severe that it will require the use of IV fluids and / or vasopressors.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special care must be taken when treating patients with hemodynamically significant stenosis of the aorta or mitral valve, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act by inhibiting the renin-angiotensin-aldosterone system. Therefore, the use of Atacand is not recommended.

Hyperkalemia

Experience with other drugs that affect the renin-angiotensin-aldosterone system suggests that the concomitant use of Atacand simultaneously with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that can increase potassium levels (e.g. heparin), may lead to increased serum potassium levels in patients with hypertension.

Hyperkalemia may occur in patients with heart failure taking Atacand. During treatment with Atacand in patients with heart failure, it is recommended to periodically monitor the level of potassium in the blood serum, especially if this drug is taken simultaneously with ACE inhibitors and potassium-sparing diuretics, for example, with spironolactone.

General information

In patients whose vascular tone and renal function mainly depend on the activity of the renin-angiotensin-aldosterone system (for example, patients with severe congestive heart failure or kidney disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotemia, oliguria, or in rare cases with acute renal failure. The possibility of such effects cannot be excluded with the use of angiotensin II receptor antagonists. As with any other antihypertensive drug, an excessive decrease in blood pressure in patients with ischemic cardiopathy or ischemic cerebrovascular disease can lead to myocardial infarction or stroke.

Atacand should not be taken in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

During pregnancy and breastfeeding

There is limited data on the appointment of Atacand during pregnancy, which is not enough to draw conclusions about the potential risk to the fetus when using the drug in the first trimester. Renal perfusion of the fetus, forming in the II trimester, depends on the development of the renin-angiotensin-aldosterone system. The risk to the fetus is increased if Atacand is taken in the second or third trimester of pregnancy. The use of drugs acting directly on the renin-angiotensin-aldosterone system during this period can harm the fetus and newborn (hypotension, renal dysfunction, oliguria and / or anuria, oligohydramnios, cranial hypoplasia, intrauterine growth retardation) and lead to death. Cases of lung hypoplasia, facial abnormalities and contractures of the limbs are described.

An animal study using candesartan tsileksetil revealed damage to the kidneys of the fetus in late pregnancy and newborns. This mechanism is considered pharmacologically mediated due to the effect on the renin-angiotensin-aldosterone system.

Based on the above information, Atacand is not recommended for use during pregnancy. If pregnancy is determined during treatment, Atacand should be discontinued.

It has not been established whether candesartan passes into breast milk, but because of the potential undesirable effect on breast-fed babies, Atacand should not be used during breast-feeding.

The effect of the drug on the ability to drive vehicles and work with mechanisms is unlikely. When driving vehicles and working with mechanisms, dizziness and fatigue that may occur during treatment should be considered.

Interactions

No clinically significant interaction was detected. Compounds studied in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinyl estradiol / levonorgestrel), glibenclamide, nifedipine and enalapril.

Candesartan is slightly excreted by hepatic metabolism (CYP 2C9). The data of the conducted interaction studies indicate that there is no effect on CYP 2C9 and CYP 3A4, however, the effect on other isoenzymes of cytochrome P450 is unknown.

The antihypertensive effect of candesartan can be enhanced by other drugs that can lower blood pressure, regardless of whether they are prescribed as an antihypertensive drug or for other indications.

Experience with other drugs that affect the renin-angiotensin-aldosterone system suggests that concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that can increase potassium levels (such as heparin) can lead to increase serum potassium levels.

There are reports of an inverse increase in serum lithium concentration and its toxicity during concomitant use of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists. Therefore, with simultaneous use, careful monitoring of serum lithium levels is recommended.

With the combined use of angiotensin II receptor antagonists with NSAIDs (for example, selective COX-2 inhibitors, acetylsalicylic acid (3 g / day) and non-selective NSAIDs), a decrease in the antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of impaired renal function, including possible acute renal failure and increased serum potassium levels, especially in patients with impaired renal function. This combination is used with caution, especially in the elderly. Patients should receive a sufficient amount of fluid, and the need to monitor renal function at the beginning of concomitant therapy and periodically throughout the course of treatment should also be considered.

Eating does not affect the bioavailability of candesartan.

Overdose

Symptoms: hypotension and dizziness. information on an individual case of an overdose (up to 672 mg of candesartan cilexetil) reported the patients recovery without consequences.

Treatment: symptomatic, control of vital functions. The patient should be placed on his back with raised lower limbs. If this is not enough, it is necessary to increase the volume of blood plasma by infusion, for example, isotonic saline solution. Candesartan is not excreted by hemodialysis.

Storage conditions

At temperatures up to 30 ° C.