Aliskiren

When ATH:
C09XA02

Pharmacological action

Antihypertensive agents, selective non-peptide renin inhibitor of structure. Renin secretion by the kidneys and the activation of the RAAS occurs with a decrease in the bcc and renal blood flow through a feedback mechanism. Renin acts on angiotensinogen, This produces an inactive decapeptide – angiotensin I (ATI), which by means of ACE, partially, without him, is converted into the active octapeptide angiotensin II (АТII). ATII is a potent vasoconstrictor, It stimulates the release of catecholamines from the adrenal medulla and presynaptic nerve terminals, and also increases the secretion of aldosterone and sodium reabsorption, what, ultimately, It increases the blood pressure.

Long-term increase in the concentration ATII stimulates the production of mediators of inflammation and fibrosis, which leads to organ damage.

ATII reduces renin secretion by negative feedback. Preparations, ingibiruyushiye of California (renin inhibitors including), suppress the negative feedback, causing a compensatory increase in the concentration of plasma renin. When treatment with ACE inhibitors and angiotensin II receptor antagonists also increased plasma renin activity, which is directly associated with increased risk of cardiovascular disease in patients with normal blood pressure, and in patients with arterial hypertension. When applied as aliskiren monotherapy or in combination with other antihypertensives neutralized negative feedback inhibition, resulting in decreased plasma renin activity (patients with hypertension on average 50-80%), and levels of ATI and ATII.

After the first dose hypotensive response is not observed (the effect of the first dose) and a reflex increase in heart rate in response to vasodilation.

Pharmacokinetics

After ingestion time to Cmax of aliskiren in plasma is 1-3 no, absolute bioavailability – 2.6%. Simultaneous eating reduces Cmax and AUC of aliskiren, but it does not significantly affect the pharmacodynamics of the drug. Therefore aliskiren can be used regardless of the meal.

Increased AUC and Cmax of aliskiren has a linear dependence on the dose ranging from 75 to 600 mg.

Css aliskiren plasma levels achieved between 5 and 7 day with daily intake 1 again / remains constant at doubling the starting dose.

After ingestion aliskiren uniformly distributed in the body. After the on / in the middle Vd at steady state is approximately 135 l, It is indicating a significant extravascular distribution aliskiren. Aliskiren is moderately bound to plasma proteins (47-51%), regardless of the concentration.

The average T1 / 2 of aliskiren 40 no (It varies between 34 to 41 no).

Write mainly unaltered through the intestine (91%). About 1.4% of an oral dose is metabolized with the participation of CYP3A4. After oral administration about 0.6% aliskiren excreted by the kidneys. After the on / in the average plasma clearance is about 9 l /.

In the application of aliskiren in patients over 65 s correction dose is not required.

The pharmacokinetics of aliskiren been studied in patients with renal failure of varying severity. The AUC and Cmax of aliskiren in patients with renal failure after a single application, and after reaching Css increased in 0.8-2 times in comparison with healthy persons. However, the correlation between the above changes and the degree of renal impairment have been identified.

The pharmacokinetics of aliskiren were not significantly altered in patients with mild to moderate hepatic impairment (5-9 points on the Child-Pugh).

Testimony

Arterial hypertension.

Dosage regimen

The recommended starting dose is 150 mg 1 time / When there is insufficient blood pressure control through 2 weeks the dose can be increased to 300 mg 1 time /

Side effect

From the digestive system: often – diarrhea.

Dermatological reactions: sometimes – skin rash.

From the laboratory parameters: rarely – a slight decrease in hemoglobin concentration and hematocrit (on average 0.05 mmol / l 0.16% respectively), did not require discontinuation of treatment, a slight increase in the concentration of potassium in blood serum (0.9% compared to 0.6% placebo).

Allergic reactions: in some cases – angioedema.

Contraindications

Children and teens under 18 years, pregnancy, lactation (breast-feeding), Hypersensitivity to aliskiren.

Pregnancy and lactation

Contraindicated for use in pregnancy and lactation (breast-feeding).

Cautions

Caution should be used alisikiren patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, diabetes, reduced BCC, hyponatremia, or hyperkalemia in patients after kidney transplantation.

The efficacy and safety of aliskiren are not installed: in patients with severely impaired renal function (sыvorotochnыy creatinine >150 mmol / L for women and >177 mmol / L for men and / or glomerular filtration rate of less than 30 ml / min), with nephrotic syndrome, renovascular hypertension and during regular hemodialysis, as well as in patients with impaired liver function, severe (more 9 points on the Child-Pugh), in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

In patients with diabetes during therapy with aliskiren in combination with an ACE inhibitor was an increase in the frequency of hyperkalemia (5.5%). When using aliskiren and other drugs, affect the RAAS, patients, diabetes, should regularly monitor the blood plasma electrolytes and renal function.

The drug should be discontinued immediately if symptoms of allergic reactions (eg, when difficulty breathing or swallowing, swelling of the face, limbs, lips, language).

The therapy aliskiren may increase the concentration of potassium, creatinine, blood urea nitrogen, characteristic of drugs, affect the RAAS.

Early treatment aliskiren in patients with reduced BCC and / or hyponatremia (incl. due to high doses of diuretics) Possible symptomatic hypotension. Prior to use, carry out the correction of violations of water-salt balance. In patients with reduced BCC and / or hyponatremia treatment should be under close medical supervision.

Drug Interactions

The probability of interaction of aliskiren with other drugs Low.

In the application of aliskiren with one of the following drugs may change its Cmax or AUC: valsartan (decline 28%), metformin (decline 28%), amlodipine (an increase of 29%), cimetidine (an increase of 19%).

Since experimental studies have found, Chto P-glycoprotein (membrane transporter molecules) It plays an important role in regulating the absorption and distribution of aliskiren, may alter the pharmacokinetics of the latter, while the use of substances, ingibiruyushtimi P-glycoprotein (depending on the degree of inhibition). Not found significant interaction of aliskiren with mild to moderately active inhibitors of P-glycoprotein, such, as atenolol, Digoxin, amlodipine and cimetidine.

In an application to an active inhibitor P-glycoprotein Atorvastatin (dose 80 mg /) in equilibrium there is an increase in AUC and Cmax of aliskiren (dose 300 mg /) on 50%.

At the same time taking an active inhibitor of P-glycoprotein ketoconazole (200 mg) and aliskiren(300 mg) there is an increase on last Cmax 80%. In experimental studies, concomitant use of aliskiren with ketoconazole resulted in an increase in the last absorption from the gastrointestinal tract and reduce its excretion in the bile. Changes in plasma concentrations of aliskiren in the plasma while the use of atorvastatin or ketoconazole are expected in the range of concentrations, determined by increasing the dose of aliskiren in 2 times. In controlled clinical studies have demonstrated the safety of a dose of aliskiren 600 mg and increasing the maximum recommended therapeutic dose 2 times. In the application of aliskiren with ketoconazole or atorvastatin dose adjustment is not required aliskiren.

When applied to such highly active inhibitor of P-glycoprotein, how cyclosporine (200 and 600 mg), in healthy subjects showed an increase in AUC and Cmax of aliskiren (75 mg) in 2.5 and 5 times, respectively, (not recommended for use while aliskiren with cyclosporine).

With simultaneous use of aliskiren with furosemide there is a decrease in AUC and Cmax of furosemide on 28% and 49% respectively. To prevent possible delays in the appointment of the liquid aliskiren together with furosemide in the beginning and during the treatment to adjust the dose of furosemide is necessary depending on the clinical effect.

Caution should be used in conjunction with aliskiren potassium salts, potassium-sparing diuretics, potassium-salt food substitutes or any other drugs, which are capable of increasing the concentration of potassium in the blood.