Description
Latin name
Gastal
release form
resorption tablets
packaging 12 pcs
Pharmacological action
Pharmacodynamic properties of each of the active substances that make up the drug Aprovask ®, irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination compared with those when using each of these drugs separately. Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers reduce blood pressure by reducing peripheral vascular resistance, blocking calcium entry into the cell and decreasing vasoconstrictor due to angiotensin II exposure are complementary mechanisms.
Irbesartan
Irbesartan is a selective potent ARA II (subtype-AT1). Angiotensin II is an important component of RAAS involved in the pathophysiology of hypertension and in sodium ion homeostasis. For the manifestation of its action, irbesartan does not need metabolic activation.
Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting effects of angiotensin II due to selective antagonism of angiotensin II receptors (subtype-AT1) located in the smooth muscle cells of blood vessels and adrenal cortex. Irbesartan has no agonistic activity towards AT1 receptors. Its affinity for AT1 receptors is 8500 times greater than for AT2 receptors (receptors that have not been shown to be associated with maintaining equilibrium [homeostasis] of the cardiovascular system).
Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), and does not affect other hormonal receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis. Blockade of irbesartan AT1 receptors breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. When irbesartan is used, the plasma concentration of aldosterone decreases, but when using the drug in the recommended doses, there are no significant changes in the serum potassium content (the average increase in serum potassium is less than 0.1 mEq / l). Irbesartan has no significant effect on the concentration of triglycerides, cholesterol or glucose in the blood serum. Irbesartan does not affect serum uric acid concentrations or kidney excretion of uric acid.
The antihypertensive effect of irbesartan develops after taking the first dose and becomes significant within 1-2 weeks of treatment with a maximum effect occurring after 4-6 weeks. In long-term observational studies, the effect of irbesartan persisted for more than 1 year.
A single dose of irbesartan in doses up to 900 mg / day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150-300 mg / day led to a greater decrease in systolic (SBP) / diastolic (DBP) blood pressure (24 hours after taking the dose) in the supine or sitting position (on average, 8-13 / 5-8 mm mercury) than with a placebo. The effect of the drug 24 hours after taking the dose was 60-70% of the corresponding maximum reduction in DBP and SBP. Optimum effectiveness in reducing blood pressure within 24 hours is achieved with a single dose of the drug per day.
blood pressure decreases approximately equally when standing and lying down. The orthostatic effect is rare, and, as with the use of ACE inhibitors, its occurrence can be expected in patients with hyponatremia or hypovolemia.
The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who cannot achieve their blood pressure targets with irbesartan monotherapy, the addition of small doses of hydrochlorothiazide (12.5 mg) to irbesartan 1 time / day leads to an additional (compared with the placebo addition) decrease in SBP / DBP, determined after 24 hours after taking them, 7-10 / 3-6 mm RT. Art., respectively.
Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect RAAS, patients of the Negroid race have a weaker antihypertensive effect with monotherapy with irbesartan. When irbesartan is taken with small doses of hydrochlorothiazide (e.g. 12. 5 mg / day) antihypertensive effect in patients of the Negroid race approaches that of patients of the Caucasian race.
After the abolition of irbesartan, blood pressure gradually returns to its original level. Withdrawal syndrome upon discontinuation of irbesartan was not observed.
Amlodipine
Amlodipine is a slow calcium channel blocker from the dihydropyridine derivative group, which inhibits the transmembrane entry of calcium ions into the myocardial cells and vascular smooth muscle. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on the smooth muscles of blood vessels.
The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks has not been fully established, but amlodipine reduces myocardial ischemia due to the following two effects.
1) Amlodipine dilates peripheral arterioles and thereby reduces OPSS, the so-called afterload. Because The heart rate when taking amlodipine practically does not increase, this decrease in the load on the heart muscle reduces the energy consumption of the myocardium and its oxygen demand.
2) The mechanism of the antianginal action of amlodipine is also apparently associated with the expansion of the main coronary arteries and coronary arterioles, both in the areas of normal myocardial blood flow and in ischemic zones of the myocardium. This expansion of the coronary vessels increases the delivery of oxygen to the myocardium in patients with spasm of the coronary arteries (with Prinzmetal angina or variant angina).
In patients with arterial hypertension, taking amlodipine 1 time / day provides a clinically significant decrease in blood pressure when lying and standing for 24 hours. Due to the slow onset of its action, amlodipine is not intended to stop hypertensive crises.
In patients with angina pectoris, taking amlodipine once a day during a physical exercise test increases the total exercise time, the time before the onset of angina pectoris, and the time until ST segment depression occurs on an ECG 1 mm deep. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.
When taking amlodipine, no adverse metabolic effects or changes in blood lipid concentrations were observed. Amlodipine can be prescribed to patients with bronchial asthma, diabetes mellitus and gout.
Clinical evidence for the efficacy of a fixed-dose combination of irbesartan and amlodipine has been obtained in two multicenter, prospective, open-label studies of parallel groups with a blind assessment of performance indicators: I-ADD and I-COMBINE studies. The results of both studies showed significantly greater efficacy of combinations with fixed doses of irbesartan and amlodipine compared with monotherapy with amlodipine or monotherapy with irbesartan.
Pharmacokinetics
Irbesartan
Absorption
Irbesartan is an oral drug that does not require biotransformation to manifest its activity. After oral administration, irbesartan is rapidly and completely absorbed. Cmax of irbesartan in blood plasma is achieved 1.5-2 hours after ingestion. Irbesartan does not inhibit the CYP3A4 isoenzyme.
The excretion of
T1 / 2 of irbesartan is 11-15 hours. The total clearance with iv administration of irbesartan is 157-176 ml / min, of which 3-3.5 ml / min is accounted for by the renal clearance.
Irbesartan and its metabolites are excreted both by the liver (with bile) and by the kidneys. After oral administration or after iv administration of 14C irbesartan, about 20% of the radioactivity is found in the urine with a small residual amount in the feces. Less than 2% of the dose is excreted by the kidneys as unchanged irbesartan.
Irbesartan, when used in the therapeutic dose range, has linear pharmacokinetics. Css is reached on the third day after the start of the drug 1 time / day. A limited accumulation of irbesartan in blood plasma (<20%) is observed against the background of a course of taking the drug 1 time / day. Amlodipine Absorption After oral administration in therapeutic doses, amlodipine is well absorbed, Cmax in the blood is reached 6-12 hours after its administration. Absolute bioavailability is 64-90%. Eating does not interfere with the absorption of amlodipine. The distribution of Vd of amlodipine is approximately 21 L / kg. In vitro studies have shown that the binding of amlodipine, which is in the systemic circulation, to plasma proteins is approximately 97.5%. Metabolism and excretion Amlodipine is extensively metabolized in the liver to form inactive metabolites. T1 / 2 from blood plasma is approximately 35-50 hours when taken 1 time / day. The kidneys excrete 10% of unchanged amlodipine and 60% of its metabolites. Pharmacokinetics in special clinical cases In the elderly and younger, the time to reach Cmax of amlodipine in the blood is the same. In elderly patients, amlodipine clearance tends to decrease, as a result of which AUC and T1 / 2 increase. In children 6-12 years old and adolescents 13-17 years old, amlodipine clearance when taking the drug inside was 22.5 and 27.4 l / h, respectively, for boys and 16.4 and 21.3 l / h, respectively, for girls. There was a large variability in systemic exposure to amlodipine in different children and adolescents. Data obtained on the use of the drug in children under 6 years of age are limited. As with other slow calcium channel blockers, liver failure may increase T1 / 2 of amlodipine. In patients with chronic heart failure (in all age groups), an increase in AUC and T1 / 2 was observed. Pharmacokinetics when using the irbesartan / amlodipine combination in adults Simultaneous administration of irbesartan and amlodipine in the form of fixed combinations in tablets or in the form of free combinations did not affect the pharmacokinetics of each of the active substances of this combination. Three fixed dose combinations of irbesartan and amlodipine (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) are bioequivalent to free dose combinations (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg ), both in terms of speed and in relation to the degree of absorption. When taken separately or simultaneously in doses of 300 mg and 10 mg, the time until the median Cmax of irbesartan and amlodipine in the blood plasma is reached remains unchanged, Aluminum hydroxide-magnesium carbonate gel and magnesium hydroxide provide immediate (immediately after administration) and long-term (about 2 hours) neutralization of hydrochloric acid in gastric juice, while maintaining acidity in the stomach at a physiological level (pH 3-5). One tablet of Gastal ® neutralizes 21.5 mmol of hydrochloric acid. The drug Gastal ® suppresses the action of pepsin, lysolecithin and bile acids, eliminates dyspeptic symptoms. Enhances protective and regenerative processes in the gastric mucosa. Aluminum ions have a cytoprotective effect due to increased secretion of mucin and sodium bicarbonate, activation of prostaglandin E2 and NO, accumulation of epidermal growth factor at the site of damage to the mucous membrane, increased concentration of phospholipids in the walls of the stomach. Pharmacokinetics. Gastal ® does not have a systemic effect in patients with normal renal function. After interacting with hydrochloric acid of gastric aluminum juice, the hydroxide reacts with phosphates and carbonates in the alkaline environment of the intestine and is excreted in the feces in the form of insoluble salts. Magnesium hydroxide reacts with hydrochloric acid in the gastric juice to form magnesium chloride, which has osmotic properties and a mild laxative effect, which neutralizes the fixing effect of aluminum hydroxide in the small intestine. Magnesium ions are excreted in the feces as an insoluble carbonate. Indications Dyspeptic symptoms, such as discomfort or epigastric pain, heartburn, sour belching after errors in diet, excessive consumption of ethanol, coffee, nicotine, etc. dyspeptic symptoms, such as discomfort or pain in the epigastrium, heartburn, sour belching (and their prevention), resulting from the use of certain drugs (non-steroidal anti-inflammatory drugs, glucocorticosteroids, etc.) conditions accompanied by increased acid formation: peptic ulcer gastritis, reflux esophagitis hernia of the esophageal opening of the diaphragm. Use during pregnancy and lactation Gastal ® is not excreted in breast milk. When used during pregnancy and during breastfeeding, it is necessary to assess the ratio of benefits for the mother and risk for the fetus and baby. Composition 1 tablet contains: active substances: aluminum hydroxide-magnesium carbonate gel 450.0 mg, magnesium hydroxide 300.0 mg excipients: mannitol (E421) 120.00 mg, sorbitol (E420) 50.00 mg, lactose monohydrate 30.00 mg, corn starch 75.80 mg, sodium cyclamate 7.00 mg, sodium saccharin 0.20 mg, talc 28.00 mg, magnesium stearate 6.00 mg, peppermint flavor 3.00 mg. Dosage and administration Inside, gradually dissolving in the mouth. Adults and children over 12 years old with a body weight of at least 50 kg 1-2 tablets 4-6 times a day, approximately 1 hour after eating and at bedtime, but not more than 8 tablets per day. Duration of admission is no more than 2 weeks. Similar doses are recommended for treating heartburn regardless of food intake. Adults and children over 12 years old with a body weight of less than 50 kg, children aged 6 to 12 years The dose is half the recommended dose for adults and children over 12 years of age with a body weight of at least 50 kg. Duration of admission is no more than 2 weeks. Patients with chronic renal failure Dose adjustment not required. Duration of admission is no more than 2 weeks. Side effects When using the drug in recommended doses, adverse reactions are rare (at least 0.01%, but less than 0.1%): nausea, constipation, diarrhea, a change in taste. In exceptional cases, allergic reactions are possible. Drug interaction Gastal ® preparation at the same time enhances the activity of levodopa and nalidoxin indirect anticoagulants, barbiturates. Tetracyclines form insoluble chelate complexes by reacting with metal ions that are part of antacids as a result of this interaction, the absorption of tetracyclines is reduced by more than 90%. Simultaneous administration of these drugs is impossible. When combined, tetracycline should be taken at least 2 hours before the antacid is taken. In the presence of the aluminum and magnesium hydroxides contained in the antacid, the absorption of ciprofloxacin and ofloxacin is reduced by 50-90%. In the presence of antacids, the bioavailability of captopril is significantly reduced, and the combined use of antacids and metoprolol leads to a decrease in the plasma metoprolol concentration. Concomitant use of high doses of antacids can reduce ranitidine absorption by 10-33%. The use of antacids does not affect the bioavailability of amoxicillin, cephalexin, and a combination of amoxicillin and clavulanic acid, but may significantly reduce the absorption of doxycycline from the gastrointestinal tract. Increasing the urine pH against antacid therapy can help to increase tubular reabsorption of essential (alkaline) drugs and reduce reabsorption of acidic compounds. Antacids can reduce and slow the absorption of salicylates, including acetylsalicylic acid, and, by increasing the urine pH, promote faster elimination of salicylates with urine from the body, with a concomitant decrease in their serum concentration by 30-70%. The absorption of cardiac glycosides, including digoxin and digitoxin, is not significantly reduced when used with antacids. M-cholin blockers, by slowing the motility of the stomach, increase the duration of the drug Gastal ®. In order to prevent the possible interaction of Gastal ® with other drugs, it is recommended that it be administered 1 hour before or 1 hour after use. Overdose Symptoms of acute overdose are not described. With prolonged use of high doses of aluminum and magnesium containing preparations, the development of hypophosphatemia, hypocalcemia, hypercalciuria, osteomalacia, osteoporosis, hypermagnesemia, hyperaluminaemia, encephalopathy, nephrocalcinosis and impaired renal function is possible. It is possible to develop more pronounced undesirable reactions from the gastrointestinal tract (gastrointestinal tract) (constipation, diarrhea), in patients with renal insufficiency – thirst, a decrease in blood pressure, and hyporeflexia. Treatment: symptomatic therapy. Storage conditions Store at a temperature not exceeding 25 ° C. Keep out of the reach of children. Shelf suitability 3 Year Deystvuyuschee substances Hydrotaltsyt, magnesium hydroxide pharmacy terms and conditions without a prescription dosage form dosage form lozenges Teva Pharmaceutical Enterprises Co., Ltd., Israel
