Hydrochlorothiazide
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Pharmacological properties
exforge n contains 3 antihypertensive drugs with complementary mechanisms for controlling hell in patients with essential hypertension: amlodipine is a class of calcium antagonists, valsartan is an angiotensin II antagonist, and hydrochlorothiazide is a thiazide diuretic. a combination of these three components is characterized by a complementary antihypertensive effect.
Amlodipine, which is part of Exforge H, inhibits the transmembrane entry of calcium ions into the heart muscles and vascular smooth muscles. The mechanism of the antihypertensive effect of amlodipine is provided by a direct relaxing effect on the smooth muscles of blood vessels, causing a decrease in the resistance of peripheral vessels and blood pressure.
Amlodipine in therapeutic doses in patients with hypertension causes vasodilation, which leads to a decrease in blood pressure in the supine and standing position. Such a decrease in blood pressure is not accompanied by pronounced changes in heart rate or plasma catecholamines with prolonged use. Plasma concentration is correlated with the effect in both young patients and elderly patients.
In patients with hypertension and normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance and an increase in glomerular filtration rate (GFR) and effective renal plasma flow without changing the filtration fraction or proteinuria.
Valsartan is an oral active, potent and specific angiotensin (ARA) II receptor antagonist. Valsartan acts selectively on subtype AT1receptors responsible for the known effects of angiotensin II.
Taking valsartan in patients with hypertension helps lower blood pressure without affecting heart rate.
In most patients, after oral administration of a single dose, the onset of the hypotensive effect occurs within 2 hours, and the maximum decrease in blood pressure is achieved within 4-6 hours. The antihypertensive effect lasts for 24 hours after administration of the drug. With repeated use, the maximum decrease in blood pressure (with all dosage modes) is achieved, as a rule, within 2-4 weeks.
Hydrochlorothiazide. The site of action of thiazide diuretics is mainly the distal convoluted tubules of the kidneys. It has been confirmed that there are high affinity receptors in the cortical layer of the kidneys, which are the main binding site for thiazide diuretics and inhibition of NaCl transport to the distal convoluted tubules. The mechanism of action of thiazides is the inhibition of Na carriers+Cl—possibly by competing for Cl centers—, which, in turn, acts on the mechanisms of electrolyte reabsorption: it directly enhances the excretion of sodium and chlorine to an approximately equivalent degree and indirectly, due to diuretic effects, reduces blood plasma volume with subsequent increase in renin activity in blood plasma, aldosterone secretion and potassium excretion in urine , as well as a decrease in potassium levels in blood plasma.
Pharmacokinetics
Linearity. Amlodipine, valsartan, and hydrochlorothiazide demonstrate linear pharmacokinetics.
Amlodipine / valsartan / hydrochlorothiazide. Following oral administration of Exforge H by healthy adult volunteers Cmax amlodipine, valsartan, and hydrochlorothiazide in plasma was reached within 6–8; 3 and 2 hours, respectively. The rate and volume of absorption of amlodipine, valsartan and hydrochlorothiazide when using the drug are similar to those noted when using its components as separate drugs.
Amlodipine. Absorption. Following oral administration in therapeutic doses of amlodipine C alonemax in blood plasma was reached after 6–12 hours. Absolute bioavailability was 64–80%. Eating does not affect the bioavailability of amlodipine.
Distribution. The volume of distribution is about 21 l / kg body weight.In vitro studies of amlodipine have shown that about 97.5% of the drug found in circulating blood binds to plasma proteins.
Biotransformation. Amlodipine is actively (about 90%) metabolized in the liver to inactive metabolites.
Amlodipine is excreted from blood plasma in 2 stages, final T½ is about 30-50 hours. Levels of equilibrium in blood plasma are achieved after continuous use for 7-8 days. 10% of the initial amlodipine and 60% of amlodipine metabolites are excreted in the urine.
Valsartan. Absorption. Following oral administration of valsartan alone, its Cmax achieved in 2–4 hours. The average absolute bioavailability is 23%. Eating reduces the exposure (as determined by AUC) of valsartan by about 40%, and Cmax in blood plasma - almost 50%, although about 8 hours after application, the concentration of valsartan is similar in the fasting and after meals groups. However, such a decrease in AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be used regardless of food intake.
Distribution. The volume of distribution of valsartan in equilibrium after iv administration is 17 L, indicating that valsartan is not distributed extensively in tissues. Valsartan is actively associated with plasma proteins (94–97%), mainly with albumin.
Biotransformation. Valsartan does not transform to a large extent, since only about 20% of the dose is excreted as metabolites. Hydroxymetabolite is identified in blood plasma at low concentrations (10% AUC of valsartan). This metabolite is pharmacologically inactive.
Valsartan is excreted mainly with feces (about 83% of the dose) and urine (13% of the dose), mainly unchanged. After iv administration, valsartan clearance is about 2 l / h, and renal clearance is 0.62 l / h (about 30% of the total clearance). T½ valsartan - 6 hours
Hydrochlorothiazide. Absorption. The absorption of hydrochlorothiazide after oral administration occurs rapidly (Tmax - about 2 hours). The increase in average AUC is linear and proportional to the dose when used in the therapeutic dose range. There was no change in the kinetics of hydrochlorothiazide with repeated use, and cumulation was minimal when taken once a day. When taken with food, both an increase and a decrease in the systemic availability of hydrochlorothiazide were observed compared with fasting. The severity of these effects is insignificant and has little clinical significance. The absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.
Distribution. The apparent volume of distribution is 4–8 l / kg body weight. Hydrochlorothiazide in the circulating blood binds to plasma proteins (40–70%), mainly with albumin. Hydrochlorothiazide also accumulates in red blood cells at a concentration that is 1.8 times higher than plasma levels.
Biotransformation. Hydrochlorothiazide is excreted unchanged.
More than 95% of the absorbed dose is excreted unchanged in the urine. Renal clearance consists of passive filtration and active secretion in the renal tubules. T½- 6-15 hours
Individual patient groups
Children (under the age of 18). There is no data on the pharmacokinetics in children.
Elderly patients (65 years and older). Time to reach Cmax amlodipine is similar in young and old patients. In elderly patients, amlodipine clearance tends to decrease, causing an increase in AUC and T½. The average systemic AUC of valsartan is 70% higher in elderly patients compared with young patients, therefore, with caution increase the dose in this category of patients.
The systemic exposure of valsartan is slightly higher in elderly patients compared with young patients, but this does not have clinical significance.
Limited data indicate that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly people and elderly patients with hypertension compared with young healthy volunteers.
Since the three components of the drug are equally well tolerated by young patients and the elderly, the usual dosage regimen is recommended.
Impaired renal function does not significantly affect the pharmacokinetics of amlodipine. As expected, for the drug, whose renal clearance is only 30% of the total clearance, there is no relationship between renal function and systemic exposure of valsartan. Therefore, patients with impaired renal function from mild to moderate severity can use the drug in the usual initial dose.
Impaired liver function. In patients with impaired liver function, amlodipine clearance is reduced, which leads to an increase in AUC by about 40-60%. On average, in patients with chronic diseases of mild to moderate severity, exposure (determined by AUC) of valsartan is 2 times higher than in adult volunteers (grouped by age, sex and body weight). Caution should be given to patients with liver disease.
The combination of amlodipine / valsartan / hydrochlorothiazide was not tested for genotoxicity and carcinogenicity, since there were no signs of interaction between these drugs on the market for a long time. However, amlodipine, valsartan, and hydrochlorothiazide have been individually tested for genotoxicity and carcinogenicity; negative results were obtained.
Indications
Treatment of essential hypertension in adult patients with hell adequately controlled by a combination of amlodipine, valsartan and hydrochlorothiazide, which use 3 separate substances or 2 drugs, one of which is combined.
Application
Mode of application. exforge n can be used regardless of food intake. tablets should be swallowed whole, washed down with water, at the same time of the day, preferably in the morning.
Dosage. The recommended dose of Exforge N is 1 tablet per day, preferably in the morning. Before switching to the use of the drug Exforge H, the patients condition should be controlled by constant doses of single drugs taken at the same time. The dose of Exforge N should depend on the doses of the individual components of the combination used at the time of drug change.
The maximum recommended dose of Exforge N is 10 mg / 320 mg / 25 mg.
Individual patient groups
Impaired renal function. Since the composition of the drug includes hydrochlorothiazide, Exforge N is contraindicated in patients with severe impaired renal function (creatinine clearance 30 ml / min). The simultaneous use of the drug Exforge N with aliskiren is contraindicated in patients with impaired renal function (glomerular filtration rate (GFR) 60 mg / min / 1.73 m2) There is no need for dose adjustment in patients with impaired renal function of mild to moderate severity.
Diabetes. The simultaneous use of Exforge N with aliskiren is contraindicated in patients with diabetes mellitus.
Impaired liver function. Since valsartan is part of the drug, Exforge N is contraindicated in patients with severe hepatic impairment. For patients with impaired liver function of mild to moderate severity, not accompanied by cholestasis, the maximum recommended dose of valsartan is 80 mg, and therefore Exforge N is not indicated for this group of patients. For patients with mild to moderate hepatic impairment, recommendations for a dosage of amlodipine have not been established.
Heart failure and coronary artery disease. The experience with Exforge N, especially in the maximum doses, is limited in patients with heart failure and coronary artery disease. It is recommended to use the drug with caution in patients with heart failure and coronary artery disease, especially the maximum dose of Exforge H 10 mg / 320 mg / 25 mg.
Elderly patients (65 years and older).It is recommended with caution, in particular often controlling blood pressure, to prescribe to elderly patients, especially the maximum dose of Exforge H 10 mg / 320 mg / 25 mg, since data on the use of the drug in this group of patients are limited.
Pediatric populations. There is no relevant data on the use of Exforge N in pediatric populations (in patients under the age of 18) according to the indications of AH.
Contraindications
Hypersensitivity to active substances, other sulfonamides, dihydropyridine derivatives or any auxiliary substance.
Pregnancy or women planning to become pregnant (see Use during pregnancy and lactation).
Impaired liver function, biliary cirrhosis or cholestasis.
Severe renal impairment (GFR 30 ml / min / 1.73 m2), anuria, as well as being on dialysis.
The simultaneous use of ARA, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or with impaired renal function (GFR 60 mg / min / 1.73 m2).
Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
Severe arterial hypotension.
Shock (including cardiogenic shock).
Left ventricular outflow tract obstruction (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Side effects
Adverse reactions are presented in table. 1 by classes of organ systems (meddra) and frequency relative to exforge n (amlodipine / valsartan / hydrochlorothiazide) and separately for amlodipine, valsartan and hydrochlorothiazide: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000); very rarely (1/10 000); frequency unknown (cannot be determined from available data).
| Organ System Class (MedDRA) | Adverse reactions | Frequency | |||
|---|---|---|---|---|---|
| Exforge H | Amlodipine | Valsartan | Hydrochlorothiazide | ||
| On the part of the blood system and lymphatic system | Agranulocytosis, bone marrow suppression | – | – | – | Rarely |
| Decreased hemoglobin and hematocrit levels | – | – | Frequency unknown | – | |
| Hemolytic anemia | – | – | – | Rarely | |
| Leukopenia | – | Rarely | – | Rarely | |
| Neutropenia | – | – | Frequency unknown | – | |
| Thrombocytopenia, sometimes with purpura | – | Rarely | Frequency unknown | Rarely | |
| From the immune system | Hypersensitivity | – | Rarely | Frequency unknown | Rarely |
| On the part of metabolism and nutrition | Anorexia | Infrequently | – | – | – |
| Hypercalcemia | Infrequently | – | – | Rarely | |
| Hyperglycemia | Rarely | – | Rarely | ||
| Hyperlipidemia | Infrequently | – | – | – | |
| Hyperuricemia | Infrequently | – | – | Often | |
| Hyperchloremic alkalosis | – | – | – | Rarely | |
| Hypokalemia | Often | – | – | Often | |
| Hypomagnesemia | – | – | – | Often | |
| Hyponatremia | Infrequently | – | – | Often | |
| Worsening metabolic symptoms of diabetes | – | – | – | Rarely | |
| From the psyche | Depression | – | Infrequently | – | Rarely |
| Insomnia / Sleep Disorders | Infrequently | Infrequently | – | Rarely | |
| Mood changes | – | Infrequently | – | – | |
| Embarrassment | – | Rarely | – | – | |
| From the nervous system | Impaired coordination | Infrequently | – | – | – |
| Dizziness | Often | Often | – | Rarely | |
| Postural dizziness, tension dizziness | Infrequently | – | – | – | |
| Dysgeusia | Infrequently | Infrequently | – | – | |
| Extrapyramidal syndrome | – | Frequency unknown | – | – | |
| Headache | Often | Often | – | Rarely | |
| Ag | – | Rarely | – | – | |
| Lethargy | Infrequently | – | – | – | |
| Paresthesia | Infrequently | Infrequently | – | Rarely | |
| Peripheral neuropathy, neuropathy | Infrequently | Rarely | – | – | |
| Drowsiness | Infrequently | Often | – | – | |
| Syncope | Infrequently | Infrequently | – | – | |
| Tremor | – | Infrequently | – | – | |
| Hypesthesia | – | Infrequently | – | – | |
| On the part of the organ of vision | Visual impairment | Infrequently | Infrequently | – | Rarely |
| On the part of the hearing organ | Tinnitus | – | Infrequently | – | – |
| Vertigo | Infrequently | – | Infrequently | – | |
| From the heart | Palpitation | – | Often | – | – |
| Tachycardia | Infrequently | – | – | – | |
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) | – | Rarely | – | Rarely | |
| Myocardial infarction | – | Rarely | – | – | |
| From the vascular system | Flushing | – | Often | – | – |
| Arterial hypotension | Often | Infrequently | – | – | |
| Orthostatic hypotension | Infrequently | – | – | Often | |
| Phlebitis, thrombophlebitis | Infrequently | – | – | – | |
| Vasculitis | – | Rarely | Frequency unknown | – | |
| From the respiratory tract, mediastinal organs and chest | Cough | Infrequently | Rarely | Infrequently | – |
| Dyspnoea | Infrequently | Infrequently | – | – | |
| Respiratory distress, pulmonary edema, pneumonitis | – | – | – | Rarely | |
| Rhinitis | – | Infrequently | – | – | |
| Throat irritation | Infrequently | – | – | – | |
| From the digestive tract | Abdominal discomfort, pain in the upper abdomen | Infrequently | Often | Infrequently | Rarely |
| Bad breath | Infrequently | – | – | – | |
| Change the frequency of bowel movements | – | Infrequently | – | – | |
| Constipation | – | – | – | Rarely | |
| Decreased appetite | – | – | – | Often | |
| Diarrhea | Infrequently | Infrequently | – | Rarely | |
| Dry mouth | Infrequently | Infrequently | – | – | |
| Dyspepsia | Often | Infrequently | – | – | |
| Gastritis | – | Rarely | – | – | |
| Gingival hyperplasia | – | Rarely | – | – | |
| Nausea | Infrequently | Often | – | Often | |
| Pancreatitis | – | Rarely | – | Rarely | |
| Vomiting | Infrequently | Infrequently | – | Often | |
| On the part of the liver and biliary tract | Increased levels of liver enzymes, including increased plasma bilirubin | – | Rarely* | Frequency unknown | – |
| Hepatitis | – | Rarely | – | – | |
| Intrahepatic cholestasis, jaundice | – | Rarely | – | Rarely | |
| On the part of the skin and its derivatives | Alopecia | – | Infrequently | – | – |
| Angioedema | – | Rarely | Frequency unknown | – | |
| Skin reactions like lupus erythematosus, reactivation of the skin form of lupus erythematosus | – | – | – | Rarely | |
| Erythema multiforme | – | Rarely | – | Frequency unknown | |
| Exanthema | – | Infrequently | – | – | |
| Hyperhidrosis | Infrequently | Infrequently | – | – | |
| Photosensitivity Reactions | – | Rarely | – | Rarely | |
| Itching | Infrequently | Infrequently | Frequency unknown | – | |
| Purpura | – | Infrequently | – | Rarely | |
| Rash | – | Infrequently | Frequency unknown | Often | |
| Skin color change | – | Infrequently | – | – | |
| Hives | – | Rarely | – | Often | |
| Necrotizing vasculitis and toxic epidermal necrolysis | – | – | – | Rarely | |
| Exfoliative Dermatitis | – | Rarely | – | – | |
| Stevens-Johnson Syndrome | – | Rarely | – | – | |
| Quinckes edema | – | Rarely | – | – | |
| From the musculoskeletal system and connective tissue | Arthralgia | – | Infrequently | – | – |
| Backache | Infrequently | Infrequently | – | – | |
| Joint swelling | Infrequently | – | – | – | |
| Muscle cramps | Infrequently | Infrequently | – | Frequency unknown | |
| Muscle weakness | Infrequently | – | – | – | |
| Myalgia | Infrequently | Infrequently | Frequency unknown | – | |
| Limb pain | Infrequently | – | – | – | |
| Swelling of the ankles | – | Often | – | – | |
| From the kidneys and urinary system | Increased plasma creatinine | Infrequently | – | Frequency unknown | – |
| Urination disorders | – | Infrequently | – | – | |
| Nocturia | – | Infrequently | – | – | |
| Pollakiuria | Often | Infrequently | – | – | |
| Renal dysfunction | – | – | – | Frequency unknown | |
| Arrester | Infrequently | – | – | Frequency unknown | |
| Renal failure and impaired renal function | – | – | Frequency unknown | Rarely | |
| From the reproductive system and mammary glands | Impotence | Infrequently | Infrequently | – | Often |
| Gynecomastia | – | Infrequently | – | – | |
| General disorders and reactions at the place of use | Abasia, gait disorders | Infrequently | – | – | – |
| Asthenia | Infrequently | Infrequently | – | Frequency unknown | |
| Discomfort, malaise | Infrequently | Infrequently | – | – | |
| Weakness | Often | Often | Infrequently | – | |
| Necardial Chest Pain | Infrequently | Infrequently | – | – | |
| Swelling | Often | Often | – | – | |
| Fever | – | – | – | Frequency unknown | |
| Pain | – | Infrequently | – | – | |
| Survey | Increased lipid levels | – | – | – | Often |
| Urea Nitrogen Increase | Infrequently | – | – | – | |
| Increased uric acid levels in the blood | Infrequently | – | – | – | |
| Glucosuria | – | – | – | Rarely | |
| Decreased plasma potassium levels | Infrequently | – | – | – | |
| Increased levels of potassium in blood plasma | – | – | Frequency unknown | – | |
| Weight gain | Infrequently | Infrequently | – | – | |
| Body weight reduction | – | Infrequently | – | – | |
* More associated with cholestasis.
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2020-07-30
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