Composition, structure and packing
Tablets 1 tab. Reserpine 100 mcg digidralazina sulphate (hydrated) 10 mg hydrochlorothiazide 10 mg.
Excipients: mannitol, corn starch, magnesium stearate, talc, disodium edetate.
Clinico-pharmacological group: antihypertensive drugs.
Pharmacological action
Adelfan-Ezidreks is a combination of three antihypertensive components having different points of application of their actions and mutually complementary antihypertensive effects of each other.
Reserpine causes depletion of the depot of catecholamines in postganglionic sympathetic nerve endings and in the CNS. Consequently, the ability to deposit catecholamines disturbed for quite a long period of time.
Catecholamine depletion leads to disruption of impulse transmission in the sympathetic nerve endings, which in turn leads to a decrease in tone of the sympathetic nervous system (the parasympathetic nervous system activity does not change). Thus, reserpine lowers high blood pressure and heart rate. In addition, reserpine causes sedation. Reserpine depletes reserves and other neurotransmitters, including serotonin, dopamine, adrenaline and neuropeptides in the central and peripheral neurons. The effects of reserpine may play a role in the implementation of its pharmacological effects and antihypertensive action. After receiving reserpine into its antihypertensive effect develops slowly, to a maximum of action is achieved only after 2-3 weeks and maintained for a long time.
Digidralazina sulfate - arterial vasodilator, lowers the tone of the smooth muscle of arterial vessels (mostly arterioles) and reduces TPVR. The mechanism of this action at the cellular level remains unclear. To a greater degree of vascular resistance decreased in the vessels of the heart, brain, kidneys and other internal organs, and to a lesser extent - in the vessels of the skin and skeletal muscles. If the blood pressure reduction is not pronounced, blood flow in the enlarged bloodstream as a whole increases. Preferential expansion of arterioles and venules are not, reduces the severity of orthostatic hypotension and improves cardiac output. Expansion vessels, leading to a decrease in blood pressure (diastolic more than systolic), accompanied by a reflex increase in heart rate, stroke volume and cardiac output.
The reflex increase in heart rate and cardiac output can be offset by the expense of combining digidralazina with reserpine, which inhibits the sympathetic nervous system.
Hydrochlorothiazide - thiazide diuretics - is acting in the cortical segment of the loop of Henle and distal renal tubules. Hinders reabsorption of sodium and chloride ions (due to an antagonistic interaction with the transport enzyme Na + Cl-) and increases the reabsorption of calcium ions (mechanism unknown). Increasing the amount and / or rate of supply of sodium ions and water in the cortical segment of collecting tubules leads to increased secretion and excretion of potassium ions and hydrogen.
In patients with normal renal function, increased urine output observed after a single use of hydrochlorothiazide in a dose of 12.5 mg. Increased urinary excretion of sodium and chlorine, and somewhat less pronounced increase kaliyureza depend on the dose of hydrochlorothiazide. After taking the drug inside the diuretic and natriuretic effects begin within 1-2 h, reaching a maximum after 4-6 h and continued for 10-12 h. Diuresis caused by thiazide, first leads to a decrease in the volume of circulating plasma cardiac output and systemic blood pressure. Possibility of activation of the renin-angiotensin-aldosterone system.
With prolonged use of hydrochlorothiazide maintain the hypotensive effect is provided, probably due to a decrease TPVR. Cardiac output returned to baseline values, remains a slight decrease in plasma volume and an increase in plasma renin.
Pharmacokinetics
Absorption
Reserpine is rapidly absorbed after oral administration. Systemic bioavailability is 50%. Digidralazin rapidly absorbed after oral administration. In blood plasma digidralazin located mainly in the form of unchanged digidralazina and gidrazonovyh substances formed by the metabolism of the basic substance. Approximately 10% digidralazina is in the blood plasma in the form of hydralazine. Hydrochlorothiazide is absorbed after oral administration of 60-80%. Tmax in plasma - 1.5-3 h. Changes in absorption under the influence of food intake have no clinical significance. In the range of therapeutic doses of systemic bioavailability of hydrochlorothiazide is approximately proportional to size of the dose. When taken regularly digidralazina its pharmacokinetics is not altered.
Distribution
Relative Vd reserpine on average 9.1 l / kg (range, 6.4 to 11.8 l / kg). Linking to plasma proteins is more than 96% (albumin and lipoproteins). Hydrochlorothiazide accumulates in erythrocytes. In the phase of elimination, its concentration in red blood cells 3-9 times higher than in plasma. Linking to plasma proteins - 40-70%. Vd in the terminal phase of elimination is 3-6 L / kg (equivalent to 210-420 hp in body weight 70 kg).
Metabolism
Reserpine is metabolized in the intestine and liver. The main metabolites are metilrezerpat and trimetoksibenzoynaya acid. Digidralazin metabolized significantly by oxidation (the formation of hydrazones), and acetylation. Hydrochlorothiazide is metabolized in a very small extent. His only found in trace amounts of metabolite is 2-amino-4-chloro-N-benzendisulfonamid.
Withdrawal
Derivation of reserpine and its metabolites from blood plasma occurs in two phases: T1 / 2 in the α-phase is 4.5 hours; T1 / 2 in β-phase - 271 h. The average value of T1 / 2 of the unmodified substance is 33 hours total clearance of reserpine an average of 245 ml / min. During the first 96 h after ingestion of 8% dose was excreted by the kidneys, mainly in the form of metabolites, and 62% - through the intestine, mainly in unchanged form. T1 / 2 of the unmodified digidralazina averages 4 hours total clearance averaged 1450 ml / min. Once inside, about 46% of applied dose was excreted within 24 hours, mostly in the form of metabolites, mainly through the intestine. About 0.5% of applied dose found in urine as unchanged substance.
Derivation of hydrochlorothiazide from plasma-phase: T1 / 2 in α-phase is 2 h, T1 / 2 in β-phase - about 10 hours in patients with normal renal function, excretion is carried out almost exclusively by the kidneys. In general, 50-75% of applied inside the dose was excreted in the urine unchanged.
Pharmacokinetics in special clinical situations
In elderly patients and patients with renal clearance of hydrochlorothiazide is considerably reduced, which leads to a significant increase of its concentration in blood plasma. Reduced clearance, were observed in elderly patients, appears to be associated with reduced kidney function. In patients with cirrhosis of the liver changes in the pharmacokinetics of hydrochlorothiazide is not marked. In elderly patients and patients with impaired renal function, the average therapeutic dose Adelfan-Ezidreks may be lower than in younger patients with normal renal function.
In patients with impaired renal function and / or liver may occur cumulation digidralazina. In patients with renal insufficiency observed slow excretion reserpine, which, however, offset by an increase in its excretion through the intestine. In these cases, to avoid the cumulation of reserpine in the body requires correction of a single dose Adelfan-Ezidreks or increased intervals between doses, taking into account the dynamics of blood pressure and tolerability.
Statement
hypertension.
Dosage regimen
Drug is taken with food and drank water. Dose should be selected individually.
Treatment begins with a minimal dose, which can be gradually (not more than every 2-3 weeks) increase, depending on patient response to treatment. The daily dose is usually 1-3 pi. The maximum daily dose - 3 Tab. Multiplicity taking the drug - 2-3 times / day.
If adequate blood pressure control could not be reached, treatment should be reviewed and possibly go to a drug other pharmacological groups (beta-blocker, calcium channel blocker of the slow, ACE inhibitor).
In elderly patients, as well as in patients with hepatic impairment a single dose of the drug or the interval between his appointment should be set with caution, taking into account the desired clinical response to treatment and tolerability.
Side effect
Components Adelfan-Ezidreks present it in lower doses, compared with the same doses of drugs prescribed for the treatment of hypertension separately. Nevertheless, may experience the following adverse events, which are characteristic of the individual components.
We used the following criteria for assessing the incidence of adverse events: the concept of "often" use if adverse events observed in more than 10% of patients, the concept of "sometimes" - from 1-10%, the term "rare" - a 0.001-1% the concept of "occasionally" - less than 0.001% of patients.
Reserpine
On the part of the gastrointestinal tract: sometimes - diarrhea, dry mouth, increased secretion of gastric juice, increased salivation, rarely - nausea, vomiting, increase appetite, ulceration, and in some cases - gastro-intestinal bleeding.
Since the cardiovascular system: Sometimes - sinus bradycardia, edema, rare - arrhythmia, pain behind the sternum, suggesting angina pectoris, orthostatic hypotension, flushing of the face, and in some cases - syncope, heart failure, ischemic.
On the part of the respiratory system: sometimes - swelling of the mucous membrane of the nose, shortness of breath, and in some cases - nosebleeds.
From the side of the central nervous system: sometimes - dizziness, depression, irritability, nightmares, fatigue, seldom - extrapyramidal disorders (including Parkinson's), headache, anxiety, impaired concentration, stupor, disorientation, and in some cases - swelling of the brain.
On the part of the urogenital system: rarely - a violation of potency and ejaculation, in some cases - dysuria, glomerulonephritis.
On the part of the endocrine system and metabolism: sometimes - an increase of body weight; rarely - increased secretion of prolactin, galactorrhea, gynecomastia, in some cases - swelling of the mammary glands.
From the senses: sometimes - blurred vision, conjunctival hyperemia, lacrimation, and in some cases - hearing impairment.
Other: rarely - eczema, itching, decreased libido, and in some cases - purpura, anemia, and thrombocytopenia.
Digidralazina sulfate
Since the cardiovascular system: often - tachycardia, palpitations, and sometimes - a rush of blood to his face, marked reduction of blood pressure, angina, rarely - edema, heart failure.
On the part of the gastrointestinal tract: sometimes - dyspepsia, nausea, vomiting, diarrhea.
From the Liver: rare - the jaundice, abnormal liver function, hepatitis.
From the side of the central nervous system and peripheral nervous systems: common - headache, and sometimes - dizziness rare - excitement, anorexia, irritability, anxiety state, anxiety, peripheral neuritis, paresthesia (these side effects are eliminated in the appointment of pyridoxine), and in certain cases - depressed mood .
From the hemopoietic system: rarely - anemia, leukopenia, thrombocytopenia.
Allergic and immunological reactions: seldom - volchanochnopodobny syndrome.
Other: sometimes - arthralgia; rarely - weight loss, fever, weakness, skin rash, itching.
Hydrochlorothiazide
From the water-electrolyte balance and metabolism: often - mainly when used in high doses - hypokalaemia, increased blood lipids, and sometimes - hyponatremia, gipomagniemiya, hyperuricemia, seldom - hypercalcemia, hyperglycemia, Glycosuria, increased metabolic abnormalities in diabetes mellitus; in some cases - gipohloremichesky alkalosis.
Dermatological reactions: occasionally - urticaria, other skin rashes, rarely - photosensitivity, in some cases - necrotizing vasculitis, toxic epidermal necrolysis, cutaneous manifestations volchanochnopodobnogo syndrome, exacerbation of cutaneous manifestations of lupus erythematosus.
On the part of the gastrointestinal tract, liver and pancreas: sometimes - loss of appetite, moderate nausea and vomiting; rarely - discomfort, constipation, diarrhea, intrahepatic cholestasis, jaundice, and in some cases - pancreatitis.
Since the cardiovascular system: sometimes - orthostatic hypotension (which may worsen while alcohol and while the application of anesthetics and sedatives), rarely - arrhythmias.
From the side of the central nervous system and sensory organs: rarely - headache, dizziness, sleep disorders, depression, paresthesia, visual disturbances (especially in the first weeks of treatment).
On the part of the hemopoietic system: rarely - thrombocytopenia, sometimes with purpura, in some cases - leukopenia, agranulocytosis, bone marrow suppression of hematopoiesis, hemolytic anemia.
Other: Sometimes - impotence, in some instances - hypersensitivity reactions, disorders of respiratory organs, including pneumonia and lung edema.
Contraindications
depression (current or in history);
Parkinson's disease;
epilepsy;
electroconvulsive therapy;
stomach ulcer and duodenal ulcer exacerbation;
ulcerative colitis
pheochromocytoma;
concomitant or recent treatment of MAO inhibitors;
systemic lupus erythematosus (idiopathic);
marked tachycardia and heart failure coupled with a high cardiac output (including with thyrotoxicosis);
heart failure due to mechanical constraints (including the presence of aortic or mitral stenosis or constrictive pericarditis);
isolated right ventricular failure due to pulmonary hypertension (pulmonary, heart);
anuria, marked renal impairment (creatinine clearance less than 30 ml / min);
hepatic impairment;
refractory hypokalemia, hyponatremia, hypercalcemia;
hyperuricemia with clinical manifestations;
Pregnancy
sensitivity to reserpine and related compounds, or other digidralazinu gidrazinoftalazinam, hydrochlorothiazide or other sulfonamide derivatives.
You should not use the drug in patients under 18 years of age (efficacy and safety have not been established).
Pregnancy and lactation
Adelfan-Ezidreks contraindicated in pregnancy for the following reasons. Reserpine, in the case of his appointment before the birth, the newborn may cause pronounced sleepiness, swelling of the nasal mucosa and anorexia. The impact of thiazide diuretics, including hydrochlorothiazide, resulted in the emergence of the fetus and newborn thrombocytopenia. Because thiazide diuretics do not prevent the appearance and does not affect the severity of signs of toxicity during pregnancy (edema, proteinuria, arterial hypertension), they should not be given for this indication. Reserpine, hydrochlorothiazide and digidralazin penetrate into breast milk. Newborn infants reserpine may cause the above reaction. Hydrochlorothiazide may suppress lactation. Apply Adelfan-Ezidreks during lactation is not recommended. No studies on the effect of Adelfan-Ezidreks the reproductive animals.
Application for violations of liver function
In patients with impaired liver function single dose of a drug or the interval between his appointment should be set with caution, taking into account the desired clinical response to treatment and tolerability. Need to systematically monitor the status of patients with impaired liver function, given the possibility of a part of the liver of rare but serious side effects digidralazina. It should also be borne in mind that even minor violations of water-electrolyte balance caused by thiazide diuretics may provoke a hepatic coma, especially in patients with cirrhosis.
Application for violations of renal function
In patients with renal clearance of hydrochlorothiazide is considerably reduced, which leads to a significant increase of its concentration in blood plasma. Reduced clearance, were observed in elderly patients, appears to be associated with reduced kidney function.
In elderly patients and patients with impaired renal function, the average therapeutic dose Adelfan-Ezidreks may be lower than in younger patients with normal renal function. In patients with impaired renal function may be a cumulative digidralazina. In patients with renal insufficiency observed slow excretion reserpine, which, however, offset by an increase in its excretion through the intestine. In these cases, to avoid the cumulation of reserpine in the body require correction of a single dose Adelfan-Ezidreks or increased intervals between doses, taking into account the dynamics of blood pressure and tolerability.
Cautions
Patients after myocardial infarction, should not appoint digidralazin until until all the stabilization period after myocardial infarction. As in the case of the appointment of any antihypertensive drugs with a marked hypotensive effect, should be very careful in the appointment of the drug Adelfan-Ezidreks patients with coronary and cerebral atherosclerosis. In these cases, to avoid sharp decline in blood pressure, because this may lead to a reduction of blood flow. The following precautions apply not only to each component separately, but also to the drug-Adelfan Ezidreks in general.
Since reserpine increases motility and secretion in the gastrointestinal tract, caution should be exercised in its application in patients with gastric ulcer and duodenal ulcer in the anamnesis, as well as in patients with erosive gastritis and cholelithiasis. Also, caution should be exercised in patients with heart failure, sinus bradycardia, conduction disturbances, as well as in patients with recent myocardial infarction.
Caution must be exercised in patients with suspected coronary heart disease. Invoked digidralazinom tachycardia can cause an attack of angina and ECG changes, indicating myocardial ischemia. In some cases, did not prevent communication of myocardial infarction receiving digidralazina.
Avoid use of the drug-Adelfan Ezidreks (especially when used in conjunction with preparations of potassium or potassium-sparing diuretics), patients receiving ACE inhibitors. As with the application of other thiazide diuretics, caution should be exercised in patients with diabetes and gout. If you suspect depression, medication should be lifted immediately, because there is a risk of suicidal actions. Depression provoked by reserpine (especially in cases of drug-Adelfan Ezidreks in high doses), may be heavy enough to trigger suicidal action. It may persist for several months following drug discontinuation.
Application digidralazina can lead to sodium and water retention in the body and, consequently, to the development of edema and reduced urine output.
Need to systematically monitor the status of patients with impaired liver function, given the possibility of a part of the liver of rare but serious side effects digidralazina. It should also be borne in mind that even minor violations of water-electrolyte balance caused by thiazide diuretics may provoke a hepatic coma, especially in patients with cirrhosis. Currently, there are few reported cases of volchanochnopodobnogo syndrome associated with receiving digidralazina. Mild forms of this syndrome manifested arthralgias, sometimes accompanied by fever and skin rashes, to remove the drug, these symptoms disappear on their own. In more severe cases, the clinical picture is similar to the manifestations of systemic lupus erythematosus; complete disappearance of symptoms can be achieved only with long-term treatment of GCS. The frequency of occurrence of this syndrome is directly dependent on the dose and duration of treatment. In connection with this for a long maintenance therapy is recommended to use the minimum effective dose.
During treatment digidralazinom seems appropriate to determine the antinuclear factor in the blood plasma every 6 months. In case of antinuclear factor should be systematically identified his credits. When developing clinical volchanochnopodobnogo Syndrome, the drug should be lifted immediately. Reserpine should cancel at least 7 days prior to electroconvulsive therapy.
Cancel reserpine before surgery is no guarantee that during the operation will not have hemodynamic instability. It is important to warn the anesthesiologist that the patient takes reserpine, and reflect this in the management of the patient. Cases are known to reduce blood pressure in patients receiving Rauwolfia preparations. During the surgical intervention in patients receiving digidralazin, there may be a pronounced decrease blood pressure.
Against the background of hydrochlorothiazide hypokalemia develops. Hypokalaemia may increase the sensitivity of the myocardium or enhance response of the heart to the toxic effects of digitalis drugs. The risk of hypokalemia increased in cirrhosis, rapidly developing increase in diuresis, insufficient intake of potassium from food, concomitant therapy of GCS, β2-adrenoceptor stimulants, or ACTH. In order to timely detect possible violations of the electrolyte balance is necessary to determine the content of electrolytes in the plasma at the beginning of treatment and at regular intervals during treatment. Nonspecific manifestations of disorders of electrolyte balance observed in some cases, have been dry mouth, thirst, weakness, drowsiness, restlessness, muscle pains and cramps, muscle weakness, reduced blood pressure, oliguria, tachycardia, nausea.
Thiazide diuretics, causing a reduction in calcium excretion. In a few patients receiving long-term thiazide diuretics, were found pathological changes in the parathyroid gland, accompanied by hypercalcaemia and hypophosphataemia. In case of hypercalcemia required to conduct additional surveys to refine the diagnosis. There were no complications, which are usually associated with hyperparathyroidism, such as the formation of kidney stones, bone resorption, peptic ulcer. Thiazide diuretics cause a rise in urinary excretion of magnesium, which may lead to gipomagniemii. When used in high doses, thiazide diuretics may cause a decrease in glucose tolerance and lead to increased concentrations of plasma cholesterol, triglycerides and uric acid.
The use of reserpine influences the results of determination of urinary 17-ketosteroids and 17-gidroksikortikosteroidov colorimetric method, leading to an underestimation of these results.
Effects on ability to drive vehicles and management mechanisms
Adelfan-Ezidreks may violate the patient's ability to make quick reactions, especially in the beginning of treatment. As with the appointment of other antihypertensive drugs, patients, managers of vehicles and machinery should be warned about the possibility of reducing the speed of psychomotor reactions, and be careful.
Overdose
Symptoms: There may be headache, dizziness, drowsiness, confusion, coma, extrapyramidal disorders, convulsions, paresthesia, persistent miosis. There may be nausea, vomiting, diarrhea. Also reported the appearance of tachycardia, marked reduction in blood pressure, collapse, and sometimes - on myocardial ischemia with such manifestations as angina and arrhythmias. There may be respiratory depression, disruption of water-electrolyte balance, muscle weakness, muscle cramps (especially calf), oliguria.
Treatment: if the patient is conscious, should induce vomiting or gastric lavage, give activated charcoal. In marked decrease in blood pressure patient should be put with raised legs and shows the introduction of plasma substitutes and correction of electrolyte disturbances, if necessary, with caution you can enter vasoactive funds. In the case of diarrhea introduced anticholinergic. In the case of seizures demonstrates the use of anticonvulsants (slow in / diazepam). In the case of pronounced respiratory depression shows an IVL. The duration of observation of the patient is not less than 72 hours since reserpine has prolonged action.
Drug Interactions
The hypotensive effect Adelfan-Ezidreks increases while receiving other antihypertensive drugs: guanetidina, alpha-methyldopa, beta-blockers, vasodilators, calcium channel blockers slow, ACE inhibitors.
It is also possible number of interactions of individual components of the drug.
Reserpine
You must undo the MAO inhibitors for at least 14 days before the start of therapy reserpine. If necessary, the appointment of MAO inhibitors, patients receiving reserpine, MAO inhibitors should be administered no less than 14 days after discontinuation of reserpine. At simultaneous application of reserpine and MAO inhibitors may be hyperactive, hypertensive crises. Reserpine enhances the depressant effects of alcohol on the central nervous system, funds for general anesthesia, some antihistamines, barbiturates and tricyclic antidepressants. Reserpine reduces the effect of levodopa. The simultaneous use of reserpine and tricyclic antidepressants can diminish hypotensive effect of reserpine.
Reserpine should be lifted for a few days before the planned operation to avoid excessive reduction of blood pressure during the general anesthetic. Appointment of reserpine in combination with antiarrhythmic drugs or medications of digitalis may cause sinus bradycardia. Reserpine may intensify the effects of epinephrine (adrenaline) or other sympathomimetic agents (be careful with the simultaneous use of bechic, nasal drops, eye drops).
Digidralazina sulfate
The simultaneous use of tricyclic antidepressants, neuroleptics, as well as etanolsoderzhaschih drugs may increase the hypotensive effect digidralazina. Appointment digidralazina just before or shortly after the appointment of diazoxide may cause a marked reduction of blood pressure.
Hydrochlorothiazide
With the simultaneous use of hydrochlorothiazide and preparations of lithium may increase the concentration of lithium in the blood, so in this case requires a systematic monitoring of the level of lithium in the blood. In cases where drugs lithium cause polyuria, hydrochlorothiazide may cause a paradoxical antidiuretic effect. Hydrochlorothiazide may increase the effects of nondepolarizing muscle relaxants. Gipokaliemichesky effect induced by diuretics may increase when used with the SCS, ACTH, amphotericin, karbenoksolona. Hypokalemia and gipomagniemiya (undesirable effects of thiazide diuretics) can contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides. In the application of hydrochlorothiazide in patients with diabetes may require adjustment of insulin doses and oral hypoglycemic agents.
Simultaneous appointment of NSAID (including indomethacin) can reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. There are isolated reports of worsening renal function in susceptible patients.
Absorption of hydrochlorothiazide is violated in the presence of anion exchange resins. Absorption of hydrochlorothiazide from the gastrointestinal tract, while a single application kolestiramina and colestipol decreased by 85% and 43% respectively due to binding of these compounds.
The simultaneous use of thiazide diuretics (including hydrochlorothiazide) may increase the risk of hypersensitivity reactions to allopurinol, increasing the risk of side effects of amantadine and enhance the hyperglycemic effect of diazoxide, reduce renal excretion of cytotoxic drugs (including cyclophosphamide, methotrexate is) and strengthen their mielosupressivnoe action.
Anticholinergic drugs (including atropine, biperiden) may increase the bioavailability of hydrochlorothiazide, which is connected with decrease gastrointestinal motor activity and rate of gastric emptying. Simultaneous reception of hydrochlorothiazide with vitamin D or calcium supplementation may lead to increased levels of calcium in the blood.
With simultaneous use of hydrochlorothiazide and cyclosporine increases the risk of developing hyperuricemia and gout. There are reports on the development of hemolytic anemia while receiving hydrochlorothiazide drugs and dopegyt.
Terms and Conditions of storage
List B. The drug should be protected from light and moisture. Keep out of reach of children at or above 30 ° C.
Shelf life - 4 years. The drug should not be used after the expiration date.
Tablets 1 tab. Reserpine 100 mcg digidralazina sulphate (hydrated) 10 mg hydrochlorothiazide 10 mg.
Excipients: mannitol, corn starch, magnesium stearate, talc, disodium edetate.
Clinico-pharmacological group: antihypertensive drugs.
Pharmacological action
Adelfan-Ezidreks is a combination of three antihypertensive components having different points of application of their actions and mutually complementary antihypertensive effects of each other.
Reserpine causes depletion of the depot of catecholamines in postganglionic sympathetic nerve endings and in the CNS. Consequently, the ability to deposit catecholamines disturbed for quite a long period of time.
Catecholamine depletion leads to disruption of impulse transmission in the sympathetic nerve endings, which in turn leads to a decrease in tone of the sympathetic nervous system (the parasympathetic nervous system activity does not change). Thus, reserpine lowers high blood pressure and heart rate. In addition, reserpine causes sedation. Reserpine depletes reserves and other neurotransmitters, including serotonin, dopamine, adrenaline and neuropeptides in the central and peripheral neurons. The effects of reserpine may play a role in the implementation of its pharmacological effects and antihypertensive action. After receiving reserpine into its antihypertensive effect develops slowly, to a maximum of action is achieved only after 2-3 weeks and maintained for a long time.
Digidralazina sulfate - arterial vasodilator, lowers the tone of the smooth muscle of arterial vessels (mostly arterioles) and reduces TPVR. The mechanism of this action at the cellular level remains unclear. To a greater degree of vascular resistance decreased in the vessels of the heart, brain, kidneys and other internal organs, and to a lesser extent - in the vessels of the skin and skeletal muscles. If the blood pressure reduction is not pronounced, blood flow in the enlarged bloodstream as a whole increases. Preferential expansion of arterioles and venules are not, reduces the severity of orthostatic hypotension and improves cardiac output. Expansion vessels, leading to a decrease in blood pressure (diastolic more than systolic), accompanied by a reflex increase in heart rate, stroke volume and cardiac output.
The reflex increase in heart rate and cardiac output can be offset by the expense of combining digidralazina with reserpine, which inhibits the sympathetic nervous system.
Hydrochlorothiazide - thiazide diuretics - is acting in the cortical segment of the loop of Henle and distal renal tubules. Hinders reabsorption of sodium and chloride ions (due to an antagonistic interaction with the transport enzyme Na + Cl-) and increases the reabsorption of calcium ions (mechanism unknown). Increasing the amount and / or rate of supply of sodium ions and water in the cortical segment of collecting tubules leads to increased secretion and excretion of potassium ions and hydrogen.
In patients with normal renal function, increased urine output observed after a single use of hydrochlorothiazide in a dose of 12.5 mg. Increased urinary excretion of sodium and chlorine, and somewhat less pronounced increase kaliyureza depend on the dose of hydrochlorothiazide. After taking the drug inside the diuretic and natriuretic effects begin within 1-2 h, reaching a maximum after 4-6 h and continued for 10-12 h. Diuresis caused by thiazide, first leads to a decrease in the volume of circulating plasma cardiac output and systemic blood pressure. Possibility of activation of the renin-angiotensin-aldosterone system.
With prolonged use of hydrochlorothiazide maintain the hypotensive effect is provided, probably due to a decrease TPVR. Cardiac output returned to baseline values, remains a slight decrease in plasma volume and an increase in plasma renin.
Pharmacokinetics
Absorption
Reserpine is rapidly absorbed after oral administration. Systemic bioavailability is 50%. Digidralazin rapidly absorbed after oral administration. In blood plasma digidralazin located mainly in the form of unchanged digidralazina and gidrazonovyh substances formed by the metabolism of the basic substance. Approximately 10% digidralazina is in the blood plasma in the form of hydralazine. Hydrochlorothiazide is absorbed after oral administration of 60-80%. Tmax in plasma - 1.5-3 h. Changes in absorption under the influence of food intake have no clinical significance. In the range of therapeutic doses of systemic bioavailability of hydrochlorothiazide is approximately proportional to size of the dose. When taken regularly digidralazina its pharmacokinetics is not altered.
Distribution
Relative Vd reserpine on average 9.1 l / kg (range, 6.4 to 11.8 l / kg). Linking to plasma proteins is more than 96% (albumin and lipoproteins). Hydrochlorothiazide accumulates in erythrocytes. In the phase of elimination, its concentration in red blood cells 3-9 times higher than in plasma. Linking to plasma proteins - 40-70%. Vd in the terminal phase of elimination is 3-6 L / kg (equivalent to 210-420 hp in body weight 70 kg).
Metabolism
Reserpine is metabolized in the intestine and liver. The main metabolites are metilrezerpat and trimetoksibenzoynaya acid. Digidralazin metabolized significantly by oxidation (the formation of hydrazones), and acetylation. Hydrochlorothiazide is metabolized in a very small extent. His only found in trace amounts of metabolite is 2-amino-4-chloro-N-benzendisulfonamid.
Withdrawal
Derivation of reserpine and its metabolites from blood plasma occurs in two phases: T1 / 2 in the α-phase is 4.5 hours; T1 / 2 in β-phase - 271 h. The average value of T1 / 2 of the unmodified substance is 33 hours total clearance of reserpine an average of 245 ml / min. During the first 96 h after ingestion of 8% dose was excreted by the kidneys, mainly in the form of metabolites, and 62% - through the intestine, mainly in unchanged form. T1 / 2 of the unmodified digidralazina averages 4 hours total clearance averaged 1450 ml / min. Once inside, about 46% of applied dose was excreted within 24 hours, mostly in the form of metabolites, mainly through the intestine. About 0.5% of applied dose found in urine as unchanged substance.
Derivation of hydrochlorothiazide from plasma-phase: T1 / 2 in α-phase is 2 h, T1 / 2 in β-phase - about 10 hours in patients with normal renal function, excretion is carried out almost exclusively by the kidneys. In general, 50-75% of applied inside the dose was excreted in the urine unchanged.
Pharmacokinetics in special clinical situations
In elderly patients and patients with renal clearance of hydrochlorothiazide is considerably reduced, which leads to a significant increase of its concentration in blood plasma. Reduced clearance, were observed in elderly patients, appears to be associated with reduced kidney function. In patients with cirrhosis of the liver changes in the pharmacokinetics of hydrochlorothiazide is not marked. In elderly patients and patients with impaired renal function, the average therapeutic dose Adelfan-Ezidreks may be lower than in younger patients with normal renal function.
In patients with impaired renal function and / or liver may occur cumulation digidralazina. In patients with renal insufficiency observed slow excretion reserpine, which, however, offset by an increase in its excretion through the intestine. In these cases, to avoid the cumulation of reserpine in the body requires correction of a single dose Adelfan-Ezidreks or increased intervals between doses, taking into account the dynamics of blood pressure and tolerability.
Statement
hypertension.
Dosage regimen
Drug is taken with food and drank water. Dose should be selected individually.
Treatment begins with a minimal dose, which can be gradually (not more than every 2-3 weeks) increase, depending on patient response to treatment. The daily dose is usually 1-3 pi. The maximum daily dose - 3 Tab. Multiplicity taking the drug - 2-3 times / day.
If adequate blood pressure control could not be reached, treatment should be reviewed and possibly go to a drug other pharmacological groups (beta-blocker, calcium channel blocker of the slow, ACE inhibitor).
In elderly patients, as well as in patients with hepatic impairment a single dose of the drug or the interval between his appointment should be set with caution, taking into account the desired clinical response to treatment and tolerability.
Side effect
Components Adelfan-Ezidreks present it in lower doses, compared with the same doses of drugs prescribed for the treatment of hypertension separately. Nevertheless, may experience the following adverse events, which are characteristic of the individual components.
We used the following criteria for assessing the incidence of adverse events: the concept of "often" use if adverse events observed in more than 10% of patients, the concept of "sometimes" - from 1-10%, the term "rare" - a 0.001-1% the concept of "occasionally" - less than 0.001% of patients.
Reserpine
On the part of the gastrointestinal tract: sometimes - diarrhea, dry mouth, increased secretion of gastric juice, increased salivation, rarely - nausea, vomiting, increase appetite, ulceration, and in some cases - gastro-intestinal bleeding.
Since the cardiovascular system: Sometimes - sinus bradycardia, edema, rare - arrhythmia, pain behind the sternum, suggesting angina pectoris, orthostatic hypotension, flushing of the face, and in some cases - syncope, heart failure, ischemic.
On the part of the respiratory system: sometimes - swelling of the mucous membrane of the nose, shortness of breath, and in some cases - nosebleeds.
From the side of the central nervous system: sometimes - dizziness, depression, irritability, nightmares, fatigue, seldom - extrapyramidal disorders (including Parkinson's), headache, anxiety, impaired concentration, stupor, disorientation, and in some cases - swelling of the brain.
On the part of the urogenital system: rarely - a violation of potency and ejaculation, in some cases - dysuria, glomerulonephritis.
On the part of the endocrine system and metabolism: sometimes - an increase of body weight; rarely - increased secretion of prolactin, galactorrhea, gynecomastia, in some cases - swelling of the mammary glands.
From the senses: sometimes - blurred vision, conjunctival hyperemia, lacrimation, and in some cases - hearing impairment.
Other: rarely - eczema, itching, decreased libido, and in some cases - purpura, anemia, and thrombocytopenia.
Digidralazina sulfate
Since the cardiovascular system: often - tachycardia, palpitations, and sometimes - a rush of blood to his face, marked reduction of blood pressure, angina, rarely - edema, heart failure.
On the part of the gastrointestinal tract: sometimes - dyspepsia, nausea, vomiting, diarrhea.
From the Liver: rare - the jaundice, abnormal liver function, hepatitis.
From the side of the central nervous system and peripheral nervous systems: common - headache, and sometimes - dizziness rare - excitement, anorexia, irritability, anxiety state, anxiety, peripheral neuritis, paresthesia (these side effects are eliminated in the appointment of pyridoxine), and in certain cases - depressed mood .
From the hemopoietic system: rarely - anemia, leukopenia, thrombocytopenia.
Allergic and immunological reactions: seldom - volchanochnopodobny syndrome.
Other: sometimes - arthralgia; rarely - weight loss, fever, weakness, skin rash, itching.
Hydrochlorothiazide
From the water-electrolyte balance and metabolism: often - mainly when used in high doses - hypokalaemia, increased blood lipids, and sometimes - hyponatremia, gipomagniemiya, hyperuricemia, seldom - hypercalcemia, hyperglycemia, Glycosuria, increased metabolic abnormalities in diabetes mellitus; in some cases - gipohloremichesky alkalosis.
Dermatological reactions: occasionally - urticaria, other skin rashes, rarely - photosensitivity, in some cases - necrotizing vasculitis, toxic epidermal necrolysis, cutaneous manifestations volchanochnopodobnogo syndrome, exacerbation of cutaneous manifestations of lupus erythematosus.
On the part of the gastrointestinal tract, liver and pancreas: sometimes - loss of appetite, moderate nausea and vomiting; rarely - discomfort, constipation, diarrhea, intrahepatic cholestasis, jaundice, and in some cases - pancreatitis.
Since the cardiovascular system: sometimes - orthostatic hypotension (which may worsen while alcohol and while the application of anesthetics and sedatives), rarely - arrhythmias.
From the side of the central nervous system and sensory organs: rarely - headache, dizziness, sleep disorders, depression, paresthesia, visual disturbances (especially in the first weeks of treatment).
On the part of the hemopoietic system: rarely - thrombocytopenia, sometimes with purpura, in some cases - leukopenia, agranulocytosis, bone marrow suppression of hematopoiesis, hemolytic anemia.
Other: Sometimes - impotence, in some instances - hypersensitivity reactions, disorders of respiratory organs, including pneumonia and lung edema.
Contraindications
depression (current or in history);
Parkinson's disease;
epilepsy;
electroconvulsive therapy;
stomach ulcer and duodenal ulcer exacerbation;
ulcerative colitis
pheochromocytoma;
concomitant or recent treatment of MAO inhibitors;
systemic lupus erythematosus (idiopathic);
marked tachycardia and heart failure coupled with a high cardiac output (including with thyrotoxicosis);
heart failure due to mechanical constraints (including the presence of aortic or mitral stenosis or constrictive pericarditis);
isolated right ventricular failure due to pulmonary hypertension (pulmonary, heart);
anuria, marked renal impairment (creatinine clearance less than 30 ml / min);
hepatic impairment;
refractory hypokalemia, hyponatremia, hypercalcemia;
hyperuricemia with clinical manifestations;
Pregnancy
sensitivity to reserpine and related compounds, or other digidralazinu gidrazinoftalazinam, hydrochlorothiazide or other sulfonamide derivatives.
You should not use the drug in patients under 18 years of age (efficacy and safety have not been established).
Pregnancy and lactation
Adelfan-Ezidreks contraindicated in pregnancy for the following reasons. Reserpine, in the case of his appointment before the birth, the newborn may cause pronounced sleepiness, swelling of the nasal mucosa and anorexia. The impact of thiazide diuretics, including hydrochlorothiazide, resulted in the emergence of the fetus and newborn thrombocytopenia. Because thiazide diuretics do not prevent the appearance and does not affect the severity of signs of toxicity during pregnancy (edema, proteinuria, arterial hypertension), they should not be given for this indication. Reserpine, hydrochlorothiazide and digidralazin penetrate into breast milk. Newborn infants reserpine may cause the above reaction. Hydrochlorothiazide may suppress lactation. Apply Adelfan-Ezidreks during lactation is not recommended. No studies on the effect of Adelfan-Ezidreks the reproductive animals.
Application for violations of liver function
In patients with impaired liver function single dose of a drug or the interval between his appointment should be set with caution, taking into account the desired clinical response to treatment and tolerability. Need to systematically monitor the status of patients with impaired liver function, given the possibility of a part of the liver of rare but serious side effects digidralazina. It should also be borne in mind that even minor violations of water-electrolyte balance caused by thiazide diuretics may provoke a hepatic coma, especially in patients with cirrhosis.
Application for violations of renal function
In patients with renal clearance of hydrochlorothiazide is considerably reduced, which leads to a significant increase of its concentration in blood plasma. Reduced clearance, were observed in elderly patients, appears to be associated with reduced kidney function.
In elderly patients and patients with impaired renal function, the average therapeutic dose Adelfan-Ezidreks may be lower than in younger patients with normal renal function. In patients with impaired renal function may be a cumulative digidralazina. In patients with renal insufficiency observed slow excretion reserpine, which, however, offset by an increase in its excretion through the intestine. In these cases, to avoid the cumulation of reserpine in the body require correction of a single dose Adelfan-Ezidreks or increased intervals between doses, taking into account the dynamics of blood pressure and tolerability.
Cautions
Patients after myocardial infarction, should not appoint digidralazin until until all the stabilization period after myocardial infarction. As in the case of the appointment of any antihypertensive drugs with a marked hypotensive effect, should be very careful in the appointment of the drug Adelfan-Ezidreks patients with coronary and cerebral atherosclerosis. In these cases, to avoid sharp decline in blood pressure, because this may lead to a reduction of blood flow. The following precautions apply not only to each component separately, but also to the drug-Adelfan Ezidreks in general.
Since reserpine increases motility and secretion in the gastrointestinal tract, caution should be exercised in its application in patients with gastric ulcer and duodenal ulcer in the anamnesis, as well as in patients with erosive gastritis and cholelithiasis. Also, caution should be exercised in patients with heart failure, sinus bradycardia, conduction disturbances, as well as in patients with recent myocardial infarction.
Caution must be exercised in patients with suspected coronary heart disease. Invoked digidralazinom tachycardia can cause an attack of angina and ECG changes, indicating myocardial ischemia. In some cases, did not prevent communication of myocardial infarction receiving digidralazina.
Avoid use of the drug-Adelfan Ezidreks (especially when used in conjunction with preparations of potassium or potassium-sparing diuretics), patients receiving ACE inhibitors. As with the application of other thiazide diuretics, caution should be exercised in patients with diabetes and gout. If you suspect depression, medication should be lifted immediately, because there is a risk of suicidal actions. Depression provoked by reserpine (especially in cases of drug-Adelfan Ezidreks in high doses), may be heavy enough to trigger suicidal action. It may persist for several months following drug discontinuation.
Application digidralazina can lead to sodium and water retention in the body and, consequently, to the development of edema and reduced urine output.
Need to systematically monitor the status of patients with impaired liver function, given the possibility of a part of the liver of rare but serious side effects digidralazina. It should also be borne in mind that even minor violations of water-electrolyte balance caused by thiazide diuretics may provoke a hepatic coma, especially in patients with cirrhosis. Currently, there are few reported cases of volchanochnopodobnogo syndrome associated with receiving digidralazina. Mild forms of this syndrome manifested arthralgias, sometimes accompanied by fever and skin rashes, to remove the drug, these symptoms disappear on their own. In more severe cases, the clinical picture is similar to the manifestations of systemic lupus erythematosus; complete disappearance of symptoms can be achieved only with long-term treatment of GCS. The frequency of occurrence of this syndrome is directly dependent on the dose and duration of treatment. In connection with this for a long maintenance therapy is recommended to use the minimum effective dose.
During treatment digidralazinom seems appropriate to determine the antinuclear factor in the blood plasma every 6 months. In case of antinuclear factor should be systematically identified his credits. When developing clinical volchanochnopodobnogo Syndrome, the drug should be lifted immediately. Reserpine should cancel at least 7 days prior to electroconvulsive therapy.
Cancel reserpine before surgery is no guarantee that during the operation will not have hemodynamic instability. It is important to warn the anesthesiologist that the patient takes reserpine, and reflect this in the management of the patient. Cases are known to reduce blood pressure in patients receiving Rauwolfia preparations. During the surgical intervention in patients receiving digidralazin, there may be a pronounced decrease blood pressure.
Against the background of hydrochlorothiazide hypokalemia develops. Hypokalaemia may increase the sensitivity of the myocardium or enhance response of the heart to the toxic effects of digitalis drugs. The risk of hypokalemia increased in cirrhosis, rapidly developing increase in diuresis, insufficient intake of potassium from food, concomitant therapy of GCS, β2-adrenoceptor stimulants, or ACTH. In order to timely detect possible violations of the electrolyte balance is necessary to determine the content of electrolytes in the plasma at the beginning of treatment and at regular intervals during treatment. Nonspecific manifestations of disorders of electrolyte balance observed in some cases, have been dry mouth, thirst, weakness, drowsiness, restlessness, muscle pains and cramps, muscle weakness, reduced blood pressure, oliguria, tachycardia, nausea.
Thiazide diuretics, causing a reduction in calcium excretion. In a few patients receiving long-term thiazide diuretics, were found pathological changes in the parathyroid gland, accompanied by hypercalcaemia and hypophosphataemia. In case of hypercalcemia required to conduct additional surveys to refine the diagnosis. There were no complications, which are usually associated with hyperparathyroidism, such as the formation of kidney stones, bone resorption, peptic ulcer. Thiazide diuretics cause a rise in urinary excretion of magnesium, which may lead to gipomagniemii. When used in high doses, thiazide diuretics may cause a decrease in glucose tolerance and lead to increased concentrations of plasma cholesterol, triglycerides and uric acid.
The use of reserpine influences the results of determination of urinary 17-ketosteroids and 17-gidroksikortikosteroidov colorimetric method, leading to an underestimation of these results.
Effects on ability to drive vehicles and management mechanisms
Adelfan-Ezidreks may violate the patient's ability to make quick reactions, especially in the beginning of treatment. As with the appointment of other antihypertensive drugs, patients, managers of vehicles and machinery should be warned about the possibility of reducing the speed of psychomotor reactions, and be careful.
Overdose
Symptoms: There may be headache, dizziness, drowsiness, confusion, coma, extrapyramidal disorders, convulsions, paresthesia, persistent miosis. There may be nausea, vomiting, diarrhea. Also reported the appearance of tachycardia, marked reduction in blood pressure, collapse, and sometimes - on myocardial ischemia with such manifestations as angina and arrhythmias. There may be respiratory depression, disruption of water-electrolyte balance, muscle weakness, muscle cramps (especially calf), oliguria.
Treatment: if the patient is conscious, should induce vomiting or gastric lavage, give activated charcoal. In marked decrease in blood pressure patient should be put with raised legs and shows the introduction of plasma substitutes and correction of electrolyte disturbances, if necessary, with caution you can enter vasoactive funds. In the case of diarrhea introduced anticholinergic. In the case of seizures demonstrates the use of anticonvulsants (slow in / diazepam). In the case of pronounced respiratory depression shows an IVL. The duration of observation of the patient is not less than 72 hours since reserpine has prolonged action.
Drug Interactions
The hypotensive effect Adelfan-Ezidreks increases while receiving other antihypertensive drugs: guanetidina, alpha-methyldopa, beta-blockers, vasodilators, calcium channel blockers slow, ACE inhibitors.
It is also possible number of interactions of individual components of the drug.
Reserpine
You must undo the MAO inhibitors for at least 14 days before the start of therapy reserpine. If necessary, the appointment of MAO inhibitors, patients receiving reserpine, MAO inhibitors should be administered no less than 14 days after discontinuation of reserpine. At simultaneous application of reserpine and MAO inhibitors may be hyperactive, hypertensive crises. Reserpine enhances the depressant effects of alcohol on the central nervous system, funds for general anesthesia, some antihistamines, barbiturates and tricyclic antidepressants. Reserpine reduces the effect of levodopa. The simultaneous use of reserpine and tricyclic antidepressants can diminish hypotensive effect of reserpine.
Reserpine should be lifted for a few days before the planned operation to avoid excessive reduction of blood pressure during the general anesthetic. Appointment of reserpine in combination with antiarrhythmic drugs or medications of digitalis may cause sinus bradycardia. Reserpine may intensify the effects of epinephrine (adrenaline) or other sympathomimetic agents (be careful with the simultaneous use of bechic, nasal drops, eye drops).
Digidralazina sulfate
The simultaneous use of tricyclic antidepressants, neuroleptics, as well as etanolsoderzhaschih drugs may increase the hypotensive effect digidralazina. Appointment digidralazina just before or shortly after the appointment of diazoxide may cause a marked reduction of blood pressure.
Hydrochlorothiazide
With the simultaneous use of hydrochlorothiazide and preparations of lithium may increase the concentration of lithium in the blood, so in this case requires a systematic monitoring of the level of lithium in the blood. In cases where drugs lithium cause polyuria, hydrochlorothiazide may cause a paradoxical antidiuretic effect. Hydrochlorothiazide may increase the effects of nondepolarizing muscle relaxants. Gipokaliemichesky effect induced by diuretics may increase when used with the SCS, ACTH, amphotericin, karbenoksolona. Hypokalemia and gipomagniemiya (undesirable effects of thiazide diuretics) can contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides. In the application of hydrochlorothiazide in patients with diabetes may require adjustment of insulin doses and oral hypoglycemic agents.
Simultaneous appointment of NSAID (including indomethacin) can reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. There are isolated reports of worsening renal function in susceptible patients.
Absorption of hydrochlorothiazide is violated in the presence of anion exchange resins. Absorption of hydrochlorothiazide from the gastrointestinal tract, while a single application kolestiramina and colestipol decreased by 85% and 43% respectively due to binding of these compounds.
The simultaneous use of thiazide diuretics (including hydrochlorothiazide) may increase the risk of hypersensitivity reactions to allopurinol, increasing the risk of side effects of amantadine and enhance the hyperglycemic effect of diazoxide, reduce renal excretion of cytotoxic drugs (including cyclophosphamide, methotrexate is) and strengthen their mielosupressivnoe action.
Anticholinergic drugs (including atropine, biperiden) may increase the bioavailability of hydrochlorothiazide, which is connected with decrease gastrointestinal motor activity and rate of gastric emptying. Simultaneous reception of hydrochlorothiazide with vitamin D or calcium supplementation may lead to increased levels of calcium in the blood.
With simultaneous use of hydrochlorothiazide and cyclosporine increases the risk of developing hyperuricemia and gout. There are reports on the development of hemolytic anemia while receiving hydrochlorothiazide drugs and dopegyt.
Terms and Conditions of storage
List B. The drug should be protected from light and moisture. Keep out of reach of children at or above 30 ° C.
Shelf life - 4 years. The drug should not be used after the expiration date.
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