ACCUSIDE
Active material: Gidroxlorotiazid, Quinapril
When ATH: C09BA06
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
Manufacturer: GOEDECKE GmbH (Germany)
DOSAGE FORM, COMPOSITION AND PACKING
Pills, coated Pink colour, Oval, lenticular, a mark on both sides and marked “PD 222” on one side.
| 1 tab. | |
| hinapril (the hydrochloride) | 10 mg |
| gidroxlorotiazid | 12.5 mg |
Excipients: magnesium carbonate, lactose monohydrate, povidone K25, krospovydon, magnesium stearate.
The composition of the coating film: Opadry pink OY-S-6937 (contains hydroxypropyl methylcellulose, Titanium dioxide (E171), hydroxypropyl cellulose, polyethylene glycol 400 and iron oxide (E172)), wax kandelila.
10 PC. – blisters (3) – packs cardboard.
Pills, coated Pink colour, Triangular, lenticular, with scribble and marking “PD 220” on one side.
| 1 tab. | |
| hinapril (the hydrochloride) | 20 mg |
| gidroxlorotiazid | 12.5 mg |
Excipients: magnesium carbonate, lactose monohydrate, povidone K25, krospovydon, magnesium stearate.
The composition of the coating film: Opadry pink OY-S-6937 (contains hydroxypropyl methylcellulose, Titanium dioxide (E171), hydroxypropyl cellulose, polyethylene glycol 400 and iron oxide (E172)), wax kandelila.
10 PC. – blisters (3) – packs cardboard.
Pills, coated Pink colour, round, lenticular, labeled “PD 223” on one side.
| 1 tab. | |
| hinapril (the hydrochloride) | 20 mg |
| gidroxlorotiazid | 25 mg |
Excipients: magnesium carbonate, lactose monohydrate, povidone K25, krospovydon, magnesium stearate.
The composition of the coating film: Opadry pink OY-S-6937 (contains hydroxypropyl methylcellulose, Titanium dioxide (E171), hydroxypropyl cellulose, polyethylene glycol 400 and iron oxide (E172)), wax kandelila.
10 PC. – blisters (3) – packs cardboard.
Pharmacological action
Combined antihypertensive drug, which contains the ACE inhibitor quinapril and the thiazide diuretic hydrochlorothiazide in three different ratios.
Quinapril – ACE inhibitor. ACE catalyzes the formation of angiotensin II, which has a vasoconstrictor effect and controls vascular tone, incl. by stimulating the secretion of aldosterone by the adrenal cortex. Quinapril inhibits circulating and tissue ACE and causes a decrease in vasopressor activity and secretion of aldosterone. Elimination of the negative effect of angiotensin II on renin secretion by the feedback mechanism leads to an increase in blood plasma renin activity. At the same time, a decrease in blood pressure is accompanied by a decrease in OPSS and renal vascular resistance, while heart rate changes, cardiac output, renal blood flow, glomerular filtration rates and filtration fraction are negligible or absent. Besides, quinapril slightly reduces potassium loss, caused by hydrochlorothiazide, which, due to its diuretic action, also increases the activity of blood plasma renin, secretion of aldosterone, reduces serum potassium levels and increases urinary excretion.
Gidroxlorotiazid – diuretic, having a direct effect on the kidneys, increasing the excretion of sodium ions, xloridov, water, as well as potassium and bicarbonate ions, and reducing the excretion of calcium ions. Although the mechanism of the antihypertensive action of diuretics is not fully understood, with their long-term use, there is a decrease in OPSS, related, probably, with a change in the exchange of sodium ions. Thus, the use of a combination of quinapril and hydrochlorothiazide leads to a more pronounced decrease in blood pressure, than therapy with each drug separately.
The antihypertensive effect of quinapril develops during 1 h after ingestion and reaches a maximum after 2-4 no. When using the recommended doses, the antihypertensive effect continues for 24 h and persists with long-term treatment. In some cases, to achieve the maximum antihypertensive effect of therapy, at least 2 weeks. The diuretic effect of hydrochlorothiazide begins within 2 no, reaches a maximum in about 4 h and lasts for about 6-12 no.
Pharmacokinetics
Quinapril and hydrochlorothiazide do not affect each other's pharmacokinetics.
Quinapril
Absorption and distribution
After oral administration, Cmax quinapril is achieved within 1 no. Quinapril is rapidly metabolized to quinaprilat, that is a potent enzyme inhibitor. The degree of absorption of quinapril is approximately 60%. Cmax quinaprilat in blood plasma is reached after about 2 hours after the intake of hinaprila.
About 38% from the dose taken, quinapril circulates in the form of quinaprilat. About 97% quinapril and quinaprilat circulate in the blood plasma in a protein-bound form. Hinapril and its metabolites do not penetrate the Geb.
Metabolism and excretion
Quinapril is metabolized to quinaprilat by cleavage of the ester group (major metabolite – quinapril dibasic acid).
T1/2 quinapril from blood plasma is about 1 no. Quinaprilat is excreted mainly by renal excretion, but his T1/2 is about 3 no.
Pharmacokinetics in special clinical situations
In patients with renal insufficiency, T1/2 hinaprilata increases with decreasing QC.
Hinaprilata also decreases excretion in the elderly (senior 65 years) and closely correlates with indicators of renal function, however, in general, there were no differences in the efficacy and safety of treatment between elderly and younger patients..
Gidroxlorotiazid
Absorption and distribution
Hydrochlorothiazide is absorbed somewhat more slowly, Cmax achieved through 1-2.5 no. The degree of absorption is 50-80%.
Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk, but does not penetrate the BBB.
Metabolism and excretion
Hydrochlorothiazide is not metabolized in the liver and is excreted in the urine unchanged. T1/2 It is between 4 to 15 no. About 61% the dose taken orally is excreted unchanged within 24 no.
Testimony
- Arterial hypertension (patients, for whom combination therapy with quinapril and a diuretic is indicated).
Dosage regimen
Patient, not receiving a diuretic (regardless of Togo, whether monotherapy with quinapril was carried out or not), recommended starting dose of Akkuzid® is 10 mg + 12.5 mg 1 time / day. In the future, if necessary, the dose can be increased to 20 mg + 12.5 mg or up to the maximum recommended daily dose 20 mg + 25 mg. The drug usually provides effective blood pressure control in doses ranging from 10 mg + 12.5 mg 20 mg + 12.5 mg.
Accuzid dose range® provides the possibility of adequate selection of doses of its individual components. So, eg, patients, taking a diuretic, the recommended starting dose of quinapril is 5 mg (to minimize the risk of an excessive decrease in blood pressure). In the future, the dose is gradually increased., to achieve the desired antihypertensive effect. If, as a result of selection, doses have been established, close to the doses of the components of the combined preparation, it is possible to appoint Akkuzid®.
In patients with renal insufficiency moderate (CC 30-60 ml / min) treatment begins with a dose of quinapril 5 mg, increasing it if necessary. Patients, for whom combination therapy with the addition of a diuretic is indicated, it is possible to appoint Akkuzid® at an initial dose 10 mg + 12.5 mg. For maintenance therapy, you can take Akkuzid® at standard doses.
Side effect
The undesirable effects do not differ from those with the use of quinapril and hydrochlorothiazide alone.
The most common side effects (>1%) there were headaches when taking any combination of quinapril and hydrochlorothiazide (6.7%), dizziness (4.8%), cough (3.2%), which was usually unproductive, persistent and disappeared after discontinuation of therapy, fatigue (2.9%). Generally, side effects were mild and transient, did not depend on age, gender, race and duration of therapy.
Adverse events, vstrechavshyesya in 0.5-1.0% patients, receiving quinapril in combination with hydrochlorothiazide, listed below.
From the hematopoietic system: gemoliticheskaya anemia, thrombocytopenia, leukopenia, agranulocytosis.
From the immune system: anaphylactic reactions.
From the central and peripheral nervous system: hypererethism, asthenia, paresthesia.
Cardio-vascular system: heartbeat, tachycardia, severe hypotension, postural hypotension, fainting; rarely – abnormal heart rhythm, myocardial infarction, ischemic stroke.
The respiratory system: breathlessness, sinusitis.
From the digestive system: dry mouth or throat, nausea, constipation or diarrhea, flatulence, pancreatitis, hepatitis.
Allergic reactions: skin rash, itch, angioedema (0.1 % patients, receiving hinapril); rarely – photosensitivity, erythema multiforme exudative, exfoliative dermatitis, pemphigus, Stevens-Johnson syndrome (associated with the presence of hydrochlorothiazide).
From the urinary system: urinary tract infections, impairment of renal function.
From the laboratory parameters: increase (more than 1.25 fold compared with CAH) serum creatinine and blood urea nitrogen, respectively, in 3% and 4% patients, treated with quinapril and hydrochlorothiazide.
On the part of the organ of vision: blurred vision.
On the part of the reproductive system: reduced potency.
Other: peripheral edema, arthralgia, alopecia.
Contraindications
- a history of angioedema as a result of previous therapy with ACE inhibitors;
- Childhood and adolescence up 18 years (the effectiveness and safety of the drug have not been established);
- Anurija;
- Hypersensitivity to the drug;
- hypersensitivity to sulfonamide derivatives.
FROM caution should designate product with a history of angioneuroticeski pain, not associated with the use of ACE inhibitors; with symptomatic hypotension in patients, have previously taken diuretics and are on a salt-restricted diet or are on hemodialysis; in severe heart failure in patients with or without concomitant renal failure; under conditions, accompanied by a decrease in the bcc (incl. vomiting and diarrhea); when hyperkalemia, suppression of bone marrow hematopoiesis, aortic stenosis, cerebrovascular diseases (a sharp decrease in blood pressure during therapy with ACE inhibitors can worsen the course of these diseases), in severe renal insufficiency (CC less than 30 ml / min), conditions after kidney transplantation, bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, severe autoimmune systemic diseases of connective tissue (incl. SLE), dysfunction or progressive liver disease, diabetes, extensive surgical interventions and general anesthesia, while taking other antihypertensive drugs, in case of electrolyte imbalance.
Pregnancy and lactation
Do not use the drug Akkuzid® Pregnancy.
ACE inhibitors can cause disease and death of the fetus and newborns. When using ACE inhibitors in II and III trimesters of pregnancy observed cases of arterial hypotension, renal failure, hypoplasia of the skull bones in newborns and / or their death. Cases of low water have also been described., that, probably, reflect decreased kidney function in the fetus; this condition was combined with contractures of the limbs, deformation of the facial part of the skull, hypoplasia of the lungs and intrauterine growth retardation. When using ACE inhibitors only in the first trimester of pregnancy, such undesirable effects did not develop, Nonetheless, Women, who received drugs of this group in the first trimester, should be informed about these adverse reactions.
If pregnancy occurs during treatment with Akkuzid®, the drug should be canceled as soon as possible. If therapy with ACE inhibitors is necessary in the II and III trimesters of pregnancy, the possibility of potential damage to the fetus should be assessed; for the purpose of diagnosing oligohydramnios (which can be detected after irreversible damage to the fetus) ultrasound examination should be performed regularly. If this condition is noted, the drug should be canceled unless, when its use is vital for the mother.
Other possible adverse effects of ACE inhibitors on the fetus and newborns are intrauterine growth retardation., prematurity and nezareatmene arteriosus; described fetal deaths. It remains unclear, whether these adverse events are related to the use of ACE inhibitors or maternal disease.
It is also not known, whether therapy has an undesirable effect on the fetus, which was carried out only in the first trimester of pregnancy.
Newborn, who have been exposed to ACE inhibitors in utero, should be monitored for arterial gipotenzii, oliguria and hyperkalemia. If oligurii appears should support hell and perfusion of the kidneys.
Thiazides cross the placenta and are found in the blood of the umbilical cord. Non-teratogenic effects of these drugs include jaundice and thrombocytopenia in the fetus or newborn, the possibility of other undesirable reactions is also allowed, observed in adults.
ACE inhibitors, including hinapril, to a limited extent made with breast milk. Thiazide diuretics are excreted in breast milk. Considering the possibility of serious adverse reactions in newborns, do not use Accuzid® lactation, and if necessary, its use should stop breastfeeding.
Cautions
When treated with ACE inhibitors, cases have been described angioedema of the head and neck, incl. in 0.1% patients, receiving hinapril. With the appearance of a laryngeal whistle or angioedema of the face, tongue or glottis Akkuzid® should be canceled immediately. The patient must be prescribed adequate treatment and observed until the edema disappears.. Swelling of the face and lips usually goes away without treatment. Antihistamines can be used to relieve symptoms. Angioedema affecting the larynx can be fatal. If swelling of the tongue, the glottis or larynx threatens the development of airway obstruction, Adequate emergency therapy is needed, includes s/to the introduction of a solution of epinephrine (adrenaline) 1:1000 (0.3-0.5 ml). In the treatment of ACE inhibitors also described instances of angioneuroticeski pain bowel. Patients reported abdominal pain (with or without nausea and vomiting); in some cases, without prior angioneuroticeski pain face and normal levels of c-1 esterase. The diagnosis is installed using abdominal CT scan, Ultrasound or at the time of surgery. Symptoms disappeared after discontinuation of ACE inhibitors. Therefore, in patients with pain in the abdominal area, taking ACE inhibitors, when carrying out a differential diagnosis, it is necessary to take into account the possibility of the development of angioedema of the intestine.
Patients, who have suffered angioedema, not associated with the enzyme inhibitor, the risk of its development may be increased by treatment with drugs of this group. Patients, receiving ACE inhibitors during desensitizing Hymenoptera venom therapy, persistent anaphylactoid reactions may develop, life-threatening. With the temporary discontinuation of ACE inhibitors, these reactions could be avoided, however, they reappeared when these drugs were accidentally taken.
Anaphylactoid reactions can also develop with the appointment of ACE inhibitors to patients, who underwent LDL apheresis by absorption of dextran sulfate or patients, undergoing hemodialysis using high-flow membranes, such as polyacrylonitrile. Therefore, this combination should be avoided., using either other antihypertensive drugs, or alternative membranes for hemodialysis.
Accusid® may cause symptomatic hypotension, however not more often, than with monotherapy with both components of the drug. Symptomatic hypotension is rare in the treatment of quinapril in patients with uncomplicated arterial hypertension, however, it can develop as a result of therapy with ACE inhibitors in patients with reduced BCC, eg, After treatment dioretikami, when following a diet with limited sodium intake or during hemodialysis. In case of symptomatic hypotension, the patient should be given a horizontal position and, if necessary, given an IV infusion using 0.9 % sodium chloride solution. Transient arterial hypotension is not a contraindication to further use of the drug, however, in such cases, it is advisable to reduce its dose.
In patients with chronic heart failure with or without renal failure, ACE inhibitor therapy for hypertension can lead to an excessive decrease in blood pressure, which may be accompanied by oliguria, azotemia and, rarely, acute renal failure and even death. Treatment of such patients with Akkuzid® should begin under close medical supervision and supervision during the first 2 weeks and with an increase in the dose of the drug.
In rare cases, therapy with ACE inhibitors may be accompanied by the development of agranulocytosis and suppression of bone marrow hematopoiesis in patients with uncomplicated arterial hypertension., but more often in patients with impaired renal function, especially with connective tissue diseases. In these cases, the number of leukocytes in the blood should be monitored..
Thiazides diuretics sometimes cause exacerbation of SLE.
Accusid® should be applied with caution in patients with severe kidney disease, tk. thiazide diuretics can cause azotemia in these patients, and their repeated use can lead to a cumulative effect.
In susceptible patients the Suppression of Renin-angiotensin-aldosterone system activity can lead to changes in kidney function. In patients with severe heart failure, renal function may depend on the activity of the renin-angiotensin-aldosterone system, therefore, treatment with ACE inhibitors, including hinapril, can lead to oliguria and / or progressive azotemia, and in rare cases – to acute renal failure and / or death.
T1/2 quinaprilat increases with a decrease in CC. At least QC 60 mL/min hinapril should be appointed in lower initial dose. In such patients, the dose of the drug should be increased taking into account the clinical effect., with constant monitoring of kidney function, Although clinical trials have been reported further deterioration in kidney function in the treatment of drug.
In some patients with arterial hypertension without obvious signs of initial renal vascular lesion when prescribing quinapril, especially in combination with a diuretic, noted an increase in blood urea nitrogen and serum creatinine levels, which was usually mild and transient. Such changes are most likely in patients with underlying renal impairment.. In such cases, it may be necessary to reduce the dose of the drug.. In all patients with arterial hypertension, renal function should be monitored..
In clinical studies in patients with arterial hypertension with bilateral or unilateral renal artery stenosis treated with ACE inhibitors, in some cases, an increase in the level of blood urea nitrogen and serum creatinine was observed. These changes were almost always reversible and disappear after the abolition of ENZYME inhibitor and/or diuretic effectively delivered. In such cases, within the first few weeks of treatment should monitor kidney function.
Accusid® should be used with caution in patients with impaired function or progressive liver disease, tk. small changes vodno-elektrolitnogo balance may cause the development of hepatic coma. The metabolism of quinapril to quinaprilat normally occurs under the action of liver enzymes. Quinaprilat concentrations decrease in patients with alcoholic liver cirrhosis due to impaired deesterification of quinapril.
Serum electrolyte levels should be monitored regularly to detect possible electrolyte disturbances.. Patients, receiving quinapril monotherapy, like other ACE inhibitors, serum potassium levels may rise. Hyperkalemia (>5.8 mmol / l) were noted by about 2% patients, taking quinapril, but in most cases this deviation was isolated and resolved during treatment. Risk factors for developing hyperkalemia include kidney failure, diabetes mellitus and concomitant use of potassium-sparing diuretics, potassium preparations and / or salt substitutes, containing potassium. Simultaneous intake of a potassium-sparing diuretic with Akkuzid®, which contains a thiazide diuretic, not recommended. Treatment with thiazide diuretics, conversely, accompanied by hypokalemia, hyponatremia and hypochloremic alkalosis. These disorders sometimes manifest with symptoms such as dry mouth., thirst, weakness, slackness, drowsiness, anxiety, muscular weakness, muscle pain or cramps, decrease in blood pressure, oligurija, tachycardia, nausea, confusion, seizures and vomiting. Hypokalemia can also increase the toxic effect of cardiac glycosides. The risk of hypokalemia is especially high with cirrhosis of the liver, forced diuresis, inadequate intake of electrolytes by mouth, concomitant therapy with corticosteroids or ACTH. Opposite effects of Akkuzid components® serum potassium levels lead to, that in many patients its value does not change. In some cases, the effect of one component may prevail over the other.. Serum electrolyte levels should be monitored periodically before and during treatment to detect possible electrolyte disturbances..
Chloride deficiency, associated with thiazide diuretic therapy, usually mild and only in exceptional cases requires special treatment (eg, for liver or kidney problems).
In hot weather, patients with peripheral edema may develop dilutional hyponatremia. Such patients are rather shown to restrict fluid intake., not salt injection, except in rare cases, when hyponatremia is life threatening. In case of actual salt loss, adequate replacement therapy is necessary.
Thiazide diuretics reduce calcium excretion. In rare cases, patients, receiving long-term therapy with thiazides, developed pathological changes in the parathyroid glands, accompanied by hypercalcemia and hypophosphatemia.
More serious complications of hyperparathyroidism (nephrolithiasis, bone resorption and peptic ulcer) not disclosed. Before conducting a study of the function of the parathyroid glands, thiazide diuretics should be canceled.
Thiazide diuretics increase urinary excretion of magnesium and may cause hypomagnesemia.
Thiazide diuretics can lower glucose tolerance and increase serum cholesterol levels, triglycerides and uric acid. These effects are usually mild., however, in susceptible patients, thiazide diuretics can trigger the development of gout or diabetes.
ACE inhibitor therapy may be accompanied by the development of hypoglycemia in patients with diabetes mellitus, receiving insulin or oral gipoglikemicakie means. Careful monitoring may be required when treating diabetic patients.
When treatment with ACE inhibitors, including hinapril, noted development of cough. In a typical case, it is unproductive, persistent and goes after cessation of therapy. In the differential diagnosis of cough should take into account its possible link with ACE inhibitors.
Patients, undergoing surgery or general anesthesia, ACE inhibitors should be used with caution, tk. they block the formation of angiotensin II, caused by compensatory Renin secretion. This can cause arterial hypotension, which is eliminated by the introduction of liquid.
Patients should be warned that, that inadequate fluid intake, excessive sweating or dehydration can lead to excessive reduction of HELL due to reduction of BCC. Other causes of dehydration, such as vomiting or diarrhea, can also lead to a drop in blood pressure. In such cases, a doctor's consultation is necessary..
When you see any symptoms of infection (eg, sore throat, fever) the patient should also see a doctor immediately, tk. these symptoms may be a manifestation of neutropenia.
Use in Pediatrics
The efficacy and safety of the drug in children and adolescents under the age of 18 years not installed.
Effects on ability to drive vehicles and management mechanisms
Use caution when driving or performing other work, requiring greater attention, especially at the beginning of treatment.
Overdose
Information about an overdose of the drug Akkuzid® and there is no special data on her treatment.
Symptoms: at overdose of quinapril – clinical manifestations of a pronounced decrease in blood pressure; overdose of hydrochlorothiazide – violations of water-electrolyte balance (kaliopenia, chloropenia, giponatriemiya) and dehydration against the background of pronounced diuresis. With cardiac glycosides, hypokalemia increases the risk of cardiac arrhythmias.
Treatment: carry out standard symptomatic and supportive therapy; with a pronounced decrease in blood pressure, intravenous administration is indicated 0.9% sodium chloride solution. Hemodialysis and peritoneal dialysis have a small effect on the excretion of hinaprila and hinaprilata.
Drug Interactions
Tetracycline and other drugs, interact with magnesium
With the simultaneous use of Akkuzid® absorption of tetracycline is reduced by about 28-37% due to the presence of magnesium carbonate in the preparation as a filler.
Preparations lithium
Lithium should not usually be given in combination with diuretics, tk. the latter reduce the renal clearance of lithium and increase the risk of intoxication. Patients, treated with drugs lithium and ACE inhibitors, noted an increase in serum lithium levels and symptoms of lithium intoxication. These changes are associated with sodium loss under the influence of ACE inhibitors.. When appointing Akkuzid® the risk of lithium toxicity may be increased. Use these drugs at the same time with caution.. Frequent monitoring of serum lithium levels is recommended.
Warfarin
Anticoagulant effect of one dose of warfarin (assessed on the basis of protrombinovogo time) did not change significantly with the simultaneous use of quinapril 2 times / day.
Barbiturates, for narcosis, opioid analgesics, alcohol
Possible increase in orthostatic hypotension with the simultaneous use of ethanol, ʙarʙituratov, general anesthetics or opioid analgesics with Akkuzid® due to the presence of hydrochlorothiazide in its composition.
Hypoglycemic agents
With the simultaneous use of Akkuzid® with oral hypoglycemic drugs and insulin, dose adjustment of hypoglycemic agents may be required.
Other antihypertensives
Tiazidnый diuretic, part of Akkuzid®, may enhance the effects of other antihypertensive drugs, especially ganglion blockers or blockers. Antihypertensive effect of thiazide diuretic, in turn, may worsen after sympathectomy.
Corticosteroids, ACTH
When used simultaneously with Akkuzid® there is an increase in the loss of electrolytes, especially potassium.
Pressor amines
When used simultaneously with Akkuzid® it is possible to reduce the action of adrenergic agonists (eg, norepinephrine), however, this effect is insignificant.
Non-depolarizing muscle relaxants
It is possible to enhance the effect of non-depolarizing muscle relaxants when used simultaneously with Akkuzid®.
NSAIDs
NSAIDs can weaken the diuretic, natriuretic and antihypertensive action “loop”, potassium-sparing and thiazide diuretics. In this regard, with their simultaneous use with Akkuzid® the effectiveness of therapy should be monitored.
Funds, increasing the content of potassium in the blood
With the simultaneous use of Akkuzid® with potassium preparations and salt substitutes, containing potassium, possibly increased serum potassium.
Ion exchange resins
Hydrochlorothiazide absorption is impaired in the presence of colestyramine and colestipol. With a single use, these drugs bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 85 and 43% respectively.
Other drugs
When using quinapril with propranolol, hydrochlorothiazide, with digoxin and cimetidine, there were no signs of a clinically significant pharmacokinetic interaction.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
List B. The drug should be kept out of reach children in a place at a temperature not higher than 25 ° С. Shelf life – 3 year.
