Hypotef, tablets 20 pcs

Hypotef is a combination drug for the treatment of arterial hypertension in patients over 45 years of age, with less side effects than monotherapy with its constituent components due to lower doses.

Vinpocetine

A semi-synthetic derivative of the alkaloid devincan, found in the periwinkle plant; the active ingredient is the ethyl ester of apovincamic acid. Vinpocetine improves cerebral circulation, activates metabolic processes in the CNS.

Vinpocetine has a significant protective effect in relation to higher brain functions, has a pronounced cerebroprotective effect. Vinpocetine intensively and selectively increases cerebral blood flow. Pharmacological effects of the drug are realized through several mechanisms.

Vinpocetine significantly improves cerebral microcirculation, inhibits platelet aggregation, reduces increased blood viscosity. The drug has a direct effect on brain metabolism by inhibiting cycloadenosine monophosphate (cAMP), thereby inhibiting the rate of cAMP breakdown. The level of cAMP also increases as a result of the indirect effect of vinpocetine on the synthesis of cAMP through the increased levels of noradrenaline and dopamine in the brain tissue, which, in turn, increase the activity of adenylate cyclase – the catalyst of the last stage of cAMP synthesis. Vinpocetine improves hypoxia tolerance of brain cells by promoting oxygen transport to the tissues, due to the decrease of red blood cell affinity for it, increasing glucose uptake and metabolism. Glucose metabolism switches to a more energetically advantageous, aerobic direction.

The other important target of action of vinpocetine is calcium. The drug inhibits calcium entry into the intracellular space or into synaptosomes induced by depolarization and the release of intracellular calcium. Vinpocetine combines vascular and metabolic effects and promotes normalization of venous outflow against the background of decreased resistance of cerebral vessels.

Vinpocetine is prescribed orally. It should be taken for a long time, at least 2 months.

Indapamide

Indapamide is a drug that has diuretic, vasodilatory and hypotensive activity. The drug is a diuretic, a derivative of sulfonamide, which inhibits reverse sodium absorption in the cortical segment of the nephron loop and increases renal excretion of sodium, chlorine, calcium and magnesium.

Indapamide reduces the sensitivity of the vascular wall to noradrenaline and angiotensin II; stimulates the synthesis of prostaglandin E2, which has vasodilator and hypotensive effects; inhibits calcium flow into the smooth muscle cells of the vascular wall and thus reduces total peripheral vascular resistance (TPR). This mechanism leads to reduction of vasoconstriction and normalization of BP.

Indapamide is used once daily (preferably in the morning). Thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the incidence of side effects continues to increase with further increasing of the drug dose.

Metoprolol acts predominantly on the beta1-adrenoreceptors of the heart and has no intrinsic sympathomimetic or membrane stabilizing activity. It reduces the stimulating effect of sympathetic innervation on the heart, has antianginal, antihypertensive, antiarrhythmic effects. It selectively blocks beta-adrenoreceptors. Reduces heart rate (HR), slows anthrioventricular (AV) conduction, reduces myocardial contractility and excitability. BP reduction occurs due to these mechanisms, as well as due to suppression of the secretion of blood renin activity. In addition, there is a decrease in pressure in the portal vein system due to the reduction of hepatic and mesenteric blood flow. The effect of metoprololol develops within 1 hour after oral administration.

Enalapril inhibits ACE, which promotes conversion of angiotensin I into angiotensin II, reduces the concentration of aldosterone in blood, increases renin release, improves functioning of kallikrein-kinin system, stimulates release of prostaglandins and endothelial relaxing factor, inhibits sympathetic nervous system. Taken together, these effects eliminate spasm and dilate peripheral arteries, reduce ROSS, systolic and diatolic BP, post- and preload on the myocardium. Dilates arteries to a greater extent than veins, and there is no reflex increase in HR.

The antihypertensive effect is more pronounced at high plasma renin concentration than at normal or reduced. Reduction of BP within therapeutic limits has no effect on the cerebral circulation. Improves blood supply to ischemic myocardium. Increases renal blood flow without changing glomerular filtration rate. In patients with initially decreased glomerular filtration its rate usually increases. Maximum effect of enalapril develops after 6-8 hours and lasts up to 24 hours after oral administration.

Hypotenef is a combined drug in which the doses of the active components are 2-4 times lower than the therapeutic doses for each component. Antihypertensive effect is achieved due to simultaneous action on most of the stages causing arterial hypertension, resulting in relaxation of vessels (enalapril, vinpocetine), reduction of fluid in the body (indapamide) and normalization of cardiac activity (metoprolol). The drug prevents an increase in the tone of the cerebral membranes, including ischemic brain damage, a condition characteristic of a very wide range of diseases, as well as in persons of advanced age. Introduction of vinpocetine in combination promotes restriction of lipid peroxidation development, maintenance of partial oxygen pressure in brain, has antiedematous effect and improves mental activity in arterial hypertension combined with cerebral ischemia.

Pharmacokinetics

Absorption

For Hypoteph, it was found that when administered orally to rabbits at a dose of 18.In rabbits at a dose of 18.5 mg/kg metoprolol is rapidly absorbed into the gastrointestinal tract, the maximal concentration (Cmax) is reached within 1.17 h with subsequent elimination of metoprolol from the blood stream. The half-life (T1/2β) is 2.15 h.

For the other components, the pharmacokinetics in combination have not been studied, but it is known that:

Vinpocetine is rapidly and completely adsorbed from the GI tract. Bioavailability is 57%. The value of therapeutic concentration of vinpocetine in blood plasma is from 10 to 20 ng/ml;

– indapamide is quickly and completely adsorbed from the GI tract. Bioavailability is high (93%). Cmax of indapamide is created 1-2 hours after oral administration. In blood plasma it is 71-79% bound to blood proteins, can also be sorbed by erythrocytes;

– enalapril – about 60% of enalapril is adsorbed from the GI tract. The volume of absorption is 60%. Cmax in blood serum is reached 3-4 hours after intake, equilibrium concentration – after 4 days. Decrease of BP appears 1 hour after intake, reaches its maximum by 6 hours and lasts for 1 day.

Distribution

The distribution in combination has not been studied.

Vinpocetine readily passes through histohematic barriers (including the BBB, placental), penetrates into breast milk.

– indapamide has a high volume of distribution, passes through the histohematic (including the placental) barriers, penetrates into the breast milk.

– metoprolol passes through the BBB and the placental barrier, penetrates into breast milk.

– enalapril easily passes through the histohematic barriers, excluding the HEB, penetrates the placental barrier.

Metabolism

Metabolism in combination has not been studied.

– Vinpocetine is extensively metabolized in the body, the main metabolites being apovincamic acid and hydroxyvinpocetine.

Indapamide is almost completely metabolized in the liver. The only pharmacologically active metabolite is formed by hydrolysis of the indole ring.

– metoprolol is extensively biotransformed in the liver to form the metabolites – o-desmethylmetoprolol and α-hydroxymetoprolol.

Enalapril undergoes biotransformation in the liver to form the metabolite enalaprilat with Cmax determined after 4 hours.

Elevation

Elevation in combination has not been studied.

Vinpocetine’s T1/2 is about 5 h. Most of vinpocetine is excreted by the kidneys as metabolites. Only a few percent of the drug is excreted unchanged.

Indapamide T1/2 is about 14 hours. Up to 80% is excreted by the kidneys as inactive metabolites and 20% – through the intestine.

– metoprolol – T1/2 is 2.15 h. It is excreted by the kidneys mainly as metabolites, about 3% – unchanged.

– Enalapril – T1/2 is 11 h. Excreted mainly by the kidneys (up to 40% is excreted as enalaprilate). Within 24 h up to 90% of the administered amount is excreted.

Indications

Grade 1 and 2 arterial hypertension in patients over 45 years of age.

Active ingredient

Composition

Active ingredients:

Vinpocetine2.5 mg;

Indapamide0.75 mg;

metoprolol tartrate25 mg;

enalapril maleate5 mg;

Associates:

hypromellose-15 thous. (hydroxypropyl methylcellulose 15) – 5.05 mg,

stearic acid – 2 mg,

copovidone (collidon VA64, collidon BA64)- 5 mg,

How to take, the dosage

To be taken by mouth before meals, 1 tablet once a day (in the morning).

In case of insufficient effectiveness and good tolerance, the dose can be increased to 2-3 tablets per day, with even distribution of time between doses.

Therapeutic effect is achieved within 2-3 weeks of therapy.

Interaction

Vinpocetine

The antihypertensive effect of concomitant use with methyldopa may be enhanced (BP control is required). Despite the lack of data confirming the possibility of interaction, caution is recommended when concomitant use with antiarrhythmic agents and anticoagulants.

Indapamide

Not recommended drug combinations

Concomitant use of indapamide and lithium drugs may increase plasma lithium concentration accompanied by signs of overdose (due to reduced lithium excretion). If it is necessary to use this combination, plasma lithium concentration should be monitored.

Combinations of drugs requiring special attention

Preparations that can cause pirouette-type arrhythmias:

– Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);

– Class III antiarrhythmic drugs (amiodarone, dofetilide, ibutilide) and sotalol;

– some neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levopromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol);

– others: Bepridil, cisapride, difemanil, erythromycin (w/v), halofantrine, misolastin, pentamidine, sparfloxacin, moxifloxacin, astemizole, vincamine (w/v).

An increased risk of ventricular arrhythmias, especially pirouette-type arrhythmias (hypokalemia is a risk factor).

Plasma potassium levels should be monitored and, if necessary, corrected before starting combined therapy with indapamide and the above drugs. The patient’s clinical condition, plasma electrolyte content, ECG should be monitored.

The NSAIDs (when used systemically), including selective COX-2 inhibitors, high doses of salicylates (≥3 g/day):

– the antihypertensive effect of indapamide may be reduced;

– acute renal failure (due to decreased glomerular filtration rate) may develop if significant fluid loss occurs. Patients should compensate for fluid loss and monitor renal function regularly, both at the beginning of therapy and during therapy.

ACE inhibitors:

The use of ACE inhibitors in patients with hyponatremia in blood (especially in patients with renal artery stenosis) is accompanied by the risk of sudden arterial hypotension and/or acute renal failure.

Patients with arterial hypertension and possibly decreased plasma sodium content due to diuretics should:

– 3 days before starting treatment with an ACE inhibitor, discontinue diuretics. Subsequently, if necessary, the use of diuretics may be resumed;

– or begin therapy with an ACE inhibitor at low doses, with subsequent gradual increase of the dose if necessary.

In chronic heart failure, treatment with ACE inhibitors should be started at low doses with possible prior reduction in doses of diuretics.

In all cases in the first week of ACE inhibitor therapy patients’ renal function (plasma creatinine concentration) should be monitored.

Other drugs that may cause hypokalemia: amphotericin B (IV), gluco- and mineralcorticoids (when used systemically), tetracosactide, laxatives that stimulate intestinal motility.

An increased risk of hypokalemia (additive effect).

Potassium content in plasma should be monitored regularly, and corrected if necessary. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. It is recommended to use laxatives that do not stimulate intestinal motility.

– Baclofen:

An increase in antihypertensive effect has been noted.

Patients need to compensate for fluid loss and carefully monitor renal function at the beginning of treatment.

– cardiac glycosides:

Hypokalemia increases the toxic effects of cardiac glycosides.

In concomitant use of indapamide and cardiac glycosides, plasma potassium and ECG should be monitored and, if necessary, therapy should be adjusted.

Combinations of drugs requiring attention

Potassium-saving diuretics (amiloride, spironolactone, triamterene):

Combination therapy with indapamide and potassium-saving diuretics is appropriate in some patients, but the possibility of hypokalemia (especially in patients with diabetes and patients with renal impairment) or hyperkalemia cannot be excluded.

Phase plasma potassium and ECG parameters should be monitored and the therapy should be adjusted if necessary.

– Metformin:

Functional renal insufficiency, which may occur with diuretics, especially loop diuretics, when concomitant administration of metformin increases the risk of lactic acidosis.

Do not take metformin if creatinine concentrations exceed 15 mg/g (135 μmol/L) in men and 12 mg/g (100 μmol/L) in women.

Iodine-containing contrast agents:

The dehydration of the body while taking diuretics increases the risk of acute renal failure, especially when high doses of iodine-containing contrast agents are used.

Patients should compensate for fluid loss before using iodine-containing contrast agents.

Tricyclic antidepressants, antipsychotics (neuroleptics):

The drugs in these classes increase the antihypertensive effects of indapamide and increase the risk of orthostatic hypotension (additive effect).

Calcium salts:

In concomitant administration, hypercalcemia may develop due to reduced excretion of calcium ions by the kidneys.

– Cyclosporine, tacrolimus:

Possible increase in plasma creatinine concentration without change in circulating cyclosporine concentration, even with normal fluid and sodium ion levels.

– corticosteroid drugs (mineral and glucocorticosteroids), tetracosactide (when administered systemically):

Attenuation of antihypertensive effects (fluid and sodium ion retention as a result of corticosteroid action).

Metoprolol

The concomitant use with MAO inhibitors is not recommended due to a significant increase in antihypertensive effect. A treatment break of at least 14 days should be taken between MAO inhibitors and metoprolol.

Beta-adrenoblockers, theophylline, cocaine, estrogens (sodium retention), indomethacin, and other NSAIDs (sodium retention and renal blocking of prostaglandin synthesis) weaken the antihypertensive effect of metoprolol.

Concomitant use with hypoglycemic agents for oral administration may decrease their effect; with insulin – increased risk of hypoglycemia, increased its severity and duration, masking of some symptoms of hypoglycemia (tachycardia, increased sweating, increased BP).

When used concomitantly with hypotensive agents, diuretics, ACE inhibitors, nitroglycerin or “slow” calcium channel blockers, a sharp decrease in BP may develop (special caution is required when combined with prazosin); the risk of bradycardia increases when combined with epinephrine; Significant slowing of HR and suppression of AV conduction up to complete blockade – when using metoprolol with verapamil, diltiazem, reserpine, methyldopa, clonidine, guanfacine, cardiac glycosides, agents for general anesthesia (along with the cardiodepressive and antihypertensive effects).

The simultaneous intravenous administration of verapamil may accompany cardiac arrest.

Drugs that induce or inhibit CYP2D6 isoenzyme may affect plasma concentrations of metoprolol. Concentrations of metoprolol in plasma may increase when concomitantly taking other drugs that are substrates for CYP2D6, such as antiarrhythmic agents, antihistamines, H2-receptor antagonists, antidepressants (selective serotonin reuptake inhibitors such as paroxetine, fluoxetine, sertraline), neuroleptics, and COX-2 inhibitors.

The class I antiarrhythmic drugs may lead to summation of negative inotropic effect with development of significant hemodynamic side effects in patients with impaired left ventricular function (this combination should be avoided in patients with sinus node weakness syndrome and AV conduction disturbances). Quinidine inhibits metoprolol metabolism in patients with “fast” metabolism, resulting in significant increase of metoprolol plasma concentration and enhancement of its beta-adrenoblocking effect.

Combination with amiodarone increases the risk of significant sinus bradycardia (including long after amiodarone withdrawal due to its long half-life).

If metoprolol and clonidine are taken concomitantly, then clonidine should be withdrawn after several days if metoprolol is withdrawn (due to the risk of withdrawal).

Hepatic microsomal enzyme inducers (rifampicin, barbiturates) lead to increased metabolism and reduced effect. Inhibitors (cimetidine, oral contraceptives, phenothiazines) – increase the plasma concentration of metoprolol.

Diphenhydramine decreases clearance of metoprolol, increasing its effect.

Concomitant use with high doses of phenylpropanolamine may lead to paradoxical increase in BP (up to hypertensive crisis).

Allergens used for immunotherapy or allergen extarts for skin tests when combined with metoprololol increase the risk of systemic allergic reactions or anaphylaxis; iodine-containing x-ray contrast agents for IV administration increase the risk of anaphylactic reactions.

Decreases clearance of xanthines (except diphylline), especially in patients with initially increased clearance of theophylline due to smoking. Reduces lidocaine clearance, increases plasma lidocaine concentration.

Enhances and prolongs the effect of antidepolarizing myorelaxants; prolongs the anticoagulation effect of coumarins.

When used together with anxiolytics and drugs with hypnotic activity, the antihypertensive effect increases, with ethanol – the risk of significant BP decrease increases and CNS depressant effect increases.

There is an increased risk of peripheral circulatory disorders – with ergot alkaloids.

Enalapril

Continuous use is not recommended

Potassium-saving diuretics (spironalactone, eplerenone, triamterene, amiloride) or potassium-containing salts, potassium supplements When concomitant use with ACE inhibitors, hyperkalemia may develop. If concomitant use of these drugs is still indicated due to diagnosed hypokalemia, they should be used with caution, with regular monitoring of serum potassium and electrocardiogram.

Contraindications

Vinpocetine

Metoprolol

Side effects

Vinpocetine

Nervous system and sense organs: rarely – dizziness, headache, insomnia, somnolence, weakness.

Cardiovascular system disorders: rare – delayed intraventricular conduction, ST-segment depression and prolonged QT interval, marked BP decrease, tachycardia, extrasystole.

Gastrointestinal disorders: rare – dry mouth, nausea, heartburn.

Skin disorders: rare – increased sweating, allergic reactions.

Indapamide

Most adverse reactions are dose-dependent.

Cardiovascular system: very rare – marked BP decrease; unspecified frequency – “pirouette” type arrhythmia (possibly fatal).

Hematopoietic organs: very rarely – thrombocytopenia, leukopenia, aplastic anemia, hemolytic anemia.

With the urinary system: very rarely – renal failure.

The digestive system: infrequent – vomiting; rare – nausea, constipation, dry mouth; very rare – pancreatitis, liver function disorder; unspecified frequency – possibility of hepatic encephalopathy in liver failure, hepatitis.

Skin disorders:

Sensitization reactions, mainly dermatological, in patients with predisposition to allergic reactions: frequent – maculopapular rash; infrequent – hemorrhagic vasculitis; very rare – angioedema and/or urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis; unspecified frequency – hyponatremia accompanied by hypovolemia, leading to dehydration and orthostatic hypotension; simultaneous hypochloremia may lead to metabolic alkalosis – in patients with acute systemic lupus erythematosus the disease course may worsen.

Cases of photosensitivity reactions have been described.

Laboratory parameters: very rare – hypercalcemia; unspecified frequency – increase of QT interval on ECG, increased concentration of uric acid and glucose in blood, increased activity of “hepatic” transaminases, decrease of potassium and development of hypokalemia, especially significant in compensated patients (possibility and severity of this effect is low).

Metoprolol

Hematopoietic disorders: very rare – thrombocytopenia, leukopenia.

Cardiovascular system disorders: frequent – sinus bradycardia, postural disturbances (very rarely accompanied by syncope), “coldness” of extremities, palpitations; infrequent – temporary increase in symptoms of heart failure, AV blockade of degree I; cardiogenic shock in patients with acute myocardial infarction, peripheral edema, heart pain; rare – gangrene in patients with previous severe peripheral circulatory disorders.

Nervous system disorders: very common – fatigue; common – headache, dizziness; infrequent – parasthesias, seizures, depression, decreased concentration, drowsiness or insomnia, nightmares; rare – increased nervous irritability, anxiety, impotence/sexual dysfunction, Peyronie’s disease; very rare – amnesia/hearing loss and tinnitus.

Sensory organs: rare – visual disturbances, dry and/or irritated eyes, conjunctivitis, impaired hearing and tinnitus.

The digestive system: frequently – nausea, abdominal pain, diarrhea, constipation; infrequently – vomiting; rarely – dry mouth; very rarely – violation of sense of taste.

Hepatic disorders: rare – liver function abnormalities and increased activity of liver transaminases; very rare – hepatitis.

The skin: infrequent urticaria, increased sweating, rarely alopecia, very rare photosensitization, exacerbation of thyrotoxicosis symptoms.

The respiratory system: often – shortness of breath when exerting physical effort; infrequent – bronchospasm; rarely – rhinitis.

Endocrine system: rare – hypo-, hyperglycemia in patients with type I diabetes, masking symptoms of thyrotoxicosis.

Musculoskeletal system disorders: very rare – arthralgia.

Metabolism: infrequent – weight gain; rarely – worsening of the course of latent diabetes mellitus.

Laboratory measures: very rare – decrease in the concentration of high-density cholesterol and increase in triglycerides in plasma.

Enalapril

Hematopoietic and lymphatic system disorders: rare – decrease in hemoglobin and hematocrit; very rare – suppression of bone marrow function, anemia, thrombocytopenia, leukopenia, neutropenia and agranulocytosis, hemolytic anemia, lymphadenopathy, eosinophilia, autoimmune diseases.

Endocrine system disorders: rare – syndrome of inadequate secretion of antidiuretic hormone.

CNS disorders: frequently – headache, dizziness, fainting; infrequent – insomnia, anxiety, panic, confusion, depression, sleep disorders, “nightmares” dreams, somnolence; rarely – parasthesias, memory disturbance, peripheral neuropathy, tremor, migraine, confusion.

An organ of vision: rare – visual disturbances, conjunctivitis, decreased visual acuity, dry and burning eyes.

Hearing organ: infrequent – vertigo, tinnitus.

Cardiovascular system disorders: frequently – marked decrease of blood pressure, orthostatic hypotension; infrequently – palpitation, chest pain, arrhythmia (atrial fibrillation, sinus bradycardia, tachycardia, ventricular fibrillation), angina, AV blockade of degree II, cerebral arrhythmia, myocardial infarction.

Respiratory system: frequently – cough; infrequently – rhinitis, stuffy nose; very rarely – sinusitis, pharyngitis, laryngitis, sore throat, hoarseness, shortness of breath, bronchitis, lung infiltrates, bronchospasm / bronchial asthma.

The digestive system: frequently – nausea, diarrhea; infrequently – abdominal pain, constipation; rarely – dry mucous membrane of the mouth, stomatitis, flatulence, vomiting, gastritis, violation of taste, ulcer disease, aphthous ulcers; very rarely – pancreatitis, intestinal obstruction, interstitial angioedema.

Hepatic and biliary tract disorders: infrequent – increased “hepatic” transaminases activity, increased bilirubin concentration; very rarely – liver dysfunction, hepatocellular or cholestatic hepatitis, jaundice.

Allergic reactions: infrequent – skin rash, itching, rarely – angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx, dysphonia, urticaria; very rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitization.

Skin disorders: rare – alopecia, psoriasis, dermatitis, dry skin; very rare – pseudolymphoma, vesicular.

Urogenital system disorders: often – renal dysfunction; rarely – uremia, acute renal failure, proteinuria; very rarely – oliguria, anuria.

Musculoskeletal system: often – muscle cramps, back pain, leg pain, myalgia; infrequently – pain in hands, arthralgia, musculoskeletal pain, stiffness and swelling of joints.

Reproductive system: infrequent impotence; rarely – gynecomastia.

Others: frequent – asthenia, fatigue, hyperkalemia; infrequent – increase of body temperature, slightly increased concentration of urea and creatinine; rarely – hyperglycemia, nasal bleeding, vasculitis, Raynaud’s syndrome, “tides” of blood to the face. A symptom complex has been described that may include fever, myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, positive antinuclear antibody test.

Overdose

Vinpocetine

There are no reports of overdose.

Treatment: gastric lavage, activated charcoal; symptomatic treatment.

Indapamide

Symptoms: disorders of water-electrolyte balance (hyponatremia, hypokalemia), nausea, vomiting, marked decrease in BP, seizures, dizziness, drowsiness, confusion, polyuria or oliguria leading to anuria (due to gopivolemia) may occur.

Treatment: emergency measures aimed at removal of the drug from the body: gastric lavage and/or administration of activated charcoal followed by restoration of water-electrolyte balance, symptomatic therapy. There is no specific antidote.

Metoprolol

Symptoms: pronounced sinus bradycardia, dizziness, nausea, vomiting, cyanosis, marked BP decrease, arrhythmia, ventricular extrasystole, bronchospasm, fainting, in acute overdose – cardiogenic shock, loss of consciousness, coma, AV blockade (up to development of complete transverse block and cardiac arrest), cardialgia, hypoglycemia, hyperkalemia, seizures, respiratory arrest.

The signs of overdose occur 20 minutes to 2 hours after taking the drug.

Treatment: gastric lavage and administration of adsorptive agents; symptomatic therapy: if BP significantly decreased – the patient should be in Trendelenburg position; in case of excessive BP decrease, bradycardia and heart failure – intravenous (IV), with 2-5 min intervals, beta-adrenomimetics – until the desired effect is achieved or IV 0.5-2 mg of atropine. In the absence of a positive effect – dopamine, dobutamine or norepinephrine (noradrenaline).

As a follow-up, an artificial pacemaker may be placed. For bronchospasm, IV beta2-adrenomimetics should be administered. Metoprolol is poorly excreted by hemodialysis.

Enalapril

Symptoms: increased diuresis, marked BP decrease with bradycardia or other cardiac rhythm abnormalities, seizures, impaired consciousness (including coma), acute renal failure, acid-base state and blood water-electrolyte balance disorders.

The treatment: gastric lavage and ingestion of activated charcoal; in more severe cases – place patient in horizontal position with elevated legs, then conduct measures aimed at BP stabilization – IV administration of plasma substitutes, infusion of 0.9% sodium chloride solution. The patient’s blood pressure, heart rate, respiration rate, serum concentrations of urea, creatinine, electrolytes and urine output should be monitored, and if necessary hemodialysis should be performed (excretion rate of enalaprilat is 62 ml/min).

Pregnancy use

The use of Hypotef during pregnancy is contraindicated. The active components of the drug Hypotef: metoprolol, enalapril, vinpocetine pass through the placental barrier, penetrate into the breast milk.

If it is necessary to use the drug Hypotenef during lactation, it is recommended to stop breast-feeding.