Lercanidipine + Enalapril (Lercanidipinum + Enalaprilum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

ACE Inhibitors

Calcium channel blockers

Included in the formulation
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    C.09.B.B   ACE inhibitors in combination with calcium channel blockers

    C.09.B.B.02   Lercanidipine and enalapril

    Pharmacodynamics:

    The drug is a combination of an ACE inhibitor and a blocker of slow calcium channels.

    Lercanidipine

    Lercanidipine, a dihydropyridine derivative, inhibits the transmembrane flow of calcium into cardiac cells and smooth muscle cells. The mechanism of antihypertensive action is caused by a direct relaxing action on the smooth muscles of the vessels, as a result of which the overall peripheral vascular resistance decreases. Has a prolonged antihypertensive effect. Due to the high selectivity to the smooth muscle cells of the vessels, a negative inotropic effect is absent.

    Enalapril

    Enalapril - ACE inhibitor, inhibits the formation of angiotensin II and eliminates its vasoconstrictive effect. Reduces blood pressure without causing an increase in heart rate and minute volume.Reduces the overall peripheral vascular resistance, reduces afterload and preload on the heart. Reduces pressure in the right atrium and a small circle of blood circulation.

    Does not affect the metabolism of glucose, lipoproteins, as well as the functions of the reproductive system.

    Pharmacokinetics:

    There are no pharmacokinetic interactions with concurrent use of lercanidipine and enalapril.

    Lercanidipine

    Lercanidipine is absorbed completely from the digestive tract after ingestion. Absolute bioavailability after ingestion after eating is approximately 10%, when taken on an empty stomach, bioavailability decreases by 1/3. Bioavailability after lercanidipine is increased 4-fold if the drug is taken no later than 2 hours after ingestion of fatty foods. Therefore, the drug should be taken at least 15 minutes before meals. Cmax lercanidipine in blood plasma is observed after 1.5-3 hours. Do not cumulate with repeated use. The duration of the therapeutic action of lercanidipine is 24 hours.

    The concentration of lercanidipine in blood plasma when taken orally is not directly proportional to the dosage (non-linear dependence).When taking 10, 20 or 40 mg Cmax lercanidipine in blood plasma was determined in a ratio of 1: 3: 8, respectively, and the concentration under the curve - in a ratio of 1: 4: 18, which suggests a progressive saturation during primary passage through the liver. The distribution of lercanidipine from plasma to tissues and organs occurs rapidly and intensively. The binding of lercanidipine to plasma proteins exceeds 98%. In patients with renal and hepatic insufficiency, the plasma protein content is reduced, so the free fraction of lercanidipine can be increased.

    Lercanidipine is metabolized by the isoenzyme of the liver CYP3A4 with the formation of inactive metabolites.

    About 50% of the accepted dose of lercanidipine is excreted by the kidneys, the half-life of lercanidipine is 8-10 hours. In patients with severe renal failure or in patients on hemodialysis, lercanidipine is excreted by the kidneys in a higher quantity (about 70%).

    Enalapril

    The percentage of absorption of enalapril after oral administration is about 60%. Cmax Enalapril in the blood plasma is observed after 1 hour. Eating does not affect absorption.

    When ingested quickly hydrolyzed to active enalaprilata,which has an inhibitory effect on the angiotensin-converting enzyme. Cmax Enalaprilat in the blood serum is observed 3-4 hours after taking the drug. The binding of enalapril to plasma proteins does not exceed 60%.

    About 40% of enalapril in the form of enalaprilat and about 20% of unaltered enalapril is excreted by the kidneys.

    In patients with renal failure, the duration of the action of enalapril and enalaprilate is increased.

    In patients with mild or moderate renal insufficiency (creatinine clearance 40-60 ml / min) with 5 mg enalapril once a day, the plateau of the concentration area under the enalaprilate curve is doubled compared to patients with normal liver function. In patients with severe renal failure (creatinine clearance ≤ 30 ml / min), the concentration under the curve increases approximately 8-fold. In this stage of renal failure, the half-life of enalaprilate increases and the time to reach the plateau stage of the concentration area under the curve slows down. Enalaprilat can be removed from the total blood flow by means of hemodialysis. The dialysis clearance is 62 ml / min.

    Indications:

    Essential hypertension with ineffective monotherapy with lercanidipine (10 mg) or enalapril (20 mg).

    ICD-10

    IX.I10-I15.I10   Essential [primary] hypertension

    Contraindications:

    Disruption of outflow from the left ventricle, including stenosis of the aortic valve; chronic heart failure in the stage of decompensation; hereditary and / or idiopathic angioedema, including anamnesis; angioedema due to the use of ACE inhibitors (in the anamnesis); unstable angina; the first month after myocardial infarction (within 28 days); severe renal failure (creatinine clearance less than 30 ml / min), including patients on hemodialysis; severe hepatic impairment; simultaneous application with potent inhibitors of the isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin), cyclosporine, grapefruit juice; children and adolescents under 18; hypersensitivity to lercanidipine, enalapril or to any other ACE inhibitor and other slow calcium channel blockers derived from dihydropyridine.

    Carefully:

    Syndrome of weakness of the sinus node (without simultaneous application of an artificial pacemaker); a violation of the function of the left ventricle and coronary heart disease; renal failure (creatinine clearance more than 30 ml / min); Renovascular hypertension; condition after kidney transplantation (application experience is limited); liver failure; oppression of bone marrow hematopoiesis; severe autoimmune diseases of connective tissue (including scleroderma, systemic lupus erythematosus); simultaneous use with immunosuppressants, allopurinol, procainamide; diabetes; surgical interventions and general anesthesia; Patients who follow a diet with restricted intake of table salt; hyperkalemia; conditions, accompanied by a decrease in the volume of circulating blood, including diarrhea, vomiting, primary aldosteronism.

    Pregnancy and lactation:

    When pregnant and lactation is contraindicated.

    ACE inhibitors can cause disease or death of the fetus or newborn in appointments in the second and third trimesters of pregnancy. The use of ACE inhibitors during this period was accompanied by a negativeeffects on the fetus and newborn, including the development of arterial hypotension, renal failure, hyperkalemia and / or hypoplasia of the skull bones in a newborn. Perhaps the development of oligohydramnion, apparently due to a decrease in the function of the kidneys of the fetus. This complication can lead to limb contracture, deformation of the bones of the skull, including its facial part, and lung hypoplasia. Teratogenic effect with the use of ACE inhibitors (enalapril) in the first trimester is not proved. Patients who are on therapy with ACE inhibitors when planning pregnancy should switch to alternative schemes of antihypertensive treatment. It is not recommended to use the drug in women of childbearing age who do not use reliable contraceptives.

    The use of the drug in the period of breastfeeding is not recommended, since enalapril and its main metabolite (enalaprilate) penetrate into breast milk.

    The category of FDA recommendations is not defined.

    Dosing and Administration:

    Inside, in the morning, at least 15 minutes before meals, without chewing, squeezed with enough water. Not intended for initial treatment of hypertension.

    Dosage lercanidipine 10 mg + enalapril 10 mg: with inefficiency of monotherapy with lercanidipine 10 mg, you should start taking the drug at a dose of 10 mg + 10 mg.

    Dosage lercanidipine 10 mg + enalapril 20 mg: with inefficiency of monotherapy with enalapril 20 mg, you should start taking the drug at a dose of 20 mg.

    Side effects:

    From the side of the central nervous system: often - dizziness; infrequently - a headache.

    From the side of the psyche: infrequent anxiety.

    From the skin: infrequently - dermatitis, swelling of the lips, erythema, urticaria, rash.

    From the genitourinary system: infrequently - erectile dysfunction, pollakiuria, polyuria, nocturia.

    From the immune system: infrequently - hypersensitivity to one of the components of the drug, angioedema.

    From the musculoskeletal system: infrequently - arthralgia.

    From the digestive system: infrequently - abdominal pain, nausea, constipation, dyspepsia, glossitis.

    On the part of the hematopoiesis system: infrequently - thrombocytopenia.

    From the respiratory system: often - cough; infrequently - dryness in the throat, pharyngeal and throat pain.

    From the cardiovascular system: often - "tides" of blood to the skin of the face; infrequent - a feeling of palpitations and tachycardia,marked decrease in arterial pressure, circulatory collapse, congestive heart failure.

    From the organ of hearing: often - vertigo, including positional vertigo.

    Laboratory indicators: infrequently - a decrease in the level of hemoglobin, an increase in the activity of hepatic transaminases.

    Other: often - peripheral edema, infrequently - asthenia, increased fatigue, a feeling of heat.

    Overdose:

    There is no information about an overdose combination. Presumably, in the case of an overdose, can cause conditions caused by an overdose of any of the active substances.

    Lercanidipine

    Symptoms: peripheral vasodilation with marked decrease in blood pressure and reflex tachycardia, vomiting.

    Treatment: symptomatic, the choice of method of treatment depends on the degree of overdose and on the observed symptoms. Apply the following methods of medical care - gastric lavage, the appointment of high doses of catecholamines, furosemide, cardiac glycosides and plasma substitutes, activated carbon, laxatives and intravenous dopamine.Also, to prevent the development of bradycardia, intravenous administration of atropine is possible.

    Enalapril

    Symptoms: The main sign of overdose is a marked decrease in blood pressure, which is accompanied by a blockade of the renin-angiotensin-aldosterone system and tetanus. Also, collapse, electrolyte imbalance, kidney failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough may develop.

    Treatment: symptomatic. In severe cases, intravenous administration of a 0.9% solution of sodium chloride and, if possible, an infusion of angiotensin II and / or catecholamines is recommended. If the symptoms of an overdose develop immediately after taking the drug, then it is necessary to induce vomiting, to wash the stomach and take drugs from the group of adsorbents or sodium sulfate.

    Interaction:

    The antihypertensive effect of the drug can be potentiated with simultaneous use with other drugs with a similar effect, such as diuretics, beta, alpha-blockers, and others. In addition, when combined, the following effects can be observed.

    Lercanidipine

    The drug should not be taken in combination with CYP3A4 inhibitors, such as ketoconazole, itraconazole, erythromycin and others, with cyclosporine and grapefruit juice (increase the concentration in the blood and lead to a potentiation of the antihypertensive effect).

    Care should be taken when taking concomitant medications with such drugs as terfenadine, astemizole and antiarrhythmic drugs of III class (for example, amiodarone) and quinidine. Simultaneous reception with anticonvulsants (for example, phenytoin, carbamazepine) and rifampicin may reduce the antihypertensive effect of lercanidipine.

    The intake of digoxin should be carefully monitored to detect clinical signs of digoxin toxicity.

    Admission of the drug with midazolam leads to an increase in the absorption of lercanidipine in the gastrointestinal tract and a decrease in the rate of absorption.

    Metoprolol reduces the bioavailability of lercanidipine by 50%.

    Cimetidine 800 mg per day does not lead to significant changes in the content and concentration of lercanidipine in the blood serum, but this combination requires extreme caution, since with higher doses of cimetidine, the bioavailability of lercanidipine and its antihypertensive effect may increase.

    Fluoxetine has no effect on the pharmacokinetics of lercanidipine.In case of taking the drug with simvastatin, the drug should be taken in the morning, and simvastatin in the evening. Taking lercanidipine simultaneously with warfarin does not affect the pharmacokinetics of the latter.

    Enalapril

    Simultaneous administration of the drug with potassium salts, with potassium-sparing diuretics (spironolactone, triamterene, eplerenone, amiloride), angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus and trimethoprim increase the risk of hyperkalemia.

    It is not recommended to use also together with lithium salts (if this combination is necessary, then carefully monitor the concentration of lithium in the blood plasma).

    Simultaneous reception with antidiabetic drugs (both oral and insulin) can cause the development of hypoglycemia at the first week of treatment.

    Diuretics (loop and thiazide) can cause a decrease in the volume of circulating blood and thus increase the risk of a marked decrease in blood pressure when treated with the drug.

    Prolonged use of non-steroidal anti-inflammatory drugs can reduce the antihypertensive effect of angiotensin-converting enzyme inhibitors. Both non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (enalapril) contribute to an increase in the potassium content in the blood, which can lead to impaired renal function.

    Baclofen increases the antihypertensive effect.

    Cyclosporine increases the risk of hyperkalemia.

    Ethanol enhances the antihypertensive effect of angiotensin-converting enzyme inhibitors.

    Tricyclic antidepressants / neuroleptics / general anesthetics / narcotic analgesics may lead to further lowering of blood pressure.

    Corticosteroids (except hydrocortisone as a substitute for Addison's disease) reduce the antihypertensive effect (fluid retention followed by an increase in the volume of circulating blood).

    Joint use with other antihypertensive drugs can enhance the antihypertensive effect of enalapril.

    Joint use with nitroglycerin and other nitrates and vasodilators leads to an even more pronounced decreaseblood pressure.

    Allopurinol, cytostatics, immunosuppressors, systemic corticosteroids and procainamide may lead to an increased risk of leukopenia.

    Antacids reduce the bioavailability of angiotensin converting enzyme inhibitors. Sympathomimetics can reduce the antihypertensive effect.

    Enalapril can be used concurrently with acetylsalicylic acid (as an antiplatelet agent).

    When used simultaneously with the drug gold (sodium aurotomy malate) intravenous development of side effects is possible.

    Special instructions:

    Particular attention in the treatment of hypertension is required by patients with severe arterial hypotension and decompensated heart failure. Transient arterial hypotension is not a contraindication to the continuation of treatment, since after replenishing the volume of circulating blood, an adequate response to the drug intake can be expected.

    Particular care should be taken in the initial stages of treatment of patients with mild to moderate renal failure. Patients with bilateral stenosis of the renal arteries or stenosis of the artery are the onlyfunctioning kidneys are particularly at risk of developing hypotension or renal failure due to the administration of ACE inhibitors. For this group of patients, treatment should be performed under the strict supervision of a physician, with careful selection of the dose and administration of low doses of the drug. Before and during the treatment it is necessary to monitor the function of the kidneys.

    Particular care should be taken in the initial stages of treatment of patients with mild to moderate degree of liver function deficiency. If there is jaundice and a significant increase in the activity of liver enzymes, it is necessary to stop taking ACE inhibitors and consult a doctor.

    Due to the increased risk of anaphylactic reactions, the drug should not be administered to patients on hemodialysis using high-strength polyacrylonitrile membranes (AN69®), when performing low-density lipoprotein apheresis with dextran sulfate and immediately before the desensitization procedure to aspen or bee venom.

    Due to the use of enalapril, angioedema can develop in the face, limbs, tongue, throat or larynx.In this case, stop taking the medication immediately. Angioedema, swelling of the tongue, pharynx or larynx can lead to obstruction of the respiratory tract, you must immediately enter epinephrine (0.3-0.5 ml epinephrine (adrenaline) solution subcutaneously in a ratio of 1: 1000) and maintain airway patency (intubation or tracheostomy). Among patients of the Negroid race receiving therapy with ACE inhibitors, the incidence of angioedema is higher than among patients of other race. Patients with an angioneurotic edema in a history not associated with the use of ACE inhibitors have an increased risk of developing angioedema while using any ACE inhibitor.

    During surgical interventions and / or general anesthesia with agents that cause arterial hypotension, ACE inhibitors can block the formation of angiotensin II in response to compensatory release of renin. If this results in a pronounced decrease in blood pressure, explained by a similar mechanism, it can be corrected by increasing the volume of circulating blood.

    Risk factors for hyperkalemia are: renal failure, advanced age, diabetes mellitus, certain concomitant conditions (decreased circulating blood volume, acute heart failure in decompensation, metabolic acidosis), simultaneous intake of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as potassium or potassium-containing substitutes for common salt and the use of other drugs that increase the potassium content in the blood plasma (for example, heparin). Hyperkalemia can lead to serious heart rhythm disturbances, sometimes with a fatal outcome. Combined use of the above drugs should be done with caution.

    It is not recommended to drink alcohol during the period of therapy with the drug.

    There is evidence of reversible biochemical changes in the heads of spermatozoa with the use of calcium channel blockers, which can disrupt their ability to fertilize.

    It should be borne in mind the possibility of the appearance of weakness and drowsiness, so you need to be careful when performing work that requires increased attention, especially at the beginning of treatment,with an increase in the dose of the drug and in the management of vehicles.

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