Amlodipine, Ramipril

Pharmacological properties

mechanism of action of ramipril. ramiprilat, the active metabolite of ramipril, inhibits the dipeptidyl carboxypeptidase enzyme (synonyms: apf, kininase ii). in plasma and tissues, this enzyme catalyzes the conversion of angiotensin i into the active vasoconstrictor substance angiotensin ii, as well as the breakdown of the active vasodilator bradykinin. a decrease in the formation of angiotensin ii and inhibition of the breakdown of bradykinin lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat helps reduce aldosterone secretion. The average response to monotherapy with ACE inhibitors was lower in patients of the Negroid race (Africans) with hypertension (usually with a low level of renin) than in patients of the Caucasian race.

Pharmacodynamic effect. The use of ramipril causes a significant decrease in peripheral resistance of the arteries. In general, significant changes in the renal plasma flow and glomerular filtration rate were not observed. The use of ramipril in patients with hypertension leads to a decrease in blood pressure in the horizontal and vertical position without a compensatory increase in heart rate.

In most patients, the onset of the antihypertensive effect of a single dose of ramipril occurs 1–2 hours after oral administration of the drug. The maximum effect after a single dose is usually achieved 3-6 hours after oral administration. The antihypertensive effect persists for 24 hours.

The maximum antihypertensive effect with long-term treatment with ramipril as a whole becomes apparent after 3-4 weeks. It was found that the antihypertensive effect with prolonged therapy persists for 2 years.

The sudden cessation of ramipril does not lead to a rapid and excessive ricochet increase in blood pressure.

The mechanism of action of amlodipine. Amlodipine inhibits the transmembrane flow of calcium ions in the cells of the heart and vascular smooth muscle (a slow calcium tubule blocker or calcium ion antagonist).

The mechanism of antihypertensive action is due to the direct relaxation effect of amlodipine on the smooth muscles of blood vessels, which helps to reduce systemic peripheral vascular resistance.

The exact mechanism by which amlodipine eliminates angina pectoris is not fully understood, but it can have the following two actions:

1) amlodipine dilates peripheral arterioles, thereby reducing the total peripheral resistance (afterload). Since it does not cause reflex tachycardia, myocardial energy consumption and oxygen demand will decrease;

2) due to the above mechanism of action, amlodipine increases the flow of oxygen into the myocardium, even in the case of spasm of the coronary arteries (Prinzmetal angina or variant angina).

Pharmacodynamic properties. In patients with hypertension, a single dose of amlodipine provides a clinically significant decrease in blood pressure over 24 hours both in the supine and standing position. Due to the slow onset of action, amlodipine does not cause acute arterial hypotension.

In patients with angina pectoris, the use of amlodipine once a day prolongs the total time of possible physical exertion, delays the onset of an attack of angina pectoris and increases the time until the ST segment is substantially inhibited, reduces the frequency of angina attacks and reduces the need for glyceryl trinitrate tablets.

Amlodipine does not adversely affect the metabolism and lipids of blood plasma, therefore it is indicated for the treatment of patients with AD, diabetes and gout.

Pharmacokinetics

Ramipril. Absorption. After oral administration, ramipril is rapidly absorbed in the digestive tract: C_max ramipril in the blood plasma is reached within 1 hour. Given the excretion of ramipril in the urine, the degree of absorption is at least 56%, it is not significantly affected by the presence of food in the digestive tract.The bioavailability of the active metabolite of ramiprilat after oral administration of ramipril at a dose of 2.5 and 5 mg is 45%.

C_max in the blood plasma of ramiprilat, the only active metabolite of ramipril, is achieved 2–4 hours after taking ramipril. The equilibrium concentration of ramiprilat in plasma in the conditions of application of usual doses (1 time per day) is achieved on the 4th day of treatment.

Distribution. The binding of ramipril to blood proteins is about 73%, and ramiprilat is 56%.

Metabolism. Ramipril is almost completely metabolized to ramiprilat, diketopiperazinovoy ether, diketopiperazinovoy acid and glucuronides ramipril and ramiprilat.

The excretion of metabolites is carried out mainly by the kidneys.

A decrease in the concentration of ramiprilat in plasma occurs in several phases. Due to its powerful saturating binding to ACE and the slow dissociation from the enzyme, ramiprilat is characterized by a prolonged terminal elimination phase at very low plasma concentrations.

After taking multiple doses of ramipril, effective T_½ ramiprilat is 13–17 hours after taking a dose of 5–10 mg or more - after taking lower doses of 1.25–2.5 mg. The difference is due to the saturating ability of the enzyme to bind to ramiprilat.

After taking a single oral dose, ramipril and its metabolite were not detected in breast milk. However, the effect of multiple doses is unknown.

Patients with impaired renal function. The renal excretion of ramiprilat is reduced in patients with impaired renal function, and the renal clearance of ramiprilat is proportionally associated with creatinine clearance. This leads to an increase in plasma concentrations of ramiprilat, which decrease more slowly than in individuals with normal renal function.

Patients with impaired liver function. In patients with impaired liver function, ramipril metabolism to ramiprilat is slowed down due to decreased activity of hepatic esterases, and ramipril plasma levels in these patients are elevated. However c_max ramiprilat in these patients did not differ from that in individuals with normal liver function.

Amlodipine. Absorption. After oral administration, amlodipine is almost completely absorbed, reaching C_max in blood plasma after 6-12 hours after administration. Eating does not affect the bioavailability of the drug. Absolute bioavailability is 64–80%.

Distribution. The distribution volume is 21 l / kg body weight. Equilibrium plasma concentration (5-15 ng / ml) is achieved within 7-8 days of drug use. An in vitro study found that 93–98% of circulating amlodipine in the blood binds to plasma proteins.

Metabolism and excretion. Amlodipine is actively metabolized in the liver (about 90%) to inactive pyridine derivatives.

10% of the starting compound and 60% of inactive metabolites are excreted in the urine, 20–25% with feces.

The decrease in plasma concentration is biphasic. Final t_½ from blood plasma is about 35-50 hours, taking into account the drug once a day.

The total clearance is 7 ml / min / kg body weight (for patients with a body weight of 60 kg - 25 l / h). In elderly patients - 19 l / h.

Use in the elderly. Time required to reach C_max amlodipine in blood plasma, the same both in the elderly and in patients of a younger age. In elderly people, there is a tendency to a decrease in clearance of amlodipine, which leads to an increase in AUC and T_½. Registered increase in AUC and T_½ drug in patients with congestive heart failure.

Patients with impaired renal function. Amlodipine is extensively metabolized to inactive metabolites. 10% of the starting compound is excreted unchanged in the urine. Changes in the concentration of amlodipine in blood plasma are not associated with the degree of impaired renal function.These patients can be treated with the usual dose of amlodipine. Amlodipine is not dialyzed.

Patients with impaired liver function. T_½ amlodipine increases in patients with impaired liver function.

Indications

For the treatment of patients with ag, whose hell is properly controlled by separate drugs, which are prescribed simultaneously in the same dose as in combination, but in the form of separate tablets.

Application

Hartil-am is indicated for patients whose hell is properly controlled by separately prescribed monocomponent drugs in the same doses that are recommended for fixed combination.

The recommended starting daily dose is 2.5 mg / 2.5 mg. Hartil-AM should be taken daily 1 time per day at the same time, regardless of food intake. Do not chew or grind the capsule.

A fixed combination is not suitable for initial therapy.

If necessary, the dose of Hartil-AM can be changed or individually titrated components of the free combination.

The daily dose can be increased to a maximum of 10 mg / 10 mg.

Adults Patients who take diuretics should be careful, as they may have excessive excretion of fluid and / or sodium chloride from the body. Renal function and potassium in plasma should be monitored.

Special patient groups

Patients with impaired liver function. In patients with impaired liver function, ramipril treatment should only be started under close medical supervision.

The maximum daily dose should be 2.5 mg of ramipril.

Doses of the drug for use in patients with mild and moderate hepatic insufficiency have not been established, therefore, the selection of the dose should be carried out with caution and begin use with a low dose.

Patients with impaired renal function. The optimal initial and maintenance dose for patients with renal failure should be adjusted individually by separately titrating the dose of ramipril and amlodipine.

• The daily dose of ramipril for patients with renal failure should be calculated on the basis of creatinine clearance indicators: if creatinine clearance is ≥60 ml / min, there is no need to adjust the initial dose; the maximum daily dose is 10 mg;
• if creatinine clearance is 30-60 ml / min, there is no need to adjust the initial dose (2.5 mg / day), and the maximum daily dose is 5 mg;
• if creatinine clearance is 10-30 ml / min, the initial daily dose is 1.25 mg, and the maximum daily dose is 5 mg;
• for patients with hypertension who are on hemodialysis: with hemodialysis, ramipril is not significantly excreted; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the drug should be taken several hours after the hemodialysis session.

Patients with renal insufficiency do not require dose adjustment of amlodipine.

Amlodipine is not dialyzed. Amlodipine should be prescribed with extreme caution to patients who are on dialysis.

During treatment with Hartil-AM, renal function and plasma potassium levels should be monitored. In case of impaired renal function, the use of Hartil-AM should be discontinued, and the dose of its components must be adequately adjusted.

Elderly patients. Initial doses of ramipril should be as low as possible; further titration of the dose should be carried out gradually because of the likelihood of adverse reactions.

The use of Hartila-AM is not recommended in patients over the age of 75 years or very weak patients.

Elderly patients can be prescribed the usual dose of amlodipine, but caution should be exercised when increasing the dose.

Contraindications

Contraindications associated with the use of ramipril:

• angioneurotic edema (hereditary, idiopathic or due to previous use of ACE inhibitors or angiotensin II receptor antagonists) in the anamnesis;
• extracorporeal treatment, which leads to contact of blood with negatively charged surfaces;
• severe bilateral renal artery stenosis or renal artery stenosis of a single kidney;
• arterial hypotension or hemodynamically unstable conditions;
• hypersensitivity to the active substance.

Contraindications associated with the use of amlodipine:

• hypersensitivity to the active substance;
• severe arterial hypotension;
• shock (including cardiogenic);
• narrowing of the outlet of the left ventricle (for example, severe stenosis of the aortic orifice);
• hemodynamically unstable heart failure after acute myocardial infarction.

Contraindications associated with the use of ramipril and amlodipine: hypersensitivity to ramipril or ACE inhibitors, auxiliary components of the drug, amlodipine, dihydropyridine derivatives.

Side effects

Adverse reactions that were noted when using the active components separately are indicated in accordance with the frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, 1/10), sometimes (≥1 / 1000, 1/100 ), rarely (≥1 / 10,000, 1/1000), very rarely (1/10 000), the frequency is unknown (it is impossible to estimate from the available data).

Ramipril

From the blood system and lymphatic system: sometimes - eosinophilia; rarely - a decrease in the number of white blood cells (including neutropenia and agranulocytosis), a decrease in the number of red blood cells, a decrease in hemoglobin level, a decrease in the number of platelets; unknown - bone marrow failure, pancytopenia, hemolytic anemia.

On the part of the immune system: unknown - anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Metabolic disorders: often - increased levels of potassium in the blood; sometimes - anorexia, decreased appetite; unknown - decreased sodium levels in the blood.

Mental disorders: sometimes - depressed mood, anxiety, nervousness, anxiety, sleep disturbance, including drowsiness; rarely - confusion; unknown - impaired attention.

From the nervous system: often - headache, dizziness; sometimes - vertigo, paresthesia, ageusia, dysgeusia; rarely - tremor, imbalance; unknown - cerebral ischemia, including ischemic stroke and transient cerebrovascular accident, impaired psychomotor function, burning sensation, parosmia.

On the part of the organs of vision: sometimes - visual impairment, including blurred vision; rarely conjunctivitis.

On the part of the organs of hearing and balance: rarely - hearing impairment, ringing in the ears.

From the cardiovascular system: often - arterial hypotension, orthostatic decrease in blood pressure, syncope; sometimes - myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, heart palpitations, peripheral edema, flushing of the face; rarely - vascular stenosis, hypoperfusion, vasculitis; unknown - Raynauds syndrome.

From the respiratory system: often - unproductive annoying cough, bronchitis, sinusitis, shortness of breath; sometimes - bronchospasm, including exacerbation of asthma, nasal congestion.

From the digestive tract: often - inflammation in the digestive tract, digestive disorders, gastrointestinal discomfort, dyspepsia, diarrhea, nausea, vomiting; sometimes - pancreatitis (isolated cases with a fatal outcome when using ACE inhibitors), an increase in the level of pancreatic enzymes, angioedema of the small intestine, pain in the upper abdomen, including gastritis, constipation, dry mouth; rarely - glossitis; unknown - aphthous stomatitis.

From the hepatobiliary system: sometimes - an increase in the level of liver enzymes and / or conjugated bilirubin; rarely - cholestatic jaundice, hepatocellular damage; unknown - acute liver failure, cholestatic or cytolytic hepatitis (in isolated cases with a fatal outcome).

On the part of the skin and subcutaneous tissues: often - a rash, in particular maculopapular; sometimes - angioneurotic edema (in exceptional cases, airway obstruction due to angioedema can be fatal), itching, increased sweating; rarely - exfoliative dermatitis, urticaria, onycholysis; very rarely - photosensitivity reactions; unknown - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

From the musculoskeletal system: often - muscle cramps, myalgia; sometimes - arthralgia.

From the urinary system: sometimes - impaired renal function, including acute renal failure, increased diuresis, exacerbation of existing proteinuria, increased levels of urea and creatinine in the blood.

From the reproductive system: sometimes - transient erectile dysfunction, decreased libido; unknown - gynecomastia.

General disorders and disorders at the injection site: often - chest pain, weakness; sometimes pyrexia; rarely - asthenia.

Amlodipine. When using amlodipine, adverse reactions such as drowsiness, dizziness, headache, palpitation, flushing, abdominal pain, nausea, swelling of the legs, swelling and fatigue were more often reported.

On the part of the blood system and lymphatic system: very rarely - leukopenia, thrombocytopenia.

Metabolic disorders: sometimes - hyperglycemia.

Mental disorders: sometimes - mood changes (including anxiety), insomnia, depression; rarely - confusion.

From the side of the nervous system: often - headache, dizziness, drowsiness (especially at the beginning of treatment); sometimes - tremors, taste disorders, syncope, hypesthesia, paresthesia; very rarely - hypertension, peripheral neuropathy.

From the side of the organ of vision: sometimes - visual impairment (including diplopia).

On the part of the organ of hearing: sometimes - ringing in the ears.

From the cardiovascular system: often - tachycardia, flushing; sometimes - arterial hypotension; very rarely - myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis.

From the respiratory system: sometimes - shortness of breath, rhinitis; very rarely - cough.

From the digestive tract: often - abdominal pain, nausea; sometimes - vomiting, dyspepsia, intestinal motility disorders (including constipation and diarrhea), dry mouth; very rarely - pancreatitis, gastritis, gum hyperplasia.

From the hepatobiliary system: very rarely - jaundice *, hepatitis *.

On the part of the skin and subcutaneous tissues: infrequently - alopecia, purpura, discoloration of the skin, increased sweating, itching, rash, exanthema; very rarely - angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.

From the side of the musculoskeletal system: often - swelling of the ankle joint; infrequently - arthralgia, myalgia, muscle cramps, back pain.

From the urinary system: sometimes - violation of urination, nocturia, increased frequency of urination.

From the reproductive system: sometimes - impotence, gynecomastia.

General disorders and reactions at the injection site: often - swelling, fatigue; infrequently - pain behind the sternum, asthenia, pain, malaise.

Laboratory indicators: rarely - increase or decrease in body weight; very rarely - increased levels of liver enzymes *.

* In most cases with cholestasis.

special instructions

Ramipril

Patients who are at particular risk of arterial hypotension. In patients with a significant increase in the activity of the renin-angiotensin-aldosterone system, there is a risk of a sudden significant decrease in blood pressure and impaired renal function due to inhibition of ACE, especially if the ACE inhibitor or concomitant diuretic is prescribed for the first time or for the first time increasing the dose. A significant increase in the activity of the renin-angiotensin-aldosterone system, requiring medical supervision, including constant monitoring of blood pressure, can be expected, for example, in patients with:

• severe hypertension;
• decompensated congestive heart failure;
• hemodynamically significant obstacle to the inflow or outflow of blood from the left ventricle (for example, with aortic or mitral valve stenosis);
• unilateral renal artery stenosis in the presence of a second functioning kidney;
• an existing or possible lack of fluid or electrolytes (including those taking diuretics);
• cirrhosis of the liver and / or ascites;
• extensive surgical interventions or during anesthesia with the use of drugs that cause arterial hypotension.

As a rule, it is recommended that dehydration, hypovolemia, or electrolyte deficiency be corrected before treatment (however, patients with heart failure should be weightedly prescribed such measures due to the risk of volume overload).

Transient or persistent heart failure after myocardial infarction. Patients at risk of cardiac or cerebral ischemia in case of acute arterial hypotension in the initial phase of treatment require special medical monitoring.

Elderly patients. See APPLICATION.

Surgical intervention. If possible, treatment with ACE inhibitors, such as ramipril, should be discontinued 1 day before surgery.

Monitoring kidney function. Renal function should be evaluated before and during treatment and the dose should be adjusted, especially in the first weeks of treatment. Particularly careful monitoring is necessary for patients with impaired renal function (see APPLICATION). There is a risk of impaired renal function, especially in patients with congestive heart failure or after a kidney transplant.

Angioneurotic edema. In patients receiving ACE inhibitors, including ramipril, angioedema was observed (see ADVERSE EFFECTS). In the case of angioedema, the use of the drug Hartil-AM should be discontinued. Emergency treatment should be started immediately. The patient should be under medical supervision for at least 12-24 hours and may be discharged after the symptoms have completely disappeared.

In patients receiving ACE inhibitors, including ramipril, angioedema of the intestine was detected (see ADVERSE EFFECTS). These patients complained of abdominal pain (with or without nausea / vomiting).

Anaphylactic reactions during desensitization. With the use of ACE inhibitors, the likelihood of occurrence and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increase. Before carrying out desensitization, you should temporarily stop taking ramipril.

Hyperkalemia In some patients who received ACE inhibitors, including ramipril, the occurrence of hyperkalemia was noted. The risk group for hyperkalemia includes patients with kidney failure, people over the age of 70 years, patients with uncontrolled diabetes mellitus, patients who take potassium salts, potassium-sparing diuretics, as well as other active substances that increase the potassium content in blood plasma, or patients with conditions such as dehydration, acute cardiac decompensation, metabolic acidosis.If the combined use of the above drugs is considered appropriate, it is recommended to regularly monitor the level of potassium in the blood plasma (see INTERACTIONS).

Neutropenia / agranulocytosis. Cases of neutropenia / agranulocytosis, as well as thrombocytopenia and anemia were rarely detected. Inhibition of bone marrow function has also been reported. In order to identify possible leukopenia, it is recommended to control the number of white blood cells in the blood. More frequent monitoring is desirable at the beginning of treatment in patients with impaired renal function, concomitant collagenosis (for example, systemic lupus erythematosus or scleroderma) or in those taking other drugs that may cause changes in the blood picture (see INTERACTIONS AND ADVERSE EFFECTS) .

Ethnic differences. ACE inhibitors often cause angioedema in patients of the Negroid race than in representatives of other races. Like other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of the Negroid race compared with representatives of other races. This may be due to the fact that in patients of the Negroid race with hypertension, hypertension with low renin activity is more often noted.

Cough. When using ACE inhibitors, coughing has been reported. It is characteristic that the cough is unproductive, prolonged, and disappears after cessation of therapy. In the differential diagnosis of cough, you should be aware of the possibility of a cough caused by ACE inhibitors.

Amlodipine. The safety and effectiveness of amlodipine for the relief of hypertensive crisis have not been established.

Patients with heart failure. Patients with heart failure require a special approach. In a long, placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group compared with placebo, but this was not associated with worsening heart failure.

Use in patients with impaired liver function. In patients with impaired liver function T_½ Amlodipine increases, however, recommendations regarding dosage of the drug have not yet been developed. For this reason, amlodipine should be used with caution in such patients.

Use in elderly patients. In elderly patients, a dose increase should be carried out with caution.

Patients with renal failure. In this category of patients, the usual dose of the drug should be used. Changes in the concentration of amlodipine in blood plasma do not correlate with the degree of impaired renal function. Amlodipine is not excreted by dialysis.

Amlodipine does not affect laboratory results.

It is not recommended to use amlodipine together with grapefruit or grapefruit juice, since in some patients the bioavailability may be increased, which will lead to an increase in the severity of the hypotensive effect of the drug.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Some side effects (for example, symptoms of a decrease in blood pressure, such as dizziness) may impair the ability to concentrate and respond, so this can affect the speed of the reaction when driving vehicles or working with other mechanisms. These adverse reactions were noted at the beginning of treatment or when switching from taking other drugs. After taking the first dose or increasing the dose, it is not recommended to drive vehicles or work with other mechanisms for several hours.

Use during pregnancy and lactation. Ramipril. Ramipril is not recommended in the first trimester of pregnancy and is contraindicated in the second and third trimester of pregnancy.

Epidemiological data on the risk of teratogenicity after the use of ACE inhibitors in the first trimester of pregnancy were not convincing, but a slight increase in risk cannot be ruled out. If continued treatment with an ACE inhibitor is considered necessary, patients planning a pregnancy should switch to an alternative antihypertensive drug with an established safety profile for use during pregnancy. If pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and alternative therapy should be started.

It is known that the use of ACE inhibitors in the II and III trimester of pregnancy causes fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) in humans. If an ACE inhibitor is used in the second trimester of pregnancy, ultrasound of the kidney and skull is recommended. Newborns whose mothers were taking ACE inhibitors should be carefully examined for arterial hypotension, oliguria and hyperkalemia. Since there is insufficient information on the use of ramipril during breastfeeding, it is not recommended for use and prefer safer treatments, especially in the case of a newborn or premature baby.

Amlodipine. Pregnancy. Use during pregnancy is recommended only when there is no safer alternative and when the disease itself carries a greater risk to the mother and fetus.

Lactation. It is not known whether amlodipine is excreted in human milk. The decision to extend / stop breastfeeding or to continue / discontinue amlodipine therapy should be made taking into account the benefits of breastfeeding for the baby and the benefits of using amlodipine for the mother.

Given the above information, it is contraindicated to use the drug Hartil-AM during pregnancy and lactation.

Children. Hartil-AM is not recommended for use in children due to the lack of data on the safety and effectiveness of its use in this age group of patients.

Interactions

Ramipril. contraindicated combinations. extracorporeal treatments that result in blood contact with negatively charged surfaces, such as dialysis or hemofiltration with certain membranes with high hydraulic permeability (e.g. polyacrylonitrile), as well as apheresis of LDL with dextran sulfate due to the increased risk of severe anaphylactic reactions. if such treatment is required, consideration should be given to using another type of dialysis membrane or another class of antihypertensive agents.

Use with caution

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase the level of potassium in the blood plasma (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): hyperkalemia may occur, therefore careful monitoring of the level of potassium in the blood plasma is necessary.

Antihypertensive drugs (e.g. diuretics) and other drugs that can lower blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): an increased risk of arterial hypotension is possible.

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that can change the number of blood cells: an increased likelihood of hematological reactions.

Lithium salts: ACE inhibitors can reduce lithium excretion, and therefore its toxicity may increase.Blood lithium control is recommended.

Antidiabetic agents, including insulin: hypoglycemic reactions are possible. It is recommended that you control your blood glucose.

NSAIDs and acetylsalicylic acid: a decrease in the antihypertensive effect of ramipril is possible. Therefore, the combined use of ACE inhibitors and NSAIDs can lead to an increased risk of impaired renal function and increased levels of potassium in the blood.

Amlodipine. Amlodipine is safe when combined with thiazide diuretics, β-adrenergic blockers, long-acting nitrates, nitroglycerin for sublingual administration, NSAIDs, antibiotics, and oral hypoglycemic agents.

The effect of other drugs on amlodipine

• CYP 3A4 inhibitors: with the combined use of amlodipine with a CYP 3A4 inhibitor erythromycin in young patients and diltiazem in the elderly, the concentration of amlodipine in blood plasma increased by about 22 and 50%, respectively. However, the clinical significance of these indicators has not been elucidated. It cannot be ruled out that strong CYP 3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) can increase plasma concentrations of amlodipine more than diltiazem. Amlodipine cl