Verapamil + Trandolapril - instructions for use, dose, side effects, contraindications

Trandolapril suppresses the activity of the renin-angiotensin-aldosterone system of blood plasma. Renin is an enzyme that is synthesized by the kidneys and enters the bloodstream, where it causes the conversion of angiotensinogen to angiotensin I (low-activity decapeptide). The latter is transformed by action angiotensin-converting enzyme (peptidyl dipeptidase) into angiotensin II - a potent vasoconstrictor that causes arterial narrowing and an increase HELL, as well as stimulating the secretion of aldosterone by the adrenal glands.

Inhibition angiotensin-converting enzyme leads to a decrease in the concentration of angiotensin II in the blood plasma, which is accompanied by a decrease in vasopressor activity and aldosterone secretion. Although the production of aldosterone decreases insignificantly, nevertheless a slight increase in potassium concentration in the serum can be observed in combination with the loss of sodium and water.

Reduction of the level of angiotensin II by the feedback mechanism leads to an increase in renin activity in the blood plasma. Another function angiotensin-converting enzyme is the destruction of kinin (bradykinin), possessing a powerful vasodilating property, to inactive metabolites. In this regard, suppression angiotensin-converting enzyme leads to an increase in the circulating and tissue levels of kallikrein-kinin, which contributes to vasodilation by activating the system prostaglandins. This mechanism, possibly, partially determines the hypotensive effect of inhibitors angiotensin-converting enzyme and is the cause of some side effects.

In patients with arterial hypertension, the use of inhibitors angiotensin-converting enzyme leads to a comparable decrease HELL in the "sitting" and "standing" positions without compensatory enlargement heart rate. The peripheral vascular resistance decreases, the cardiac output does not change or increases, the renal blood flow increases, and the glomerular filtration rate usually does not change. A sharp cessation of therapy is not accompanied by a rapid increase HELL. The hypotensive effect of trandolapril is manifested 1 h after administration and persists for at least 24 h. In some cases, optimal control HELL can only be achieved in a few weeks after the start of treatment. With prolonged therapy, the hypotensive effect persists. Trandolapril does not worsen the circadian profile HELL.

Verapamil

Verapamil blocks the transmembrane current of calcium ions in the smooth muscle cells of the myocardium and coronary vessels. Verapamil causes a decrease HELL both at rest and during exercise due to the expansion of peripheral arterioles. As a result of total peripheral resistance of blood vessels (afterload) decreases myocardial oxygen demand and energy consumption. Verapamil reduces myocardial contractility. Negative inotropic effect of the drug can be compensated by a decrease total peripheral resistance of blood vessels. The cardiac index does not decrease, except for patients with left ventricular dysfunction.

Verapamil does not affect the sympathetic regulation of cardiac activity, since it does not block beta-adrenergic receptors.

Pharmacokinetics:

Trandolapril

Suction

After oral administration trandolapril quickly absorbed. Absolute bioavailability of about 10%. T_maxin the blood plasma for about 1 hour.

Distribution

The binding of trandolapril to plasma proteins is about 80% and is independent of concentration. V_dTrandolapril about 18 liters. Half-life <1 hour. For repeated use of C_ssis reached in about 4 days, both in healthy volunteers, and in patients of young and elderly age with arterial hypertension.

Metabolism

In the blood plasma trandolapril is hydrolyzed to form an active metabolite of trandolaprilate. T_max Trandolaprilat in blood plasma is 4-10 h. C_max or AUC do not depend on food intake. Absolute bioavailability of trandolaprilate is about 70%. Binding to blood proteins depends on the concentration and varies from 65% at a concentration of 1000 ng / ml to 94% at a concentration of 0.1 ng / ml. Trandolaprilat has a high affinity for angiotensin-converting enzyme.

Excretion

Renal clearance of trandolaprilat varies from 1 to 4 l / h, depending on the dose. When C_ss effective half-life Trandolaprilat, together with a small fraction of the drug taken, varies between 16 h and 24 h, which probably reflects a binding to plasma and tissue angiotensin-converting enzyme. In the form of trandolaprilat, 10-15% of the dose of trandolapril is excreted by the kidneys, <0.5% of the dose is excreted by the kidneys unchanged. After receiving the labeled trandolapril, 33% of the radioactivity inside is detected in the urine and 66% - in feces.

Pharmacokinetics in special clinical cases

The pharmacokinetics of trandolapril have not been studied in children younger than 18 years.

The concentration of trandolapril in the blood plasma increases in elderly patients (over 65 years). However, the plasma concentration of trandolaprilate and its ACE inhibitory activity in patients with hypertension of the elderly of both sexes are the same.

Renal failure. Compared with healthy volunteers in patients on hemodialysis and with creatinine clearance <30 ml / min, the plasma concentration of trandolaprilat is approximately 2 times higher, and the renal clearance is reduced by approximately 85%.

Liver failure. Compared with healthy volunteers in patients with mild alcoholic cirrhosis, the plasma concentration of trandolapril and trandolaprilate increases 9 and 2 times, respectively, but the ACE inhibitory activity does not change.

Verapamil

Suction

After oral administration, about 90-92% of the dose of verapamil is rapidly absorbed into the small intestine. Bioavailability is only 22% because of the pronounced effect of "first passage" through the liver. With repeated use, the average bioavailability can increase to 30%. Time to reach C_maxin plasma is 4-15 hours.

Distribution

C_ss with repeated application once a day is achieved after 3-4 days. Binding to plasma proteins is about 90%.

Metabolism

One of the 12 metabolites found in urine is noravapamil, whose pharmacological activity is 10-20% of that of verapamil; its share is 6% of the withdrawn drug. C_ssnorverapamil and verapamil are similar.

Excretion

Half-life with repeated application is an average of 8 hours 3-4% of the dose is excreted by the kidneys unchanged. Metabolites are excreted by the kidneys (70%) and through the intestine (16%).

Pharmacokinetics in special clinical cases

The pharmacokinetics of verapamil does not change with renal dysfunction. Impaired renal function does not affect the excretion of verapamil.

Bioavailability and half-life verapamil increased in patients with cirrhosis of the liver.However, the pharmacokinetics of verapamil remains unchanged in patients with compensated liver dysfunction.

Indications:

Essential arterial hypertension (in patients who are shown combined therapy).

ICD-10

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

IX.I10-I15.I15 Secondary Hypertension

Contraindications:

- history of angioedema, associated with treatment with inhibitors angiotensin-converting enzyme;

- cardiogenic shock;

- chronic heart failure of IIB and III stage;

- simultaneous use of beta-blockers;

- AV blockade II and III degree (except for patients with an artificial pacemaker);

acute myocardial infarction;

- syndrome of weakness of the sinus node (except for patients with an artificial pacemaker);

- acute heart failure;

- atrial fibrillation / flutter;

- Wolff-Parkinson-White syndrome;

- Laun-Ganong-Levin syndrome;

- pronounced bradycardia;

- severe arterial hypotension;

- impaired renal function (creatinine clearance <30 ml / min.);

- Pregnancy;

- the period of breastfeeding;

- age under 18 years (effectiveness and safety not established);

- known hypersensitivity to any component of the drug or to any other inhibitor angiotensin-converting enzyme.

Carefully:

With caution should be used in aortic stenosis, hypertrophic obstructive cardiomyopathy, liver and / or kidney function disorders, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), oppression of bone marrow hematopoiesis, AV-blockade of I degree, bradycardia, arterial hypotension , conditions accompanied by a decrease in the volume of circulating blood (including diarrhea, vomiting), bilateral stenosis of the renal arteries, artery stenosis of the only kidney, condition after kidney transplantation, in patients who follow a diet with salt restriction on hemodialysis, when combined with diuretics.

Pregnancy and lactation:

Contraindicated use of the drug during pregnancy and during lactation.

The safety of the drug in pregnant women is not established. There are separate observations of lung hypoplasia in newborns, intrauterine growth retardation of the fetus,open arterial duct and hypoplasia of the skull after the application of inhibitors angiotensin-converting enzyme during pregnancy. Inhibitors angiotensin-converting enzyme can cause arterial hypotension, accompanied by anuria in the fetus or newborn or oligohydroamnion.

The risk of teratogenic effects is highest with the appointment of inhibitors angiotensin-converting enzyme in the II and III trimesters of pregnancy. Information about possible teratogenicity or embryo / fetotoxicity of inhibitors angiotensin-converting enzyme in the first trimester of pregnancy is not available.

Verapamil is excreted in breast milk. During treatment with the drug should stop breastfeeding.

Dosing and Administration:

1 capsule (trandolapril 2 mg + verapamil 180 mg) once a day. The drug should be taken orally, preferably in the morning after eating. Capsule swallowed whole, washed down with water.

Side effects:

Headache, dizziness; AV-blockade of the 1st degree; increased cough; constipation, asthenia.

Infections: bronchitis.

On the part of the system hematopoiesis: leukopenia, neutropenia, lymphopenia, thrombocytopenia.

From the side of metabolism and nutrition: hyperkalemia, hyponatremia.

From the nervous system: disturbance of balance, insomnia, drowsiness, fainting, hypesthesia, paresthesia, anxiety, impaired thinking.

From the side of the organ of vision: visual impairment, "fog before the eyes."

From the organ of hearing and the vestibular apparatus: dizziness, noise in the ears.

From the cardiovascular system: complete AV blockade, angina, bradycardia, palpitations, tachycardia, blockade of the bundle of the bundle, acute myocardial infarction, ventricular extrasystole, nonspecific changes in the ST-T segment on the ECG, marked decrease in blood pressure, blood flushes to the face.

From the respiratory system: shortness of breath, congestion of the paranasal sinuses.

From the digestive tract: nausea, diarrhea, indigestion, dyspepsia, dry mouth.

From the skin and subcutaneous fat: angioedema, skin itching, rash.

From the musculoskeletal system: arthralgia, myalgia, gout (hyperuricemia).

From the side of the kidneys and urinary tract: frequent urination, polyuria, hematuria, proteinuria, nocturia.

On the part of the reproductive system: impotence, endometriosis.

General and local reactions: pain in the chest, peripheral edema, fatigue.

Laboratory indicators: increased hepatic enzymes and / or bilirubin, serum creatinine, residual urea nitrogen.

Significant adverse events that were observed with the use of verapamil

From the cardiovascular system: AV blockade of I, II, III degree, stop of sinus node, AV dissociation, intermittent claudication, occurrence or weighting of heart failure, angina pectoris, arrhythmia, pulmonary edema, tachycardia, bradycardia, severe arterial hypotension, blood flushes to the face.

From the nervous system: acute disturbance of cerebral circulation, confusion, drowsiness, psychotic symptoms, tremor, headache, dizziness, paresthesia.

From the side of the organ of hearing and balance: dizziness.

From the digestive tract: gingival hyperplasia, pain or discomfort in the abdomen, reversible non-obstructive intestinal obstruction, nausea, vomiting, constipation.

From the skin and subcutaneous fat: angioneurotic edema, Stevens-Johnson syndrome, urticaria, purpura, pruritus, ecchymosis, bruising, hair loss, hyperkeratosis, increased sweating, erythema multiforme, maculopapular rash.

From the musculoskeletal system: muscle weakness, myalgia, arthralgia.

From the reproductive system and the mammary glands: gynecomastia, galactorrhea, impotence.

Immune disorders: hypersensitivity, allergic reactions.

From the side of the kidneys and urinary tract: frequent urination.

Common reactions: peripheral edema, fainting, fatigue.

Laboratory indicators: hyperprolactinemia, increased activity of hepatic transaminases.

Significant adverse events that were observed with the use of trandolapril

On the part of the hematopoiesis system: agranulocytosis.

From the digestive tract: vomiting, abdominal pain, pancreatitis.

From the skin and subcutaneous fat: alopecia.

Immune disorders: hypersensitivity.

From the genitourinary system: decreased libido.

Common symptoms: fever.

Undesirable phenomena that are registered with the use of all inhibitors angiotensin-converting enzyme

From the side of the central nervous system: transient impairment of cerebral circulation, headache.

From the cardiovascular system: myocardial infarction, cardiac arrest, cerebral hemorrhage, arterial hypotension.

From the skin and subcutaneous fat: exudative erythema multiforme, toxic epidermal necrolysis, angioedema, rash.

From the side of the kidneys and urinary tract: acute renal failure.

Others: pain in the chest, cough.

Laboratory indicators: pancytopenia, decreased hemoglobin and hematocrit, neutropenia, agranulocytosis, hyperkalemia.

Overdose:

In clinical trials, the maximum dose of trandolapril was 16 mg. At the same time, there were no signs of his intolerance.

In case of an overdose of the drug, the following symptoms may be caused verapamil: marked decrease in blood pressure, AV blockade, bradycardia, asystole. Cases of death from an overdose have been recorded.

In case of an overdose of the drug, the following symptoms may be caused trandolapril: marked decrease in blood pressure, shock, stupor, bradycardia, electrolyte disorders, renal failure.

Treatment: symptomatic. Treatment of an overdose of verapamil includes parenteral administration of calcium preparations, the use of beta-adrenomimetics and gastric lavage. Considering the delayed absorption of the prolonged-action drug, the patient's condition should be monitored for 48 hours; during this period, hospitalization may be required. Verapamil not removed during hemodialysis.

Interaction:

Interactions due to verapamil

Research in vitro evidence that verapamil metabolized under the action of isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18.

Verapamil is an inhibitor of CYP3A4. A clinically significant interaction was observed with simultaneous application with CYP3A4 inhibitors, with an increase in verapamil level in blood plasma, while inducers of CYP3A4 reduced the concentration of verapamil in blood plasma. Accordingly, with the simultaneous use of such tools, the possibility of interaction should be taken into account.

Other possible interactions

With the simultaneous use of antiarrhythmics and beta-blockers with the drug, it is possible to increase the adverse effect on the cardiovascular system (more pronounced AV blockade, a more significant decrease in the rate of heart rate, the development of heart failure and increased arterial hypotension).

With the simultaneous use of quinidine with the drug, the hypotensive effect is enhanced. In patients with hypertrophic obstructive cardiomyopathy, pulmonary edema may develop.

With the simultaneous use of antihypertensive agents, diuretics and vasodilators with the drug, the hypotensive effect is enhanced.

With simultaneous use with the drug prazosin, terazosin, the hypotensive effect is enhanced.

With simultaneous use with the drug, some drugs for the treatment of HIV infection (ritonavir) can inhibit the metabolism of verapamil, which leads to an increase in its concentration in the blood plasma. With simultaneous application of a dose of verapamil should be reduced.

With the simultaneous use of carbamazepine with the drug, the level of carbamazepine in the blood plasma increases, which can be accompanied by carbamazepine-specific side effects - diplopia, headache, ataxia or dizziness.

With the simultaneous use of lithium with the drug, the neurotoxicity of lithium increases.

With the simultaneous use of rifampicin with the drug, hypotensive action of verapamil may be reduced.

With the simultaneous use of sulfinpyrazone with the drug, hypotensive action of verapamil may be reduced.

With simultaneous use with the drug, the effect of muscle relaxants can increase.

With the simultaneous use of acetylsalicylic acid with verapamil, bleeding increases.

Patients receiving verapamil, treatment with inhibitors of HMG-CoA reductase (i.e., simvastatin / lovastatin) should be started from as low as possible with a gradual increase during therapy. If it is necessary to appoint verapamil patients who are already receiving HMG-CoA reductase inhibitors, then their doses should be revised accordingly and serum cholesterol concentrations, respectively. Similar tactics should be followed and with the simultaneous appointment of verapamil with atorvastatin.

Fluvastatin, pravastatin and rosuvastatin are not metabolized under the action of the isoenzyme CYP3A4, so their interaction with verapamil is least likely.

Interactions caused by trandolapril

Diuretics or other antihypertensive drugs may increase the antihypertensive effect of trandolapril. Trandolapril can reduce potassium loss when combined with thiazide diuretics.

Potassium-sparing diuretics (spironolactone, amiloride,triamterene) or potassium preparations increase the risk of hyperkalemia with concomitant use with trandolapril.

The simultaneous use of trandolapril (as well as any inhibitors angiotensin-converting enzyme) with hypoglycemic agents (insulin or oral hypoglycemic agents) may increase the hypoglycemic effect and lead to an increased risk of hypoglycemia.

Trandolapril may worsen the excretion of lithium. It is necessary to control the level of lithium in the blood serum.

Other interactions

With simultaneous use with verapamil, the concentration of colchicine in the blood can be significantincrease significantly, as the latter is a substrate for CYP3A and P-glycoprotein, which in turn inhibit the metabolism of verapamil.

In animal experiments, it has been shown that inhalational anesthetics reduce the flow of calcium into the cell, exerting a depressing effect on the cardiovascular system. With simultaneous application with verapamil, the oppressive effect on the myocardium can be increased.

The hypotensive effect of some inhalation anesthetics can be enhanced by inhibitors angiotensin-converting enzyme.

When used during hemodialysis, high-flux polyacrylonitrile membranes in patients receiving inhibitors angiotensin-converting enzyme, anaphylactoid reactions have been described. In patients taking inhibitors angiotensin-converting enzyme, the use of such membranes during hemodialysis should be avoided.

Non-steroidal anti-inflammatory drugs reduce the hypotensive effect of trandolapril.

Cytotoxic or other immunosuppressive drugs and glucocorticosteroids increase the risk of developing leukopenia when combined with inhibitors angiotensin-converting enzyme.

Special instructions:

Patients with a dysfunction of the liver need careful monitoring during the treatment with the drug.

In patients with uncomplicated arterial hypertension after the first dose of trandolapril, as well as after its increase, the development of arterial hypotension accompanied by clinical symptoms was noted. The risk of arterial hypotension is higher if the water-electrolyte balance is disturbed by prolonged therapy with diuretics, limiting salt intake, dialysis, diarrhea, or vomiting.In such patients, before therapy with trandolapril should be stopped, diuretic therapy should be completed and the volume of circulating blood and / or salt content should be replenished. It is necessary to monitor blood pressure especially carefully when appointing or canceling non-steroidal anti-inflammatory drugs during the period of application of the drug. When treated with inhibitors angiotensin-converting enzyme described cases of agranulocytosis and suppression of bone marrow function. These adverse events are more common in patients with impaired renal function, especially with systemic connective tissue diseases. In such patients (for example, with systemic lupus erythematosus or scleroderma) it is advisable to regularly monitor the number of leukocytes in the blood and the protein content in the urine, especially if the kidney function is impaired, treated with glucocorticosteroids and cytostatics-antimetabolites.

Trandolapril can cause angioedema, swelling of the face, tongue, throat and / or larynx.

The composition of the drug is verapamil, therefore the use of a combination drug should be avoided in patients with severe left ventricular dysfunction (eg, with an ejection fraction <30%, an increase in pulmonary capillary wedge pressure> 20 mmHg.or severe heart failure symptoms) and in patients with any degree of left ventricular dysfunction if they receive a beta-blocker.

When examining patients with hypertension, kidney function should always be evaluated. In patients with chronic heart failure, bilateral stenosis of the renal arteries, or unilateral renal artery stenosis in patients with a single kidney (eg after transplantation), the risk of impaired renal function is increased, and in patients with renal insufficiency, the risk of further impairment of kidney function is increased.

In some patients with hypertension who do not have kidney disease, with the appointment of trandolapril in combination with a diuretic, there may be an increase in urea nitrogen in the blood and serum creatinine.

In patients with hypertension, especially with impaired renal function, the drug can cause hyperkalemia.

With surgical interventions or general anesthesia using drugs that cause arterial hypotension, trandolapril can block the formation of angiotensin II, associated with compensatory release of renin.

With care, you should choose doses of inhalational anesthetics with simultaneous application with verapamil.

With the simultaneous use of colchicine and verapamil, tetraparesis was reported. Joint use is not recommended.

In some patients receiving diuretics, especially recently, after the appointment of trandolapril, a sharp decrease in blood pressure is observed.

Since data on the interaction of verapamil and disopyramide are absent, disopyramide should not be used within 48 hours before or 24 hours after taking verapamil.

Use in Pediatrics

The use of the drug in children under 18 years old, so the use of it in this age group is not recommended.

Impact on the ability to drive vehicles and manage mechanisms

It is necessary to refrain from driving and working with machinery in the early stages of treatment, as the ability to drive or use sophisticated technology can deteriorate.

Instructions

Verapamil + Trandolapril (Verapamilum + Trandolaprilum)