Diltiazem - instructions for use, dose, side effects, contraindications

It blocks potential-dependent L-type calcium channels and inhibits the entry of calcium ions into the depolarization phase of cardiomyocytes and vascular smooth muscle cells. As a result of inhibition of the slow depolarizing calcium flow into cells of excitable tissues, the formation of the action potential depresses and separates the process of "excitation-contraction". Reduces the contractility of the myocardium, reduces the heart rate and slows the atrioventricular conductivity. It relaxes the smooth muscles of the vessels, lowers the overall peripheral vascular resistance. Has a dose-dependent antihypertensive effect in mild to moderate hypertension.The degree of decrease in blood pressure correlates with the level of hypertension (in people with normal blood pressure there is only a minimal decrease). The hypotensive effect is manifested both in the horizontal and in the vertical position. Rarely causes postural hypotension and reflex tachycardia. Does not change or slightly reduces the maximum heart rate during exercise.

Long-term therapy is not accompanied by hyperkatecholamineemia, an increase in the activity of the renin-angiotensin-aldosterone system. Reduces the renal and peripheral effects of angiotensin II. The antianginal effect is caused by a decrease in myocardial oxygen demand, due to a decrease in heart rate and systemic arterial pressure, vasodilation of the epicardial vessels, and the ability to eliminate coronarospasm. Relaxes the smooth muscles of the coronary vessels in a concentration that does not cause a negative inotropic effect. Efficacy in supraventricular tachycardia is associated with an increase (by 20%) in the effective and functional refractory period atrioventricular node and an extension of the lead time in atrioventricular node (at normal heart rate, the effect on atrioventricular node is minimal). Slows the ventricular rhythm in patients with a high incidence of ventricular contractions with flicker and atrial flutter. Restores the normal sinus rhythm with paroxysmal supraventricular tachycardia, interrupts the circulation of excitation by the type of re-entry for nodular tachycardia and tachycardia with reciprocal conduction, including in the case of Wolff-Parkinson-White syndrome. Long-term use is accompanied by a slight increase in the sinoatrial interval PR on the ECG. In the syndrome of weakness of the sinus node significantly increases the duration of the sinus cycle. Atrial fibrillation and flutter, under bolus administration, effectively reduces the heart rate (at least 20% in 95% of patients). The action usually comes in 3 minutes and reaches a maximum within 2-7 minutes. Decrease in rhythm is maintained for 1-3 hours. With prolonged infusion introduction, a decrease in the heart rate by 20% is noted in 83% of patients and persists after administration for a period of 0.5 h to 10 h.Efficacy in restoring sinus rhythm in paroxysmal supraventricular tachycardia is 88% within 3 minutes. In patients with severe left ventricular myocardial changes (heart failure, myocardial infarction, hypertrophic cardiomyopathy) does not change contractility, terminal diastolic arterial pressure in the left ventricle, and pulmonary capillary wedge pressure. Has a minimal effect on the smooth muscles of the gastrointestinal tract. Long-term (8 months) therapy is not accompanied by the development of tolerance and changes in the lipid profile of the plasma. It is able to cause regression of left ventricular hypertrophy in patients with arterial hypertension. In usual therapeutic doses does not affect mortality, but in patients with signs of stagnation in the lungs increased the incidence of cardiovascular complications by 40%. In patients with acute myocardial infarction with thrombolytic therapy, the plasminogen activator increased the frequency of hemorrhagic complications 5-fold.

Pharmacokinetics:

Good (more than 90% of the dose) is absorbed from the digestive tract. Bioavailability is 40% (the effect of "first passage" through the liver is expressed). C_max is achieved after 2-4 hours (tablets), 3.9-4.3 hours (180 mg capsules), 5-7 hours (retard tablets), 6-14 hours (prolonged-action capsules). The volume of distribution is 5.3 l / kg. The half-life period is 1-3 hours (with intravenous administration), 3-4.5 hours (tablets), 5-7 hours (retard tablets), 7.3-14.7 hours (capsules 180 mg). It binds to plasma proteins by 70-80% (40% - with acid alpha-glycoprotein, 30% - with albumin). The action develops within 3 minutes with a rapid intravenous injection, after 2-3 hours (prolonged action capsules) or 30-60 minutes (tablets) when administered orally. Duration of action with oral administration is 4-8 hours (tablets) and 12-24 hours (long-acting capsules). Metabolised in the liver by deacetylation, demethylation with the participation of cytochrome P450 (in addition to conjugation). The two main metabolites that are found in the plasma after ingestion are deacetyl-di-thiazine and desmethyl-di-thiazem. The deacetylated metabolite has the properties of a coronary vasodilator (plasma concentration is 10-20%, activity is 25-50% of that of diltiazem), is capable of cumulation. With a single intravenous administration, these metabolites are not detected in the plasma. Concentrates in the bile and undergoes enterohepatic circulation.Excretion (including metabolites) is carried out mainly through the gastrointestinal tract (65%) and to a lesser extent by the kidneys (35%). In urine, 5 metabolites and 2-4% of unchanged drug are detected. Penetrates into breast milk. With prolonged ingestion increases bioavailability and decreases clearance, which leads to increased therapeutic effects and side effects.

Based on the results obtained in 24-month experiments in rats and mice and in bacterial tests in vitro, does not have carcinogenic and mutagenic activity. In experiments on rats, mice, rabbits, using doses 5-10 times higher than the recommended daily doses for humans, caused the death of embryos and fetuses, a decrease in the survival rate of newborn rats and the development of skeletal anomalies. At doses 20 or more times higher than those recommended for humans, it increased the rate of stillbirth in experimental animals.

It is possible to use in transplantology: after kidney transplantation (prophylaxis of graft failure), during immunosuppressive therapy (to reduce nephrotoxicity of cyclosporin A).

Indications:Angina pectoris (stable,vasospastic); prophylaxis of coronarospasm in coronary angiography or aortocoronary bypass surgery; arterial hypertension (monotherapy or in combination with other antihypertensive drugs), including after a myocardial infarction (mainly retard forms, when beta-blockers are contraindicated), in patients with concomitant angina (in the presence of contraindications to the appointment of beta-blockers), patients with diabetic nephropathy (when ACE inhibitors are contraindicated); paroxysmal supraventricular tachycardia.

ICD-10

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

IX.I20-I25.I20.90 Angina pectoris unspecified with hypertension

IX.I20-I25.I20.9 Angina pectoris, unspecified

IX.I30-I52.I47.1 Nadzheludochkovaya tachycardia

IX.I30-I52.I47.2 Ventricular tachycardia

IX.I30-I52.I48 Atrial fibrillation and flutter

IX.I30-I52.I49.4 Other and unspecified depolarization

Contraindications:Severe bradycardia, AV-blockade of II and III degree (except for patients with pacemaker), syndrome of weakness of the sinus node, cardiogenic shock, atrial fibrillation with Wolff-Parkinson-White syndrome and Launa- Ganong-Levine syndrome, myocardial infarction with congestive pulmonary events,arterial hypotension, chronic heart failure IIB-III stage, acute heart failure, hemodynamically significant aortic stenosis, violations of liver and kidney function, pregnancy, lactation, hypersensitivity to benzothiazepine derivatives.

Carefully:They are used with caution for AV blockade of I degree, violations of intraventricular conduction, in patients prone to arterial hypotension, chronic heart failure, myocardial infarction with left ventricular failure, ventricular tachycardia with QRS complex expansion, hepatic insufficiency, renal insufficiency, in elderly patients, in children (efficacy and safety of use not investigated).

Pregnancy and lactation:

Contraindicated in pregnancy and lactation (breastfeeding).

In experimental studies, the teratogenic effect of diltiazem was established.

The action category for fetus by FDA is C.

Dosing and Administration:

When administered orally, the initial dose is 60 mg 3 times a day or 90 mg 2 times a day. With insufficient effectiveness, the dose is increased to 180 mg twice a day. Prolonged forms are applied 1-2 times a day, depending on the dose.

The maximum daily intake for oral administration is 360 mg.

When administered intravenously, a single dose of 300 μg / kg.

For intravenous drip, the dose is 2.8-14 μg / kg / min. The maximum daily dose is 300 mg.

Side effects:

From the side of the central nervous system and the peripheral nervous system: headache, dizziness, fainting, fatigue, asthenia, sleep disorders, drowsiness, anxiety, extrapyramidal (parkinsonism) disorders (ataxia, masky face, shuffling gait, stiffness of hands or feet, trembling of hands and fingers, difficulty swallowing), depression ; when used in high doses - paresthesia, tremor, visual impairment (transient loss of vision).

From the cardiovascular system: asymptomatic reduction in blood pressure; rarely angina pectoris, arrhythmia (including flutter and fibrillation of the ventricles), bradycardia (less than 50 beats per minute) or tachycardia, AV blockade II and III degree up to asystole, development or worsening of heart failure; when used in high doses and with intravenous administration - angina, bradycardia, AV blockade, marked decrease in blood pressure, worsening of chronic heart failure.

From the digestive system: dry mouth, increased appetite, nausea, vomiting, constipation or diarrhea, increased activity of hepatic transaminases, gingival hyperplasia (bleeding, soreness, swelling).

On the part of the hematopoiesis system: rarely - thrombocytopenia, agranulocytosis.

Allergic reactions: hyperemia of the skin of the face, skin rash, arthritis, multi-form exudative erythema (including Stevens-Johnson syndrome).

Other: when used in high doses - pulmonary edema (difficulty breathing, coughing, stridorous breathing); peripheral edema (edema of the lower limbs - ankles, feet, shins), an increase in the serum creatinine content; rarely - galactorrhea, weight gain.

Overdose:

Symptoms: bradycardia, hypotension, intracardiac blockade and heart failure.

Treatment: gastric lavage, the appointment of activated charcoal, plasmapheresis and hemoperfusion using activated charcoal. Antidote properties are possessed by calcium preparations (calcium gluconate) with intravenous administration, symptomatic therapy - the administration of atropine, isoproterenol, dopamine or dobutamine, diuretics, fluid infusion. At high degrees of AV blockade, electrical pacing is possible.

Interaction:

At simultaneous application with beta-adrenoblockers (including with propranolol, atenolol, metoprolol, pindolol, sotalol), additive cardiodepressive effect is possible along with an increase in antianginal action in the majority of patients. In patients with a previous impairment of left ventricular function or conduction disorders, the risk of developing severe and menacing bradycardia is increased.

Diltiazem inhibits the metabolism of propranolol, metoprolol, but not atenolol.

With simultaneous use with amiodarone, a negative inotropic effect, bradycardia, conduction disturbance, AV blockade is intensified.

Because the diltiazem inhibits the isoenzyme CYP3A4, which is involved in the metabolism of atorvastatin, lovastatin and simvastatin, theoretically possible manifestations of drug interaction caused by increased concentrations of statins in blood plasma. The cases of development of rhabdomyolysis are described.

With simultaneous use with buspirone, the concentration of buspirone in the blood plasma increases, its therapeutic and side effects are intensified.

With the simultaneous use of vecuronium chloride, an increase in the duration of neuromuscular blockade is possible.

With simultaneous use with digoxin, digitoxin, an increase in the concentrations of digoxin and digitoxin in the blood plasma is possible.

When used simultaneously with imipramine, the concentration of imipramine in the blood plasma increases and there is a risk of unwanted changes in the ECG.

The cases of an increase in plasma concentrations of trimipramine and nortriptyline with simultaneous application with diltiazem are described.

Diltiazem increases the bioavailability of imipramine by reducing its clearance. Changes in the ECG are due to an increase in the concentration of imipramine in the blood plasma and the additive inhibitory effect of diltiazem and imipramine on AV-conduction. It is believed that diltiazem in the same way interacts with trimipramine and nortriptylin.

With simultaneous use with insulin, a case of decreasing the effectiveness of insulin is described.

Due to the inhibition of metabolism of anticonvulsants in the liver under the influence of diltiazem and decrease in their clearance from the body, it is possible to increase the concentrations of carbamazepine and phenytoin in the blood plasma with the risk of developing toxic effects.

With simultaneous application of lithium carbonate, the cases of the development of an acute syndrome of parkinsonism, psychosis are described.

With simultaneous use with midazolam, triazolam, the concentration of midazolam and triazolam in the blood plasma increases and their effects are enhanced due to the inhibition of the isoenzyme CYP3A4 under the influence of diltiazem, with the participation of which the metabolism of these benzodiazepines is carried out.

With the simultaneous use of sodium amidotrizoatom may increase the antihypertensive effect diltiazem.

With simultaneous use with sodium nitroprusside, a significant increase in efficacy with controlled arterial hypotension is possible.

At simultaneous application with nifedipine the antihypertensive action amplifies.

Rifampicin induces the activity of liver enzymes, speeding the metabolism of diltiazem, which leads to a decrease in its effectiveness.

With simultaneous use with theophylline, a slight decrease in the metabolism of theophylline in the liver is possible, apparently due to the inhibition of the CYP1A2 isoenzyme under the influence of diltiazem.

With simultaneous use with cisapride, a case of impaired consciousness has been described, apparently due to the pronounced lengthening of the QT interval. It is believed that diltiazem inhibits the activity of the isoenzyme CYP3A4, which leads to an increase in the concentration of cisapride in the blood plasma and, possibly, an increase in its cardiotoxicity.

With simultaneous application diltiazem inhibits the metabolism of cyclosporine in the liver, which leads to a decrease in its excretion and an increase in the concentration in the blood plasma. At the same time, a decrease in manifestations of nephrotoxicity and an increase in immunosuppressive action were noted.

With simultaneous use with cimetidine, the concentration of diltiazem in the blood plasma increases due to the inhibition of its oxidative metabolism in the liver under the influence of cimetidine. It is possible to enhance the effects of diltiazem.

With concomitant use with enflurane, there have been cases of violation of AV conduction of the myocardium.

Special instructions:

Intravenous is used only for emergency therapy, but if necessary, administration is possible within a few days. When diltiazem is introduced, careful monitoring of cardiovascular function is necessary. Against the background of a regular intake of beta-blockers should be strictly specified indications for intravenous diltiazem and apply it only after ECG monitoring in the intensive care unit,while the possible need to use a pacemaker should be considered.

It is not recommended simultaneous use of beta-adrenoblockers and diltiazem for parenteral administration.

Sudden abolition of diltiazem can lead to the development of an anginal attack.

Patients with impaired hepatic and / or renal function and elderly persons require a correction of the dosing regimen.

Instructions

Diltiazem (Diltiazemum)