Diltiazem retard, 180 mg 30 pcs

Diltiazem is a benzothiazepine derivative; it has antiarrhythmic, antianginal and hypotensive activity. It is a blocker of “slow” calcium channels (BMCC), reduces intracellular calcium content in cardiomycytes and smooth muscle cells, dilates coronary and peripheral arteries and arterioles, reduces total peripheral vascular resistance (TPR), smooth muscle tone, increases coronary, brain and renal blood flow, reduces heart rate (HR).

. Antiarrhythmic action is caused by inhibition of ionized calcium transport in heart tissue that leads to increase of effective refractory period and prolongation of conduction time in atrioventricular (AV) node (it has clinical importance in patients with sinus node weakness syndrome and elderly patients in whom calcium channel blockade can prevent impulse generation in sinus node and cause sinoatrial (SA) blockade. Normal atrial action potential or intraventricular conduction is not altered (normal sinus rhythm is usually not affected), but the rate of depolarization and conduction velocity are decreased when the amplitude of atrial contraction decreases. The anterograde effective refractory period in additional bypass conduction bundles may be shortened.

The antianginal action is due to peripheral vasodilation and reduction of systemic arterial pressure (afterload), which leads to reduction of myocardial wall tension and myocardial oxygen demand. In concentrations that do not lead to the appearance of a negative inotropic effect, it causes relaxation of the smooth muscle of coronary vessels and dilatation of both large and small arteries.

The antihypertensive effect is due to dilatation of the resistive vessels and reduction of RPS. The degree of blood pressure (BP) reduction correlates with its initial value (minimal effect on BP is noted in patients with normal BP). Reduces BP in both “lying” and “standing” position. Rarely causes postural arterial hyyotension and refractory tachycardia. It does not change or insignificantly decreases maximal HR during exercise. Long-term therapy does not lead to hyperkalemia, increased activity of the renin-angiotensin-aldosterone system (RAAS). Reduces renal and peripheral effects of angiotensin II. It improves diastolic myocardial relaxation in arterial hypertension, coronary heart disease, hypertrophic cardiomyopathy and reduces platelet aggregation.

It has minimal effect on the smooth muscle of the gastrointestinal tract (GIT). During long-term (8 months) therapy tolerance does not develop. Does not affect the blood lipid profile.

It is able to cause regression of left ventricular hypertrophy in patients with arterial hypertension. Onset of action when taken orally is 2-3 hours. Duration of action is 12-24 hours.

The maximum intensity of the hypotensive effect is reached within 2 weeks.

Pharmacokinetics

On oral administration, it is quickly and almost completely absorbed in the gastrointestinal tract (90%). Time to reach maximum plasma concentration is 6-14 hours. Values of plasma concentrations vary widely in individual patients. Binding with plasma proteins is 70-80% (with albumin – 35-40%). Distribution volume of diltiazem in the body is about 5.3 l/kg body weight.

After absorption from the gastrointestinal tract, the active substance undergoes intensive metabolism due to the “first pass” effect mainly through the liver. It is metabolized in liver by deacetylation and demethylation (with participation of CYPZA4, CYP3A5 and CYP3A7 isoenzymes) with formation of active metabolite deacetylthiazem, which is determined in blood plasma concentration 5-10 times lower than initial diltiazem and has 2-4 times lower activity.

The T1/2 when administered orally is biphasic: early – 20-30 min, final – 3.5 h (5-8 h – at high and repeated doses).

It is excreted through the intestine with the bile (65%) and the kidneys (35%, including 2-4% unchanged).

The pharmacokinetics of diltiazem does not change with long-term use. Diltiazem does not cumulate and does not induce its own metabolism.

The pharmacokinetics of diltiazem does not change in patients with angina pectoris and impaired renal function. In patients with hepatic insufficiency the bioavailability is increased and T1/2 is prolonged. Diltiazem clearance may also be decreased in elderly patients. It is not excreted with hemodialysis and peritoneal dialysis.

Indications

Active ingredient

Composition

Active ingredient:

diltiazem 180 mg;

Supplementary substances:

Sugar grits (sucrose, starch treacle),

copolymer of methyl methacrylate,

trimethylammonioethyl methacrylate and ethyl acrylate (1:2:0.1)

Methyl methacrylate copolymer,

trimethylammonioethyl methacrylate chloride and ethyl acrylate (1:2:0.2),

paraffin,

talc

How to take, the dosage

The tablets should be taken orally, before meals, whole, without chewing or crushing, with a small amount of liquid.

The starting dose of Diltiazem retard is 1 tablet of 90 mg twice daily. Average daily dose is 180-240 mg. It is possible to correct the dosage regimen only after 2 weeks.

The maximum dose is 360 mg/day (used in hospital only).

Interaction

Pharmacodynamic

When diltiazem is used concomitantly with hypotensive agents, an increase in the hypotensive effect is noted.

Concomitant use of diltiazem and digoxin may increase blood concentration of digoxin.

Concomitant use with antiarrhythmic agents, beta-adrenoblockers, cardiac glycosides may lead to bradycardia, atrioventricular conduction disorders, symptoms of heart failure.

Concomitant use with adenosine increases the risk of prolonged bradycardia.

Salicylates additionally inhibit the ability to aggregate platelets.

Ethanol: aggravation of hypotensive effect.

Procainamide, quinidine and other drugs that cause prolongation of the QT interval increase the risk of significant prolongation.

Inhaled anesthetics (hydrocarbon derivatives), thiazide diuretics, and other BP lowering agents increase the hypotensive effect of diltiazem.

Phenytoin decreases the effect of diltiazem.

Antipsychotics (neuroleptics) increase the hypotensive effect. Concomitant administration of nitrates (including prolonged forms) is possible. Lithium drugs may increase the neurotoxic effect of diltiazem (nausea, vomiting, diarrhea, ataxia, tremor and/or tinnitus).

Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs), glucorticosteroids and estrogens, and symtomatic medications reduce the hypotensive effect.

Pharmacokinetic

Concomitant use with cimetidine leads to a significant increase in plasma concentrations of diltiazem, which in turn may lead to its toxic effects on the cardiovascular system.

Diltiazem increases plasma concentrations of theophylline and carbamazepine (40-70%) and increases the risk of adverse reactions, including ataxia, nystagmus, diplopia, headache, vomiting, confusion, and increases concentrations of cyclosporine, digoxine (up to 50%), imipramine, lithium, and midazolam.

Enhance the effects of hypoglycemic agents for oral administration (e.g., chlorpropamide and glipizide).

In concomitant use of diltiazem and cyclosporine in patients with kidney transplantation, intoxication and paresthesias may occur. Therefore, it is necessary to control plasma concentrations of cyclosporine in this group of patients. Food intake increases absorption and bioavailability of diltiazem up to 20-30%. May increase the bioavailability of propranololol. Increases the plasma concentration of moracizin.

Phenobarbital, diazepam, rifampicin decrease the plasma concentration of diltiazem. Increases the blood concentration of quinidine, valproic acid (dosage reduction may be required).

Antiviral agents: ritonavir may increase plasma concentrations of PBMC.

Anxiolytics and hypnotics: Diltiazem inhibits the metabolism of midazolam (increased plasma concentration with increased sedation).

BDCs: excretion of nifedipine is reduced by diltiazem (increased plasma concentration).

Diltiazem significantly increases the plasma concentration of lovastatin. It also increases the effect of simvastatin, therefore in their concomitant use the dose of simvastatin should be reduced. In concomitant use of diltiazem with lovastatin and simvastatin it is necessary to monitor patients, because of the possibility of development of myositis or rhabdomyolysis.

Contraindications

Side effects

Cardiovascular system: angina, arrhythmia, bradycardia (less than 50 bpm) or tachycardia, AV-blockade, Gis bundle leg block, development or aggravation of heart failure, ECG changes, blood “flushes”, marked BP decrease, palpitations, fainting, ventricular extrasystole.

Nervous system disorders: sleep disturbance, amnesia, depression, gait disturbance, hallucinations, insomnia, nervousness, paresthesias, personality changes, somnolence, tremor.

Digestive system disorders: dry mouth, anorexia, constipation or diarrhea, impaired taste, dyspepsia, moderate increase of alkaline phosphatase (ALP), aspartate aminotransferase (ACT), alanine aminotransferase (ALT), lactate dehydrogenase (LDH); thirst, vomiting, weight gain.

Skin disorders: petechiae, photosensitization, itching, urticaria.

Others: amblyopia, increased creatine phosphokinase (CPK) activity, dyspnea, nasal bleeding, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nycturia, bone and joint pain, polyuria, sexual dysfunction, tinnitus.

Postmarketing experience: Allergic reactions, alopecia, angioedema (including facial edema and periorbital edema), erythema multiforme (including Stevens-Johnson syndrome), toxic eidermal necrolysis, extrapyramidal syndrome, gum hyperplasia, hemolytic anemia, prolonged bleeding time, leukopenia, purpura, retinopathy, myopathy, thrombocytopenia, exfoliative dermatitis. There have been cases of generalized rash, which in some cases was a manifestation of leukocytoclastic vasculitis; cases of myocardial infarction, which are not always easy to distinguish from manifestations of the existing disease, have been reported.

Overdose

Symptoms: marked bradycardia, marked BP decrease, turning into collapse, atrioventricular and sinoatrial conduction disorders, confusion, stupor, nausea, vomiting, metabolic acidosis, hyperglycemia, heart failure, cardiogenic shock, asystole.

Treatment: depending on the severity of overdose manifestations. It is necessary to wash the stomach, take activated charcoal, further treatment is symptomatic. If necessary, it is recommended to prescribe atropine, isoprenaline, dopamine or dobutamine, and also, in case of pronounced conduction disorders, electrocardiostimulation may be used.

Hemodialysis and peritoneal dialysis are ineffective.

Similarities