Verapamil

General characteristics. Structure:

Active ingredient: 40 mg or 80 mg of verapamil of a hydrochloride in 1 tablet.

Excipients: lactose (sugar milk), potato starch, кросповидон (коллидон CL), calcium stearate, talc.

Excipients for a cover: gipromelloz (gidroksipropilmetiltsellyuloz), makragol-6000 (polyethyleneglycol 6000), titanium dioxide, dye quinolinic yellow.

Pharmacological properties:

Pharmacodynamics. a locator of "slow" calcium channels (brakes transmembrane transport of Ca2 + to sokratitelny fibers of smooth muscle cells), derivative a difenilalkilamina. Possesses anti-anginal, antiarrhytmic and hypotensive action. The anti-anginal effect is connected both with direct action on a myocardium, and with influence on a peripheral hemodynamics (reduces a tone of peripheral arteries, the general peripheric resistance of vessels (GPRV)). Blockade of receipt of Ca2 + in a cell leads to reduction of the transformation concluded in energy ATP energy-rich bonds in mechanical work, to decrease in contractility of a myocardium. Reduces the need of a myocardium for oxygen, renders vazodilatiruyushchy, negative other and chronotropic actions. Significantly conductivity reduces AV, extends the period of a refrakternost and suppresses automatism of a sinus node.

Increases the period of diastolic relaxation of the left ventricle (LV), reduces a myocardium wall tone (is supportive application for treatment of a hypertrophic subaortic stenosis (GOKMP)).

Perhaps, use as the medicine (M) for prevention of a headache of vascular genesis: interferes with the vasoconstriction arising in a prodromal stage, blockade of Ca2+-channels can weaken or prevent reactive vasodilatation.

Suppresses metabolism with P450 cytochrome participation.

The beginning of effect at intake – in 1-2 h, the maximum effect develops in 30-90 min. (usually during 24-48 h), effect duration – 8-10 h for usual peroral forms and 24 h - for prolonged. The anti-anginal effect has dozozavisimy character, tolerance does not arise.

Pharmacokinetics. At intake it is quickly soaked up in a small intestine, absorption – 90-92%, bioavailability after a single dose – 24-35% owing to intensive metabolism at "the first passing" through a liver and increases by 1,5-2 times at prolonged use. At prolonged use in the increasing doses bioavailability can increase.

Time of achievement of the maximum concentration in plasma (TCmax) at oral administration – 1-2 h for the dosage forms (DF) of usual action, 5-9 h - for the prolonged LF. The maximum concentration (Cmax) – 80-400 ng/ml. Communication with proteins of plasma – 90%. Gets through a blood-brain barrier (GEB), a placental barrier (20-92% of concentration in a blood plasma of mother) and into breast milk (in low concentration).

It is quickly metabolized in a liver by N-dealkylation and O-demethylation, with formation of several metabolites (at the person 12 are identified). Accumulation of drug and its metabolites in an organism explains strengthening of action at course treatment. Pharmacological the active metabolite – norverapamit the main (20% of hypotensive activity of verapamil). Isoenzymes of CYP3A4, CYP3A5 and CYP3A7 participate in metabolism of drug.

Elimination half-life (T½) at oral administration – 3-7 h at a single dose, 4-12 h - at prolonged use (in connection with saturation of fermental systems of a liver and increase in plasma concentration of T1/2 increases almost twice), for the prolonged LF – 11 h.

At a liver failure bioavailability increases and T1/2 increases. 70% by kidneys (3-5% in not changed look), 16-25% – with bile are removed. It is not removed at a hemodialysis.

Indications to use:

- Treatment and prevention of disturbances of a cordial rhythm: Bouveret's supraventricular disease, chronic form of trembling and atrial fibrillation (takhiaritmichesky option), supraventricular premature ventricular contraction.

- Treatment and prevention: stable stenocardia (angina of exertion), unstable stenocardia, vasospastic stenocardia (Printsmetal's stenocardia, alternative stenocardia).

- Treatment of the arterial hypertension (AH).

Route of administration and doses:

The mode of dosing and duration of treatment establish individually depending on a condition of the patient, severity, features of a course of a disease and efficiency of therapy.

For intake, on 40-80 mg 3 times a day (for LF of usual duration of action) – at stenocardia and supraventricular tachycardia in 3 receptions, at AG – in 2 receptions, a daily dose at AG – to 480 mg.

To children at AG – 10 mg/kg/days (in stages), at supraventricular arrhythmia (up to 2 years) – on 20 mg 2-3 times a day. A daily dose of verapamil to children under 5 years – 40-60 mg; for children from 6 to 14 years – 80-360 mg (for 3-4 receptions).

At long therapy the daily dose should not exceed 480 mg. Exceeding of a dose is possible only for very short time under careful medical control.

Tablets and capsules to accept not rassasyvy and without chewing, washing down with a small amount of liquid, it is preferable before meal or right after food.

For patients with a heavy liver failure the daily dose should not exceed 120 mg.

Features of use:

· Before therapy at heart failure it is necessary to compensate a state previously.

· At treatment control of functions CCC, respiratory system, of the content of glucose and electrolytes in blood, the volume of the circulating blood and amount of the emitted urine is necessary.

· It is not recommended to stop treatment suddenly.

Influence on ability to manage the vehicle and other mechanisms: During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Use at pregnancy and during breastfeeding. It is contraindicated at pregnancy. For the period of treatment it is necessary to stop breastfeeding.

Side effects:

From cardiovascular system (CCC): hypotension, bradycardia (sinus), AV blockade, heart failure.

From a nervous system and sense bodys: headache, dizziness, nervousness, block, drowsiness, weakness, fatigue, paresthesias.

From bodies of the digestive tract (DT): nausea, dispeptic phenomena, lock, hyperplasia of gums, increase in activity of hepatic transaminases, alkaline phosphatase.

Allergic reactions: skin rash, small tortoiseshell, skin itch, Quincke's disease, Stephens-Johnson's syndrome.

Others: a dermahemia of the person, a bronchospasm (at intravenous administration), peripheral hypostases, a gynecomastia, increase in secretion of prolactin (separate cases).

Interaction with other medicines:

Increases the area under a curve "concentration time" (AUC) of carbamazepine at patients with steady partial epilepsy (risk of development of side effects, such as a diplopia, a headache, an ataxy and dizziness).

Raises AUC, equilibrium concentration in blood serum (Css) and Cmax of cyclosporine.

Increases concentration of theophylline (owing to decrease in clearance), ethanol (and extends its effect), quinidine (risk of the expressed decrease in the ABP, especially at patients with IGSS).

Can increase concentration of an atorvastatin and lovastatin at simultaneous use.

Raises significantly AUC and Cmax of a simvastatin, an almotriptan, Glibenclamidum, doxorubicine, a buspiron and midazolam; a metoprolol and propranolol (at patients with stenocardia).

Increases concentration of a sirolimus and takrolimus, cardiac glycosides (demands careful observation and a dose decline of glycosides).

Increases plasma concentration of colchicine (substrate for CYP3A and a p-glycoprotein).

Slightly raises AUC of Imipraminum; does not influence concentration of an active metabolite of desipramine.

Raises Cmax of Prazozinum and a terazozin and AUC of a terazozin.

CYP3A4 inhibitors (including erythromycin, ритонавир and other antiviral drugs, including for treatment of HIV), телитромицин increase plasma concentration of verapamil.

Grapefruit juice raises AUC and Cmax R-and S-isomer of verapamil.

Cimetidinum either does not change, or reduces clearance of verapamil.

Rifampicin can reduce considerably bioavailability (to 92%), and also AUC and Cmax of verapamil.

Phenobarbital increases clearance of verapamil by 5 times.

Sulfinpyrazonum increases clearance of verapamil approximately by 3 times and reduces bioavailability (to 60%).

Drugs of the St. John's Wort which is made a hole reduce AUC R-and S-isomer of verapamil and according to Cmax.

At simultaneous use with inhalation anesthetics the risk of development of bradycardia, AV of blockade, heart failure increases.

The combination with beta adrenoblockers can lead to strengthening of a negative inotropic effect, increase in risk of development of disturbances of atrioventricular conductivity, bradycardia (administration of verapamil and beta adrenoblockers needs to be carried out at an interval of several hours).

Prazozinum and other alpha adrenoblockers, and also other hypotensive HP (angiotensin-converting enzyme inhibitors, vazodilatator, diuretics, beta adrenoblockers) strengthen hypotensive effect.

And флекаинид it is not necessary to appoint Disopyramidum during 48 h to or 24 h after verapamil use (summation of a negative inotropic effect, up to a lethal outcome).

Increases risk of emergence of neurotoxic effect of the drugs Li+.

Strengthens action of peripheral muscle relaxants (can demand change of the mode of dosing).

At simultaneous use with acetylsalicylic acid (ASK) a little bigger increase in a bleeding time was noted, than at use only of ASK.

Contraindications:

Hypersensitivity, heavy hypotension, cardiogenic shock, AV blockade of II and III degrees, a myocardial infarction (acute or recently postponed and complicated by the phenomena of bradycardia, hypotension, a left ventricular failure), chronic heart failure of the III stage, a WPW syndrome and a syndrome of weakness of a sinus node (if the electrocardiostimulator is not implanted), sinuatrial blockade, Morganyi-Adams-Stokes's syndrome, digitalis intoxication, a heavy stenosis of the mouth of an aorta, pregnancy, feeding by a breast.

With care: AV blockade of the I degree, the chronic heart failure (CHF) of I and II stages, the expressed bradycardia (less than 50 beats/min), slight or moderate hypotension, the expressed myopathy (Dyushenn's syndrome), an abnormal liver function or kidneys, ventricular tachycardia with the wide QRS complex (for intravenous maintaining).

Overdose:

Symptoms: bradycardia, AV blockade, the expressed lowering of arterial pressure (ABP), aggravation of heart failure, shock, an asystolia, a sinoauricular block.

Treatment: at early identification – a gastric lavage, reception 1aktivirovannogo уголя; at disturbance of a rhythm and conductivity – intravenously изопреналин, Norepinephrinum, atropine, 10-20 ml of 10% of solution of calcium of a gluconate, an artificial pacemaker; intravenous infusion of plasma substituting solutions.

For increase in the ABP at patients with the idiopathic hypertrophic subaortal stenosis (IHSS) appoint alpha адреностимуляторы (Phenylephrinum); it is not necessary to apply изопреналин and Norepinephrinum. The hemodialysis is inefficient.

Storage conditions:

In the dry place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 40 mg and 80 mg. On 10, 15, 20 or 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2, 3, 4 or 5 blister strip packagings together with the application instruction place in a pack from a cardboard.