Digoxin

General characteristics. Structure:

Active agent: digoxin - 0,25 mg

Excipients: silicon dioxide colloid, magnesium stearate, gelatin, talc, starch corn, lactoses monohydrate.

Pharmacological properties:

Pharmacodynamics. Digoxin - cardiac glycoside. Has positive inotropic effect. It is caused by a direct inhibiting effect of Na+ / To a +-ATP-phase on membranes of cardiomyocytes that leads to increase in intracellular maintenance of ions of sodium and, respectively, decrease in potassium ions. The increased maintenance of ions of sodium causes activation sodium / calcic exchange, increase in maintenance of calcium ions owing to what force of reduction of a myocardium increases.
As a result of increase in a kontraktilnost of a myocardium the stroke output of blood increases. Decreases final systolic and final diastolic heart volumes that, along with increase in a tone of a myocardium, leads to reduction of its sizes and thus to decrease in need of a myocardium for oxygen. Has negative chronotropic effect, reduces excessive sympathetic activity by increase in sensitivity of cardiopulmonary baroreceptors. Thanks to increase in activity of a vagus nerve has the antiarrhytmic effect caused by reduction of speed of carrying out impulses through an atrioventricular node and lengthening of the effective refractory period. This effect amplifies direct action on an atrioventricular node and sympatholytic action.
The negative dromotropic effect is shown in increase in a refrakternost of an atrioventricular (AV) node that allows to use at paroxysms of supraventricular tachycardias and tachyarrhythmias.
At a ciliary tachyarrhythmia promotes delay of frequency of ventricular reductions, extends a diastole, improves an endocardiac and system hemodynamics.
The positive bathmotropic effect is shown at purpose of subtoxic and toxic doses.
Has direct vasopressor effect which is most accurately shown in the absence of congestive peripheral hypostases.
At the same time the indirect vazodilatiruyushchy effect (in response to increase in minute volume of blood and decrease in excessive sympathetic stimulation of a vascular tone), as a rule, prevails over direct vasopressor action therefore the general peripheric vascular resistance (GPVR) decreases.

Pharmacokinetics. Absorption from the digestive tract (DT) - is variable, makes 70-80% of a dose and depends on motility of a GIT, a dosage form, the accompanying meal, on interaction with other medicines. Bioavailability of 60-80%. At normal acidity of a gastric juice the insignificant amount of digoxin collapses, at hyperacid states its bigger quantity can collapse.
Full absorption requires sufficient exposure in intestines: at decrease in motility of a GIT bioavailability maximum, at a hyperperistalsis - minimum. Ability to collect in fabrics (to kumulirovat) explains lack of correlation in an initiation of treatment between expressiveness of pharmakodinamichesky effect and its concentration in a blood plasma. The maximum concentration of digoxin in a blood plasma is reached in 1-2 h. Communication with proteins of a blood plasma makes 25%.
The relative volume of distribution - 5 l/kg. It is metabolized in a liver. Digoxin is removed preferential by kidneys (60-80% in an invariable look). The elimination half-life makes about 40 h. Removal and an elimination half-life is defined by function of kidneys. Intensity of renal removal is defined by the size of glomerular filtering. At an insignificant chronic renal failure decrease in renal removal of digoxin is compensated for the account of hepatic metabolism of digoxin to inactive metabolites. At a liver failure compensation happens due to strengthening of renal removal of digoxin.

Indications to use:

As a part of complex therapy of chronic heart failure of II (in the presence of clinical manifestations) and the III-IV functional class;
takhisistolichesky form of blinking and atrial flutter of a paroxysmal and chronic current (especially in combination with chronic heart failure).

Route of administration and doses:

Route of administration - Inside.
As well as for all cardiac glycosides, the dose should be selected with care, individually for each patient.
If the patient before purpose of digoxin accepted cardiac glycosides, in this case the dose of drug needs to be reduced.

Adults
The dose of digoxin depends on need of bystry achievement of therapeutic effect.

Moderately bystry digitalization (24-36 h) is applied in case of emergency
The daily dose of 0,75-1,25 mg divided into 2 receptions under control of an ECG before each subsequent dose.
After achievement of saturation pass to the supporting treatment

Slow digitalization (5-7 days).
The daily dose of 0,125 - 0,5 mg is appointed 1 time a day within 5-7 days (before achievement of saturation) then pass to the supporting treatment.

Chronic Heart Failure (CHF)
At patients with HSN digoxin has to be applied in small doses: to 0,25 mg a day (for patients with body weight more than 85 kg to 0,375 mg a day) At elderly patients the daily dose of digoxin has to be lowered to 0,0625-0,125 mg (1/4; 1/2 tablets).

Maintenance therapy.
The daily dose for a maintenance therapy is established individually and makes 0,125-0,75 mg. The maintenance therapy is carried out, as a rule, it is long.

Features of use:

All the time of treatment by Digoxin the patient has to be under observation to avoid the side effects arising owing to overdose. The patients receiving foxglove drugs cannot appoint calcium drugs for parenteral administration.
It is necessary to lower the Digoxin dose to patients with a chronic pulmonary heart, coronary insufficiency, disturbances of water and electrolytic balance, a renal or liver failure: Careful selection of a dose is also required from patients of advanced age, especially in the presence at them is one or several above-named states. At the same time it is necessary to consider that at these patients even at a renal failure of value of the clearance of creatinine (CC) can be within norm that is connected with decrease in muscle bulk and reduction of synthesis of creatinine.
As at a renal failure pharmacokinetic processes are broken, selection of a dose should be carried out under control of concentration of digoxin in blood serum. If it is impracticable, then it is possible to use the following recommendations. Generally the dose should be reduced approximately on as much percent on how many the clearance of creatinine is reduced. If KK was not defined, then it can be calculated approximately, proceeding from an indicator of concentration of creatinine in blood serum (KKS). For men on a formula (140 age): KKS. For women the received result should be increased on 0,85.

At a heavy renal failure concentration of digoxin in blood serum should be defined every 2 week, at least, during an initial stage of treatment.
At an idiopathic subaortal stenosis (obstruction of an output path of a left ventricle asymmetric a hypertrophied interventricular partition) purpose of digoxin leads to increase of expressiveness of obstruction. At the expressed mitral stenosis and normo-or bradycardia heart failure develops owing to decrease in diastolic filling of a left ventricle.
Digoxin, increasing contractility of a myocardium of a right ventricle, causes further increase in pressure in system of a pulmonary artery that can provoke a fluid lungs or aggravate a left ventricular failure. The patient with a mitral stenosis cardiac glycosides are appointed at accession of right ventricular insufficiency, or in the presence of a ciliary tachyarrhythmia.

At patients with AV with blockade P degrees purpose of cardiac glycosides can aggravate and lead it to development of an attack of Morganyi-Adams-Stokes. Purpose of cardiac glycosides at AV to blockade of the I St demands care, frequent control of an ECG, and in some cases - pharmacological prevention by the means improving AV conductivity.
Digoxin at a WPW-syndrome, slowing down AV conductivity, promotes carrying out impulses in additional ways of carrying out bypassing an AV node and, thereby, provokes development of a Bouveret's disease. The probability of developing of glikozidny intoxication increases at a hypopotassemia, a hypomagnesiemia, a hypercalcemia, the hypernatremia, a hypothyroidism expressed to dilatation of cardial cavities, "pulmonary" heart, myocarditis and at elderly people.
As one of control methods of the maintenance of a digitalization at purpose of cardiac glycosides use monitoring of their plasma concentration.

Cross sensitivity
Allergic reactions to digoxin and other drugs of a foxglove develop seldom.
If there is a hypersensitivity concerning some one drug of a foxglove, other representatives of this group it is possible to apply as cross sensitivity is not inherent to drugs of a foxglove.

The patient is obliged to follow the following instructions precisely
1 To use drug just as it is appointed, not to change a dose independently;
2 Every day to use drug only in due time;
3 If heart rate is lower than 60 blows in min., it is necessary to consult immediately with the doctor;
4 If reception of the next dose of drug is missed, it needs to be accepted at once as there is an opportunity;
5 It is impossible to increase or double a dose;
6 If the patient did not accept drug more than 2 days, it is necessary to report about it to the doctor.
Before drug phase-out, it is necessary to inform on it the doctor.
At emergence of vomiting, nausea, a diarrhea, the speeded-up pulse it is necessary to see a doctor immediately.
Before surgeries or when rendering acute management it is necessary to warn about digoxin use.
Without the permission of the doctor use of other medicines is undesirable.

Side effects:

Noted side effects often are initial signs of overdose.
Digitalisky intoxication:
from cardiovascular system - a ventricular Bouveret's disease, ventricular premature ventricular contraction (often a bigeminal pulse, polytopic ventricular premature ventricular contraction), nodal tachycardia, a sinus bradycardia, sinoaurikulyarny (SA) blockade, blinking and an atrial flutter, AV blockade; on an ECG - decrease in a segment of ST with formation of a two-phase tooth of T.
From a digestive tract: anorexia, nausea, vomiting, diarrhea, abdominal pains, intestines necrosis.
From the central nervous system: sleep disorders, a headache, dizziness, neuritis, radiculitis, a maniac-depressive syndrome, paresthesias and a faint, in rare instances (it is preferential at the patients of advanced age having atherosclerosis) a disorientation, confusion of consciousness, one-color visual hallucinations.
From sense bodys: coloring of visible objects in flavovirent color, flashing of "front sights" before eyes, decrease in visual acuity, macro - and a micropsia.
Allergic reactions are possible: skin rash, seldom urticaria.
From bodies of a hemopoiesis and system of a hemostasis: Werlhof's disease, nasal bleedings, petechias.
Others: hypopotassemia, gynecomastia.

Interaction with other medicines:

At co-administration of digoxin with the drugs causing disturbances of electrolytic balance, in particular a hypopotassemia (for example, diuretics, glucocorticosteroids, insulin, beta-adrenergic agonists, Amphotericinum In), the risk of developing of arrhythmia and development of other toxic effects of digoxin increases. The hypercalcemia can also lead to development of toxic effects of digoxin therefore it is necessary to avoid intravenous administration of salts of calcium by the patient accepting digoxin. In these cases the dose of digoxin needs to be reduced.
Some drugs can increase concentration of digoxin in blood serum, for example, quinidine, blockers of "slow" calcium channels (especially verapamil), Amiodaronum, Spironolactonum and Triamterenum.

Absorption of digoxin in intestines can be reduced under the influence of Colestyraminum, a kolestipol, aluminum-bearing antacids, Neomycinum, tetracyclines. There are data that simultaneous use of Spironolactonum not only changes concentration of digoxin in blood serum, but also can influence results of a method of definition of concentration of digoxin therefore the special attention at assessment of the received results is required.
Decrease in bioavailability: absorbent carbon, the knitting HP, a kaolin, Sulfasalazinum, (binding in a GIT gleam); Metoclopramidum, прозерин (strengthening of motility of a GIT).
Increase in bioavailability: the antibiotics of a broad spectrum of activity suppressing intestinal microflora (reduction of destruction in a GIT).
Beta adrenoblockers and verapamil increase expressiveness of negative chronotropic effect, reduce force of an inotropic effect.
Inductors of a microsomal oxidation (barbiturates, phenylbutazone, Phenytoinum, rifampicin, antiepileptic, oral contraceptives) can stimulate digitoxin metabolism (at their cancellation digitalis intoxication is possible).

At simultaneous use with digoxin below the specified medicines their interaction owing to which medical action decreases is possible or side or toxic effect of digoxin is shown: the mineralokortikosteroida, glucocorticosteroids possessing considerable mineralkortikosteroidny influence; Amphotericinum In for injections; karboangidraza inhibitors; adrenocorticotropic hormone (AKTG); the diuretic drugs promoting release of water and potassium (буметадин, Acidum etacrynicum, furosemide, индапамид, Mannitolum and derivatives of a tiazid); sodium phosphate.
The hypopotassemia caused by the mentioned medicines increases risk of toxic effect of digoxin therefore at their simultaneous use with digoxin constant observation of potassium concentration in blood is required.
- St. John's Wort drugs (their interaction and digoxin induces the R-glycoprotein and P450 cytochrome, i.e. reduces bioavailability, increases metabolism and considerably reduces concentration of digoxin in plasma).
- Amiodaronum (increases concentration of digoxin in a blood plasma to toxic level). Interaction of Amiodaronum and digoxin oppresses activity sinus, both atrioventricular hearts of nodes and conductivity of nervous impulse on the carrying-out system of heart. Therefore, having appointed Amiodaronum, digoxin is cancelled or its dose is reduced by a half;
- Drugs of salts of aluminum, magnesium and other antiacid means can reduce absorption of digoxin and reduce its concentration in blood;
- Simultaneous use with digoxin: antiarrhytmic means, calcium salts, the pankuroniya, alkaloids of Rauwolfia, suktsinilkholin and sympathomimetics can provoke development of disturbances of a cordial rhythm therefore in these cases it is necessary to control cordial activity and an ECG of the patient;
- The kaolin, pectin and other adsorbents, Colestyraminum, колестипол, purgatives, Neomycinum and Sulfasalazinum reduce digoxin absorption and by that reduce its medical action;
- Blockers of "slow" calcium channels, captopril - increase concentration of digoxin in a blood plasma therefore, applying them together, it is necessary to reduce a digoxin dose that toxic influence of drug was not shown;
- Edrofony (antikholinesterazny means) - raises a tone of a parasympathetic nervous system therefore interaction it with digoxin can cause the expressed bradycardia;
- Erythromycin — its action improves absorption of digoxin in intestines;
- Heparin - digoxin reduces anticoagulating effect of heparin therefore the dose it should be increased;
- Indometacin reduces release of digoxin therefore danger of toxic influence of drug increases;
- Sulfate magnesium solution for injections is applied to decrease in toxic influence of cardiac glycosides;
- Phenylbutazone - reduces concentration of digoxin in blood serum;
- Drugs of salts of potassium, they cannot be accepted if under the influence of digoxin disturbances of conductivity on an ECG appeared. However potassium salts are often appointed together with foxglove drugs for the prevention of disturbances of a heart rhythm;
- Quinidine and quinine - these drugs can sharply increase concentration of digoxin;
- Spironolactonum - reduces the speed of release of digoxin therefore it is necessary to adjust a drug dosage at combined use;
- The waist chloride (TL 201) - at a research of perfusion of a myocardium drugs a waist, digoxin reduces extent of accumulation a waist in places of damage of a cardiac muscle and distorts these researches;
- Hormones of a thyroid gland - at their appointment the metabolism therefore the digoxin dose surely should be increased amplifies.

Contraindications:

Hypersensitivity to drug, glikozidny intoxication, Wolf's syndrome - Parkinson-Whyte, atriventrikulyarny blockade of the II degree, the alternating total block.
With care (comparing advantage/risk): AV blockade of the I degree, a sick sinus syndrome without pacemaker, probability of unstable carrying out on an AV node, instructions in the anamnesis on attacks of Morganyi-Edams-Stoksa, a hypertrophic subaortal stenosis, the isolated mitral stenosis from rare ChSS, cardiac asthma at patients with a mitral stenosis (in the absence of a takhisistolichesky form of a ciliary arrhythmia), an acute myocardial infarction, unstable stenocardia, the arteriovenous shunt, a hypoxia, heart failure with disturbance of diastolic function (a restrictive cardiomyopathy, a heart amyloidosis, chronic cardial compression, a cardiac tamponade), premature ventricular contraction, the expressed dilatation of cardial cavities, "pulmonary" heart.
Electrolytic disturbances: hypopotassemia, hypomagnesiemia, hypercalcemia, hypernatremia. Hypothyroidism, alkalosis, myocarditis, advanced age, renal liver failure, obesity.

Pregnancy and period of a lactation.
Drugs of a foxglove get through a placenta. At the time of delivery concentration of digoxin in blood serum of the newborn and mother is identical. Digoxin on safety of its use at pregnancy on classification of administration of foodstuff and medicines of the USA belongs to the category "C": the risk at use is not excluded. Researches at pregnant women are insufficient, however foreseen medical influence of drug can justify risk of its use.

Lactation period.
Digoxin is emitted in mother's milk. But data, about the impact on newborns caused by drug, are not provided.

Overdose:

Symptoms: loss of appetite, nausea, vomiting, diarrhea, abdominal pain, intestines necrosis; a ventricular Bouveret's disease, ventricular premature ventricular contraction (often polytopic or a bigeminal pulse), nodal tachycardia, SA blockade, blinking and an atrial flutter, AV blockade, drowsiness, confusion of consciousness, delirious psychosis, decrease in visual acuity, coloring of visible objects in flavovirent color, flashing of "front sights" before eyes, perception of objects in the reduced or increased look; neuritis, radiculitis, maniac-depressive syndrome, paresthesias.

Treatment. Digoxin cancellation, purpose of absorbent carbon (for absorption reduction), introduction of antidotes (Unithiolum, EDTA, antibodies to digoxin), symptomatic therapy.
To carry out continuous monitoring of an ECG.
In cases of a hypopotassemia potassium salts are widely applied: 0,5-1 g of potassium of chloride dissolve in water and accept several times a day to a total dose 3-6 g (40-80 мЭкв K+) for adults on condition of adequate function of kidneys. It is in case of emergency shown in/in drop introduction of 2% or 4% of solution of potassium of chloride. The daily dose makes 40-80 мЭкв K+ (divorced to concentration 40 мЭкв K+ on 500 ml).
The recommended rate of administering should not exceed 20 мЭкв / h (under control of an ECG).
At a hypomagnesiemia purpose of salts of magnesium is recommended.
In cases of a ventricular tachyarrhythmia it is shown slow in/in administration of lidocaine. At patients to normal function of heart and kidneys usually happens effectively slow in/in introduction (within 2-4 min.) lidocaine in an initial dose of 1-2 mg/kg of body weight, to the subsequent transition to drop introduction with a speed of 1-2 mg/min. At patients with a renal failure and/or hearts the dose needs to be reduced as appropriate. In the presence of AV of blockade P-III of degree it is not necessary to appoint lidocaine and salts of potassium until the artificial pacemaker is established.
During treatment it is necessary to watch the content of calcium and phosphorus in blood and daily urine.
There is an experience of use of the following drugs with possible positive effect: beta adrenoblockers, procaineamide, bretylium, and Phenytoinum. Cardioversion can provoke fibrillation of ventricles. For treatment of bradyarrhythmias and AV of blockade atropine use is shown. At AV blockade of the II-III degree, asystolia and suppression of activity of a sinus node installation of a pacemaker is shown.

Storage conditions:

List A.
To store at a temperature from 15 to 30 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets on 0,25 mg.
On 50 tablets in a white polypropylene bottle. Each bottle together with the application instruction is placed in a cardboard pack.