Amiodarone

Pharmacological properties

antiarrhythmic properties. lengthening of the third phase of the action potential of cardiomyocytes is mainly due to a decrease in the potassium ion current (class iii according to the classification of vogen - Williams).

Slowing of the heart rhythm occurs due to inhibition of the automatism of the sinus node. This effect is not blocked by atropine.

Non-competitive alpha and beta antiadrenergic action.

Slowing of the sinoatrial, atrial and nodal conduction of the impulse in the myocardium, the severity of which increases with the acceleration of the rhythm.

The absence of changes in the intraventricular conduction.

An increase in the refractory period and a decrease in myocardial excitability at atrial, nodal and ventricular levels.

Slowing the conductivity and lengthening of refractory periods in additional AV-conducting paths.

Other properties. Reduced oxygen consumption due to a moderate decrease in heart rate and heart rate.

Increased coronary blood flow due to a direct effect on the smooth muscles of the myocardial vessels; maintaining cardiac output against the background of decreased blood pressure and heart rate, as well as in the absence of negative inotropic effects.

Pharmacokinetics Amiodarone is a compound that is characterized by slow transport and high tissue affinity. Its bioavailability after oral administration, depending on the individual characteristics of the patient, can be from 30 to 80% (on average - 50%). After a single dose of C_max in plasma is reached after 3-7 hours. Therapeutic activity is manifested on average within 1 week after the start of the drug (from several days to 2 weeks).

T_½ amiodarone is long, has a significant level of interindividual variability (from 20 to 100 days). During the first days of treatment, the drug accumulates in most body tissues, especially in the fatty tissue. Elimination begins in a few days, and the ratio between intake and excretion reaches equilibrium within one or several months, depending on the patient.

Such characteristics justify the use of a loading dose to quickly achieve the level of drug uptake in tissues necessary for the manifestation of its therapeutic activity.

A certain amount of iodine is released, which is excreted in the urine as iodide; when using amiodarone in a daily dose of 200 mg, iodine excretion is 6 mg / 24 hours. The remainder of the compound and, accordingly, most of the iodine are excreted in the feces after metabolism in the liver.

Since a small amount of the drug is eliminated in the urine, the usual dose can be used in patients with renal failure.

After the abolition of treatment, elimination from the body continues for several months. It should be borne in mind that after discontinuation of the drug, its effect lasts from 10 days to 1 month.

Indications

Relapse prevention:

• ventricular tachycardia, which poses a threat to the patient’s life: treatment must be started in a hospital with constant monitoring of the patient’s condition;
• symptomatic ventricular tachycardia (documented), which leads to disability;
• supraventricular tachycardia (documented), requiring treatment, and in cases where other drugs are ineffective or contraindicated;
• ventricular fibrillation.

Treatment of supraventricular tachycardia: slowing or reducing atrial fibrillation / flutter;

IHD and / or dysfunction of the left ventricle.

Application

Initial treatment. usually the recommended dose for adults is 200 mg (1 tablet) 3 times a day for 8-10 days.in some cases, at the beginning of treatment, higher doses (4-5 tablets per day) can be used, which are taken for a short time and under ECG control.

Supportive treatment. The minimum effective dose should be used. Depending on the patient’s reaction to the use of the drug, the maintenance dose for adults can range from ½ tablet per day (1 tablet every 2 days) to 2 tablets per day.

Contraindications

Sinus bradycardia and sinoatrial blockade of the heart in the absence of an endocardial pacemaker (artificial pacemaker).

Sick sinus syndrome in the absence of an endocardial pacemaker (risk of stopping the sinus node).

Violations of AV-conduction of a high degree in the absence of an endocardial pacemaker.

Impaired thyroid function.

Known hypersensitivity to iodine, amiodarone or one of the excipients.

Combination with drugs that can cause paroxysmal ventricular tachycardia such as torsades de pointes:

• class Ia antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic drugs (sotalol, dofetilide, ibutilide);
• other drugs, such as arsenic, bepridil, cisapride, difemanil, dolasetron (iv), erythromycin (iv), misolastine, vincamine (iv), moxifloxacin, spiramycin (iv), Toremifene, some antipsychotics (see INTERACTIONS).

Side effects

From the side of the organ of vision: microdeposition in the cornea in almost all adults, usually within the area under the pupil, which do not require the abolition of amiodarone. in exceptional cases, they are associated with colored halo in blinding light or blurred vision. microdeposits in the cornea are complex lipid deposits, they are always completely reversible after drug withdrawal.

Optic neuropathy (optic neuritis), which can progress to complete blindness, and, according to the fundus examination, with swelling of the optic nerve, which can progress to a more or less serious decrease in visual acuity. The causal relationship of this side effect with the use of amiodarone has not yet been established. However, in the absence of other obvious reasons for the development of this side effect, it is recommended to cancel amiodarone.

On the part of the skin: photosensitivity. It is recommended to avoid exposure to solar radiation (and ultraviolet radiation in general) during drug treatment.

Pigmentation of the skin is cyanotic or cyanotic-gray, which occurs against the background of prolonged use of the drug in high daily doses and slowly disappears after discontinuation of the drug (within 10-24 months).

Erythema on the background of radiation therapy; skin rashes, usually nonspecific; exfoliative dermatitis (although the causal relationship of this side effect with the use of the drug is not clearly established at this time); alopecia; hives.

On the part of the endocrine system: some “mismatch” in the level of thyroid hormones (increase in T4 level with a normal or slightly reduced T3 level), in the absence of clinical signs of distyroidism, does not require discontinuation of treatment.

Hypothyroidism causes typical symptoms: weight gain, cold intolerance, apathy, drowsiness. A significant increase in TSH levels confirms this diagnosis. Euthyroidism is usually achieved within 1-3 months after stopping the drug. Drug withdrawal is not required: in the case where the use of amiodarone has reasonable indications, treatment with this drug can continue in combination with thyroid hormone therapy with levothyroxine.Doses of levothyroxine may be adjusted depending on TSH levels.

Hyperthyroidism is more difficult to diagnose, since the symptoms are less pronounced (a slight causeless decrease in body weight, lack of effectiveness of antianginal and / or antiarrhythmic drugs); in elderly patients, mental symptoms, even thyrotoxicosis, are observed.

A significant decrease in the levels of highly sensitive TSH confirms this diagnosis. In this case, it is necessary to cancel amiodarone, which, as a rule, is sufficient for the onset of clinical normalization within 3-4 weeks. Since serious cases of this side effect can be fatal, proper therapy must be started immediately.

In the case where the cause of the problems is thyrotoxicosis (both directly and because of its effect on the vulnerable balance of the myocardium), the variability of the effectiveness of synthetic antithyroid drugs makes it necessary to recommend the use of high doses of corticosteroids (1 mg / kg) for a sufficiently long period of time (3 months). Cases of hyperthyroidism have been reported for several months after amiodarone withdrawal.

Very rare cases of SNSAG (syndrome of inadequate secretion of antidiuretic hormone), especially if the drug is used simultaneously with drugs that can induce hyponatremia.

From the respiratory system, chest and mediastinum: there have been cases of diffuse interstitial or alveolar pneumopathy and obliterating bronchiolitis with pneumonia, sometimes with a fatal outcome. The appearance of shortness of breath during physical exertion or dry cough, both isolated and associated with a deterioration in general health (increased fatigue, weight loss and a slight increase in body temperature), requires an X-ray examination and, if necessary, drug withdrawal, since these are lung diseases may lead to pulmonary fibrosis.

The early withdrawal of amiodarone, together with the appointment of corticosteroid therapy with or without it, leads to the gradual disappearance of symptoms. Clinical signs usually disappear within 3-4 weeks; the improvement of the radiological picture and pulmonary function is slower (within a few months).

Several cases of pleurisy, usually associated with interstitial pneumopathy, are known.

Bronchospasm in patients with acute respiratory failure, especially in patients with AD. Acute respiratory distress syndrome, in some cases with a fatal outcome, sometimes in the early postoperative period after surgery (possibly due to interaction with high doses of oxygen).

There is evidence of cases of pulmonary hemorrhage, which in some cases can manifest as hemoptysis. These pulmonary side effects are often associated with amiodarone-induced pneumopathy.

From the nervous system: tremor or other extrapyramidal symptoms; sleep disturbances, including nightmares; sensory, motor, or mixed peripheral neuropathy; myopathy Sensory, motor, or mixed peripheral neuropathy and myopathy can develop after a few months of treatment, but sometimes they occur after a few years. These side effects are usually reversible after drug withdrawal. However, recovery can be incomplete, very slow and can be observed only a few months after stopping the use of the drug.

Cerebellar ataxia; benign intracranial hypertension; headache. If there are isolated cases of headache, it is necessary to perform an examination to determine their possible cause.

On the part of the liver and biliary tract: there are data on cases of liver damage (diagnosed with elevated levels of transaminases in the blood plasma); usually a moderate and isolated increase in transaminase levels (1.5–3 times higher than normal), which disappeared after a decrease in the dose of the drug or even spontaneously; acute liver damage with an increase in the level of transaminases in the blood and / or jaundice, including liver failure, sometimes fatal, which requires the withdrawal of the drug; chronic liver damage requiring long-term treatment. Histological changes correspond to the picture of pseudo-alcoholic hepatitis or cirrhosis. Since clinical and laboratory signs are not clearly expressed (variable hepatomegaly, an increase in transaminase levels in the blood 1.5–5 times the norm), regular monitoring of liver function is indicated.

In the case of increased levels of transaminases in the blood, even moderate, occurring after the use of the drug for more than 6 months, there is a likelihood of developing chronic liver damage. These clinical and biological changes usually disappear after drug withdrawal. Several cases of irreversible effects have been reported.

From the cardiovascular system: bradycardia (usually moderate and dose-dependent); conduction disturbances (sinoatrial and AV block of varying degrees) severe bradycardia and, in exceptional cases, a stop of the sinus node (against the background of sinus node dysfunction, in elderly patients); occurrence or worsening of existing arrhythmia, which is sometimes accompanied by cardiac arrest; paroxysmal ventricular tachycardia torsades de pointes; vasculitis.

From the gastrointestinal tract: mild digestive disorders (nausea, vomiting, dysgeusia), which usually occur at the beginning of treatment with the drug and disappear when the dose is reduced.

From the mammary glands and the reproductive system: epididymitis (a causal relationship of this side effect with the use of this drug is not clearly established at this time); impotence.

On the part of the blood system and lymphatic system: hemolytic and aplastic anemia, thrombocytopenia.

On the part of the immune system: cases of angioedema are possible.

Research: rare cases of hyponatremia (may indicate the development of SNSAG); kidney damage with a moderate increase in creatinine levels.

special instructions

Effects from the heart. Before starting the use of the drug, it is necessary to make an ECG and determine the level of potassium in the blood plasma.

In elderly patients, with the use of the drug, the slowdown of heart rate may increase.

Amiodarone induces ECG changes. These changes induced by amiodarone include lengthening of the Q – T interval due to elongated repolarization, with the possible appearance of a U wave. This is a symptom of the therapeutic effect of the drug, and not its toxicity.

The occurrence of treatment of AV-blockade II or III degree, sinoatrial blockade or bifascicular blockade requires the withdrawal of the drug. The development of AV blockade of the first degree requires intensified monitoring of the patient.

Cases (sometimes fatal) of the appearance of a new arrhythmia or worsening of an existing and treated arrhythmia have been reported (see ADVERSE EFFECTS).

The arrhythmogenic effect of amiodarone is weak or even lower than that registered in most antiarrhythmic drugs and usually manifests itself against the background of the use of certain combinations of drugs (see INTERACTIONS) or in the case of electrolyte imbalance. Despite the fact that amiodarone can cause a prolongation of the Q – T interval, its ability to provoke paroxysmal ventricular tachycardia torsades de pointes is weak. An ECG is recommended during treatment.

From the thyroid gland. This medicine contains iodine, and therefore has an effect on the results of some indicators of thyroid function (binding of radioactive iodine, protein-bound iodine). But the determination of thyroid function indicators (T3, T4, highly sensitive TSH) can be performed.

Amiodarone can cause thyroid dysfunction, especially in patients with a history of thyroid dysfunction. Quantitative determination of TSH content is recommended for all patients before starting the use of the drug, then regularly during treatment and for several months after drug withdrawal, as well as in case of clinical suspicion of thyroid dysfunction.

Violations of the lungs. The appearance of shortness of breath or dry cough, both isolated and associated with a deterioration in the general condition, should be considered as a possible sign of pulmonary toxicity of the drug, for example, the development of interstitial pneumopathy, and requires an x-ray examination of the patient. It is necessary to reconsider the feasibility of using amiodarone, since interstitial pneumonitis is usually reversible provided that amiodarone is withdrawn early.

Violations of the liver. Regular monitoring of liver function is recommended at the beginning of the use of the drug, then periodically during treatment with amiodarone. It is necessary to reduce the dose of amiodarone or to discontinue this drug if the levels of transaminases increase by more than 3 times in comparison with normal values. When using amiodarone, acute liver disorders (including severe hepatocellular insufficiency or liver failure, sometimes fatal) and chronic liver disorders can develop.

Neuromuscular disorders. Amiodarone can cause sensory, motor, or mixed peripheral neuropathy and myopathy (see ADVERSE EFFECTS).

Violations of the organ of vision. If blurred vision or decreased visual acuity is necessary to immediately perform a complete ophthalmological examination, including fundoscopy. The development of neuropathy or optic neuritis due to amiodarone requires the withdrawal of the drug, since continued treatment can lead to the progression of disorders to blindness.

Disorders associated with interactions with other drugs. Combinations with drugs such as:

• β-adrenoreceptor blockers, except sotalol (a contraindicated combination) and esmolol (a combination that requires precautions for use);
• verapamil and diltiazem should be considered only for the prevention of life-threatening ventricular arrhythmias.

The simultaneous use of amiodarone with such drugs is not recommended: β-adrenergic receptor blockers, calcium channel blockers that reduce heart rate (verapamil, diltiazem), laxatives that can cause hypokalemia.

The use of amiodarone is not recommended in combination with cyclosporine, diltiazem (for injection) and verapamil (for injection), some antiparasitic drugs (halofantrine, lumefantrine and pentamidine), some antipsychotics (amisulpride, chlorpromazine, cyamemazine, droperidolazole, leferazidazine, levoprazidazole, galopinazine, galopinazole, , pipamperone, pipothiazine, sertindole, sulpiride, sultopride, tiapride, zuclopentixol) and methadone (see INTERACTIONS).

Disorders associated with excipients. This medicine contains lactose, therefore it is not recommended for use by patients with galactose intolerance, lactase deficiency or glucose and galactose malabsorption syndrome (rare hereditary diseases).

Electrolyte disturbances, especially hypokalemia: it is important to consider situations that may be associated with hypokalemia, which may contribute to the manifestation of the proarrhythmic effects of the drug.

Hypokalemia must be eliminated before starting amiodarone.

The adverse effects indicated below are most often associated with excessive use of the drug; they can be avoided or minimized by carefully observing the minimum maintenance dose.

Patients should be warned about the need to avoid sun exposure during drug treatment, as well as the need to use sunscreens.

The safety and efficacy of amiodarone in children have not been evaluated in controlled clinical trials.

Due to the possible increase in the defibrillation threshold and / or stimulation by implanted cardiac defibrillators or artificial pacemakers, it is necessary to check this threshold before treatment with amiodarone and several times after the start of its use, as well as each time when adjusting the dose of the drug.

Anesthesia. Before the operation, the anesthetist should be warned that the patient is using amiodarone.

Long-term use of amiodarone can increase the hemodynamic risk associated with general or local anesthesia and the risk of side effects, especially such as bradycardia, arterial hypotension, decreased cardiac output and impaired cardiac conduction. In addition, in patients receiving amiodarone in the early postoperative period, there were several cases of acute respiratory distress syndrome. In this regard, it is recommended to carefully monitor such patients during mechanical ventilation.

Use during pregnancy and lactation. Pregnancy. Given the effect on the thyroid gland of the fetus, amiodarone is contraindicated during pregnancy, unless the benefit to the mother outweighs the risk to the fetus.

Lactation. Amiodarone passes into breast milk in significant quantities, so the use of the drug during lactation is contraindicated.

Children. The safety and effectiveness of the use of amiodarone in children was not evaluated, therefore the use of a drug in this category of patients is not recommended.

The ability to influence the reaction rate when driving or working with other mechanisms. Data on the effect of the drug on the ability to drive a car and perform work requiring increased attention are not available. However, the possibility of developing adverse reactions from the nervous system and organ of vision should be considered.

Interactions

Antiarrhythmic drugs. many antiarrhythmic drugs inhibit cardiac automatism, myocardial conduction and contractility.

The simultaneous use of antiarrhythmic drugs belonging to different classes can ensure the achievement of a favorable therapeutic effect, but most often treatment with this combination is a very delicate process that requires careful clinical and ECG monitoring. The simultaneous use of antiarrhythmic drugs that can induce the occurrence of torsades de pointes (such as disopyramide, quinidine compounds, sotalol) is contraindicated.

The simultaneous use of antiarrhythmic drugs of the same class is not recommended, except in exceptional cases, since such treatment increases the risk of cardiac side effects.

The simultaneous use of drugs with a negative inotropic effect, helps to slow down the heart rate and / or slows down AV-conduction, therefore, requires careful clinical and ECG monitoring.

Medicines that can induce the development of torsades de pointes. This arrhythmia can be induced by certain drugs, regardless of whether they are antiarrhythmic drugs or not. Favorable factors include hypokalemia (see the subsection “Medicines that reduce potassium”), bradycardia (see the subsection “Medicines that slow down the heart rhythm”), or congenital or acquired prolongation of the Q – T interval.

Medicines that can cause the development of torsades de pointes include antiarrhythmic drugs of classes Ia and III and some antipsychotics. For erythromycin, spiramycin and vincamycin, this interaction is realized only when using dosage forms that are administered iv.

The simultaneous use of two drugs, each of which is a tool that contributes to the occurrence of torsades de pointes, is usually contraindicated.

However, methadone and some subgroups of drugs are an exception to this rule, namely:

• antiparasitic drugs (halofantrine, lumefantrine, pentamidine) are not recommended for use in combination with other agents that contribute to the occurrence of torsades de pointes;
• antipsychotics that can induce torsades de pointes are also not recommended for use in combination with other agents that contribute to the occurrence of torsades de pointes, but such a combination is not contraindicated.

Medications that slow down your heart rate. Many drugs can cause bradycardia. This applies in particular to class Ia antiarrhythmic drugs, β-adrenergic blockers, some class III antiarrhythmic drugs, some calcium channel blockers, digitalis drugs, pilocarpine and anticholinesterase drugs.

Contraindicated combinations (see CONTRAINDICATIONS). Medicines that can induce the occurrence of torsades de pointes (with the exception of antiparasitic drugs, antipsychotics, and methadone; see the section “Recommended Combinations”).

Increased risk of ventricular arrhythmias, especially torsades de pointes.

Not recommended combinations

Cyclosporin. Increased serum concentrations of cyclosporine due to a deterioration in its metabolism in the liver, with a risk of nephrotoxic effects.

Quantitative determination of serum concentrations of cyclosporine, monitoring of renal function and dose adjustment of cyclosporin during treatment with amiodarone are necessary.

Fluoroquinolones. During treatment with amiodarone, the use of fluoroquinolones should be avoided.

Diltiazem for injection. The risk of developing bradycardia and AV blockade.

If the use of this combination cannot be avoided, it is extremely important to carry out careful clinical observation and continuous monitoring of the ECG.

Verapamil for injection. The risk of developing bradycardia and AV blockade.

If the use of this combination cannot be avoided, it is extremely important to carry out careful clinical observation and continuous monitoring of the ECG.

Antiparasitic drugs that can induce torsades de pointes (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, especially torsades de pointes. If possible, you should cancel one of the simultaneously used drugs. If the use of this combination cannot be avoided, it is extremely important to carry out a preliminary assessment of the Q – T interval and monitor the ECG.

Antipsychotics that can induce torsades de pointes (amisulpride, chlorpromazine, cyamemazine, droperidol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipothiazine, sertindole, sulpiride, sultopride, zipentipide, tipridipide.Increased risk of ventricular arrhythmias, especially torsades de pointes.

Methadone Increased risk of ventricular arrhythmias, especially torsades de pointes.

Combinations that require precautions for use.

Oral anticoagulants. Increased anticoagulant effect and increased risk of bleeding. More frequent monitoring of international normalized relations (INR) is needed. Possible dose adjustment of oral anticoagulant during treatment with amiodarone and within 8 days after drug withdrawal.

Β-adrenoreceptor blockers, except sotalol (a contraindicated combination) and esmolol (a combination that requires precautions when used). Violation of automatism and conduction (inhibition of compensatory sympathetic mechanisms). ECG and clinical monitoring are required.

Β-adrenergic blockers used for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Violation of automatism and myocardial conduction with a risk of excessive slowdown of the heart rhythm. Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and regular ECG monitoring is required.

Dabigatran. An increase in plasma concentrations of dabigatran with an increased risk of hemorrhagic events. Clinical monitoring and dose adjustment of dabigatran is necessary if necessary, but not higher than 150 mg / day.

Because amiodarone has a long T_½, then the occurrence of interactions can be observed for several months after termination of treatment with amiodarone.

Substrates of P-glycoprotein. Amiodarone is an inhibitor of P-glycoprotein. It is likely that with simultaneous use with substrates of P-glycoprotein, their concentration in the blood will increase.

Digitalis medicines. Inhibition of automatism (excessive slowdown in heart rate) and impaired AV conduction.

When using digoxin, an increase in blood levels of digoxin is observed due to a decrease in digoxin clearance.

ECG and clinical monitoring, quantitative determination of digoxin levels in the blood and, if necessary, dose adjustment of digoxin are required.

Diltiazem for oral use. The risk of developing bradycardia or AV blockade, especially in elderly patients. ECG and clinical monitoring are required.

Some macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmias, especially torsades de pointes.

ECG and clinical monitoring are necessary against the background of the simultaneous use of these drugs.

Verapamil for oral use. The risk of developing bradycardia and AV blockade, especially in elderly patients. ECG and clinical monitoring are required.

Esmolol. Violation of contractility, automatism and conduction (inhibition of compensatory sympathetic mechanisms). ECG and clinical monitoring are required.

Medicines that reduce potassium: diuretics that reduce potassium (alone or in combination), stimulant laxatives, amphotericin B (for iv administration), glucocorticoids (for systemic use), tetracosactide. It is necessary to prevent the occurrence of hypokalemia (and correct hypokalemia); the Q – T interval should be carefully monitored. In the case of paroxysmal ventricular tachycardia torsades de pointes, antiarrhythmic drugs should not be used (it is necessary to start ventricular pacemaking; possibly intravenous administration of magnesium drugs). Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalemia is a contributing factor). It is necessary to eliminate hypokalemia before prescribing the drug and monitor the ECG, electrolyte content and clinical monitoring.

Lidocaine.The risk of increased plasma concentrations of lidocaine, with possible neurological and cardiac side effects, in connection with the inhibition of amiodarone drug metabolism in the liver. Clinical and ECG monitoring, as well as, if necessary, quantitative determination of plasma concentrations of lidocaine are required. If necessary, dose adjustment of lidocaine during treatment with amiodarone and after its withdrawal.

Orlistat. Risk of decreased plasma concentrations of amiodarone and its active metabolite. Clinical monitoring and, if necessary, ECG monitoring are required.

Phenytoin (by extrapolation - also fosphenytoin). An increase in plasma concentrations of phenytoin with signs of overdose, especially neurological signs (inhibition of phenytoin metabolism in the liver). Clinical monitoring, quantitative determination of plasma concentrations of phenytoin are required, and dose adjustment is also possible.

Simvastatin. Increased risk of side effects (dose-dependent), such as rhabdomyolysis (inhibition of the metabolism of simvastatin in the liver). Given this type of interaction, do not exceed the dose of simvastatin 20 mg / day or use another statin.

Tacrolimus. Increased blood tacrolimus concentrations due to under