Amiodarone

Chemical formula

(2-butyl-3 - benzofuranyl) - 3,5-diiodophényl] méthanone hydrochlorate

Mechanism of action

The principal effect of the amiodarone is to delay the cardiac repolarization and to lengthen the refractory period in a homogeneous way:

reduction in the amplitude of the Potential of action, without modifying the membrane potential of rest
increase in the duration of the potential of action (phase 2 is shortened by reduction in the calcic conductance but phase 3 is very lengthened by reduction of the potassic conductance).

The amiodarone also has a antiarythmic activity of class I related to the blocking of the sodic channels in their inactivated conformation. This effect is at the origin of a deceleration the maximum speed of depolarization of phase zero of the potential of action and takes part in the deceleration of conduction (negative dromotrope effect).
The amiodarone slows down the sinusal rate/rhythm (bradychardisant effect), however without cardiodepressor effect, as well as conduction, mainly on the level of the node auriculoventriculaire, but also at the sino-auricular level and the level of the network of His-Purkinje.

The lengthening of the refractory period is observed with all the stages (sinusal, atrial++, node auriculoventriculaire, network of His-Purkinje, ventricular) like on the level of the additional beam in the event of syndrome of Wolf-Parkinson-White.
Its effects appear at the electrocardiographic level by lengthenings of the intervals PR and QTC which, after a prolonged oral treatment, are the of about respectively 10 17% and of 10 23%.

The amiodarone in addition has an antagonistic activity alpha and beta-adrénergique noncompetitive. Finally its coronarodilatatrice activity led to its use as antiangoreux.

Pharmacokinetic

Absorption

The absorption of the amiodarone by oral way is slow and very variable. Its biodisponibility is on average of 40% and varies from 20 to 86%, knowing that it is better if the administration is joint with food. The plasmatic peak is variable according to the individual, from 3,1 to 14,2 microgrammes/ml, 5:00 after an oral amount of 1500 to 1800 Mg. The antiarythmic activity appears in general only after 1 to 3 weeks and would be maximum after 1 to 5 months of treatment.

Distribution

The amiodarone has a fixing with plasmatic proteins close to 95%, including 62% with albumin and 33% probably with bêtalipoprotéines. The amiodarone is characterized by a very important tissue fixing at the origin of tissue concentrations being able to be 100 to 1.000 times higher than the concentrations plasmatiques.
Its volume of distribution is of 62 l/kg. Its important liposolubility leads to concentrations particularly high in fat fabric. Its metabolite, the déséthylamiodarone, accumulates in fabrics in a comparable way and can be present at concentrations higher than those of the amiodarone it-même.
This tissue accumulation is at the origin of effects persisting several weeks after the stop of the treatment. The amiodarone and its metabolite cross the placental barrier and their concentrations in the blood of the cord reach 10 to 50% of the maternal blood concentrations. These substances also pass in the mother's milk.

Half-life

The amiodarone is characterized, after a prolonged administration, by a half-life of particularly long final elimination, with an average of about 50 days and an important interindividual variance (20 to 100 days). The half-life of its metabolite is close 60 days.

Metabolism and elimination

The amiodarone is largely metabolized, mainly at the hepatic level and, partly, the intestinal level. Principal the metabolite is the déséthylamiodarone, which has a antiarythmic activity comparable with that of the amiodarone. This metabolite is present at the plasmatic level with concentrations close to those of the amiodarone. The metabolism of the amiodarone would imply mainly the CYP 3A4.
The amiodarone undergoes only little or not renal elimination. It is eliminated in deposit mainly in metabolized form.

Counter-indications

auricular Bradycardia and disorder of auricular conduction
Turbid of ventricular conduction
Over-sensitiveness with the amiodarone
Dysthyroïdie (hyperthyroïdie; hypothyroïdie: substitute treatment by thyroid hormones if amiodarone essential)
Pregnancy and breast feeding

Side effects

interstitial Pneumopathy: it is about one of the most frequent undesirable effects (up to 10% of the covered subjects) and most serious of the amiodarone. The quick change towards the pulmonary fibrosis and a fatal evolution is possible. The stop of the treatment by the amiodarone essential, is possibly associated with a corticothérapie.

Dysthyroïdie : the treatment by the amiodarone reduces the peripheral conversion of the thyroxine (T4) into tri-iodothyronine (T3) and increases the formation of reverse-T3. The plasmatic concentration of T4 is thus increased, whereas that of T3 is decreased. The plasmatic concentration of TSH can increase moderately at the beginning of the treatment, but is standardized spontaneously in less than 3 mois.
Ces modifications are not accompanied by no clinical demonstration and their observation must thus involve any modification of the treatment. On the other hand, the amiodarone involves sometimes a hypothyroïdie (frequent) or a hyperthyroïdie (rarer).

hepatic Toxicity: an increase moderate in serum transaminases is frequent (15 to 20% of the covered subjects), generally asymptomatic and transitory. The regression of the anomalies, often spontaneous in spite of the continuation of the treatment, is usual after its stop. The persistence of anomalies can on the other hand present a risque.
Dans certain cases, an evolution towards the fibrosis and the cirrhosis was reported. Whenever a hepatic biopsy were carried out, the lesions were close to those due to an alcohol excessive consumption (hepatitis pseudoalcoolic) and associated with an accumulation of phospholipides in the lysosomes of the hépatocytes.

Turbid eyepieces: they are corneal deposits brown-yellowish localized in the surface under pupillary. They are nearly constant in the adult, but are usually asymptomatic. Their observation during an ophthalmologic examination thus does not require modification of the treatment by the amiodarone. These deposits are completely reversible after the stop of the traitement.
In addition some cases of optical neurites were brought back.

Photosensitization and cutaneous pigmentation.

References

Amiodarone in the new AHA guidelines for ventricular tachyarrhythmias . CHARON Michael F.; KLUGER Jeffrey; WHITE C. Michael. 2001
Cardiac arrhythmias in pregnancy: clinical and therapeutic considerations . Int J Cardiol. Gowda RM, Khan IA, Mehta NJ, Vasavada BC, Sacchi TJ. 2003
DICP Ann Pharmacother 1990;24: 1001-1006.

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