Pharmacotherapeutic Group: Cardiac therapy, anti-arrhythmics, class I and III, anti-arrhythmics, class III. ATC Code: C01BD01.
Pharmacology: Pharmacodynamics: In myocardial tissue, amiodarone inhibits the potassium efflux during stage III of the action potential and thus selectively prolongs the duration of repolarisation and the refractory period of the action potential (class III effect is defined by Vaughan Williams). This leads to depression of ectopias and re-entry mechanisms without impaired contractile force of the myocardium.
Amiodarone reduces conduction velocity and extends the refractory time in accessory atrioventricular paths.
The prolongation of the slow diastolic depolarisation in the pacemaker potential leads to a depressed automatism in the pacemaker tissue with deceleration of the heart rate which is atropine-resistant.
Amiodarone exhibits a dose-dependent, non-competitive inhibition of alpha- and beta-adrenergic activities, which is haemodynamically expressed by a coronary-dilative and vasodilative effect and also by improvement in the oxygen balance.
Amiodarone administered orally does not show any significantly negative inotropic effect.
In case of i.v. administration, reduced contractility may occur particularly after injection.
Paediatric population: No controlled paediatric studies have been undertaken.
In published studies the safety of amiodarone was evaluated in 1118 paediatric patients with various arrhythmias. The following doses were used in paediatric clinical trials.
Oral: Loading dose: 10 to 20 mg/kg/day for 7 to 10 days (or 500 mg/m2/day if expressed per square meter).
Maintenance dose: the minimum effective dose should be used, according to individual response, it may range between 5 to 10 mg/kg/day (or 250 mg/m2/day if expressed per square meter).
Pharmacokinetics: Amiodarone is metabolised mainly by CYP3A4, and also by CYP2C8. Amiodarone and its metabolite, desethylamiodarone, exhibit a potential in vitro to inhibit CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and 2C8. Amiodarone and desethylamiodarone have also a potential to inhibit some transporters such as P-gp and organic cation transporter (OCT2) (one study shows a 1.1% increase in concentration of creatinine (an OCT2 substrate). In vivo data describe amiodarone interactions on CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.
After oral administration, approximately 50% of amiodarone is absorbed in the gastrointestinal tract.
After administration of one single dose, plasma levels are reached after 3-7 hours.
Accumulation of the substance at its site of action or saturation of the myocardial tissue, respectively, is decisive for therapeutic efficacy.
Depending on the saturation dose, the onset of action can be expected within a period of a few days up to two weeks.
Following injection, the maximum of action is achieved after 15 minutes. Afterwards, re-distribution into tissue and rapid decrease in the plasma concentrations occur within 4 hours.
For saturation of tissue depots, therapy must be continued intravenously or orally.
Amiodarone has a long half-life interindividually varying between 20 and 100 days.
During saturation, the substance accumulates mainly in fat tissue. Steady state is attained within a period of one month up to several months.
Due to these characteristics, the recommended saturation dose should be administered in order to attain rapid saturation in tissue which is required for therapeutic efficacy.
The main excretion route is through liver and bile; 10% of the substance is excreted renally.
Due to low renal excretion, the usual dose can be administered to patients suffering from renal insufficiency.
After withdrawal, amiodarone is still excreted for several months.
Paediatric population: No controlled paediatric studies have been undertaken. In the limited published data available in paediatric patients, there were no differences noted compared to adults.
Toxicology: Preclinical safety data: Acute toxicity: Acute toxicity of amiodarone seems to be relatively low, and LD50 values are more than 3 g/kg BW. Clinical symptoms were vomiting in the dog, CNS effects (sedation, tremor, convulsions, dyspnoea) in rodents.
Chronic toxicity/subchronic toxicity: Chronic toxicity studies revealed that amiodarone has a similar toxicological potential in animals as well as in humans. Amiodarone caused pulmonary damage such as fibrosis or phospholipidosis (in hamster, rat and dog) as well as CNS disturbances (in rats). Oxidative stress and free radicals seem to be very important for inducing pulmonary damage. Furthermore, amiodarone caused hepatic damage in rats. Effects of amiodarone on serum lipids may be indirectly caused by alterations in the plasma concentrations of thyroid hormones.
Mutagenic and tumorigenic potential: Amiodarone is a highly phototoxic substance. There is evidence that free cytotoxic radicals are formed via UV irradiation in the presence of amiodarone. This may not only lead to acute phototoxic reactions, but also to damage of DNA (photomutagenicity) and subsequently to photocancerogenic effects. These potentially severe adverse reactions of amiodarone have not been investigated in experiments up to now. Therefore, the photomutagenic and photocancerogenic potential of amiodarone is not known.
In a 2-years carcinogenicity study in rats, amiodarone caused an increase in thyroid follicular tumours (adenomas and/or carcinomas) in both sexes at clinical relevant exposures. Since mutagenicity findings were negative, an epigenic rather than genotoxic mechanism is proposed for this type of tumour induction. In the mouse, carcinomas were not observed but a dose-dependent thyroid follicular hyperplasia was seen. These effects on the thyroid in rats and mice are most likely due to effects of amiodarone on the synthesis and/or release of thyroid gland hormones. The relevance of these findings to man is low.
Reproductive toxicity: Increased serum levels for LH and FSH pointing to testicular dysfunction were measured in male patients after longer-term treatment.