Rythma Mechanism of Action





United Lab
Full Prescribing Info
Pharmacotherapeutic Group: Antiarrhythmics (class III).
Pharmacology: Pharmacodynamics: Tablet: In myocardial tissue, amiodarone HCl inhibits the potassium efflux during stage III of the action potential and thus, selectively prolongs the duration of repolarization and the refractory period of the action potential (class III effect as defined by Vaughan Williams). This leads to depression of ectopias and re-entry mechanisms without impaired contractile force of the myocardium.
Amiodarone HCl reduces conduction velocity and extends the refractory time in accessory atrioventricular paths. The prolongation of the slow diastolic depolarization in the pacemaker potential leads to a depressed automatism in the pacemaker tissue with deceleration of the heart rate which is atropine-resistant.
Amiodarone HCl exhibits a dose-dependent, non-competitive inhibition of α- and β-adrenergic activities, which is hemodynamically expressed by a coronary-dilative and vasodilative effect and also by improvement in the oxygen balance.
Amiodarone HCl administered orally does not show any significantly negative inotropic effect. In case of IV administration, reduced contractility may occur particularly after injection.
Injection: Amiodarone is both an antiarrhythmic and a potent vasodilator. Amiodarone is considered a "broad-spectrum" antiarrhythmic with multiple and complex electrophysiological effects. Although its exact mechanism of action is not completely known, amiodarone is considered a class III compound using the traditional Vaughn-Williams classification scheme for antiarrhythmic compounds.
Like the other class III antiarrhythmics, bretylium and sotalol, amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. Delayed repolarization is a result of inhibition of potassium ion fluxes that normally occur during phase 2 and 3 of the action potential. This results in prolongation of the effective refractory period in all cardiac tissue (eg, atria, ventricles, AV node and His-Purkinje system). Amiodarone exerts this antifibrillatory effect without significantly altering the myocardial membrane potential.
By definition, class III agents act only on the repolarization phase of the action potential and therefore, should leave conduction unchanged. However, amiodarone has also been shown to inhibit the inward sodium currents which is a use-dependent class I activity. The result of this cellular action is a slowing of the upstroke velocity of phase 0 which reduces the rate of membrane depolarization and impulse conduction. Amiodarone also depresses the automaticity of both the sino-atrial (SA) and atrio-ventricular (AV) nodes directly (class II effect), and slows conduction in the His-Purkinje system and in the accessory pathway of patients with Wolff-Parkinson-White syndrome.
Amiodarone HCl also noncompetitively inhibits α- and β-receptors, and possesses both vagolytic and calcium-channel blocking properties. Rythma relaxes both smooth and cardiac muscles, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload.
Pharmacokinetics: Tablet: After oral administration, approximately 50% of amiodarone HCl is absorbed in the gastrointestinal tract. After administration of 1 single dose, plasma levels are reached after 3-7 hrs. 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 dosage, the onset of action can be expected within a period of a few days up to 2 weeks.
Following injection, the maximum of action is achieved after 15 min. Afterwards, redistribution into tissue and rapid decrease in the plasma concentrations occur within 4 hrs. For saturation of tissue depots, therapy must be continued IV or orally.
Amiodarone HCl has a long t½ interindividually varying between 20 and 100 days. During saturation, the substance accumulates mainly in fat tissue. Steady state is attained within a period of 1 month up to several months. Due to these characteristics, the recommended saturation dosage 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 dosage can be administered to patients suffering from renal insufficiency.
After withdrawal, amiodarone HCl is still excreted for several months. Bioavailability: Mean bioavailability is 42% (22-80%).
Injection: After IV administration, amiodarone is rapidly and widely distributed. Peak serum concentrations after single 5 mg/kg 15-min IV infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 10-min infusions of 150 mg amiodarone HCl injection in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% of peak values within 30-45 min after the end of the infusion.
In vitro, amiodarone is approximately 96% bound to plasma proteins, mainly to albumin and, to a lesser extent, to a high density lipoprotein that is probably β-lipoprotein.
Amiodarone is metabolized to N-desethyl amiodarone (DEA) by the cytochrome P-450 (CYP450) enzyme group, specifically cytochrome P-450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.
Amiodarone and possibly, DEA, cross the placenta to a limited extent. In pregnant women receiving amiodarone, ratios of umbilical venous to maternal venous plasma concentrations of amiodarone and DEA were 0.1-0.28 and 0.25-0.55, respectively.
Amiodarone and DEA are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations. Limited data in a breastfeeding woman indicate amiodarone and DEA milk-to-plasma ratios ranging from 2.3-9.1 and 0.8-3.8, respectively.
Amiodarone's elimination is primarily by hepatic metabolism and biliary excretion. Amiodarone or DEA excretion in the urine is negligible. Neither amiodarone nor DEA is dialyzable.
After IV administration in healthy individuals, amiodarone's total plasma clearance averages approximately 1.9 mL/min/kg. Although not clearly established, total apparent plasma clearance of the drug appears to decrease with time. Factors of age, gender and renal or hepatic disease appear to have no effect on the disposition of amiodarone or DEA.
Toxicology: Tablet: Preclinical Safety Data: Acute Toxicity: Acute toxicity of amiodarone HCl seems to be relatively low, and lethal dose (LD50) values are >3 g/kg body weight. Clinical symptoms were vomiting in the dog, central nervous system (CNS) effects (sedation, tremor, convulsions, dyspnea) in rodents.
Chronic Toxicity/Subchronic Toxicity: Chronic toxicity studies revealed that amiodarone HCl has a similar toxicological potential in animals as well as in humans. Amiodarone HCl caused pulmonary damage eg, 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 HCl caused hepatic damage in rats. Effects of amiodarone HCl on serum lipids may be indirectly caused by alterations in the plasma concentrations of thyroid hormones.
Mutagenic and Tumorigenic Potential: Amiodarone HCl is a highly phototoxic substance. There is evidence that free cytotoxic radicals are formed via ultraviolet (UV) irradiation in the presence of amiodarone HCl. This may not only lead to acute phototoxic reactions, but also to photocancerogenic effects. These potentially severe adverse reactions of amiodarone HCl have not been investigated in experiments up to now. Therefore, the photomutagenic and photocancerogenic potential of amiodarone HCl is not known.
A cancerogenicity study in rats showed that amiodarone HCl caused increased follicular tumors of the thyroid gland (in male animals at doses from 5 mg/kg/day, in female animals at doses from 16 mg/kg/day). These effects appear to be caused by impacts of amiodarone HCl on synthesis and/or release of thyroid hormones. No cancerogenic potential can therefore be deduced from these investigations for the therapeutic use of amiodarone HCl in humans.
Reproductive Toxicity: Increased serum levels for LH and FSH pointing to testicular dysfunction were measured in male patients after longer-term treatment.
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