Amiodarone, metabolite

The Vaughan-Williams classification of antiarrhythmic drugs has been criticized for a number of reasons. The classification is based on the effects of drugs on normal, rather than diseased, myocardium. In addition, many of the drugs may be placed into more than one class. For example, the class IA drugs prolong repolarization/refractoriness, either via the parent drug8,9 or an active metabolite,10 and therefore also maybe placed in class III. Sotalol is also a 3-blocker, and therefore fits into class II. Amiodarone inhibits sodium and potassium channels, is a non-competitive inhibitor of 3-receptors, and inhibits calcium... 

In addition to the slow onset of action of amiodarone, the half-life of the biological effects of the drug are extremely long [30]. This may be due in part to the principal metabolite of (11), which is desethylamiodarone (18). 

Amiodarone (Figure 8.2) is an efficacious drug that causes a number of side-effects. The presence of iodine in the molecule is unusual and hypo- and hyperthyroidism have been reported in patients. Although the loss of iodine is relatively slow the relatively large daily dose size and long half-life of the drug and its de-ethylated metabolite suggest that the presence of iodine in the molecule is responsible for its toxicity [3]. 

Distribution - Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg. One major metabolite, desethylamiodarone (DEA), accumulates to an even greater extent in almost all tissues. The drug is highly protein bound (approximately 96%). 

Wefabo//sm-Amiodarone is metabolized principally by CYP3A4 into DEA, the major active metabolite of amiodarone. DEA serum concentrations greater than 0.05 mg/L are not usually seen until after several days of continuous infusion but with prolonged therapy reach approximately the same concentration as amiodarone. 

Excretion - Following discontinuation of chronic oral therapy, amiodarone has a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 107 days. A much slower terminal plasma elimination phase shows a half-life of the parent compound of approximately 53 days. For the metabolite, mean plasma elimination half-life was approximately 61 days. Antiarrhythmic effects persist for weeks or months after the drug is discontinued. 

The main route of elimination is via hepatic excretion into bile some enterohepatic recirculation may occur. The drug has a very low plasma clearance with negligible renal excretion. Neither amiodarone nor its metabolite is dialyzable. 

Amiodarone decreases the slope of phase 4 depolarization. The rate of spontaneous discharge of the sinoatrial node is increased by amiodarone as well as by its metabolite, desethylamiodarone. The depressant action of amiodarone on sinoatrial pacemaker function is, in addition to p-receptor blockade, related to an inhibition of the slow inward current carried by the calcium ion. 

Amiodarone, like its major metabolite desethylamiodarone, increases A-V nodal conduction time and refractory period. 

The dominant effect on ventricular myocardium that has been chronically exposed to either amiodarone or desethylamiodarone is a prolongation in the action potential with an associated increase in the refractory period and a modest decrease in Vmax as a function of stimulus frequency. Amiodarone inhibits the delayed outward potassium current, a finding consistent with the observation of a prolonged action potential. Both amiodarone and its metabolite significantly decrease the ac-... 

Amiodarone is slowly and poorly absorbed after oral administration. It is metabolised slowly in liver to active metabolite. 

Ohyama K, Nakajima M, Suzuki M, et al. Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities prediction of in vivo drug interactions. Br J Clin Pharmacol 2000 49 244—253. 

AMIODARONE DRUG DEPENDENCE THERAPIES-BUPROPION T plasma concentrations of amiodarone, with risk of toxic effects Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 Initiate therapy of these drugs at the lowest effective dose... 

AMIODARONE GRAPEFRUIT JUICE Possibly 1 effect of amiodarone Inhibition of CYP3A4-mediated metabolism of amiodarone to its active metabolite Warn patients to avoid grapefruit juice if amiodarone becomes less effective, ask the patient about grapefruit juice ingestion... 

GRAPEFRUIT JUICE AMIODARONE Markedly T plasma concentrations of amiodarone (AUC >50%, maximum concentration >84%). Possibly 1 effect of amiodarone (1 in P-R and Q-Tc intervals). This could lead to l therapeutic effect due to 1 production of active metabolite Due to inhibition of CYP3A4-mediated metabolism of amiodarone by grapefruit juice, which results in near-complete inhibition of the production of N-DEA (desethylamiodarone, the active and major metabolite of amiodarone) Warn patients to avoid grapefruit juice if amiodarone becomes less effective, ask the patient about grapefruit juice ingestion... 

Disposition in the Body. Slowly and incompletely absorbed after oral administration distributed to the tissues where it is strongly bound. Metabolised by V-dealkylation to monodesethylamiodarone which is the major plasma metabolite during chronic dosing. High concentrations of amiodarone and monodesethylamiodarone are found in the liver, lungs, and adipose tissue. Enterohepatic circulation may occur. Only a small amount is excreted in the urine as unchanged drug. 

Loratadine is well absorbed after oral administration, with peak plasma concentrations at approximately 1.5 hours. Clinically significant relief of symptoms is usually obtained within 2 to 4 hours of the first dose. Excretion of loratadine occurs almost equally through the urine and feces.This dual mechanism of secretion provides a measure of safety in patients with liver or kidney disease, but caution should be exercised in both groups. Also, torsades de pointes may occur with the concurrent use of loratadine and amiodarone. Desloratadine is a metabolite of loratadine. 

Particle-loaded membranes with embedded Cg hydrophobic adsorbents were intensively investigated for several dmg separations. Tricyclic antidepressants, antiarrhythmic dmgs, amiodarone and its metabolite desethylamiodarone, and mexiletine and flecainide were extracted from serum using a 11 mm Cg membrane adsorber with recoveries ranging from 82% to 98% [14,220]. 

The authors suggested that torsade de pointes induced by intravenous amiodarone depended on heart rate during a bout of bradycardia, while that after oral amiodarone depended on increased sympathetic nervous system activity, and that therefore different electrophysiological mechanisms had been at play. However, it is by no means clear from their description of this case that that was so. They did not report plasma concentrations of amiodarone or desethylamiodarone, its active metabolite. 

Amiodarone increases the plasma concentrations of phenytoin, probably by inhibiting its metabolism (259,260), while phenytoin increases the metabolism of amiodarone and perhaps also of its metabolite desethylamiodarone (261). 

Plomp, T.A. Engels, M. Robles de Medina, E.O. Maes, R.A. Simultaneous Determination of Amiodarone and its Major Metabolite Desethylamiodarone in Plasma, Urine and Tissues by High-Performance Liquid Chromatography, J. Chromatogr. 273,379-392 (1983). 

Siegers, C.R Moller-Hartmann, W. Cholestyramine as an antidote against paracetamol-inducedhepato-and nephrotoxicity in the rat. Toxicol.Lett., 1989, 47, 179-184 [rat urine extracted metabolites] Lam, S. Malikin, G. An improved micro-scale protein precipitation procedure for HPLC assay of therapeutic drugs in serum. J.Liq.Chromatogr., 1989, 12, 1851-1872 [serum also amiodarone, aspirin, caffeine, chloramphenicol, flecainide, pentobarbital, procainamide, pyrimethamine, quinidine, theophylline, tocainide, trazodone fluorescence detection UV detection]... 

Drug interactions also can result from inhibition of other CYPs. Amiodarone and its active metabolite desethylamiodarone promiscuously inhibit several CYPs, including CYP2C9, the principal enzyme that eliminates the active -enantiomer of warfarin. Because many patients treated with amiodarone e.g., subjects with atrial fibrillation) are also receiving warfarin, the potential exists for major bleeding complications. 

Figure 96.3 Structures of amiodarone, DEA and thyroid hormones. Amiodarone is a type 3 anti-arrhythmio drug that is an iodine-rich benzofuran derivative. It is metabolized through dealkylation to desethylamiodarone (DEA), whioh is the aotive metabolite. Amiodarone and DEA share a structural resemblance with thyroid hormones.

---