Amiodarone structures

Figure 72.2 Amiodarone structure in comparison with i-thyroxine. Note the high iodine content (broken circies) and the simiiar structures of the two moiecuies.

Ventricular extrasystoles are treated only if they may degenerate into life-threatening arrhythmia. In milder forms the proarrhythmic risk of the diugs overshadows their benefits. In such cases (3-adrenoceptor antagonists may be attempted. For the treatment of ventricular extrasystoles, such as series or runs of extrasystoles, amiodarone or sotalol are used. In the absence of structural heart disease, class I anti-arrhythmic diugs can be considered an alternative. However, they may not be administered during the post-infarction period. 

Figure 5.6 The difference between liposome-water and octanol-water partitioning as a function of the octanol-water partition coefficient for a series of unrelated structures [149,385,386,429]. For example, acyclovir partitions into liposomes over 3000 times more strongly than into octanol, and amiodarone partitions into liposomes 100 times more weakly than into octanol. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

Several drug classes, including tetracycline, sulfonamide, and quinolone antibiotics, as well as chlorothiazide, chlorpromazine, and amiodarone hydrochloride, have been shown to be photoantigens. Photosensitivity may persist even after withdrawal of the drug, as has been observed with the antiarrhythmic drug amiodarone hydrochloride, since it is lipophilic and can be stored for extended periods in the body fat (Unkovic et al., 1984). In addition, it is quite common for cross-reactions to occur between structurally related drugs of the same class. 

In addition to the amiodarone-related compounds, (81) and (82), described above, BASF has been exploring some novel heterocyclic compounds as Class III antiarrhythmic agents. A series of imidazo[l,2-c]pyrro-lo[l,2-a]quinazoline derivatives have been patented which are several times more potent than (-I- )-sotalol in lengthening QT interval of the electrocardiogram in the anaesthetized guinea-pig model [230], One of the most potent compounds is (85), which was 17-times more potent than the standard. These compounds represent one of the unique Class III structural types described to date. 

The drug is also a highly lipophilic base and accumulates in a number of tissues including the lung. This combination of extreme physicochemical properties can result in more specific interactions such as the condition of phospholipidosis (increase in total lung phospholipids) caused by inhibition of phospholipid breakdown [4]. The medicinal chemist has to decide if extreme lipophilicity and the presence of iodine are essential for activity and, in the case of amiodarone, proven clinical efficacy or whether alternative structures are possible. 

From the chemical point of view, amiodarone is completely different from other antiar-rhythmics. It has two iodide atoms and a diethylaminoethanol group as substituents in the benzoyl part, and overall it is very similar to the structure of thyroxin-like molecules. 

Classes I, III, and IV all involve transmembrane ion channels Classes I and III involve Na+ channels. Class I compounds are designed to block cardiac Na channels in a voltage-dependent manner, similar to local anesthetics. Not surprisingly, many of these Class I agents are either local anesthetics or are structurally based on local anesthetics. Class I compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of these compounds possess two or three of the fundamental structural building blocks found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III compounds include molecules that block outward K channels, such as sotalol (7.22) and dofetilide (7.23), and molecules that enhance an inward Na current, such as... 

Dronedarone is a structural analog of amiodarone and lacks iodine atoms. The design was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the drug. Dronedarone has multiple actions like amiodarone, blocking IKr, IKs, ICa, INa, and adrenoceptors. The drug has a half-life of 24 hours and was administered twice daily in the initial clinical trials. No thyroid or pulmonary toxicity has been noted during early use. 

Drugs that cause phospholipidosis are cationic amphiphiles they contain a hydrophobic ring structure and a hydrophilic side chain with a positively charged amine group. Such chemicals can interact with either the ionic (e.g., chlorophentermine) or hydrophobic (e.g., amiodarone) moieties of phospholipids. 

It seems that for drugs to cause accumulation of phospholipids, the necessary physicochemical characteristic is the presence of both hydrophilic and lipophilic parts to the molecule, as exemplified by chlorphentermine (see chap. 3) (chap. 5, Fig. 1). They contain a hydrophobic ring structure and a hydrophilic side chain with a positively charged (cationic) amine group. Such molecules are known as cationic amphipathic drugs or CADs. Other drugs, all in use, known to cause phospholipidosis are amiodarone, chloroquine (chap. 5, Fig. 1), tafenoquine, and gentamycin. 

The clinical significance of phospholipidosis is related to secondary damage to tissue structure or impaired function possibly at the cellular level, for example, reduced immunological response. In the case of amiodarone, the phospholipidosis in the lung causes cough and breathing difficulties. 

Benzofuran-based structures are used as important chiral building blocks in the synthesis of biologically active compounds. Several 2-substitued benzofuran drugs are available nowadays such as Amiodarone (cardiac and anti-arrythmic) and Benziodarone (coronary vasodilator), adding to that they can be used in inhibiting HIV-1 reverse transcriptase or acting as antiaging compounds. 

Another example worth mentioning is X-ray diffraction studies on amiodarone [80, 81], a drug that accumulates extensively in membranes (see Section 4.4). The effect of cholesterol on membrane structure has also been studied by X-ray diffraction. The results indicated the existence of microdomains in the DPPC-cholesterol mixed ripple phase [82]. 

Small-angle X-ray diffraction was used to identify the time-averaged location of amiodarone in a synthetic lipid bilayer. The drug was located about 6 A from the center of the lipid bilayer (Figure 4.13) [125, 126]. A dielectric constant of k = 2, which is similar to that of the bilayer hydrocarbon region, was used to calculate the minimum energy conformation of amiodarone bound to the membrane. The studies were performed below the thermal phase transition and at relatively low hydration of lipid. The calculated conformation differed from that of the crystal structure of amiodarone. Even though the specific steric effects of the lipid acyl chains on the confor-... 

Actions Amiodarone [a MEE oh da rone] contains iodine and is related structurally to thyroxine. It has complex effects showing Class I, II, III and IV actions. Its dominant effect is prolongation of the action potential duration and the refractory period. Amiodarone has antianginal as well as antiarrhythmic activity. 

Amiodarone is a structural analog of thyroxine, and much of its toxicity is related to interactions that occur at thyroid hormone receptors. Pulmonary fibrosis is a frequent adverse effect tliat is related to dose, and drug level doses <200mg/day and maintenance of peak levels <2jLig/mL can help avoid this fife-threatening side effect. 

Solid-state NMR has been used extensively for characterizing the structures of N-desmethylnefopam HC1 (38), patellin (39), erythromycin A dihydrate (40), and the amorphous nature of ursodeoxycholic acid (41). The conformations of 3 -amino-3 -deoxythymidine (42), gramicidin A (43), and amiodarone HC1 (44) have been confirmed by solid-state NMR. 

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