The historical development, cellular electrophysiology and pharmacology of amiodarone

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<ul><li><p>Progress in </p><p>Cardiovascular Diseases VOL XxX1, NO 4 JANUARY/FEBRUARY 1989 </p><p>The Historical Development, Cellular Electrophysiology and Pharmacology of Amiodarone </p><p>Bramah N. Singh, Nagammal Venkatesh, Koonlawee Nademanee, Martin A. Josephson, and Ram Kannan </p><p>A LTHOUGH SYNTHESIZED originally as a coronary vasodilator and antianginal compound, amiodarone hydrochloride (Fig 1) subsequently attracted considerable experimen- tal and clinical interest as an antiarrhythmic agent. No other antidysrhythmic compound has stimulated as much scrutiny as has amiodarone over the last ten years. Its extreme potency in the prophylactic control of most supraventricular and ventricular arrhythmias is now well estab- lished.- However, the fundamental mechanism whereby amiodarone induces its salutary effects for the most part remains uncertain. For this reason, the effects of the compound on cardiac electrophysiology relative to its associated phar- macologic properties are of much theoretical as well as practical importance. As in the case of numerous antiarrhythmic agents, the overall effects of amiodarone on cardiac action poten- tials may result from its direct as well as indirect actions. Barring its intrinsic effects, the com- pound has the propensity to noncompetitively antagonize (Y- and P-adrenergic receptors*12 with a poorly understood and complex interrela- tionship with thyroid hormone metabolism. This article discusses the overall pharmacologic actions of the drug with a particular reference to its electrophysiologic, hemodynamic, and phar- macokinetic properties with a note on the inter- esting historical development of the compound. </p><p>DEVELOPMENT OF AMIODARONE </p><p>It should be remembered that amiodarone was not developed specifically as an antiarrhythmic compound. It was synthesized by Labaz labora- tories in Belgium as an antianginal agent during a systemic search for potent coronary vasodila- tors.3-5 Amiodarone was one of a series of </p><p>derivatives that were synthesized on the basis of the benzofuran moiety of the khellin molecule and its natural congeners, all of which were reasonably potent coronary vasodilators. The very first compound was benziodarone. The pres- ence of two iodine atoms in the benziodarone molecule was believed to augment the overall pharmacologic properties compared to those of its precursor, benzarone. Preliminary clinical trials with benziodarone promptly revealed its proclivity to induce jaundice and hepatotoxicity in man. It was soon superseded by amiodarone, a more potent coronary vasodilator. In a series of comprehensive pharmacologic studies Charlier et a112*3 in a variety of isolated tissue prepara- tions and in intact conscious dogs clearly demon- strated somewhat unusual properties of the com- pound. The studies indicated a slow onset and offset of action of amiodarone. For example, when it was given orally to instrumented dogs, decreases in heart rate, tension-time index, and systemic pressure were gradual and did not appear to attain a steady state at a constant daily dose for about five to six weeks. Similarly, the regression of the observed changes was not com- plete even after five weeks of drug withdrawal.12 </p><p>From the Department of Cardiology and Cardiovascular Research Laboratory, Wadsworth VA Hospital and Depart- ment of Medicine. UCLA School of Medicine. Los Angeles. </p><p>Supported by grants from the Medical Research Service of the Veterans Administration and the American Heart Association, the Greater Los Angeles Affiliate, Los Angeles. </p><p>Address reprint requests to Bramah N. Singh, MD. Department of Cardiology 691/I 11 E, Wadsworth VA Hos- pital, Wilshire and Sawtelle Blvds. Los Angeles, CA 90073. </p><p>o 1989 by Grune &amp; Stratton, Inc. 0033-0620/89/3104-0001$5.00/0 </p><p>Progress in Cardiovascular Diseases, Vol XXXI, No 4 (January/February), 1989: pp 249-280 249 </p></li><li><p>250 SINGH ET AL </p><p>DEETHYL METABOLITE </p><p>Fig 1. Structural formulas of amiodarone. desethylam- iodarone, and thyroxine. Note the presence of iodine in amiodarone and desethylamiodarone. </p><p>When intravenous (IV) amiodarone was given there was an increase in coronary blood flow and reduced myocardial oxygen consumption. Intra- venous amiodarone also tended to attenuate the tachycardia and enhanced contractility produced by isoproterenol, suggesting an interaction with the autonomic nervous system. Although the differences between the effects of the parenter- ally and orally administered amiodarone were not emphasized by Charlier et al, the overall effects noted in their studies were construed as representing a new biologic profile for an antian- ginal compound. The first report documenting the clinical antianginal actions of the compound appeared in 1967.14 </p><p>The first publication to document the antiar- rhythmic effects of amiodarone in experimental animals appeared in 1969. Attempts to delin- eate the fundamental mechanism of action in cardiac muscle were reported in 197016 and again in 197 1 as an integral part of a doctoral disserta- tion. In common with the drug sotalol,18 it was suggested that amiodarone might be a potent antiarrhythmic compound. These early studies with sotalol and amiodarone emphasized the potential significance of lengthening refractori- </p><p>ness in cardiac muscle by selectively prolonging cardiac repolarization as a discrete mechanism for the control of cardiac arrhythmias. There are now emerging data with a variety of compounds that attest to the validity of these earlier predic- tions.9.20 </p><p>The first clinical report on amiodarone as an antiarrhythmic agent documented the effects of IV administered drug in 1970,2 while reports documenting results of oral therapy did not appear until 1974. 22 The use of amiodarone as an antianginal agent in France and other European countries revealed the drug; propensity to pro- duce cornea1 microdeposits in most adult patients. There was major concern that such changes might irreversibly interfere with vision. Subsequent experience has, however, failed to substantiate such a possibility. It was found that rarely is vision impaired by amiodarone. Other concerns about the potential toxicity of amioda- rone as a therapeutic agent remained, however. A major source of trepidation was related to the presence of so much iodine in the drug, the deiodination of which led to a prolonged persis- tence of free iodine in the body. The question, therefore, arose whether large numbers of patients given amiodarone might develop clini- cally significant changes in thyroid hormone metabolism. In 1975 Pritchard, Singh, and Hur- leyz3 showed that although the drug did increase serum thyroxine levels and decreased triiodothy- ronine levels modestly, there was no significant change in thyroid stimulating hormone levels. These effects were confirmed a year later by Burger et al. 24 It became clear that the major actions of the drug were not mediated by an alteration in thyroid state. The nature of the link between thyroid hormone metabolism and amio- darone action, however, became the focus of an intense electrophysiologic study stemming from the observations by Singh and Singh and Vaughan Williamsi that the effects of chronic amiodarone administration and those of hypo- thyroidism on rabbit heart muscle25 were nearly identical. Since the effect of the drug on the action potential was dominated by marked pro- longation, it was suggested, as in the case of the P-blocker sotalol,7,8 that such an electrophysio- logic effect represented a new mode of antiarr- hythmic action. These observations became the basis for the earliest clinical trials with oral </p></li><li><p>AMIODARONE: DEVELOPMENT, PHARMACODYNAMICS </p><p>amiodarone undertaken by Rosenbaum et al in Argentina in the early 197Os.** </p><p>The effects of the compound have now been studied in a variety of experimental and clinical arrhythmias. 26 The emergence of amiodarone has been a major landmark in the development of antiarrhythmic therapy, lg.*6 but the precise cellu- lar mode of action of the compound remains incompletely understood. In this review, the rele- vant data that bear on this issue are discussed within a brief compass. The discussion of the electrophysiologic actions of the compound will be preceded by a brief description of the com- pounds interaction with the autonomic nervous system. It is our contention that this is an integral component of the drugs mechanism of action as an antiarrhythmic compound. The thesis will be developed that the precise understanding of the action of this unusually potent compound may provide further ideas about the development of similar but safer compounds while leading to newer insights into the fundamental mechanisms of arrhythmias themselves. </p><p>AMIODARONE AN5 ANTlADRENERGtC ANTAGONISM </p><p>The acute antiadrenergic actions of amioda- rone have been experimentally established both in vitro as well as in vivo.27-2g Polster and Broekhuysen compared the effects of the com- petitive @-antagonist, propranolol, in isolated rabbit atria to those of amiodarone. The pA, value for propranolol was 8.33. Amiodarone acted as a noncompetitive ,&amp;antagonist with a pD, value of 4.17 with isoproterenol as an ago- nist. The effects of amiodarone on a-receptor blockade were investigated in isolated rat-aortic strips induced to contract by norepinephrine. The pA, value for phentolamine was found to be 8.69, whereas the pD, value for amiodarone was 4.06, the drug having no effect on calcium permeabil- ity in this preparation. Subsequently, Charlier* found that in anesthetized dogs, amiodarone produced bradycardia independent of ,&amp;receptor blockade as the effect persisted after the admin- istration of propranolol. Although amiodarone has been found to decrease cholinergic receptors in the rat heart and brain,30 some studies have failed to demonstrate a significant interaction with the cholinergic component of the autonomic nervous system.16*29 </p><p>251 </p><p>:1. 1 A DI-PROPRANOLOL I 0 DESETHYLAMIODARONE </p><p>P 0 AMIODARONE </p><p>-r 1 -7 -6 -5 -4 -3 </p><p>LOG,,[ADRENERGIC ANTAGONISTI </p><p>Fig 2. Differences between amiodarone, desethylamio- darone, and propranolol in their ability to bind &amp;receptors using the radio-ligand binding technique for demonstration. Note differences in the curves: the competitive nature for propranolol and noncompetitive for the benzofuran deriva- </p><p>tives. Based on data from Venkatesh et aL3 </p><p>It is known that bradycardia develops in a stepwise manner as a function of time on a constant dose of amiodarone,12*6*7 raising the possibility of a progressive decrease in myocar- dial /3-adrenoceptors. This observation has recently drawn increasing attention.312 It is now confirmed that amiodarone does antagonize /3- receptors in a noncompetitive fashion (Fig 2) and exerts a significant effect on P-receptor density following acute as well as chronic administration. For example, Venkatesh et a13 have shown that when amiodarone and its principal metabolite desethylamiodarone were given acutely and chronically to rabbits, there was a significant reduction in myocardial P-receptor density (B,,,) without an effect on receptor affinity (IQ. The effect of chronic amiodarone adminis- tration over six weeks was more pronounced (-45%) than that (-25%) following acute IV drug injection (Fig 3). However, this difference </p></li><li><p>252 SINGH ET AL </p><p>Fig 3. Effects of acute and chronic treatment with amiodarone and desethylamiodarone on &amp;receptor density </p><p>(B,,,) in the rabbit ventricular myocardium. Both agents depress B,, with amiodarone exhibiting the trend to pro- </p><p>duce a greater reduction following chronic than after acute drug administration. The data raise the possibility that the chronic effect may be due to the summated effects of the parent compound and those of the metabolite. The greater chronic effect may also result from an added effect of selective hypothyroidism (see text). (Reproduced with per- mission3) </p><p>was unrelated to dose since the effects of 20 mg/kg and 40 mg/kg chronic dosing regimens on B,,, were statistically indistinguishable. Nor was the greater effect following chronic therapy attributable to serum and tissue levels following chronic drug administration, since both the serum and myocardial levels 15 minutes follow- ing acute IV amiodarone administration were considerably higher than the corresponding lev- els following six weeks of chronic drug dosing. Nokin et a13* also performed direct ligand- binding assays on rat myocardial P-adrenocep- tors; the data of Venkatesh et a13 differ in providing evidence for a greater effect following chronic drug administration than after acute, and are in line with the electrophysiologic changes that also develop in a stepwise manner as a function of time. The observations of Nokin et a13* are of interest in that they showed that both pretreatment with propranolol as well as with amiodarone abolished the increases in P-receptor density induced by myocardial ischemia follow- ing coronary artery ligation. The effects of amio- darone on adrenergic receptors are similar in different animal species. For example, Sharma et a1,33 who studied the effects of chronic (six weeks) oral amiodarone administration in cats on p- and a-receptor density in ventricular muscle found no effect on a-receptor density, and a significant reduction in @-receptor density with- </p><p>out a change in receptor affinity. The reason for the dissociated effects of amiodarone on (Y- and P-receptors as determined by radio-ligand bind- ing is at present unclear especially in light of the fact that in different in vitro systems noncompe- titive effects against (Y- and P-catecholamine receptors have been demonstrated. Gagnol et a134 have also found that in rat heart membrane preparations, amiodarone noncompetitively an- tagonized the activation of adenylate cyclase by isoproterenol, glucagon, and secretin but not sodium fluoride. The authors suggested that the noncompetitive P-antagonistic properties of am- iodarone might be due to the inhibition of the coupling of P-receptors with the regulatory unit of the adenylate cyclase complex and/or to a decrease in the number of functional P-receptors at the surface of the myocardial cell. The net result in vivo is the attenuation of the positive chronotropic actions of catecholamines,34 a prop- erty of obvious significance in mediating the antiarrhythmic and antiischemic effects of the compound. </p><p>The fact that bradycardia during chronic amiodarone therapy develops as a function of time is consistent with the data of Venkatesh et a1,31 indicating a gradual decrease in the number of ,&amp;receptors during chronic drug administra- tion. In part, this is undoubtedly due to the additive effect of the metabolite of amiodarone during chronic drug administration. In part, it may also be explained on the basis of a secondary consequence of selective hypothyroidism induced by amiodarone.10~16~17~g~31 It is known that in hypothyroidism a significant decrease in the den- sity of myocardial fl-adrenoceptors occurs, while hyperthyroidism is character...</p></li></ul>

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