DRUG E VA L UA T I ON

Drugs 43 (I ): 69- 110, 1992 00 I 2-6667/92 /(xx) 1-0069/$ 21.00/ 0 © Adis Internat ional Limited. All rights reserved. DRE172

Amiodarone

An Overview of its Pharmacological Properties, and Review of its Therapeutic Use in Cardiac Arrhythmias John Gill, Rennie C. Heel and Andrew Fitton Adis International Limited , Chester, UK and Auckland, New Zealand

Various sections of the manuscript reviewed by: B. Belhassen, Department ofCardiology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; I.H.N. Bett, Director of Cardiology, The Prince Charles Hospital, Brisbane, Queensland , Australia; P. Brugada, Postgraduate School of Cardiology, O.L Vrouwziekenhuis, Aalst, Belgium; A.J. Camm, Department of Cardiological Sciences, St George's Hospital Medical School, London , England; R.W.F. Campbell, Academic Department of Cardiology, Freeman Hospital , University of Newcastle Upon Tyne, Newcastle Upon Tyne, England; P.l. Counihan, Department of Cardiological Sciences, St George's Hospital Medical School, London , England; D.C. Harrison, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; H.A. Kopelman, Cardiac Electrophysiology, St Joseph 's Hospital of Atlanta , Atlanta, Georgia, USA; S. Nattel, Institut de Cardiologie de Montr eal, Montreal , Quebec, Canada ; A. Pfeiffer, Department of Medicine, Stadt Krankenhaus Miinchen-Bogenhausen, Munich, Federal Republic of Germany; M. Pfisterer, Division of Card iology, Un iversity Hospital Basel, Basel, Switzerland; P.l. Podrid, Section of Cardiology, The University Hospital, Boston University Medical Center, Boston, 'Massacbusette, USA; L. Rakita, Division of Cardiology, Cleveland Metropolitan Genera l Hospita l, Case Western Reserve University, Cleveland, Ohio, USA.

Contents 70 72 72 72

73 74 74 76 76 77

78 78 78 78 78 79 79 79 79 80 83

Summary I. Pharmacodynamic Properti es I.l Electrophysiological Properties I. I.l Cellular Electrophysiology 1.1.2 Clinical Electrophysiology 1.2 Antiarrhythmic Activity in Animal Models 1.3 Haemod ynamic Effects 1.4 Other Effects 2. Pharm acokinetic Propert ies 2.1 Absorption , Bioavailability and Plasma Concentrations 2.2 Distribution 2.3 Elimination 2.3.1 Metabolism 2.3.2 Excretion 2.3.3 Rate of Elimination 2.4 Plasma Concentration Versus Clinical Effect 3. Therapeutic Use 3.1 Ventricular Arrhythmias 3. I.l Noncomparative Studies 3.1.2 Comparative Studies 3.1.3 Predictors of Clinical Efficacy

70

Drugs 43 (1) 1992

83 87 88 88 90 91 91 92 92

93 93 93 95 96

4. 5.

97 97 97

98 98 99

99 101

6. 7. 8.

3.1.4 Effect on Mortality and Survival 3.2 Atrial Tachyarrhythmias 3.2.1 Noncomparative Studies 3.2.2 Comparative Studies 3.3 Wolff-Parkinson-White Syndrome and Supraventricular Tachycardia 3.4 cardiomyopathy-Associated Arrhythmias 3.4.1 Hypertrophic Cardiomyopathy 3.4.2 Dilated Cardiomyopathy 3.5 Arrhythmias in the Young Overdosage Tolerability 5.1 Cardiac Effects 5.2 Thyroid Effects 5.3 Pulmonary Effects 5.4 Hepatic and Gastrointestinal Effects 5.5 Ocular Effects 5.6 Neurological Effects 5.7 Dermatological Effects 5.8 Other Effects Drug Interactions Dosage and Adm inistration Place of Amiodarone in Therapy

Summary

Synopsis

Amiodarone, originally developed over 20 years ago. is a potent antiarrhythmic drug with the actions of all antiarrhythmic drugclasses. It has been successfully used in the treatment ofsymptomatic and life-threatening ventricular arrhythmias and symptomatic supraventricular arrhythmias. In patients with left ventricular dysfunction amiodarone does not usually produce any clinicallysignificant cardiodepression and the drughas relatively highantiarrhythmic efficacy. Preliminary studies indicatethat amiodarone may havea beneficial effect on mortality and survival in certain groups ofpatients with ventricular arrhythmias. an actionprobably related to both its antiarrhythmic and antifibriilatory effects. The adverse effect profileof amiodarone is diverse, involving the cardiac. thyroid, pulmonary. hepatic. gastrointestinal. ocular. neurological and dermatological systems. Interstitialpneumonitis and hepatitis are potentially fatal. but the vast majority of adverse events are less serious. and some may be dose dependent. Pretreatment monitoring, regular assessments and the use of minimum effective doses are, therefore. necessary. Thus. with appropriate monitoring to control its well recognised adverse effects amiodarone has an important place as an effective 'broad specuum' iantiarrhythmic drug which has, so far, beenused when othertreatments,haveprovedineffective. Morerecent preliminary data alsosuggest that it may also have a benefiCi~)!. effect in the prevention ofsudden death in some patients. .!:

Pharmacodynamic Properties Amiodarone was originally described as a class III antiarrhythmic owing to its ability to increase the action potential duration, thereby prolonging repolarisation and refractoriness. In addition, class I antiarrhythmic effects, calcium channel blocking effects and a propensity to noncompetitively antagonise a~ and d-adrenergic receptors have been seen. On acute administration amiodarone inhibits inactivated membrane sodium channels, producing a decrease in the rate of phase 0 depolarisation (Vmax). h) ischaemic conditions class I antiarrhythmic effects predominate. Long term administration resultsin prolongation of the action potential duration in conjunction with a decrease in Vmax. '

Amiodarone: An Overview

71

In clinical electrophysiological studies long term oral amiodarone increases atrial, atrioventricular nodal, His-Purkinje and ventricular refractoriness, sinus cycle length and QT interval , and moderately slows intracardiac conduction. In animal models of arrhythmia amiodarone reduced the incidence of ischaemia-induced ventricular arrhythmias in the dog; Furthermore, there is some evidence of a cardioprotective effect in ischaemic models, with reductions in the area of necrosis following infarction. Neither intravenous nor oral amiodarone appears to alter haemodynamic function in a clinically significant way, although in patients with severely depressed left ventricular function hypotension has been reported.

Pharmacokinetic Properties The pharmacokinetics of amiodarone and its main metabolite , desethylamiodarone (DEA), are not completely understood and there are large interindividual variations in bioavailability , plasma concentrations and elimination half-life. Oral bioavailability of amiodarone is approximately 40%, probably reflecting incomplete and slow gastrointestinal absorption, and the time to reach peak plasma concentration ranges from 2 to 10 hours. Long term oral treatment does not produce steady-state plasma concentrations for at least I month , although antiarrhythmic effects are seen before this time . A therapeutic plasma concentration range of 1 to 2.5 rng/L has been suggested as a rough guide, but clinical response should also be used for determining dose. Amiodarone displays extensive tissue distribution, with the highest concentrations found in adipose tissue. DEA concentrations exceed those of amiodarone in all tissues except fat. The volume of distribution is high, approximately 5000L, and in plasma the drug is approximately 95% protein bound. Metabolism is partly intestinal but mainly hepatic and virtually all the drug is metabolised. Biliary and faecal excretion are the major routes of elimination, with renal excretion responsible for less than I%of the administered dose, making dosage adjustment unnecessary in cases of renal impairment. Elimination appears biphasic following single oral and intravenous doses, with terminal elimination half-lives of 3.2 to 21 hours reported. Following long term oral administration the average terminal elimination half-life is 40 days. This has important implications for dosage adjustment, as it fIlay take at least I month for new plasma concentrations to stabilise, while total clearance from the body can take more than 4 months.

Therapeutic Use The vast majority of patients treated with amiodarone have generally presented with the more severe and sustained refractory arrhythmias. In ventricular arrhythmias intravenous amiodarone (usually 5 mg/kg over 20 to 30 minutes as a loading dose) has suppressed life-threatening sustained ventricular tachycardia or ventricular fibrillation in approximately 40% of patients. Oral treatment (loading plus maintenance therapy) has reduced the recurrence of ventricular tachycardia or ventricular fibrillation in 70 to 95% of patients in noncomparative studies and these effects persisted for long periods. In comparative studies oral amiodarone has proved significantly more effective than placebo, and of comparable efficacy to sotalol, propranolol , flecainide, encainide , propafenone and moricizine in patients with ventricular arrhythmias. Several studies indicated that amiodarone may .reduce the incidence of sudden death in patients with arrhythmias associated with organic heart disease, an effect probably related to its antiarrhythmic and antifibrillatory effects. In patients with atrial tachyarrhythmias amiodarone has proved very successful in both restoring and maintaining sinus rhythm in 30 to 95% of patients when used in conjunction with electrocardioversion, particularly in paroxysmal arrhythmias. Amiodarone has generally been more successful than either verapamil or quinid ine, and appears promising in moderate to marked left atrial dilatation. Suppression of paroxysmal supraventricular tachycardia (SVT) [with or without Wolff-Parkinson-White syndrome] is seen in approximately 75%of patients following treatment with amiodarone . This, along with efficacy in a range of re-entry arrhythmias, may relate to amiodarone's

Drugs 43 (1) 1992

72

propensity to suppress premature beats and increase the refractory periods of the atrioventricular node and accessory conduction pathways. In both hypertrophic and dilated cardiomyopathy amiodarone has proved effective in suppressing both ventricular tachycardia and SVT , and may be associated with improved survival in those patients with hypertrophic cardiomyopathy.

Tolerability Adverse effects of amiodarone are mainly dose dependent, and predominantly endocrine (hypoor hyperthyroidism), pulmonary (interstitial pneumonitis), hepatic (abnormally elevated liver enzymes, hepatitis), cardiac (proarrhythmia, bradycardia, worsening congestive heart failure), gastrointestinal (nausea, anorexia, constipation), ocular (corneal microdeposits), neurological (tremor, neuropathy) and dermatological (photosensitivity, grey/blue discoloration). These range from minor asymptomatic problems requiring no intervention to life-threatening problems necessitating drug withdrawal and supportive measures. Interstitial pneumonitis is probably the most serious toxic reaction. Pretreatment assessment and regular monitoring, in conjunction with the use of minimum effective doses, provide the basis for early recognition and appropriate effective management.

Drug Interactions Amiodarone alters the pharmacokinetics of digoxin, oral anticoagulants, class I antiarrhythmic drugs, l3-blockers and calcium channel blockers. Importantly, the long plasma elimination halflife of amiodarone means that the potential for significant drug interaction persists for some time after treatment has stopped. Dosages of digoxin should be reduced by 25 to 50%, while those of oral anticoagulants (warfarin, acenocoumarol) should be reduced by about 50%. Close monitoring of plasma digoxin levels and prothrombin time is essential. There is a possibility of potentiating sinus bradycardia or arrest, or proarrhythmic effects when amiodarone is used in conjunction with class I antiarrhythmics, l3-blockers and calcium channel blockers.

Dosage and Administration The recommended dosage of amiodarone administered intravenously in adults with any tachyarrhythmia is up to 5 mg/kg over 20 to 120 minutes, in conjunction with ECG monitoring. Doses of 10 to 20 mg/kg may be infused in a 24-hour period. Rapid intravenous bolus injection may induce hypotension. When administered orally loading doses of 600 to 1200 mg/day are generally given for I to 2 weeks and then the dose is titrated down to 400 to 800 mg/day for a month. Maintenance therapy is usually 200 to 400 rug/day.

Amiodarone (fig. I) is an iodinated benzofuran derivative which was developed more than 20 years ago, originally as an antianginal vasodilator. Subsequently, it was found to possess potassium channel blocking activity , prolonging cardiac repolarisation and refractoriness, and was thus described as a class III antiarrhythmic agent. Since that time , its potent antiarrhythmic effects have been thoroughly investigated in a wide range of animal and human studies, although to date its precise mode of action remains uncertain (for reviews see Counihan & McKenna 1990; Greene 1989; Kadish &

Morady 1989;Katritsis & Camm 1991 ; Puech 1991; Rosenbaum et al. 1983; Rotmensch & Belhassen 1988; Singh et al. 1989; Vrobel et al. 1989).

1. Pharmacodynamic Properties 1.1 Electrophysiological Properties 1.1.1 Cellular Electrophysiology The cellular electrophysiologyof amiodarone has been studied in the specialised cardiac conduction tissue and myocytes of a variety of animals, in-

Amiodarone: An Overview

73

Amiodarone

Desethylamiodarone

HO~ ;>--o~ I

;>-CH.b::OOH

I

Thyroxine Fig. 1. Structural formulae of amiodarone, desethylamiodarone and thyroxine.

eluding guinea-pigs, cats and dogs. The effects of both single dose and long term amiodarone administration have been studied in superfused and ischaemic tissue preparations, with the emphasis on measurements of action potential duration (APD) and the maximum rate of depolarisation of phase o (""max) of the action potential. Amiodarone has a particular propensity for blocking inactive sodium channels (Aomine 1989; Mason et al. 1984; Singh et al. 1989), more so than activated ones (Follmer et al. 1987), producing the typical decrease in ""max associated with class I antiarrhythmics. Blockade of calcium channels has also been reported (Aomine 1988c; Nattel et al. 1987; Nishimura et al. 1989; Takanaka & Singh 1990) and in some studies it seems that decreases in potassium ion conductance, which tend to increase APD, are masked by effects which shorten APD, presumabl y by a blockade of sodium and calcium channels (Aomine 1988d). Acute administration of amiodarone (44 J.tmol/L) shortens APD (Aomine 1988a), although this is not a universal finding (Aomine 1988b). Ischaemic conditions ap-

pear to negate amiodarone's class III effects and, in that situation, its class I (membrane-stabilising) effects predominate (Campbell & Hemsworth 1990; Cobbe & Manley 1987). Long term administration of amiodarone produces qualitatively and quantitatively different effects to single dose administration (Gallagher et al. 1989): the cardiac APD lengthens in conjunction with decreases in ""max (Aomine 1988e), although typical class III activity (prolongation of the APD without affecting phase 0) has been observed in ventricular cells but not in Purkinje fibres (Varro et al. 1988). Moreover, desethylamiodarone (DEA), the main metabolite of amiodarone, produces increasing depression of ""max over a clinically relevant range of plasma concentrations (Pallandi & Campbell 1987) and like amiodarone its maximal action is not immediately apparent, in that acute and chronic effects differ (Singh et al. 1989). Thus , the changing electrophysiological effects of amiodarone as treatment continues may well reflect accumulation of both amiodarone and DEA (Kato et al. 1988; Nattel 1986; Nattel & Talajic 1988; Talajic et al. 1987; Varr6 et al. 1987), although the delay in the onset of drug action is not solely attributable to the accumulation of DEA (Singh et al. 1989). Overall, chronic administration of amiodarone results in increases inthe refractory periods of all cardiac conduction tissue and a decrease in sinus and AV node automaticity (Kerin et al. 1989; Morady et al. 1986; Rosen & Wit 1983); however, the full electrophysiological profile of amiodarone has yet to be delineated.

1.1.2 Clinical Electrophysiology A large number of studies have assessed the. electrophysiological effects of arniodarone in patients with arrhythmias, .primarily of the ventricles, using programmed electrical stimulation (PES) and/or ambulatory Holter monitoring (Fisher et al. 1986; Horowitz & Borggrefe 1988; Katritsis & Camm 1991 ; Rotmensch & Belhassen 1988; Singh et al. 1989). Overall, the results appear to show that long term oral administration (of sufficient duration to produce therapeutic plasma concentrations) of amiodarone increases the refractory pe-

74

Drugs 43 (1) 1992

riods of the atria (by 17 to 34%), atrioventricular node (by 18 to 25%), His-Purkinje fibres and the ventricles (by 9 to 23%), with a concomitant increase in sinus cycle length (by 9 to 38%) [Feld et al. 1988; Finerman et al. 1982; Greenberg et al. 1989; Mas et al. 1987; Mitchell et al. 1989; Nademanee et al. 1982a; Touboul et al. 1982; Waxman et al. 1982]. Furthermore, prolongation of ventricular tachycardia cycle length has been observed (Vaitkus et al. 1990; Yazaki et al. 1987). Long term oral therapy predictably lengthens cardiac repolarisation and refractoriness as reflected in prolongation of the PR interval (15%), AH interval (20%)and QT interval (13%), without substantially affecting QRS or HV intervals (Nademanee et al. 1982a; Singh et al. 1989). However, some .studies suggestthat amiodarone may increase QRS and HV intervals to a moderate extent (Nattel 1991). The major differences between intravenous and long term oral treatment with amiodarone are that intravenous therapy does not appear to prolong the PR interval , but does increase AV nodal refractoriness and intranodal conduction (for review see Singh et al. 1989). In contrast to the potentially proarrhythmic QT interval prolongation observed with certain class I antiarrhythmics, that produced by amiodarone is closely associated with antiarrhythmic efficacy (Counihan & McKenna 1990). In the former case, the proarrhythmic effect is attributable to increased dispersion of repolarisation, whereas with amiodarone the increase in QT interval reflects a global prolongation of repolarisation and diminished ventricular dispersion (Singh 1989). This latter action may underlie the increase in ventricular fibrillation threshold seen with amiodarone (section 1.2) and the drug's potentially beneficial effect in patients at risk of sudden cardiac death (Counihan & McKenna 1990).

1.2 Antiarrhythmic Activity in Animal Models A number of studies have shown the effectiveness of both single dose and long term administration of amiodarone, and its main metabolite DEA, in various animal models of arrhythmia.

Following experimentally induced myocardial infarction in the dog, single doses of amiodarone (2 and 10 mg/kg) given intravenously reduced the incidence of associated spontaneous ventricular arrhythmias (Patterson et al. 1983; Winslow et al 1990); this effect was also seen with long term (~ 8 weeks)oral dosing regimens (Abdollah et al. 1990; Patterson et al. 1983;Winslow et al. 1990) and following intravenous DEA administration (Abdollah et al. 1989). For a given plasma concentration, DEA was a more potent antiarrhythmic than amiodarone in this model (Nattel et al. 1988). However, no such reductions occurred in electrically-induced ventricular arrhythmias following intravenous amiodarone administration in the cat chronic infarction model (5 mg/kg bolus followed by a continuous infusion of 0.42 mg/kg/h) [Marinchak et al. 1989]. Experimental data suggest that both short term intravenous and long term oral amiodarone may prevent spontaneous ventricular fibrillation in dogs subjected to acute myocardial ischaemia (Patterson et al. 1983). However, conflicting results have been observed in short and long term studies of amiodarone given orally or intravenously with regard to its effects on defibrillation energy requirements. Short term intravenous administration (5 or 10 mg/ kg) either failed to alter (Frame 1989), decreased (Fain et al. i 1987) or increased (Arredondo et al. 1986) energy requirements in defibrillation studies in the dog model. More importantly, oral administration may have no effect (Fain et al. 1987), or may increase defibrillation energy requirements in a dose-dependent manner (Frame 1989). The ventricular fibrillation threshold of the normal and ischaemic canine heart is significantly elevated by short term intravenous administration of amiodarone (5 mg/kg) [Arredondo et al. 1986]. 1.3 Haemodynamic Effects The haemodynamic effects of amiodarone appear to differ depending on the route of administration and whether single dose or longer term administration is studied. Overall, the dosages of amiodarone administered, intravenously or orally,

75

Amiodarone: An Overview

to control arrhythmias do not appear to alter haemodynamic function in a clinically significant way in patients with arrhythmias, even if ventricular function is somewhat compromised (Remme et al. 1985; Remme & van Hoogenhuyze 1990; Rotmensch & Belhassen 1988; Singh et al. 1989). In studies of intravenous administration (Branzi et al. 1988; Holt 1989; Munoz et al. 1988; Pfisterer et al. 1985; Schwartz et al. 1983), a dose of 5 mg/ kg was generally used, but the rate of infusion varied widely between studies and this may be related to some of the findings (table I). While relatively rapid infusion produced some evidence of a hypotensive and negative inotropic effect (cardiac index reduced by 5%), it is likely that this was due partly to the vehicle (Tween 80) [Munoz et al. 1988]; slow infusion over 2 hours increased stroke volume index (by 29%) [Holt 1989]. This acute cardiodepressant effect of amiodarone was more pronounced at the higher dose of 7.5 mg/kg, and was associated with a concomitant (presumably reflex) increase in heart rate and afterload (Pfisterer et al. 1985). In patients with ischaemic heart disease,the cardiodepressant effects of amiodarone were similar in subgroups with normal and moderately impaired (ejection fraction < 0.50) left ventricular function (fig. 2), and the exercise-induced deterioration in left ventricular function in the latter

I

group was not exacerbated by amiodarone (Pfisterer et al. 1985). Longer term oral treatment with amiodarone, usually following a loading dose phase of 1 week, does not appear to have any clinically significant adverse haemodynamic effects(Pfisterer et al. 1985; Sheldon et al. 1988). On comparing the haemodynamic profiles.of short and long term amiodarone administration in patients with chronic ischaemic heart disease, Pfisterer et al. (1985) noted that the acute cardiodepressant effect of the drug was largely abolished on long term (3 weeks) therapy, both in patients with normal and moderately impaired left ventricular function. This improvement in left ventricular function was accompanied by a decrease in heart rate on long term administration. Nademanee et al. (1983a), in a long term study (mean follow up 15 months) of 96 patients, found that cardiac failure was not aggravated by amiodarone (maintenance dose 200 to 600 mg/day) even .in patients with markedly depressed left ventricular function (ejection fraction < 0.20). Nevertheless, the prognosis of patients with arrhythmias who receive amiodarone therapy can be significantly affected by the baseline ejection fraction and by development of congestive heart failure (De Paola et al. 1987).

Table I. Systemic and cardiac haemodynamic changes following intravenous infusion of amiodarone Reference

Branzi et al, (1988) Holt (1989) Munoz et al. (1988) Pfisterer et al. (1985) Schwartz et al. (1983)

No. of patients

Characteristics Dose

10

HCM

5

10 20

VT CAng

4.3 5

120 3

10

IHD

7.5

5

18

VT

5

(mg/kg)

Infusion time (min)

Haemodynamic parameter CI

SVI

SVR

10

20

t = increased ; I = decreased ; = .... no significant change vs baseline (p > 0.05); CI = cardiac index; SVI = stroke volume index; SVR = systemic vascular resistance; HCM = hypertrophic cardiomyopathy ; VT = ventricular tachycardia; CAng = undergoing evaluative coronary angiography; IHD = chronic ischaemic heart disease.

Abbreviations:

76

Drugs 43 (l) 1992

II Single dose intravenously

30

o Long

term orally

~ 20 Ql :::l

0;

>

ec

10

8 E

,g

0

Ql

Ol

c:

«l

amiodarone

Abbreviations: t max = time to maximum plasma concentration;

tv,

=

DEA

elimination

half-life ; Vd

= desethylam iodarone .

=

volume of distr ibution ;

Following oral administration, amiodarone has a limited bioavailability, averaging approximately 40% (Nattel & Talajic 1988), with a reported range of 20 to 86% (Paton et al. 1984; Robinson et al. 1987). This probably results from incomplete and slow absorption from the gastrointestinal tract; whether differences in the extent of hepatic firstpass metabolism playa part in the intersubject variability is not clear (Pourbaix et al. 1985; Rotmensch & Belhassen 1988; Urso & Aarons 1983). In addition, the time to reach peak plasma concentration (tm ax ) is also variable, ranging from 2 to 10 hours (Sloskey 1983). In a recent controlled absorption study, Pfeifferet aI. (1990)suggested that fluctuations in .the pharmacokinetics of amiodarone are due mainly to intersubject variation in drug metabolism and tissue distribution, as absorption rates were relatively constant. Long term oral treatment results in a gradual increase in plasma concentrations of amiodarone (and DEA) and there is a period of several weeks to several months before peak plasma concentrations are achieved (Robinson et ill. 1990; Rotmensch et al. 1984; Rotmensch & Belhassen 1988). Notably, however, significant and beneficial electrophysiological effects may be seen before steadystate is attained (Rosenfeld et al. 1987>', and this has important implications for monitoring of serum concentrations to guide amiodarone therapy. Plasma amiodarone concentrations show considerable intersubject variation following both intravenous and oral administration, but mean values seem to be related to dose on long term oral administration. Patients stabilised on maintenance therapy with 200 to 600 rug/day displayed mean steady-state plasma concentrations ranging from 0.99 to 1.3 mg/L (200 mg/day); 1.5 to 2.4 mg/L (400 mg/day) and 3.34 to 3.65 mg/L (600 mg/day) [Holt et al. 1983; Plomp et al. 1984; Rotmensch et al. 1984]. Following a single intravenous infusion

78

Drugs 43 (1) 1992

of 400mg of amiodarone, Plomp et al. (1984) reported a mean plasma concentration of 10.8 mgt L at 1 hour. A 20-minute intravenous infusion of 5 mg/kg produced mean levels of 8.3 mg/L by the end of the infusion (Pourbaix et al. 1985). 2.2 Distribution The extent of plasma protein binding of amiodarone is high and levels of around 95% have been observed (Singh et al. 1989; Vozeh & Schmidlin 1987), with 62% bound to albumin and 33.5% to {j-lipoprotein (Lalloz et al. 1984). Following absorption, amiodarone is slowly distributed from the plasma to tissues, with a very high volume of distribution (Vd) of approximately 5000L (Holt et al. 1983; Robinson et al. 1987), indicating extensive tissue distribution. Due to its high lipid solubility, higher concentrations of the parent compound are reached in adipose tissue than in other tissues (Adams et al. 1985;Holt et al. 1983). Interestingly, concentrations of DEA are higher than those of amiodarone in the myocardium (Giardina et al. 1990)and in ~ll bther tissues except fat (Plomp et al. 1984; Rotmensch & Belhassen 1988). As a consequence 'of its .distribution characteristics, the use of large loading doses of amiodarone is necessary (see section 7). 2.3 Elimination

2.3.1 Metabolism Biotransformation of amiodarone has not been fully elucidated, but is thought to be primarily hepatic (Somani 1989) and, to a lesser degree, intestinal, involving N-dealkylation in the gut lumen or on intestinalmucosal transfer during absorption (Berdeaux et al. 1984). Virtually all the drug is metabolised (Singhet al. 1989). The main metabolite, DEA, is pharmacologically active and may contribute to the antiarrhythmic effect of the parent compound (Abdollah et al. 1989; Nattel & Talajic 1988). DEA reaches serum concentrations 60 to 80% of those ofamiodarone with long term treatment (Rotmensch & Belhassen 1988).

2.3.2 Excretion Full details of excretory routes for amiodarone are not completely described. Biliary excretion has been reported (Andreasen et al. 1981) and amiodarone and DEA have also been detected in faeces (Royal Pharmaceutical Society of Great Britain 1989), and these probably represent the major routes of elimination (Somani 1989). Renal excretion is minimal, with less that I % of an oral dose appearing unchanged in the urine (Rotmensch et al. 1983); thus, dosage alterations are unnecessary in the event of renal impairment (Mason 1987; Puech 1991).

2.3.3 Rate of Elimination A rapid short phase of tissue distribution followed by a long slow phase of elimination is seen following single dose intravenous administration of amiodarone, with a similar pattern occurring after a single oral dose. This contrasts with the complex and extended elimination seen following long term administration (Paton et al. 1984). Whereas plasma terminal elimination half-life values ranging from 3.2 to 20.7 hours have been noted after single oral and intravenous doses (Singh et al. 1989), the terminal elimination half-life of amiodarone following long term oral treatment is extended, averaging approximately 40 days (Holt et al. 1983; Nattel & Talajic 1988), although large variations in mean values (14 to 53 days) have been reported between studies (Singh et al. 1989). Corresponding values for DEA are generally slightly longer (Somani 1989); for example, Holt et al. (1983) reported 61 ± 31 days for DEA :compared with 53 . ± 24 days for amiodarone. Overall, the long elimination half-lifevalues following long term administration probably reflect the distribution and binding properties of amiodarone (Kannan et al. 1982). Clinically, this may mean that complete elimination of amiodarone and DEA from the body could take 4 to 6 months or longer following termination of long term treatment (Poirier et al. 1988).

79

Amiodarone: An Overview

2.4 Plasma Concentration Versus Clinical Effect Relating plasma concentration to clinical effect is difficult with amiodarone (Holt et al. 1983) and, although control of both ventricular and supraventricular arrhythmias is achievable with plasma concentrations ranging from 0.5 to 1.5 mg/L (Brennan et al. 1991; Mason 1987; Robinson et al. 1987), there is some evidence that concentrations of 1 to 2.5 mg/L constitute the effective therapeutic range (Maling 1988; Rotmensch & Belhassen 1988; Singh et al. 1989). In addition, the potential independent and modulatory effects of DEA must also be considered (Brennan et al. 1991; Nattel & Talajic 1988; Singh et al. 1989). Furthermore, considerable intersubject variability exists and empirical therapy guided by the clinical response is the most commonly used approach (Greenberg et al. 1987). Overall, plasma concentrations permit only a rough approximation of tissue concentrations and, hence , of the likely therapeutic response, and clinical monitoring (preferably with electrophysiological assessment) is the primary approach to dosage adjustment (see section 7). Moreover, the time taken for plasma concentrations to stabilise after dosage adjustments (due to the long elimination half-life) means that plasma concentrations are a poor guide to efficacy. With long term oral treatment, plasma amiodarone concentrations greater than 2.5 mg/L were usually associated with an increased incidence of adverse effects (Falik et al. 1987; Rotmensch et al. 1983; 1984; Rotmensch & Belhassen 1988), although this finding has been disputed (Greenberg et al. 1987).

3. Therapeutic Use Amiodarone has proven efficacious in patients with a wide range of ventricular and atrial tachyarrhythmias (Kadish & Morady 1989; Mason 1987; Rosenbaum et al. 1983), in both its oral and intravenous formulations. In North America, toxicity problems have mainly limited its clinical applicability to patients who have failed to respond to other treatments and, consequently, patients involved in

the majority of American trials with amiodarone have generally had more severe and sustained refractory arrhythmias. Despite this , amiodarone has produced favourable results in a variety of patients, including those with ischaemic heart disease, dilated and hypertrophic cardiomyopathy, and those at risk of sudden death. 3.1 Ventricular Arrhythmias When treating patients with ventricular arrhythmias, prevention of haemodynamic instability and sudden cardiac death associated with the arrhythmia is of prime importance (for reviews, see Greene 1989; Prystowsky et al. 1985). Furthermore, the response to treatment may vary for different arrhythmias and patient groups .

3.1.1 Noncomparative Studies Results of some of the main noncomparative studies of intravenous and oral amiodarone in patients with ventricular arrhythmias are summarised in table III. In these studies oral amiodarone has frequently been administered after intravenous amiodarone (in addition to other adjunctive measures) , or in some cases in nonresponders to intravenous amiodarone therapy (Helmy et al. 1988). Concomitant intravenous and oral administration has also been utilised (Schmidt et al. 1988). In a number of trials, the effects of intravenous amiodarone have been studied in patients with lifethreatening ventricular tachyarrhythmias (sustained ventricular tachycardia/ventricular fibrillation) which have proven refractory to other treatment(s). Intravenous loading doses of approximately 5 rug/kg have generally been followed by a continuous infusion (approximately 1 gjday for up to 3 or 4 days). In a comparatively high proportion of patients the arrhythmia has been quickly controlled: complete resolution of ventricular tachyarrhythmias occurred within 2 hours of commencing treatment in 20 to 33% of patients (Helmy et al. 1988; Mooss et al. 1990), while termination

80

of sustained ventricular tachycardia was demonstrated within 20 minutes in 42% of patients (Schutzenberger et al. 1989). Patients in these studies tended to have a history of coronary disease, myocardial infarction and poor left ventricular function, and thus represent a poor prognostic group. In addition, the causes of arrhythmia were generally unknown, although in the study of Mooss et al. (1990) identifiable reversible causes were ruled out (hypokalaemia, hypomagnesaemia, acute myocardial infarction). Nevertheless, the results of short term treatment with amiodarone were consistently good in this high mortality group. In longer term studies, the efficacy of oral amiodarone in drug-resistant ventricular arrhythmias has been clearly demonstrated (Nademanee et al. 1983a; Peter et al. 1983; Primeau et al. 1989; Rasmussen et al1982; Schmidt et al. 1985; Vazquez Blanco et al. 1983; Veltri ei al. 1986). Again, patients tended to be those with the more severe forms of organic cardiac disease in whom the prognosis, in terms of recurrence of arrhythmia and mortality, is generally poor. Due to its distribution characteristics, loading doses of amiodarone (ranging from 600 to 1800 rug/day) were usually used to minimise any delay in the onset of antiarrhythmic activity. In some cases the loading period lasted up to 4 weeks (Nademanee et al. 1983a) with doses as large as 1800 rug/day being given during this period (see table III); this was generally followed by daily maintenance doses (up to 800 rug/day), although Vazquez Blanco et al. (1983) discontinued treatment for 1 week every month. Furthermore, a high loading dose regimen (1400 mg/day) has been shown to have a significant advantage over a stepped dose regimen (200 mg/day increased in 200mg increments to a maximum of 800 rug/day) [Rakita & Sobol 1983] (fig. 3). Response rates (usually related to suppression of symptomatic ventricular arrhythmias) of at least 67% were produced and maintained over prolonged periods, with mean follow-up times of up to 20 months , indicating good prophylactic control. However, the time required to achieve such high response rates varied considerably. Schmidt

Drugs 43 (1) 1992

et al. (1985) demonstrated a progressive increase in the percentage of responders with time: 40% at 10 days; 50% at 1 month ; 70% at 3 and 6 months (amiodarone was ineffective in 20% and discontinued owing to adverse effects in 10%). Moreover, large interpatient variability in the response time to amiodarone was evident, ranging from 15 to 32 days (Rasmussen et al. 1982). The reason for this interpatient variability in response times is unknown.

3.1.2 Comparative Studies Results of comparative studies with amiodarone and placebo, sotalol, propanolol, flecainide, encainide, propafenone and moricizine are summarised in table IV. These studies were of diverse design and assessed not only antiarrhythmic efficacy but, in some cases, haemodynamic effects, mortality and survival as well. Consequently, the data will be examined by clinical condition and by route of administration. Mortality results are discussed in section 3.1.4. Salerno et al. (1990a) performed a large metaanalysis of the efficacy of a wide range of antiarrhythmic drugs used for the suppression of ventricular ectopic depolarisations, which provides a useful framework against which the relative efficacy of amiodarone can be assessed. The analysis was of 97 published articles, 27 drugs and 2989 patient-treatment trials, and by logistic regression found that drug response was significantly affected by a number of factors: increased by the use of dose titration; increased by the use of a higher daily dose; decreased by older age; decreased by the use of blinding; increased by the presence of male patients; and decreased by the presence of cardiovascular disease. Using a response ~riteria of 80% or greater suppression of ventricular ectopic depolarisations, amiodarone (n = 115) was associated with a response rate of 90%- the highest level achieved in the analysis - compared with encainide (80%; n = 125), flecainide (79%; n = 230) and propafenone (74%; n = 187). Acute Myocardial Infarction (AMI) Hockings et al. (1987) demonstrated that oral amiodarone (maintenance dose of200 mg/day), initiated 48 hours after the onset of chest pain, sig-

81

Amiodarone: An Overview

Table III. Results of some noncomparative studies of the therapeutic efficacy of intravenous and/or oral amiodarone in patients with ventr icular tachycard ia (VT) and/or ventricular fibrillation (VF) Reference

No. of charactensncss patients

Intravenous administration Life-threaten ing Helmy et al. 46 VT or VF (1988)

Dose b

Duration Response of criteria follow-up

5 mg/kg (over 30 min); 1 g/d

3.5d

Resolution of VT

58.5

Responders Comments (%)

'EF > 25%assoc iated with increased chance of response Cumulative 2y morta lity 46% 59% on oral treatment (mean follow-up 19 months)

Mooss et al. (1990)

35

Life-threate ning VT

5 mg/ kg (over 30 min); 20-30 mg/kg/d

3d

No sustained VT requiring card iovers ion

63

Ochi et al. (1989)

22

Life-threatening VT or VF

4-6 mg/kg (over 5-60 min)

2d

Suppression of arrhythm ia

64

Patients had severely depressed LV funct ion

Schiitzenberger et at (1989)

19

Recurrent , susta ined VT or VF

5 mg/kg (over 20 min); 1.05 g/ d

1d

Sustained VT -SR Prevention of VT/ VF recurrence

42

All patients had ~ LV function

300mg; (over 20 min); 900-1200 mg/d

2d

Suppression of arrhythm ia

81

Life-threatening VT and/or VF

600-1800 mg/d ; 200-600 mg/d

Mean 15m

Prevention of symptomatic VT or VF; elimination of .. 90% VEs

93.7

rr

Sustained VTfVF

200-800 mg/d (no loading)

Mean 21m

Excellent or good (.. 75% reduction in symptom frequency)

68

Primeau et al. (1989)

82

Refractory , recurrent VT

800 mg/d 200-400 mg/d

Mean 19m

Elimination of symptoms or arrhythmias

95

Rasmusse n et al. (1982)

33

Refractory, recu rrenfVT

800-1000 mg/d ; empirical reductio n

Mean 6.1m

No VT or VF

66.7

Vazquez Blanco et al. (1983)

25

Life-threatening VT

200-600 mg/d (no loading)

Mean 15.9m

VT suppression

84

Veltri et al. (1986)

52

Refractory, recurrent VT

800-1000 mg/d 200-400 mg/d

Mean 11.6m

No clinical arrhythmic events

71

Intravenous ± oral adm inistration Life-threatening Schmidt et al. 36 ventr icular (1988) arrhyt hmias

Oral administration Nademanee et 96 al. (1983a)

Peter et at, (1983)

a b

60 VF and poo r LV funct ion associated with poor response ; VT assoc iated with good response (> 90%)

Holter monitoring associated with increased predictive accuracy of VT

As used by the respective authors ; however, life-threatening VT or VF and sustained VT or VF are frequently used synonymously . Doses were generally given as a loading dose followed by a lower maintenance dose.

Abbreviations: EF

= ejection fract ion; LV = left ventricle; SR = sinus rhythm; VE = ventricular ectopy ; d = days ; m = months .

82

Drugs 43 (I) 1992

'"• ... ~ o-r--o: / "~'"

Fig.3. Time required to achieve control of ventricular tachycardia in all patients achieving effective arrhythmia control with oral amiodarone. Group A - 200 rug/day for I week, increased in 200mg steps up to a maximum of 800 rug/day; group B - 1400mg on day I, 800 mg/day for 6 days, and dosage then adjusted up or down by 200mg depending on response; group C - 1400 rug/day for I week and reduced to 200 mg/day if control was obtained . If control was then lost, the cycle was repeated with reduction to 400 mg/day (after Rakita & Sobol 1983).

Heart Failure Lethal ventricular arrhythmias represent a significant problem in patients with heart failure. In 2 small cohort studies oral amiodarone (at relatively low doses of 200 to 600 mg/day) significantly reduced the incidence of ventricular arrh ythmias without adversely affecting haemodynamic parameters in patients with heart failure (Cleland et al. 1987a; Hamer et al. 1989) [see also section 1.3 and table III]. Interestingly, Bayes de Luna et aJ. (1990) used amiodarone as first choice therapy in postAMI patients with potentially malignant ventricular arrhythmias (usually related to frequency and complexity of premature ventricular contractions) and low ejection fraction, in the absence of specific contraindications. More recently, the concomitant use of {1-blockers and amiodarone has significantly reduced mortality rates in patients with left ventricular dysfunct ion (ejection fraction < 0.30) following an attack of sustained monomorphic ventricular tachycardia, when compared to patients receiving class I antiarrhythmic drugs (Leclercq et al. 1991).

nificantly reduced the frequency and complexity of ventricular arrhythmias (premature ventricular contractions, multifocal, early cycle, or repetitive, bigeminy, trigeminy and ventricular tachycardia) in patients with AMI in comparison with placebo. Similarly, when compared with a glucose/insulin/ potassium (GIK) infusion, intravenous amiodarone produced a significantly greater reduction in the incidence of sustained ventricular arrhythmias (Greco et aJ. 1989). The effects of amiodarone (maintenance dose of 400 to 600 rug/day) were also foundto be superior to those of propranolol (60 to 100 mg/day) in reducing the severity of ventricular extrasystoles (~ 10 premature ventricular contractions/hour; multiform, paired or runs of premature ventricular contractions) [Fournier et aJ. 1989], although the strict exclusion criteria may have excluded a number of patients with extensive infarcts who were particularly susceptible to major ventricular arrhythmias.

Patients Without Major Structural Heart Disease A randomised study in patients with ventricular tachycardia or ventricular fibrillation unassociated with acute myocardial infarction who were refractory to or intolerant of class I antiarrhythmic drugs compared the effects of amiodarone (400 rug/day maintenance) and sotalol (160 to 640 rug/day). After 1.week a significantly higher proportion of patients in the amiodarone group than the sotalol group recorded no ventricular ectopic activity. This difference, however, was not sustained during longer term treatment, and no overall differences were seen between the 2 drugs in terms of antiarrhythmic efficacy (Amiodarone vs Sotalol Study Group 1989). Similarly , other longer term studies have not identified any statistically significant advantages of amiodarone over other antiarrhythmics, but have furth er demonstrated its effectiveness. In a controlled trial comparing amiodarone with flecainide , encainide, propafenoneand moricizine, Salerno et aJ. (1 990b) reported suppression of ventricular ec-

eE 0 0

100 90 80

({ ,,, I

(ij

t 70 as .9: 60

:;

0. "0

E!

eE 0 0

50

,

I

I' .I , I

t ,

40

I

30 20

/

t' 6•

III

E Q)

"

"

I

t'I ,

,.

• Group A (n = 14) o Group B (n = 12) • Group C (n= 9)

II

II

'0 10 /. I/. ~ 0

O..L-----r--,-----,--~

7

14

21

28

Duration of treatment (days)

Amiodarone: An Overview

topic activity and nonsustained ventricular tachycardia in 92 and 99%, respectively, of patients receiving amiodarone. Interestingly, most patients in the amiodarone group had lethal arrhythmias with histories of sustained ventricular tachycardia or fi-. brillation, and a higher percentage of patients in this group had ischaemic heart disease. In patients who had undergone coronary artery bypass surgery, intravenous amiodarone (300 mg/ day) produced rapid control of nonsustained ventricular tachycardia from 12 hours postsurgery when compared with placebo (Hohnloser et al. 1991). 3.1.3 Predictors of Clinical Efficacy Inducibility of ventricular arrhythmias during programmed electrical 'stimulation (PES) does not appear to preclude clinical efficacy on long term amiodarone therapy (Nademanee et al. 1~83a; Rasmussen et al. 1982). Indeed , the ability of electrophysiological testing to predict clinical outcome in patients with ventricular tachycardia and fibrillation remains controversial (Brugada 1987; Kreamer et al. 1989; Rosenheck et al. 199I). In a number of studies using a loading dose phase followed by daily maintenance administration of amiodarone, patients in whom sustained ventricular tachycardia or fibrillation were noninducible appeared to have a lower incidence of recurrent arrhythmias or sudden death (Strasberg et al. 1990; Zhu et al. 1987). On the other hand, persistent fast tachyarrhythmias and a low ejection fraction seemed to be related to a poorer prognosis (Manolis et al. 1989; Schmitt et al. 1987). These findings are as might be expected, but in some other studies continued inducibility of ventricular tachycardia (sustained or nonsustained) during long term administration of amiodarone has been associated with a good clinical response (Nademanee et al. 1982a; Waxman 1983; Waxman et al. 1982), and, therefore, this electrophysiological characteristic may not significantly affect the clinical outcome of amiodarone therapy (Kadish et al. 1987; Proclemer et al. 1990). Overall, however, PES does appear to have a positive predictive value for arrhythmia recurrence (Levy 1991 ; Strasberg et al. 1990), while changes in ventricular tachycardia rate and mode

83

of induction are also helpful in predicting long term outcome. When used in combination with other techniques (map-guided surgery, coronary revascularisation surgery) amiodarone administration can improve survival in post-myocardial infarction patients with sustained malignant ventricular tachyarrhythmias (Gomes et al. 1991). 3.1.4 Effect on Mortality and Survival Sudden death due to arrhythmias is a significant problem in organic heart disease and patients with a history of myocardial infarction are particularly at risk (Singh 1990). A number of studies have reported the effect of amiodarone on mortality and survival in patients with ventricular tachycardia or ventricular fibrillation in the absence and presence of heart failure or previous cardiac arrest (table V). The incidence of sudden death appears to range between 5 to 15%, depending on the length of follow-up. This appears lower than the estimated 20 to 30% per year expected in patients with compromised left ventricular function and sustained ventricular tachycardia (Katritsis & Camm 1991) - although such indirect comparisons must be viewed with caution. In a small open study by Strasberg et al. (1990), a low maintenance dose (200 mg/day) of amiodarone was administered, either alone or with a class I agent, to patients who had converted to sinus rhythm following episodes of ventriculartachycardia or ventricular fibrillation and .with proven healed myocardial infarction. At 24 and 48 months the actuarial probabilities of freedom from any arrhythmia (ventricular tachycardia or fibrillation) were 80 and 62%, respectively, and from sudden death were 90 and 85%, respectively. .Notably, however, patients with ventricular fibrillation had a much poorer prognosis. The results of this study, although derived from a limited number of patients, are in general agreement with those of Herre et al. (1989), but are slightly less favourable than those of Myers et ai. (1990). Herre et ai. (1989) treated 462 patients with either documented spontaneous sustained ventricular tachycardia or cardiac arrest unresponsive to other antiarrhythmic drugs (2.6 per patient) for up

84

Drugs 43 (l) 1992

Table IV. Results of some comparat ive studies of the therapeutic efficacy of intravenous or oral amiodarone (A) in patients with various cardiac conditions Reference

Study design

No. of patients

db, x

22

Character istics Arrhythmia

Dosea

Duration Response of therapy criteria (months)

:leart failure

600 mg/d ;

3

(NYHA class

200 mg/d

Results b

Placebo Cleland et al. (1987a)

A: 979 -17S-

PVC

(median no.)

II-III)

PI: 979 VT

A: 6 -

900

0-

. episodes PI: 6-9 Hamer et al.

r, db

34

(1989)

Heart failure

600 mg/d ;

(NYHA class

200 mg/d

6

tEF~20%

A: 71% of patients PI: 2S% of

II-III)

patients Patients with PVCs

~

1%

A: 7S%- 29% PI: 64%- 33%

baseline VT

(~3

complexes at ~

A: 88%- 21% PI: 43% -

SO%

120 beats/

min) Hockings

r, sb

200

AMI

VA

600 mg/d ;

6-9

200 mg/d

et al. (1987)

Patients with: > 1 PVC/h

A: 5%-

Complex arrhythmias

A: 8% PI: 28%

Incidence of

A: 3%-

NSVT

PI: 16%

Death or

No overall

PI: 34%

77

Hohnloser

300mgC ;

CABG

et al. (1991) Other antlarrhythmlcs Amiodarone SotPr-atall

10 PVCs/h;

d;

Major minor VA;

multiform ,

Pr: 60-100 mg/d

remaining in

~

paired or runs

minor

of PVCs

category

Minor VA:

visits

Amiodarone. An overview of its pharmacological properties, and review of its therapeutic use in cardiac arrhythmias.

Amiodarone, originally developed over 20 years ago, is a potent antiarrhythmic drug with the actions of all antiarrhythmic drug classes. It has been s...
7MB Sizes 0 Downloads 0 Views