Pharmacology D.
Michael
Classified
MD, FCP, and
Freedman,
is a unique
Amiadarone
antiarrhythmic
electrophysiologically
antisympathetic orally
and Pharmacokinetics of Amiodarone
and
as direct,
administered
fast
amiodarone
agent a Type
John
originally
negative
developed
111 antiarrhythmic,
channel-membrane (a
C. Somberg,
inotropic vasodilatian,
as
it also effects. agent)
MD,
has
a
both
vasadilator.
nonspecific
Hemadynamic are
usually
FCP
effects negligible,
of
and
are usually compensated for by induced Effects an thyroid and hepatic function may help to explain same of the unique pharmacologic as well as toxicologic effects of the drug. Amiodarone is poorly bioavailable (20-80%) and undergoes extensive enterohepatic circulation before entry into a central compartment. The principal metabalite, mono-n-desethyl amiadarone is also an antiarrhythmic. From this central compartment, it undergoes extensive tissue distribution (exceptionally high tissue/plasma partition coefficients). The distribution half-life of amiadarone out of the central compartment to peripheral and deep tissue compartments (tl/2,,) may be as short as 4 hours. The terminal half-life (t#{189}0) is both long and variable (9-77 days) secondary to the slow mobilization of the lipophilic medication out of (primarily) adipocytes. A phormocokinetically based loading scheme is described, and data suggesting a role for routine amiadarane plasma levels ore presented.
A
miodarone HC1 (2-butyl-3-benzofuranyl 4-[2(diethylyamino)-ethoxy]-3-5-diiodophenyl ketone HCL, molecular weight = 681.8) was developed by R. Charlier at Labaz Laboratories in Belgium.1. It is a di-iodinated benzofuran derivative, containing a diethylated tertiary amine chain. Originally recognized to be an antianginal agent (1967),2 within 2 years its antiarrhythmic abilities had become appreciated.3 Early investigations were primarily confined to Europe and South America, where the use of amiodarone as an antianginal and antiarrhythmic gained widespread acceptance.4’5’6 The pharmacokinetics of amiodarone and its metabolites are unlike those observed with any of the currently available antiarrhythmics (of any class). This is reflected by early clinical reports using amiodarone in which the number of dosing regimens appear to be only surpassed by the number of investigators. Although amiodarone has been existent since the early 1960s, an understanding of its biological/ metabolic fates and kinetics has emerged only within the last decade. This knowledge can be put to sound clinical use to improve our understanding of
appropriate loading (acute care) and maintenance therapy. Amiodarone is available in both oral and parenteral preparations. However, only the oral preparation (200 mg/tablet) has been approved by the Food and Drug Administration for use in the U.S. (Cordarone, Wyeth Laboratories, Philadelphia, PA). Insoluble in aqueous solutions, it is miscible in polysorbate-80 (Tween 80) and either ethanol or benzyl alcohol. An intravenous form (40 mg/mL), while available in Europe (Cordarone-X, Sanofi, Pharma S.A., Paris), remains in clinical trials in the U.S. This article focuses on the orally available form. The physical characteristics of pharmacology are outlined in Table I. This section serves as an outline to amiodarone pharmacology and assists in the conceptualization of amiodarone pharmacokinetics, rather than a definitive treatise on that subject. PHARMACOLOGY Electrophysiologic
From
the
New
York
Medical
College
(Dr. Freedman), Valhalla, New Division (Dr. Somberg), Chicago
York, and the Clinical Pharmacology Medical School, Chicago, Illinois.
Address
berg, MD. 3333
N. Chicago,
J COn Pharmacol
Green
Bay Road,
1991;31:1061-1069
for
reprints: IL 60064.
John
C. Som-
At a fundamental onstrated an demonstrated
Effects
(basic) level, amiodarone has antifibrillatory effect. This has in canine ventricular fibrillation7
dembeen and 1061
FREEDMAN
feline atrial fibrillation.8 Amiodarone is further characterized as possessing Vaughn-Williams “Class III” properties.91#{176} Depressing impulse initiation in the isolated rabbit sinus node,11 amiodarone appears to both prolong repolarization and refractoriness in all cardiac tissue.12 Sinus cycle length, (monophasic action potential and surface QT interval). AV nodal conduction time, His-Purkinje, and ventricular repolarization times are generally increased with increased refractoriness.13’14 Additionally, amiodarone appears to depress conduction velocity greater at higher rates of depolarization (repolarization time 30% greater after 6 weeks of therapy),15 suggesting that it (directly or indirectly) blocks inactivated cardiac sodium channels.16’17 Pathologic conduction is also slowed. In patients with Wolff-Parkinson-White syndrome, the anterograde effective refractory period (ERP) of the accessory pathway is lengthened.18 Amiodarone exerts antisympathetic effects to both alphaand beta-adrenergic responses after sympathetic stimulation or catecholamine injection.19 Additionally, amiodarone dissolved in ethanol noncompetitively antagonizes the chronotropic response of rabbit atria to isoproterenol and inhibits norepinephrine-induced contractions of myocardial strips in rats and rabbits. Table II summarizes the electrophysiologic actions of amiodarone. Hemodynamic
Actions
Hemodynamically, the weakly negative inotropic activity of amiodarone is usually more than offset by concurrently acting vasodilator effects.2#{176}Generally there is little change in either ejection fraction21 or systemic blood pressure after oral administration. It has been reported, however, that in patients with
AND
SOMBERG
TABLE Electrophysiologic
Amiodarone Physical
Heart
Activity
characteristics =
Pharmacology
Metabolic
oral absorption fate:
minimal,
principally
Extremely lipophilic Nonspecific antiadrenergic effects Direct membrane effects Class III antiarrhythmic Sodium/calcium channel-blocking
1062
S
J CIin Pharmacol
rate
RR PR
QRS QT
Observation Slowed Prolonged Prolonged Unchanged/prolonged
PA
Lengthened Prolonged
AH Atrial ERP* HV conductiont
Prolonged Prolonged Prolonged
AV nodal ERP AV nodal FRPI: Ventricular ERP
Prolonged Prolonged Prolonged
AVNW U waves
Prolonged Often present,
#{149} ERP = effective refractory period. f His.ventricular. t FRP = functional refractory period. § Atrial pacing cycle length producing Wenkebach. From: Zipes DP, et al, Singh BN, Vaughan Williams Zipes DP et 81,22 and Harris L.
merging
into
I
EM,1#{176} Rosen MR, eta!,12
severely decompensated left ventricular function, critically dependent on augmented sympathetic tone, that the nonspecific beta-blocking effect of amiodarone may be deleterious.15’22 (NB: The aforementioned summary of amiodarone’s hemodynamic actions are in contrast to those observed when the intravenous material is administered. In both experimental animals and humans administered IV amiodarone, significant decreases in systemic blood pressure and total vascular resistance are accompanied by negligible increase in cardiac output that may last 15 minutes or longer after injection.) Pharmacologic
Actions
I
Molecular weight 681.8 Structure: dilodinated benzofuran derivative Highly protein bound, (albumin, /3-lipoprotein) Incomplete
Effects
Parameter
Other TABLE
II
metabolized
actions
1991;31:1061-1069
by the liver
A potent inhibitor of thyroxine 5’deiodinase, amiodarone inhibits the peripheral formation of 3,5,3’,5’tetraiodothyronine (T4) to 3,5, 3’-triiodothyronine (T3) causing a doseand duration-dependent increase in serum reverse T3.23’24’25 This action suggested to Singh that this might be a primary mechanism of action1#{176}since changes produced by amiodarone were similar to those seen after thyroid ablation.26 Serum reverse T3 levels were initially used as an alternative to measuring plasma levels of amiodarone directly (since it was believed to be linearly drug dependent and correlate with therapeutic response as well as with the rate of adverse reaction formation). This test has been largely precluded by
PHARMACOLOGY
AND
newer (widely available and accurate) HPLC assays directly measuring plasma drug levels. In addition to inhibition of T4-T3 converting enzyme, amiodarone use has also been associated with multiple aberrations of thyroid function (hypoand hyperthyroidism). Although it is believed to be directly dependent on the pharmacology of amiodarone, both hyperand hypothyroidism could result directly from the supratherapeutic iodine load associated with amiodarone therapy (approximately 75 mg organic iodine/tablet). Amiodarone use has also been associated with elevation in serum transaminasis and appears to induce a phospholipidosis and consequent fibrosis within the liver.27 A similar, systemically occurring phospholipidosis (characterized by foamy macrophages and lamellated inclusion bodies) has been observed in other tissues (mesenteric lymph nodes and lungs) after prolonged administration of the drug to experimental animals.28 The alveolitis observed (also characterized by foamy macrophages) as an adverse reaction with amiodarone may be consequent to this pharmacologic action(s). PHARMACOKINETICS Bioavailability, and Metabolism
AND Tissue
METABOLISM
Distribution,
Amiodarone has been shown to have variable (2080%) oral bioavailability.29’3#{176} After absorption, the drug undergoes extensive enterohepatic circulation before distribution into the central compartment and subsequently to tissue compartments. Examination of hepatic and portal vein samples after oral administration of amiodarone indicates a large first-pass (de-ethylation) effect resulting in mono-N-desethyl amiodarone. Peak amiodarone serum levels after oral dosing are achieved within 3-7 hours. Amiodarone is highly protein bound (96_99%),3132 predominately to albumin, but also to 3-lipoprotein.33 (Figure 1) Hepatic metabolism has been demonstrated to be partially the result of a P-450 cytochrome oxidasedependent oxidative de-ethylation. Both phenobarbita134 and 3-methyl cholanthrene35 have been established as inducing agents for this reaction(s). MonoN-desethyl amiodarone, the primary de-ethylated metabolite formed, has also been recognized to have antiarrhythmic abilities.36 A second dealkylation may then occur (N-dealkylation), resulting in the primary amine. Other metabolic pathways shown to exist include deiodinations (monoand di-), 0-dealkylation, and hydroxylation.37 Finally a glucuronidation reaction has been found to be present, proba-
LV DYSFUNCTION
AND ARRHYTHMIAS
OF AMIODARONE
PHARMACOKINETICS
bly accounting for the major mechanism of amiodarone clearance. Renal clearance is negligible, and the dose of the drug is not reduced in patients with renal failure or those undergoing dialysis.38 An outline of the aforementioned metabolic pathways is found in Figure 2. Comprehension of amiodarone pharmacokinetics further requires a cognizance of its tissue distribution. Tissue distribution also explains the particular and characteristic toxicity of the drug. Fortunately, by using refined HPLC techniques, both plasma and tissue drug levels can be evaluated.39’40 Tissue distribution of amiodarone and its active metabolites have been studied in both animals and humans. Highest amiodarone and mono-N-desethyl amiodarone levels have been found in adipose tissue, lung, liver, and lymph nodes (deep compartments). Lowest levels have been found in brain, thyroid, and muscles (peripheral compartments).4142’43 The tremendous lipid solubility of amiodarone is expressed by an estimated log P0 = 6.66, for octanol/ water partition of the neutral (non ionized) form. Amiodarone myocardial concentrations, determined in patients who are undergoing coronary artery bypass grafting, were found to be higher in the cardiac tissue than in the plasma,45 with a partition coefficient (PC) of 35. The partition coefficient for the metabolite mono-N-desethyl amiodarone has been demonstrated to be 91 (2.6 x greater than for the parent molecule), and thus is even more lipophilic than its precursor. Initial
Drug
Distribution
Because of the differing solubilities of the drug within many tissues (characterized by the differing partition coefficients), amiodarone pharmacokinetics are usually described using multi-compartmental models (Figure 1). In the simplest of these models, the tissue compartments are distinguished as being central, deep, or peripheral depending on the solubility of amiodarone within that space. With a limited volume of distribution (Vd) and restricted solubility, serum levels in the central or plasma compartment increase rapidly after absorption. Drug levels in the other more poorly perfused tissue compartments (both deep and peripheral) with large Vds associated with relatively large drug solubility would be expected to rise at a much slower rate. Similarly, total tissue load would decrease at a slower rate in the tissue (peripheral and deep) compartments as described by the rate constants (K4.K7.K6 Figure 4) and prolonged t#{189}8. Early information on pharmacokinetic parameters was obtained using radiolabeled material bY Broek-
1063
FREEDMAN
SOMBERG
AND
BIO*ILABILITY
30-80%
ABSORPTION
HEPATIC K1
METABOLISM
CENTRAL
BILIARY
COMMRTMENT
KhiIIIIiJ ‘(4
PERIPHERAL
K6\
COMRTMENT
/
> MED.
GOLUSILITY
COUP..
REL
LARGE
Vd)
EXCRETION
/
DEEP NIGH
COMRTMENT SOLUSILITY
c9IF.
bIa
K8
Figure
1. Amiodarane
S
.1 Clin
Vd
AdIpo.#{149}
#{149} Ilvsr
pharmacakinetics.
huysen in 1969.46 After administration of radiolabeled amiodarone to humans the kinetics of (1251 and 14C)-amiodarone were evaluated (whole body radioscintigraphy). Although the first elimination (distribution) phase was found to be variable from one subject to another, the importance of this phase progressively decreased with the term of therapy.47 After single-dose administration of 200-mg amiodarone, Anastasciou-Nana evaluated several pharmacokinetic parameters using drug levels obtained by HPLC and found an apparent t#{189}of 18.7 ± 4.0 hours. Riva, administering 400 mg (single dose study), noted a t#{189} of 35.9 ± 38.0 hours.48’49 Haffajee et al. also measured serum amiodarone levels after administration of a single 800-mg dose of amiodarone in eight patients and found wide interpatient variability with a mean t#{189}=4.62 hours.5#{176}The apparent half-lives observed in these acute models represent the distribution (a phase, t#{189}a) into tissue compartments, in which amiodarone is sequestered. (Table ifi) Since poorly perfused compartments, in particular the deep compartments, represent areas with much greater affinity for amiodarone (denoted by their partition coefficients), they represent enormous “sinks” or reservoirs for amiodarone storage.
1064
LARGE
Pharmacol
1991;31:1061-1069
Elimination
(Terminal)
Kinetics
The existence of deep compartments, their respectively enormous distribution volumes (Vds), and slow individual clearance(s) has been demonstrated in several studies. Holt3#{176}and other investigators51’52 have shown that the (terminal) elimination pharmacokinetics of amiodarone appear to be first order, with a linear relationship between the amount of drug administered and the steady-state plasma level (Table IV). When 400 mg orally per day (typically a therapeutic dose) is delivered, the steady-state plasma concentration of amiodarone was shown to be 1.93 ± 0.80 mg/L and the serum concentration of mono-N-desethyl amiodarone was 1.79 ± 0.65 mg/L (Holt et al.). Studying plasma concentrations from six healthy volunteers after intravenous injection of 400 mg amiodarone, Holt found plasma concentrations were best fitted to a multicompartmental (multi-exponential function) model with a distribution t#{189}a of 4 minutes (consistent with earlier data from Haffajee et al.)41 and elimination (terminal, 3 phase) t#{189}$ of 24.8 ± 11.7 days53 (single dose, IV administration). The total body clearance was 8.6 ± 1.9 mL/min and the total body Vd of amiodarone at steady state was 4936
PHARMACOLOGY
L
AND
OF AMIODARONE
PHARMACOKINETICS
C2HS
/ -O-CH2CH2H C2HB
IIjC4HS
H
O-DEALKYLATION
/-O-CH2CH2N C2HE
DE ODINATI
/ \ C 2H6
C4H9
N-DEALKYLATION
AMIODARONE HYDROXYLATION C2HE
PH
-0 -C H2CH2N
OH
I/
C4H9
\ C2HS
IIXIJC4HS H2 C H 2 N\ C 2H6
-0-C
\
I
C2H6
,
A /
-O-CH2CH2NHE
5;o
/ O-CH2CH2N
\ OH
Figure
2. Major
metabolic
pathways-amiodarone.
± 3290L. This investigator also carried out an analysis of plasma concentrations from eight patients who withdrew from chronic oral amiodarone therapy. Under these conditions, amiodarone t#{189}fl=52.6± 23.7 days and mono-N-desethylamiodarone t#{189}$= 61.2 ± 31.1 days. Differences between the results of the volunteers and the patients were suggested to be secondary to an underestimation of projected steady-state plasma levels in the computerized simulation (volunteers), as well as to a time-dependent pharmacokinetic factor(s). Other investigators have similarly documented lengthy terminal half lives (t#{189}fl)after cessation of maintenance therapy (Table III). Differences in both the rate of acquisition of amiodarone into body stores (range: t#{189}fl = 9-77 days) and subsequently the required loading dose(s) address the tremendous interindividual variability present in the treated population.
ASSESSMENT AMIODARONE
OF THE RESPONSE ADMINISTRATION
Optimization of amiodarone a rapid assessment of the
LV DYSFUNCTION
C4HS
C 1H5
ri
administration response of the
AND ARRHYTHMIAS
TO
requires myocardial
conduction tissues to appropriate therapy. Appropriate therapy is generally reflected by establishing that certain plasma levels (therapeutic window of activity) have been attained. Originally it was hypothesized that the steady-state serum levels of amiodarone did not require monitoring since a known therapeutic range could not be established for this drug,54 as measured by plasma levels.
TABLE Terminal
Half- Life (t112)
III
After
Oral Administration Terminal
Number Studied
Amiodarone
et al.
8
53 ± 24
Marchiset, et al. Haffajee, et al. Kannon, et al. Harris, et al.
12 3
47 ± 13 19 ± 9 39 ± 17 @52
Holt,
From: a!.
,85
Holt OW et and Harris et al.
4
70 Marchiset
D et 81,83
Haffajee
Half-life
(d)
Monodesetylamiodarone
61 ± 8 54 ± 23
@60 et al.,#{176}Kannen
et
1065
FREEDMAN
TABLE Plasma
Levels
Dose Administered
IV
at Varying
Chronic
Mono-Desethyl. Amiodarone (mg/I)
Amiodarone (mg/I)
n
Dosages
200 mg/day Holt
et al.’#{176}1
400
1.45 1.1
± 0.43 ± 0.50 ± 0.30
1.04 1.38
1.93 3.05 2.2
± 0.80 ± 1.36 ± 0.9
1.79 2.33
3.46 3.78 3.9
± 1.50 ± 1.61 ± 1.6
2.79 2.92
1.06
Heger et al.55 Bopanna et al.
± 0.34 ± 0.74 -
mg/day
Holt et al.5’ Heger et al.55 Bopanna et al. 600 mg/day Holt et al.’8 Heger et al.55 Bopanna et al. From:
Halt et al.,42 Heger
et a!.
52
and Bopanna
± 0.65 ± 1.22 -
± 1.17 ± 1.40 -
et al.8’
As experience has been gained, a vast amount of contradictory evidence, supporting as well as mitigating the role of tissue and plasma levels of amiodarone, has been published. One of the primary difficulties has been the standardization of methodologies employed to determine drug level and outcome events (both efficacy as well as toxicity events). Essentially the three criteria of efficacy that have evolved are acute surface electrocardiographic response, response to programmed electrical stimulation, and response during intermittent subchronic surface electrocardiography (Holter monitoring). The first evidence of efficacy were obtained utilizing acute surface electrocardiographic confirmation of arrhythmia suppression. Early studies and reviews by Horowitz55 and Haffajee5#{176} suggested that the antiarrhythmic effect of amiodarone does not correlate to any degree with plasma level. Others have shown that amiodarone plasma levels (1.0-1.5 mg/ L)56’57’58’59 have been associated with a decrease in the amount of ventricular ectopy, and that doses in excess of 2.5 mg/L do not appear to provide any additional antiarrhythmic benefit. Efficacy of amiodarone has also been determined by prevention of ventricular arrythmia induction during programmed electrical stimulation. The predicative value of inducibility (as an indicator of efficacy) has been noted to range from poor60’61’62’63 to reasonable (predictive in 50-75% of patients).TM’65 Difficulties in deriving efficacy data using programmed electrical stimulation are probably secondary to varied stimulation protocols as well as times of testing. Many authors have confirmed that patients
1066
#{149} J COn Pharmacol
1991;31:1061-1069
SOMBERG
AND
treated with amiodarone frequently remain inducible and that furthermore, inducibility does not (necessarily) predict a bad outcome.TM67SSTM6970 The Collaborative Group for Amiodarone Evaluation71 analyzed the plasma amiodarone levels in patients who were considered to be responders (based on Holter monitor results) and found no differences between responders and nonresponders. Kim et al.72 found that the predictive value of Holter monitoring was low in several studies, and that suppression did not guarantee a good outcome. Nevertheless, even in these groups, patients who appeared to be responders (in terms of ventricular arrythmia) generally had plasma levels in the range of 1.0 to 3.5 mg/L, whereas plasma levels of 2.5 mg/L are associated with increased neurologic and gastrointestinal adverse reactions.5#{176} Additionally, a mass of literature supports the hypothesis that the risk of pulmonary toxicity, ocular changes, and cutaneous changes increases in a dose-duration-dependent (non-acute, and probably not serum-level related) manner, becoming particularly obvious at higher daily doses over increased lengths of time (>500mg/d).50’76 Therefore, plasma levels of amiodarone appear to be most useful during the acute stage of administration for determination of which patients are receiving either too little drug (2.5 mg/L) without attendant increase in efficacy. In this way, a therapeutic window has been defined based on maximization of acute risk/benefit ratio. This definition has allowed for a more rational approach to initiation and maintenance of therapy, based on drug levels, and hopefully an individualization of therapy. INITIATION MAINTENANCE
OF
THERAPY DOSING
AND
Loading doses used when chronic therapy is contemplated, have largely been developed empirically. Given the lengthy t1,,2, both the amounts used and the time required for appropriate loading become easier to understand. Early in its history, oral doses as
large
as several
for up to I week to maintenance
grams
before doses
per
day
were
administered
the patient was switched of 400 or 200 mg/day.77
over One
PHARMACOLOGY
AND
(more) rational oral dosing schedule (based on pharmacokinetic modeling) for the treatment of ventricular arrhythmias has been proposed by Siddoway et al.78 In this schedule, 2,000 mg is administered on day 1. This is followed by 3 days of 1400 mg/day and then 7 days of 1,000 mg/day. 800 mg/day is given for another 1 to 2 weeks before the dose is reduced to 400 mg/day. Using this program, a total loading dose of 6,200 mg is delivered. In the case of treatment of supraventricular arrhythmias, some authors have suggested the aforementioned regimen be reduced 25 to 50% (1,000 mg/day x 1 day, followed by 700800 mg X 3 days then 7 days of 600 mg/day followed by maintenance of 200-400 mg/day) because of the increased sensitivity of supraventricular arrhythmias to amiodarone.79 Alternatively, a loading dose schedule developed by Ward et al.8#{176} allows a total loading dose as low as 1,200 mg administered as 600 mg/d X 7 days followed by 400 mg/day X 7 days was also found to be effective. Using either regimen antiarrhythmic effect is extremely variable. After loading, it is only necessary to administer the chronic therapy of 200 to 400 mg per day to achieve therapeutic efficacy. Many authors believe that 400 mg is in fact the maximum “prudent” dose that should be used for prolonged periods.81 Terminal half-lives after cessation of prolonged oral therapy are found in Table III. CONCLUSIONS The riddle of ariiodarone pharmacokinetics is slowly being elucidated. They are in fact enigmatic of a pharmacokinetically unique drug. One with multiple metabolic fates, each of which probably has multiple modes of action. A firm understanding of pharmacokinetics becomes essential since the usefulness of amiodarone is limited by its time-effect and adverse reaction profiles (both of which are probably related). Future questions include the determination of the role of following tissue as well as plasma levels of amiodarone, the role of following plasma levels to possibly deter adverse reactions and utilization of the unique kinetic profile of amiodarone to allow for alternatives in dosing that would lead to greater patient compliance without loss of efficacy. REFERENCES 1. Charlier R, Deltour serie des benzofurannes du butyl-2 (diiodo-3’, benzofuranne. Arch 2. Vastesaeger velle Medication 3.
LV
Van
M,
G, Tondeur R, Binion R: Reserches dans VII. Etude pharmacologique preliminaire 5-b-N-diethylamino-ethoxy-4’ benzaly)-3 Intl Pharmacodyn 1962:139:255.
Gillot P. Rasson G: Etude Antiangoreuse. Acta Cardiol
Schepdael
DYSF’JNCTION
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Solvay
AND
H: Etude
ARRHYTHMIAS
Clinique
Clinique (Brux) De
OF
PHARMACOKINETICS
d’une Nou1967:22:483. L’Amiodarone
la
Dans
Les
AMIODARONE
Troubles
du
Rhythme
Cardiaque.
Presse
Med
1970:78:1849. 4. Ward DE, Camm AJ, Spurrell fects of amiodarone in patients cardia. Br Heart 1 1980:44:91. 5. Rosenbaum amiodarone 1976:38:934.
MB, as
6. Rosenbaum RS, Lazrri antiarrhythmic
an
RA: Clinical with resistant
Chiale PA, Halpern antiarrhythmic
MB. Chiale
PA, Halper MVS: Clinical Am J Cardial
JO, Ekiazari agent.
antiarrhythmic paroxysmal
MS: agent.
Clinical Am
eftachyefficacy
of
Cordial
J
J, Levi
N. Nau GJ. Prybylski efficacy of amiodarone 1976:38:934.
as an
7. Patterson E, Eller BT, Abrams GD, Vasiliades J, Lucches BR: Ventricular fibrillation in a conscious canine preparation of sudden coronary death - Prevention by short and long-term amiodarone administration, Circulation 1983:68:857-864. 8. Winslow E: Hemodynamic and arrhythmogenic effects of aconitine applied to left atria of anesthetized cats: Effects of amiodarone and atropine. J Cardiovasc Phormacol 1981:3:87-100. 9. Zipes DP, Troup P1: New antiarrhythmic agents: Amiodarone, aprindine, disopyramide. ethmozin, mexiletine, tocainide, verapamil. Am I Curdial 1978:57:845-853. 10. Singh BN, new antianginal I 970;39:675-687.
Vaughan drug,
11. Goupil node activity
N,
12. Rosen drugs. Am
MR. Heart
Williams on the
EM: cardiac
The
Lenfant J: The effects of the rabbit heart. Eur Wit
AL:
effect muscle.
of amiodarone, Br I Pharmacal
of amiodarone I Pharmacol
Electropharmacology
a
on the sinus 1976:39:23-31. of antiarrhythmic
J 1983;106:829-839.
13. Singh BN, Jewitt DE, Downey JM, et al: Effects of amiodarone and L 8040, novel antianginal and antiarrhythmic drugs, on cardiac and coronary hemodynamics and cardiac intracellular potentials. Clin Exp Pharmacol Physiol 1976:3:427-442. 14. Singh BN, Vaughan Williams mic action. Effects on atrial and tials, and other pharmacological 1999 and AH 3474. Br 1 Pharmacol 15. Singh BN: cologic profile. 16. Mason inactivated 81.
17. vated
Amiodarone: Am Heart
Historical 11983:106:788-797.
JW. Hondeghem cardiac sodium
Eksp Biol Med
development
LM, Katzung BC: channels. Pjlugers
SV,
Revenko sodium
EM: A third class ofanti-arrhythventricular intracellular potenactions on cardiac muscle of MJ 1970:39:675-687.
Khodorov channels by 1980:89:702-704.
and
pharma-
Amiodarone blocks Arch 1983:396:79-
BI, Avrutskii MA: the antiarrhythmic
Blocking of inacticordarone, Bull
18.
McKenna WJ, Rowland E, Holt DW, Krikler DM: Electrophysiological assessment of amiodarone in atrial fibrillation complicating Wolff-Parkinson-White Syndrome. Br Heart J1981;45:617. 19. Charlier of amiodarone, Arzneimittelforsch
20. Schwartz A, Shen Chatterjee K: Hemadynamic patients with depressed ventricular tachycardia. 21. Pfisterer one depresses Circulation
apy.
with
J,
MI, Burkart F, Muller-Brand cardiac function acutely 1983:68:1122.
Nademanee K, Singh JAMA 1982:247:217-222.
a new
C: Pharmacology biological profile,
E, Morady F, Gillespie K, Scheinman effects of intravenous amiodarone left ventricular function and recurrent Am Heart 11983:106:849-855.
22. Zipes DP, Prystowsky EN, ologic actions, pharmacokinetics Cordial 1984:3:1059-1071.
23.
1’ Deltour
R. Delaunois C. Bauthier and antianginal drug 1968;18:1408-1417.
BN:
Heger
but
Kiowski W: Amiodardoes not chronically.
JJ: Amiodarone: and
clinical
Advances
in
A, in
effects.
ElectrophysiI Am
antiarrhythmic
Call ther-
1067
FREEDMAN
24.
Sogeol
PB,
Hershman
of amiodarone 5’-monodeiodination
25.
JM,
on serum
Balsam
A, Sexton paired in vitro generation ine in the livers 1979;105:1115-1121.
26. Freedberg altered thyroid
AS.
AW,
Dillman
WH:
The
death
GY,
Vaughan
Williams
intracellular
EM:
The
effect
45.
46.
E, Larratt L, phos-
47.
J Physiol
1970:207:357.
27. Poucell S, Ireton Patterson J, Blendis pholipidosis
and
28. Mazue
J, Valencia-Mayoral P, Downar L, Phillips MJ: Amiodarone-associated
fibrosis
of the
C, Vic P, Gouy
Barchewitz.
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