See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/315913025

Therapeutic monitoring of amiodarone: Pharmacokinetics and evaluation of

the relationship between effect and dose/concentration

Article  in  Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia · March 2017
DOI: 10.5507/bp.2017.016

CITATIONS READS

6 484

4 authors, including:

Milan Grundmann Jana Duricová

University of Ostrava University Hospital Ostrava
151 PUBLICATIONS   673 CITATIONS    24 PUBLICATIONS   117 CITATIONS   

SEE PROFILE SEE PROFILE

Ivana Kacirova
University of Ostrava
81 PUBLICATIONS   285 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Finnish berries and honeys and their polyphenols as therapeutic agents View project

All content following this page was uploaded by Milan Grundmann on 06 December 2017.

The user has requested enhancement of the downloaded file.

 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

Therapeutic monitoring of amiodarone: pharmacokinetics and evaluation

of the relationship between effect and dose/concentration
Erika Hrudikova Vyskocilovaa,b, Milan Grundmanna, Jana Duricovaa,b, Ivana Kacirovaa,b

Amiodarone is the most effective agent in the therapy of arrhythmias. However, the clinical effect of acute and chronic
treatment is unclear and there are differences irrespective of comparable plasma/myocardial amiodarone and its me-
tabolite desethylamiodarone concentations as well. Its unusual pharmacokinetics results in interindividual variation
in plasma levels. The association between amiodarone and desethylamiodarone plasma levels and clinical efficacy is
difficult to evaluate. This review was carried out to assess whether there is any objective correlation between amioda-
rone and desethylamiodarone plasma levels and the clinical effect. We summarized the results of relevant studies and
clarified the relationship between plasma levels and effect vis á vis the pharmacokinetics and pharmacogenetics of
this drug. Certain correlation was seen with oral amiodarone therapy, in others, plasma amiodarone levels were unre-
lated to therapeutic response and showed no correlation with changes in electrocardiogram or electrophysiological
parametres. Several studies show that plasma concentration ranging between 0.5 and 2.5 mg/L appears to be the most
effective, others demonstrate no difference between responders and non-responders. One way of interpreting plasma
levels is to establish an individual patient´s effective concentration. Therapeutic drug monitoring can contribute to
determining optimal concentration.

Key words: amiodarone, pharmacokinetics, effects, therapeutic drug monitoring

Received: July 27, 2016; Accepted with revision: March 22, 2017; Available online: March 31, 2017
https://doi.org/10.5507/bp.2017.016
a
Department of Clinical Pharmacology, Faculty of Medicine, University of Ostrava, Czech Republic
b
Institute of Clinical Pharmacology, Department of Laboratory Diagnostics, University Hospital Ostrava, Czech Republic
Corresponding author: Milan Grundmann, e-mail: [email protected]

INTRODUCTION Amiodarone is highly bound to human plasma pro-

teins. Its free fraction is independent of the total drug con-
Amiodarone is the most effective antiarrhythmic medi- centration and albumin level, indicating that the binding
cations available today for the treatment of both atrial is not concentration dependent over the normal therapeu-
and ventricular arrhythmias. Its efficacy is likely related tic range6. There is some evidence that DEA is less lipid
to diverse effects on a number of cardiac receptors and soluble than the parent compound and is somewhat less
ionic currents1. protein-bound7. Amiodarone is high lipid-soluble. This
could lead to a large volume of distribution (Vd) (ref.8).
Pharmacokinetics Duration of administration is a crucial factor in determin-
Amiodarone has a large individual variation in system- ing the volume of deep compartments. With studies of
ic bioavailability after oral administration2 because gastro- shorter administration less drug has time to enter the pe-
intestinal absorption appears to be slow and incomplete3. ripheral compartments, therefore the deep compartments
The relatively poor bioavailability is probably mediated by appear smaller. It is quite possible that a true steady state
intestinal wall metabolism via CYP3A4 in addition to gas- in terms of volume of distribution and elimination is never
trointestinal excretion mediated by P-glycoprotein. DEA reached but rather amiodarone continues to accumulate
inhibits the activities of both CYP3A4 and P-glycoprotein, with long-term therapy9.
thus it is suggested that the bioavailability of amiodarone The highest concentrations of amiodarone were found
is gradually increased over time in patients receiving long- in fat, liver, bone marrow, and lung tissue. It was shown
term amiodarone therapy4. The time from oral intake to that DEA was present in these tissues at several-fold
the peak serum concentration (Cmax) was estimated to be higher concentrations than the parent compound, except
about 7.3 h (ref.3). AUC0–∞ after the first oral dose was for fat tissue10. This tendency of DEA to accumulate in
more than three times lower than the AUC0-24h after the tissues more than amiodarone is in agreement with the
9th, 37th, and 11th dose in three patients (AUC normalized higher red blood cell/plasma ratio of this compound11.
for the dose) (ref.2). With regard to myocardium, it was shown that the range
In the case of intravenous administration the Cmax of amiodarone concentration was wide after rapid intra-
of amiodarone after a 15-min intravenous infusion of venous administration. This variability may explain the
5 mg/kg ranged between 8.604 and 19.441 mg/L, even time of myocardial sampling after amiodarone injection,
with 100% bioavailability5. as well as differences in the patients´ body weights, in

134
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

the variable regional coronary blood flow from patient form involved in amiodarone metabolism. The activity
to patient at the time of sampling, in the extent of myo- of CYP1A1 might vary depending on smoking status as
cardial fibrosis, and in the variations in myocardial con- smoking has been shown to induce CYP1A1 metabolic
centration dependent on the specific site and depth of activity. In this condition, the DEA formation by human
biopsy12. There was also demonstrated placental transfer CYP1A1 might however be a consideration19. CYP2C8
of amiodarone and DEA in humans13. It is surprising that activity might be influenced by genetic polymorphism.
even at steady state, plasma amiodarone concentrations Soyama et al. showed that the variant CYP2C8 P404A but
can be expected to fall by 25% within a few days of the not CYP2C8*3 has a lower intrinsic clearance for amioda-
cessation of therapy and 50% in 36 days. Thus a 2- to rone N-deethylation compared with CYP2C8*1. These au-
3-day interruption of dosing could produce a clinically thors suggested that polymorphic alleles of CYP2C8 may
useful decrease in concentration, potentially providing lead to variations in the clinical response to amiodarone20.
relief to patients with acute onset of bradycardia, tremor, A higher frequency of variant CYP2C8 alleles is expected
ataxia, or gastrointestinal distress9. Although miniscule in Caucasian Americans with a Southern European an-
amounts of amiodarone can be detected in serum for up cestry than in individuals with Northern European an-
to 9 months, these minimal concentrations are unlikely cestry21. The contribution of other metabolite enzymes,
to confer antiarrhythmic protection10. CYP1A2, CYP2C19, or CYP2D6, to amiodarone metabo-
After administration of a single dose of amiodarone, a lism seems to be minor, these isoforms might alternatively
wide interpatient variable half-life (t1/2) is found2. After in- contribute to metabolism in clinical situations in which
travenous administration the drug concentration declined CYP3A4 or CYP2C8 is inhibited by coadministered
during the second phase with a mean half-life of 4.3 h drugs18. Less than 1% of the dose is excreted unchanged
(ref.14). The initial rapid elimination phase was observed in the urine22 therefore minimal fluctuations of serum
within 3-5 min, and the serum concentration declined to levels between dialysis are observed23. The ratio of DEA
less than 2.0 mg/L within 30-45 min after completion of to amiodarone remained relatively constant over different
the infusion. This initial decrease in serum concentration dosage or drug concentration ranges, but increased with
might be due to uptake into peripheral tissues high in fat. duration of treatment (reaching approximately 80% than
In contrast, the elevation of DEA concentrations lagged of amiodarone after several months), suggesting a time-
behind the change in amiodarone concentrations, which dependent metabolic function11. Individual variation of
were also below clinically effective levels. This discrep- the clearance decreases in subjects receiving long-term
ancy presumably reflects slow biotransformation of the amiodarone therapy4. Age-related changes in amiodarone
parent drug5. The slow elimination may be understood and DEA disposition have been shown, but their clinical
conceptually by means of a multicompartment model. relevance appears negligible24. The pharmacokinetics pro-
The long life of the terminal elimination phase of the file of amiodarone is summarized in Table 1.
plasma curve reflects the slow release of amiodarone from
the reservoir, or deep compartment, into the plasma15.
Cytochrome P450 3A4 (CYP) is the major isoform in- MECHANISM OF ACTION
volved in amiodarone metabolism. Amiodarone undergoes
deethylation to the major metabolite DEA and it is fur- The cellular actions of amiodarone differ somewhat in
ther metabolized by CYP3A4 to subsequent metabolites16. acute compared to chronic administration25.
DEA (probably together with amiodarone) is degraded to
other compounds by hydroxylation17. Furthermore, CYP Acute therapy
2C8 and CYP1A1 may also significantly contribute to Acute amiodarone therapy results in a use-dependent
amiodarone metabolism18. inhibition of inward sodium (Vaughan-Williams class I
CYP3A4 which constitutes 30% of the total CYP effect) and inward calcium currents (Vaughan-Williams
content in human liver is expected to be the major iso- class IV efffect) (ref.26), as well as a non-competitive al-

Table 1. Amiodarone pharmacokinetic profile(9,10,15,24).

pharmacokinetic parameter
binding to plasma proteins < 99%
Vd 50-100 L/kg
Metabolism CYP3A4, 1A1, 2B6
enzyme inhibition CYP3A4, 1A1, 1A2, 2B6, 2C9, 2D6
clearance (amiodarone) after single dose i.v. administraton 90-158 mL/h/kg
clearance (desethylamiodarone) after single dose i.v. administraton 197-290 mL/h/kg
Excretion bile, renal elimination is minimal
t1/2 (amiodarone) after single dose 11-20 h
t1/2 (amiodarone) after long-term therapy mean 50 days
t1/2 (desethylamiodarone) after long-term therapy mean 60 days

Vd - volume of distribution, t1/2 - elimination half-life

135
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

Table 2. Intravenous administration of amiodarone (DEA levels were not measured.

n Dosage Amiodarone Type Effect Ref.

(mg/L) of arrhythmia
5 5-10 mg/kg Sustained VT Terminated within 20 min in all patients 10
9 5 mg/kg 3.1±1.8 AV nodal reentrant tachycardia AVRNT terminated in 7 patients, reinducible 49
(AVRNT) tachycardia in 3 patients
9 10-20 mg/kg/day 1.7±1.0 Refractory sustained ventricular Terminated in 5 patients 50
for 4-7 days tachycardia
8 125 mg/day Incessant VT Terminated in 0.94 h 42
14 500 mg/day Terminated in 1.92 h
15 1000 mg/day Terminated in 0.85 h
13 125 mg/day Incessant VT Terminated in 4.58 h 51
12 1000 mg/day Terminated in 4.23 h
78 525 mg/day VT Successful response during 6-24 h in 41% 52
80 1050 mg/day Successful response during 6-24 h in 45%
79 2100 mg/day Successful response during 6-24 h in 53%

n – number of patient

Table 3. Oral administration of amiodarone.

n Dosage Amiodarone (mg/L) DEA Type Effect Ref.

(mg/l) of arrhythmia
18 single dose 30 mg/kg 5.2; 8.6 Permanent AF Sinus rhythm restored in 5 54
(in 2 patients) patients within 5±1.5 h
17 single dose 30 mg/kg 71% reached median <0.2 Chronic atrial tachycardia No patients converted 55
concentration 2.4 pharmacodynamically to
(range 0.96-4.7) sinus rhythm within 24 h
129 600 mg/day •2.0±0.8 •1.4±0.7 Refractory atrial • 23 patients converted to 56
fibrillation/ flutter sinus rhythm during a
4-week period
•1.4±0.7 •1.0±0.5 • 106 patients not converted
to sinus rhythm during a
4-week period
23 • initial doses Sustained, recurrent, • No recurrences during a 57
600-2000 mg/day, symptomatic VT follow-up of 21.5 months in
average maintenance 15 patients
dose 713 mg/day
• initial doses • Isolated recurrences during
600-2000 mg/day, a follow-up of 32.2 months
average maintenance in 5 patients
dose 375 mg/day
8/10 1600-4400 mg/day 2.08-2.80 0.60-0.75 Refractory, sustained, The mean 3.6 days to the first 58
hemodynamically com- 24 h ECG showing no VT
promising ventricular
arrhythmias / potentially
life-threatening ventricular
arrhythmias
48 • responders: mean • responders Refractory symptomatic Successfully controlled in 61
349±122 mg/day; 1.5±0.6; atrial tachyarrhythmias 41 patients during a mean
• nonresponders • nonresponders follow-up of 10.1 months
460±135 mg/day 1.7±0.7
50 • responders: mean • responders Sustained VT 38 patients resonded during
3371±145 mg/day; 1.8±0.7; a mean follow-up of 10.9
• nonresponders • nonresponders months
500±175 mg/day 1.9±0.7

136
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

Table 3. Continued

n Dosage Amiodarone (mg/L) DEA Type Effect Ref.

(mg/L) of arrhythmia
64 200-600 mg/day 0.8-8.0 in responders Supraventricular/ Controlled in 87.5% of 10
ventricular patients during the mean 5.5
tachyarrhythmias months
127 loading doses • patients withount • patients Resistant ventricular Supressed in 78% of patients 60
600-1600 mg/day for 10 reccurences: withount arrhythmis (VA) (81% of patients with VA /
to 18 days; maintenance 2.8±1.4 (VA) / reccurences: / supraventricular 70% of patients with SA)
dose 200-600 mg either 1.7±1.2 (SA) 1.6±0.6 (VA) arrhythmias (SA)
6-7 days per week /1.0±0.4 (SA)
• patients with • patients with
reccurences: reccurences:
1.9±1.0 (VA) / 1.2±0.6 (VA) /
1.3±1.2 (SA) 0.7±0.5 (SA)
25 • >2.0 Complex VA • Significant reduction of 62
PVCs and pairer PVCs
and VT
• >1.5 • Significant reduction in VT
12 600 mg/day 0.86±0.48 0.23±0.15 VPDs At least 75% suppression of 63
VPDs in 13.2 days (range
1-36 days)
24 loading: 900 mg/day 1.3 Refractory VT Reduced spontaneous 64
(800-1200 mg) (range 0.44-4.10) arrhythmia in 5 patients after
maintenance: 560 mg/ 31 days (range 21-88)
day (400-800 mg) of therapy
40 • 825±357 mg/day • 1.37±0.63 • 0.83±0.16 Sustained VT/ VF • In 9 patients arrhythmia 65
could not be induced
• 776±301 mg/day • 1.40±1.28 • 0.84±0.29 • In 31 patients arrhythmia
could be induced

n – number of patient

pha- and beta – blockade effect (Vaughan-Williams class Chronic therapy

II effect) (ref.27). Acute amiodarone also caused a concen- The major effect of chronic amiodarone therapy is
tration-dependent decrease in delayed rectifier potassium inhibition of outward potassium currents (Vaughan-
current28 and inhibition of ligand-gated potassium chan- Williams class III efffect) resulting in a prolongation
nel29. Amiodarone significantly shortened action potential of APD, not only in atrial and ventricular muscles but
duration (APD) in Purkinje fibers, while prolonging it in also in the SA and AV nodes. This APD prolongation
ventricular muscle cells30. Acute effects result clinically is associated with a comparable prolongation of ERP
in a depressed automaticity of the sinoatrial (SA) node (ref.36). APD prolongation is most likely explained by
resulting in a decrease in sinus rate31 and increased re- a decrease of current density for delayed rectifier potas-
fractoriness of the atrioventricular (AV) node resulting sium current and 4AP-sensitive transient outward cur-
in depression of AV node function32. Amiodarone slows rent. This may be due to a modulation of gene expression
AV nodal conduction by blocking the calcium current33. of ion channels26. Oral amiodarone has been shown to
However, the effects of the drug on AV node conduc- have significant effects on the QT interval in addition to
tion are often masked by the effects of the reduction on slowing the sinus rate34. Desethylamiodarone (DEA), the
the heart rate34. The QT interval has been shown to be major amiodarone metabolite, has stronger class I prop-
relatively unaffected and a prolongation of effective re- erties and weaker class IV actions than the parent com-
fractory period (ERP) in ventriclular muscle is minimal pound7. DEA produced concentration-related increases in
or negligible26. In patients with impaired ventricular func- QRS, QT, and QTc intervals with a potency significantly
tion though, intravenous amiodarone increased the right greater than that of amiodarone37. Therefore accumula-
ventricular ERP and showed rate-dependent prolongation tion of DEA probably accounts for some of the delayed
of the QRS interval5. In addition to electrophysiologic electrophysiologic effects in patients receiving long-term
properties, intravenous amiodarone also has effects on treatment with amiodarone38. The antiarrhythmic effect
hemodynamics. Despite negative inotropic effects on the of DEA was shown to be in part dependent on gene ex-
left ventricle, the decrease in systemic vascular resistance pression rather than a direct effect on cell membrane
and myocardial oxygen demand results in a slightly in- channels or receptors39.
creased cardiac output35.

137
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

ADVERSE EFFECTS RELATIONSHIP BETWEEN AMIODARONE

DOSE/CONCENTRATION AND CARDIAC
Amiodarone has been reported to cause a variety of EFFECTS
cardiac and extracardiac side effects, both in its oral and
intravenous formulation36. It alters thyroid metabolism Differences between early and later antiarrhythmic
(clinically hypo- or hyperthyroidism), both as a result effects remain, despite the achievement of comparable
of inhibition of deiodination of thyroxinE and as a re- plasma amiodarone concentration47. The discrepancy be-
sult of iodine release from the amiodarone molecule. tween short- and long-term effects of amiodarone cannot
Amiodarone may produce excessive bradycardia, which be explained solely on the basis of amiodarone myocardial
is more likely in patients with sinus node dysfunction. It concentration because coronary arterial concentrations
is generally considered to have a smaller proarrhythmic of amiodarone and myocardial concentrations after the
potential than other antiarrhythmic drugs7. Nevertheless, second hour of intracoronary infusion were in the same
female sex is associated with an increased risk of tors- range as those observed after long-term amiodarone treat-
ades de pointes in the setting of potassium antagonists40. ment, however only conduction velocity was affected48.
The risk of severe hypotension after intravenous amio-
darone can be largely avoided by using a slower rate of Intravenous administration
infusion, especially in patients with hypovolemic status41. It is well established that the onset of amiodarone
Hypotension may arise due in part, to polysorbate 80, an antiarrhythmic action after oral administration may
excipient with vasodilator properties42. The development be delayed for several days. In contrast, an immediate
of corneal microdeposits and their rate of progression is therapeutic effect has been obtained after intravenous
dose-dependent, but discontinuation of amiodarone be- administration in a study by Rotmensch et al.10. However
cause of microdeposits is usually not necessary and in tachycardia re-occurred in 3 patients of 7 patients com-
cases where amiodarone is withdrawn the ocular changes pared with long-term oral therapy. The authors concluded
regress completely in 3-4 months. At normal doses, the that oral therapy prevented recurrence and reinducibility
probability that amiodarone is the cause of liver toxicity by its predominant effect in prolonging refractoriness
is actually quite low43. Dermatological side effects (for ex- of the atrium and ventricle, and depressing conduction
ample photosensitivity) are common44 and several forms through the retrograde fast pathway49. Saksena et al. also
of pulmonary disease occur among patients treated with observed no effect on cycle length of spontaneous ven-
amiodarone with a prevalence about 5% (ref.45). tricular tachycardia after intravenous administration50.
Nanas et al. examined the time course of development
of electrophysiological effects during intracoronary infu-
DRUG-DRUG INTERACTION sion of amiodarone in dogs48. A significant correlation
was found between the extent of reduction of conduction
Amiodarone influences the activity of many CYP velocity and myocardial amiodarone concentration but
enzymes and can lead to multiple drug interactions. It not coronary arterial or systemic concentration. In this
inhibits CYP1A2, CYP2C9, CYP2D6, CYP3A4 and also study, amiodarone levels in the myocardium increased
P-glycoprotein resulting mainly in increased concentra- from a mean of 5.95 ug/g at 15 min of infusion to 188.88
tions of other drugs metabolized via these pathways. E.g., ug/g at the 10th hour. However the effect observed was
amiodarone administration results in 70% higher digoxin initially very small and became pronounced only after
plasma concentrations after one day of concomitant ad- several hours. In addition, no significant change in repo-
ministration. Co-medication with amiodarone also results larization interval was observed at any time48. No change
in increased warfarin concentrations, which lead to el- in the repolarization interval was observed after 10 h of
evated prothrombin time and international normalized amiodarone infusion in humans. At 2.5±1.2 min after
ratio35. The time course of onset of this interaction is amiodarone administration, the mean myocardial con-
highly variable, ranging from 1 to 28 days, in most cases centration was 95.7±67.4 ug/g. In this study no significant
the delay was longer than 6 days. Moreover the inhibi- electrocardiographic changes were measured. Species
tion of warfarin metabolism may last 2 to 16 weeks after and methodological differences may account for these
discontinuing amiodarone administration22. A significant discrepant electrophysiologic effects (small sample size
interaction between amiodarone and metoprolol via DEA- with wide range of amiodarone myocardial concentrations
induced inhibition of CYP2D6 has been reported16. On in study in humans and absence of evaluation of early
average, metoprolol plasma concentration was doubled antiarrhythmic effect) (ref.12). Scheinman et al. found a
after an amiodarone loading dose (1.2 g/day over a pe- beneficial dose-response relationship using i.v. amioda-
riod of 6 days). The interaction was more pronounced rone in patients with life-threatening arrhythmias. Patients
in patients with ≥2 compared with 1 functional CYP2D6 treated with 500 to 1000 mg/day doses of i.v. amiodarone
allele, indicating a clear “gene-dose“ relation46. showed significantly lower event rates and longer time to
arrhythmia recurrence than patients in the 125 mg/day
dose group. They found a significant dose-related increase
in the time to first event and a significant dose-related de-
crease in the number of supplemental boluses per hour42.
Similar results were suggested in the study by Kowey et

138
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

al. which was designed to compare the safety and efficacy darone. In contrast, reduction of the ventricular rate dur-
of a high and a low dose of intravenous amiodarone with ing ongoing atrial fibrillation was clearly correlated with
bretylium. The primary analysis of the arrhythmia event plasma levels of amiodarone itself56.
rate during the first 48 h of therapy, showed comparable The long delay between initiation of therapy and the
efficacy between the bretylium group and the high - dose onset of action remains a serious problem because with
(1000 mg/day) amiodarone group that was greater than conventional loading regimens, mean delays of 9.5 days
that of the low - dose (125 mg/day) amiodarone group. have been reported57. Mostow et al. tested the hypothesis
Similar results were obtained in the secondary analyses of that rapid loading with amiodarone to a target plasma
time to first event and the proportion of patients requir- concentration can overcome much of the long delay be-
ing supplemental infusion51. In another study by Levine tween the initiation of therapy and the onset of effective
et al. no clear dose-response relation was found in the suppression of arrhythmia58. Dosage was adjusted on the
treatment of recurrent sustained hypotensive ventricular basis of amiodarone serum concentrations to maintain
tachyarrhythmias, with respect to success rates, time to the trough serum concentrations between 2.0–3.0 mg/L.
first recurrence of tachyarrhytmia or mortality over 24 h. A significant reduction in premature ventricular com-
However, there was reported a significant dose-response plexes (PVCs) and paired PVCs was observed beginning
relation between the 500-mg dose group and the combined on the first day of therapy and a reduction in ventricular
1000- and 2000-mg dose groups in the time to first event tachycardia beginning on the second day. In spite of the
when the first 12 h were considered. This discrepancy large doses of amiodarone used, hemodynamic monitor-
could be explained by the small sample size of the study ing revealed no significant change in cardiac output, pul-
or the relative insensitivity of these end points52. Kinetic monary capillary pressure or blood pressure.
analysis of plasma levels of i.v. amiodarone (5 mg/kg in 5 Greenberg et al. compared electrophysiological pa-
min) in four patients during the electrophysiological study rameters after 9 days of acute amiodarone loading dose
(before and 1 and 2 h after injection) did not support a (1200-1400 mg/day) and after an additional month of
direct association between plasma concentration and its maintenance therapy (400 mg/day) in patients with sus-
effect53. We were unable to gain more informations about tained ventricular tachycardia59. Both short- and long-term
the study protocol. amiodarone therapy caused significant changes in QTc,
right ventricular effective refractory period and ventricular
Oral administration tachycardia cycle length. However, there was no significant
Escoubet et al. showed the onset of the antiarrhythmic change in electrophysiological parameters between the end
effect of a single oral dose of a 30-mg/kg of amiodarone of the acute amiodarone loading period and 1 month of
within 4 to 5 h on premature complexes, within 3 h on additional therapy. Amiodarone and desethylamiodarone
atrioventricular node and after 2 to 8 h on VT in about plasma concentrations remained stable after amiodarone
60% of patients54. In 28% of those with permanent fibril- loading dose (1.19±0.13 and 0.72±0.06 mg/L after loading
lation, amiodarone restored the sinus rhythm within 5±1.5 dose; 1.08±0.22 and 0.84±0.05 mg/L after an additional
h. A significant relationship between amiodarone plasma month of maintenance therapy), but this did not correlate
concentrations and the onset of the antiarrhythmic ef- with the magnitude of electrophysiological changes.
fect was observed, the threshold amiodarone plasma Rotmensch et al. found that in patients who had treat-
concentration averaged 1.5 to 2.0 mg/L and the associ- ment-resistant ventricular or supraventricular arrhythmias
ated myocardial concentration ranged from 10 to 20 mg/ or were intolerant to other drugs, arrhythmias recurred in
kg. In the analysis, patients with refractory arrhythmias 47% of patients with serum amiodarone concentrations
were excluded. On the other hand, Nielsen and Moller of less than 1.0 mg/L whereas in only 14% of patients
using same dose of amiodarone were not able to convert with higher concentrations recurrences were observed60.
to sinus rhythm though 71% patients reached the rec- Although in long-term amiodarone therapy of refractory
ommended plasma concentration of amiodarone (2.0- symptomatic atrial and symptomatic life threatening-ven-
2.5 mg/L)(ref.55). However, the concentration of DEA tricular tachyarrhythmias, the mean serum amiodarone
remained low. The discrepancy between these two studies concentration did not differ between responders and non-
may be caused by the type and duration of arrhythmias. responders, some of responders relapsed when their se-
While in the first study, there were patients with constant rum concentration fell below 1.0 mg/L (ref.61). Similarly,
fibrillation which had been established for longer than 5 in another study by Rotmensch et al. serum amiodarone
days, in the second, patients with chronic atrial fibrilla- concentrations in patients whose supraventricular and
tion or flutter with a median duration of 10 months (range ventricular tachyarrhythmias were controlled were not
3-45 months). predictive of clinical efficacy10. In a retrospective study
The importance of DEA plasma concentrations for by Mostow at al., reduction in the frequencies of PVCs
conversion to sinus rhythm was demonstrated by Tielman and paired PVCs, as well as ventricular tachycardia was
et al. Conversion was related to increased desethylamio- linked with trough plasma amiodarone concentrations
darone plasma levels and concomitant treatment with greater than 2.0 mg/L, resp. 1.5 mg/L. Even negative cor-
verapamil. Patients with an amiodarone level < 1.2 mg/L relations between serum amiodarone concentration and
or a desethylamiodarone level < 0.9 mg/L were unlikely the frequencies of PVCs, paired PVCs and ventricular
to convert. This may be related to a high myocardium/ tachycardia were found. No correlations existed between
plasma concentration ratio in the case of desethylamio- amiodarone dose and these arrhythmias62. From these

139
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

studies it can be concluded, that keeping plasma concen- Oral versus intravenous amiodarone administration
tration at least above 1.0 mg/L seems to be optimal for Intravenous amiodarone can be successful in sup-
prevention of recurrences. pressing life-threatening ventricular arrhythmias even
In contrast, Conolly et al. observed that 67% of pa- when chronic oral amiodarone has failed, as concluded
tients with frequent ventricular premature depolariza- by Kavesh et al. In this case report, the patient experi-
tions (VPDs) responded at amiodarone concentrations enced “electrical storm“ despite long-term oral use of
below 1.0 mg/L (ref.63). This concentration is consider- amiodarone (400 mg/day) with an amiodarone plasma
ably lower than that reported previously. The main dif- level of 2.546 mg/L (DEA level of 1.361 mg/L). However,
ference between this study and Mostow et al.62 is that in his arrhythmia was successfully treated by i.v. amioda-
the former, the lowest concentration associated with an rone (150 mg/10 min, then 1 mg/min for 6 h, followed
antiarrhythmic response was systematically determined by 0.5 mg/min). After 6 weeks of continuous i.v. amio-
by repeated Holter monitoring during drug loading dose. darone therapy, during which time sustained ventricular
In previous studies, serum concentrations were analyzed arrhythmias did not occur, cardiac transplantation was
retrospectively in patients receiving amiodarone without performed. The amiodarone level was 1.796 mg/L and
any systematic attempt being made to determine the low- DEA level was 1.684 mg/L two days prior to transplan-
est concentration associated with an effect. A relationship tation. This appears to be due to different mechanism
between amiodarone and DEA plasma concentrations of action of the two formulations. Earlier experiments
and suppression of VPDs was observed in all patients, in rats suggest that intravenous amiodarone has a much
which suggests that concentrations of amiodarone and its more potent sympatholytic effect at the myocardial level
metabolite are an important factor in determining the an- than the oral formulation. There are also differences in
tiarrhythmic effect of amiodarone. There was a trend for the hemodynamic responses-i.v. amiodarone results in
DEA to be more strongly related than amiodarone. For vasodilatation, increased coronary artery blood flow, left
each patient there was a progressive decrease in frequency ventricular filling pressures and cardiac output, while oral
of VPDs as both amiodarone and desethylamiodarone amiodarone can decrease cardiac index despite vasodila-
concentrations increased. The patients in this study were tation68.
not being treated for sustained ventricular tachycardia or
fibrillation. Therefore the results of this study should not
be extrapolated to patients with sustained ventricular ar- THERAPEUTIC DRUG MONITORING (TDM)
rhythmias63.
In the publication by Saksena at al., serum amioda- In 1969, the antiarrhythmic effect of amiodarone was
rone levels were unrelated to therapeutic response and observed in experimental animal models. However, the re-
a multiple linear regression analysis did not show any lationship between dose, plasma concentration and effect
correlation of serum levels with the changes in ECG or is still unclear26,69. The use of amiodarone is complicated
electrophysiologic parameters. In this study, serum DEA by its very unusual pharmacokinetics69. The plasma lev-
concentrations were not assessed. Although the arrhyth- els resulting from orally administered amiodarone varied
mia recurrence rate on amiodarone was still substantial considerably between individuals14 and considerable inter-
(21%), these arrhythmias were much better tolerated64. individual variation is found with regard to the minimum
Similarly Greenberg et al. found no correlation between effective concentration of amiodarone. This indicates
either amiodarone plasma level or drug dose and any that measurment of amiodarone or DEA concentrations
electrophysiological effect measured after one month of alone cannot replace assessment of the clinical response
treatment with oral amiodarone65. The opposite results to treatment of individual patients63. While efficacy has
were reported by Debbas et al. who found good correla- been observed for amiodarone plasma concentrations as
tion between plasma and myocardial concentrations, and low as 0.1 and as high as 11.9 mg/L (ref.22), there are some
both correlated well with the percentage increase in the studies showing that plasma levels of 1.0 – 1.5 mg/L are
QTc interval66. However, the sample was small and the associated with a decrease in the amount of ventricular
mean amiodarone concentration very low65. ectopy, and that levels > 2.5 mg/L do not provide any ad-
With reference only to amiodarone dosage Ward et al. ditional antiarrhythmic benefit36. Other authors suggested
observed that only six of 23 patients with total supression that lower amiodarone plasma concentration (above 0.5
required the maintenance dose of amiodarone more than mg/L) seems to be sufficient for efficacy, but there are
200 mg daily whereas Rosenbaum et al. reported a mainte- no convincing data showing a correlation between actual
nance dose greater than 300 mg/daily in 9 of 11 patients67. plasma concentration and antiarrhythmic effect. Similarly,
This discrepancy could be due to differences in patients. serious toxicity seems to be more likely at concentrations
The controversial results of individual studies may re- above 2.5 mg/L but its incidence correlates more with cu-
sult from various criteria for efficacy (e.g. elimination of mulative dose, suggesting the importance of amiodarone
spontaneous ventricular ectopic activity vs. supression accumulation in target tissues over time69.
of sustained arrhythmias), patient selection, severity of Plasma concentrations, although potentially useful for
underlying heart disease, duration of follow-up and moni- monitoring long-term therapy, are likely to be unhelpful or
toring before study, the timing of the efficacy assessment misleading during the 4- to 6-week loading period at the
and drug dosage schedules. Each type of arrhythmia may beginning of treatment because rising plasma concentra-
also require different dosage, resp. serum concentrations. tions before steady state are not in equilibrium with tissue

140
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

concentrations9,15. During maintenance therapy, plasma CONCLUSION

amiodarone concentrations are probably in equilibrium
with the higher amounts of amiodarone found in body Association between amiodarone and desethylamio-
tissues. This may explain why the plasma concentrations darone plasma level and their clinical efficacy is difficult
during long-term therapy fluctuate little compared with to evaluate. The effects of acute and chronic as well intra-
single-dose kinetics. Thus, plasma levels during chronic venous and oral amiodarone differ, independently of the
therapy may reflect tissue levels and therapeutic effect achievement of comparable plasma/myocardial amioda-
more accurately than they would during acute administra- rone concentration. Although several studies show that
tion61. Robinson et al. indicated that neither the plasma plasma concentration range between 0.5 and 2.5 mg/L
concentrations of amiodarone nor its metabolite show appears to be the most effective, others demonstrate no
any significant change with time once steady state has difference between responders and non-responders in
been achieved, suggesting that amiodarone neither inhib- terms of to plasma levels. Nevertheless keeping plasma
its nor enhances its own metabolism70. No relationship concentration at least above 0.5 mg/L, resp. 1.0 mg/L
between height and weight, and plasma concentrations seems to be optimal. Another way of interpreting plasma
of the drug were found either and even dose was a poor amiodarone levels is to establish individual concentration
predictor of the steady state amiodarone concentration. at which optimal therapeutic response is achieved.
However in chronic oral therapy compliance should be
taken into account. In contrast, Mailing et al. defined Search strategy and selection criteria
individual variability of amiodarone distribution during Our research strategy was aimed at evaluating stud-
long-term stable amiodarone therapy in plasma and eryth- ies on any objective correlation between amiodarone and
rocytes. The data underlined the highly variable cellular desethylamiodarone plasma level and their clinical effect.
distribution of amiodarone and DEA in the same patient We summarized the results of studies using PubMed da-
on stable dosage over time. The authors concluded that tabase (English-language reports from 1967 to November
no a clinically useful relationship between plasma con- 2015) and clarified the relationship between plasma lev-
centration and effect could be consistently demonstrated els and effect with respect to the pharmacokinetics and
for amiodarone in the same individual during stable dos- pharmacogenetics of amiodarone. The search terms used
age71. However, we were unable to find any information included “amiodarone”, “plasma levels and effect”, ”phar-
about the study protocol. The absorption of amiodarone macokinetics“, “pharmacogenetics” and “therapeutic drug
following nasogastric administration is poor compared monitoring”.
with oral administration. To achieve similar concentra-
tions, an approximately 3-fold increase in dosage of amio-
darone was required when patients were given the drug ABBREVIATIONS
nasogastrically rather than orally. In this case, therapeutic
drug monitoring is necessary to optimize dose particularly ICD, implantable cardioverter-defibrillator; VT, ven-
during the early stages of amiodarone therapy72. Candinas tricular tachycardia; VF, ventricular fibrillation; APD,
et al. found a good correlation between myocardial con- action potential duration; SA, sinoatrial; AV, atrioven-
centration of amiodarone and desethylamiodarone and tricular; ERP, effective refractory period; DEA, des-
the cumulative ingested dose of amiodarone. Tissue drug ethylamiodarone; MRP, multidrug resistance-associated
concentrations correlated only poorly with plasma amio- proteins; BCRP, breast cancer resistance protein; ABC,
darone and DEA levels. Their data confirm the slow equi- ATP-binding cassette; t1/2, half-life; CYP, cytochrom
librium of amiodarone and DEA concentrations between P450; PVCs, premature ventricular complexes; ECG, elec-
plasma and myocardium. Therefore, monitoring of the trocardiogram; VPDs, ventricular premature depolariza-
total cumulative dose may be more relevant clinically than tions; VA, ventricular arrhythmis; SA, supraventricular
monitoring plasma levels73. arrhythmias; TDM, therapeutic drug monitoring
With respect to adverse effects, corneal deposits seem
to correlate with dosage and duration of treatment74. Acknowledgment: This project was supported by grant of
Hypotension usually occurs during the highest rate of University of Ostrava SGS15/LF/2016-2017.
intravenous drug delivery with no significant dose-relat- Author contributions: EHV: manuscript writing, literature
ed increase42. The majority of patients, who developed search; MG: final approval; JD: literature search; IK: con-
pulmonary toxicity, were being given maintenance doses ception and manuscript writing.
greater than 400 mg/day75. Elevation of hepatic enzyme Conflict of interest statement: The authors state that there
activities was related to higher mean daily dose and plas- are no conflicts of interest regarding the publication of
ma concentrations of amiodarone in study by Greenberg this article.
et al. whereas skin discoloration was related to accumu-
lated dose65.
Another way of interpreting plasma amiodarone and REFERENCES
DEA levels is attempting to determine an “individual ther-
apeutic concentration”76. This means the concentration 1. Kumar K, Zimetbaum PJ. Antiarrhythmic drugs 2013: state of the art.
Curr Cardiol Rep 2013;15(10):410. doi:10.1007/s11886-013-0410-2
at which a “pharmacological” arrhythmias is achieved. 2. Riva E, Gerna M, Latini R, Giani P, Volpi A, Maggioni A.

141
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

Pharmacokinetics of amiodarone in man. J Cardiovasc Pharmacol 26. Kodama I, Kamiya K, Toyama J. Cellular electropharmacology of
1982;4(2):264-9. amiodarone. Cardiovasc Res 1997;35(1):13-29.
3. Andreasen F, Agerbaek H, Bjerregaard P, Gøtzsche H. 27. Charlier R. Cardiac actions in the dog of a new antagonist of adren-
Pharmacokinetics of amiodarone after intravenous and oral ad- ergic excitation which does not produce competitive blockade of
ministration. Eur J Clin Pharmacol 1981;19(4):293-9. adrenoceptors. Br J Pharmacol 1970;39(4):668-74.
4. Kashima A, Funahashi M, Fukumoto K et al. Pharmacokinetic char- 28. Kodama I, Kamiya K, Honjo H, Toyama J. Acute and chronic ef-
acteristics of amiodarone in long-term oral therapy in Japanese fects of amiodarone on mammalian ventricular cells. Jpn Heart J
population. Biol Pharm Bull 2005;28(10):1934-8. 1996;37(5):719-30.
5. Shiga T, Tanaka T, Irie S, Hagiwara N, Kasanuki H. Pharmacokinetics 29. Mori K, Saito T, Masuda Y, Nakaya H. Effects of class III antiarrhythmic
of intravenous amiodarone and its electrocardiographic effects drugs on the Na(+)-activated K+ channels in guinea-pig ventricular
on healthy Japanese subjects. Heart Vessels 2011;26(3):274-81. cells. Br J Pharmacol 1996;119(1):133-41.
doi:10.1007/s00380-010-0047-7 30. Yabek SM, Kato R, Singh BN. Acute effects of amiodarone on the
6. Veronese ME, McLean S, Hendrik R. Plasma protein binding of amio- electrophysiologic properties of isolated neonatal and adult cardiac
darone in a patient population: measurement by erythrocyte par- fibers. J Am Coll Cardiol 1985;5(5):1109-15.
titioning and a novel glass-binding method. Br J Clin Pharmacol 31. Goupil N and Lenfant J. The effects of amiodarone on the sinus node
1988;26(6):721-31. activity of the rabbit heart. Eur J Pharmacol 1976;39(1):23-31.
7. Nattel S, Talajic M, Fermini B, Roy D. Amiodarone: Pharmacology, 32. Pickoff AS, Singh S, Flinn CJ, Torres E, Ezrin AM, Gelband H. Dose-
Clinical Actions, and Relationships Between Them. J Cardiovasc dependent electrophysiologic effects of amiodarone in the imma-
Electrophysiol 1992;3(3):266-80. ture canine heart. Am J Cardiol 1983;52(5):621-5.
8. Holt DW, Tucker GT, Jackson PR, Storey GC. Amiodarone pharmaco- 33. Nattel S, Talajic M, Quantz M, DeRoode M. Frequency-dependent
kinetics. Am Heart J 1983;106(4 Pt 2):840-7. effects of amiodarone on atrioventricular nodal function and slow-
9. Pollak PT, Bouillon T, Shafer SL. Population pharmacokinetics of long- channel action potentials: evidence for calcium channel-blocking
term oral amiodarone therapy. Clin Pharmacol Ther 2000;67(6):642- activity. Circulation 1987;76(2):442-9.
52. 34. Hamer AW, Mandel WJ, Zaher CA, Karagueuzin HS, Peter T. The
10. Rotmensch HH, Swanson BN, Greenspon AJ, Shoshani D, Greenspan electrophysiologic basis for the use of amiodarone for treatment of
AM. Amiodarone: individualizing dosage with serum concentrations. cardiac arrhythmias. Pacing Clin Electrophysiol 1983;6(4):784-94.
Pacing Clin Electrophysiol 1983;6(6):1327-35. 35. Cahoon W Jr, Flattery MP, Hess ML. Amiodarone: development, clini-
11. Heger JJ, Prystowsky EN, Zipes DP. Relationships between amio- cal indications, and safety. Prog Cardiovasc Nurs 2007;22(3):173-6.
darone dosage, drug concentrations, and adverse side effects. Am 36. Van Herendael H and Dorian P. Amiodarone for the treatment and
Heart J 1983;106(4 Pt 2):931-5. prevention of ventricular fibrillation and ventricular tachycardia.Vasc
12. Anastasiou-Nana MI, Nanas JN, Alexopoulos G, Karli JN, Margari ZJ, Health Risk Manag 2010;6(9):465-7.
Agapitos E, Patsi EN, Stamatelopoulos SF. Amiodarone concentra- 37. Nattel S. Pharmacodynamic studies of amiodarone and its active
tion in human myocardium after rapid intravenous administration. N-desethyl metabolite. J Cardiovasc Pharmacol 1986;8(4):771-7.
Cardiovasc Drugs Ther 1999;13(3):265-70. 38. Talajic M, DeRoode MR, Nattel S. Comparative electrophysiologic
13. Robson' DJ, Jeeva Raj MV, Storey CAG, Holt DW. Use of amioda- effects of intravenous amiodarone and desethylamiodarone in dogs:
rone during pregnancy. Postgrad Med J 1985;61:75-7. doi:10.1136/ evidence for clinically relevant activity of the metabolite. Circulation
pgmj.61.711.75 1987;75(1):265-71.
14. Anastasiou-Nana M, Levis GM, Moulopoulos S. Pharmacokinetics 39. Varbiro G, Toth A, Tapodi A, Bognar Z, Veres B, Sumegi B, Gallyas F Jr.
of amiodarone after intravenous and oral administration. Int J Clin Protective effect of amiodarone but not N-desethylamiodarone on
Pharmacol Ther Toxicol 1982;20(11):524-9. postischemic hearts through the inhibition of mitochondrial perme-
15. Siddoway LA, McAllister CB, Wilkinson GR, Roden DM, Woosley RL. ability transition. J Pharmacol Exp Ther 2003;307(2):615-25.
Amiodarone dosing: a proposal based on its pharmacokinetics. Am 40. Wolbrette DL. Risk of proarrhythmia with class III antiarrhyth-
Heart J 1983;106(4 Pt 2):951-6. mic agents: sex-based differences and other issues. Am J Cardiol
16. Fukumoto K, Kobayashi T, Tachibana K, Kato R, Tanaka K, Komamura 2003;91(6A):39D-44D.
K, Kamakura S, Kitakaze M, Ueno K. Effect of amiodarone on the se- 41. Munoz A, Karila P, Gallay P, Zettelmeier F, Messner P, Mery M, Grolleau
rum concentration/dose ratio of metoprolol in patients with cardiac R. A randomized hemodynamic comparison of intravenous amioda-
arrhythmia. Drug Metab Pharmacokinet 2006;21(6):501-5. rone with and without Tween 80. Eur Heart J 1988;9(2):142-8.
17. Ha HR, Bigler L, Binder M, Kozlik P, Stieger B, Hesse M, Altorfer HR, 42. Scheinman MM, Levine JH, Cannom DS, Friehling T, Kopelman HA,
Follath F. Metabolism of amiodarone (part I): identification of a Chilson DA, Platia EV, Wilber DJ, Kowey PR. Dose-ranging study of
new hydroxylated metabolite of amiodarone. Drug Metab Dispos intravenous amiodarone in patients with life-threatening ventricu-
2001;29(2):152-8. lar tachyarrhythmias. The Intravenous Amiodarone Multicenter
18. Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi Investigators Group. Circulation 1995;92(11):3264-72.
T. A significant role of human cytochrome P450 2C8 in amiodarone 43. Pollak PT. How Toxic is Amiodarone to the Liver? J Gastrointestin
N-deethylation: an approach to predict the contribution with rela- Liver Dis 2010;19(1):11-3.
tive activity factor. Drug Metab Dispos 2000;28(11):1303-10. 44. Shukla R, Jowett NT, Thompson DR, Pohl JE. Side effects with amio-
19. Elsherbin ME, El-Kadi AO, Brocks DR. The metabolism of amiodarone darone therapy. Postgrad Med J 1994;70(825):492-8.
by various CYP isoenzymes of human and rat, and the inhibitory 45. Schwaiblmair M, Berghaus T, Haeckel T, Wagner T, von Scheidt W.
influence of ketoconazole. J Pharm Pharm Sci 2008;11(1):147-59. Amiodarone-induced pulmonary toxicity: an under-recognized
20. Soyama A, Hanioka N, Saito Y, Murayama N, Ando M, Ozawa S, and severe adverse effect? Clin Res Cardiol 2010;99(11):693-700.
Sawada J. Amiodarone N-deethylation by CYP2C8 and its variants, doi:10.1007/s00392-010-0181-3
CYP2C8*3 and CYP2C8 P404A. Pharmacol Toxicol 2002;91(4):174-8. 46. Werner D, Wuttke H, Fromm MF, Schaefer S, Eschenhagen T, Brune
21. García-Martín E, Martínez C, Ladero JM, Agúndez JA. Interethnic K, Daniel WG, Werner U. Effect of amiodarone on the plasma levels
and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms of metoprolol. Am J Cardiol 2004;94(10):1319-21.
in healthy individuals. Mol Diagn Ther 2006;10(1):29-40. 47. Nattel S, Davies M, Quantz M. The antiarrhythmic efficacy of amio-
22. Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amioda- darone and desethylamiodarone, alone and in combination, in dogs
rone. Clin Pharmacokinet 1984;9(2):136-56. with acute myocardial infarction. Circulation 1988;77(1):200-8.
23. Harris L, Hind CR, McKenna WJ, Savage C, Krikler SJ, Storey GC, Holt 48. Nanas JN, Mason JW. Pharmacokinetics and regional electro-
DW. Renal elimination of amiodarone and its desethyl metabolite. physiological effects of intracoronary amiodarone administration.
Postgrad Med J 1983;59(693):440-2. Circulation 1995;91(2):451-61.
24. Chow MS. Intravenous amiodarone: pharmacology, pharmacokinet- 49. Gambhir DS, Bhargava M, Nair M, Arora R, Khalilullah M. Comparison
ics, and clinical use. Ann Pharmacother 1996;30(6):637-43. of electrophysiologic effects and efficacy of single-dose intravenous
25. Ikeda N, Nademanee K, Kannan R, Singh BN. Electrophysiologic ef- and long-term oral amiodarone therapy in patients with AV nodal
fects of amiodarone: experimental and clinical observation relative reentrant tachycardia. Indian Heart J 1996;48(2):133-7.
to serum and tissue drug concentrations. Am Heart J 1984;108(4 Pt 50. Saksena S, Rothbart ST, Shah Y, Cappello G. Clinical efficacy and elec-
1):890-8. tropharmacology of continuous intravenous amiodarone infusion

142
 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Jun; 161(2):134-143.

and chronic oral amiodarone in refractory ventricular tachycardia. correlation of serum concentration with suppression of complex
Am J Cardiol 1984;54(3):347-52. ventricular ectopic activity. Am J Cardiol 1984;54(6):569-74.
51. Kowey PR, Levine JH, Herre JM, Pacifico A, Lindsay BD, Plumb VJ, 63. Connolly SJ, Gupta RN, Hoffert D, Roberts RS. Concentration re-
Janosik DL, Kopelman HA, Scheinman MM. Randomized, double- sponse relationships of amiodarone and desethylamiodarone. Am
blind comparison of intravenous amiodarone and bretylium in the Heart J 1988;115(6):1208-13.
treatment of patients with recurrent, hemodynamically destabilizing 64. Saksena S, Rothbart ST, Cappello G. Chronic effects of amiodarone
ventricular tachycardia or fibrillation. The Intravenous Amiodarone in patients with refractory ventricular tachycardia. Int J Cardiol
Multicenter Investigators Group. Circulation 1995;92(11):3255-63. 1983;3(3):339-52.
52. Levine JH, Massumi A, Scheinman MM, Winkle RA, Platia EV, Chilson 65. Greenberg ML, Lerman BB, Shipe JR, Kaiser DL, DiMarco JP. Relation
DA, Gomes A, Woosley RL. Intravenous amiodarone for recurrent between amiodarone and desethylamiodarone plasma concentra-
sustained hypotensive ventricular tachyarrhythmias. Intravenous tions and electrophysiologic effects, efficacy and toxicity. J Am Coll
Amiodarone Multicenter Trial Group. J Am Coll Cardiol 1996;27(1):67- Cardiol 1987;9(5):1148-55.
75. 66. Debbas NM, du Cailar C, Bexton RS, Demaille JG, Camm AJ, Puech P.
53. Giani P, Maggioni AP, Volpi A, Cavalli A, Latini R, Neyroz P, Riva E, The QT interval: a predictor of the plasma and myocardial concentra-
D'Aranno V. Blood levels and electrophysiological effects of intra- tions of amiodarone. Br Heart J 1984;51(3):316-20.
venous amiodarone in patients with junctional reciprocating tachy- 67. Ward DE, Camm AJ, Spurrell RA. Clinical antiarrhythmic effects of
cardia. Preliminary observations. Acta Cardiol 1984;39(1):9-17. amiodarone in patients with resistant paroxysmal tachycardias. Br
54. Escoubet B, Coumel P, Poirier JM, Maison-Blanche P, Jaillon P, Leclercq Heart J 1980;44(1):91-5.
JF, Menasche P, Cheymol G, Piwnica A, Lagier G, et al. Suppression 68. Kavesh NG, Olsovsky MR, Freudenberger RS, Conte JV, Peters RW,
of arrhythmias within hours after a single oral dose of amiodarone Shorofsky SR, Gold MR. Intravenous amiodarone suppression of
and relation to plasma and myocardial concentrations. Am J Cardiol electrical storm refractory to chronic oral amiodarone. Pacing Clin
1985;55(6):696-702. Electrophysiol 1999;22(4 Pt 1):665-7.
55. Nielsen KD and Møller S. Amiodarone for rapid cardioversion of 69. Campbell TJ and Williams KM. Therapeutic drug monitoring: antiar-
chronic atrial tachyarrhythmia? Pharmacol Toxicol 2000;86(6):283-6. rhythmic drugs. Br J Clin Pharmacol 2001;52(S1):21S-34S.
56. Tieleman RG, Gosselink AT, Crijns HJ, van Gelder IC, van den Berg MP, 70. Robinson K, Johnston A, Walker S, Mulrow J, Holt D, McKenna W.
de Kam PJ, van Gilst WH, Lie KI. Efficacy, safety, and determinants of Stability of plasma amiodarone levels during chronic oral therapy.
conversion of atrial fibrillation and flutter with oral amiodarone. Am Cardiovasc Drugs Ther 1990;4(2):529-30.
J Cardiol 1997;79(1):53-7. 71. Maling TJ, Siebers RW, Burgess CD, Taylor C, Purdie G. Individual
57. Kaski JC, Girotti LA, Messuti H, Rutitzky B, Rosenbaum MB. Long- variability of amiodarone distribution in plasma and erythro-
term management of sustained, recurrent, symptomatic ventricular cytes: implications for therapeutic monitoring. Ther Drug Monit
tachycardia with amiodarone. Circulation 1981;64(2):273-9. 1989;11(2):121-6.
58. Mostow ND, Vrobel TR, Noon D, Rakita L. Rapid suppression of 72. Kotake T, Takada M, Goto T, Komamura K, Kamakura S, Morishita H.
complex ventricular arrhythmias with high-dose oral amiodarone. Serum amiodarone and desethylamiodarone concentrations fol-
Circulation 1986;73:1231-8. lowing nasogastric versus oral administration. J Clin Pharm Ther
59. Greenberg ML, Lerman BB, Haines DE, Baron JA, Dimarco JP. Stability 2006;31(3):237-43.
of electrophysiological parameters after acute amiodarone loading: 73. Candinas R, Frielingsdorf J, Ha HR, Carrel T, Turina M, Follath F.
implications for patient management. Pacing Clin Electrophysiol Myocardial amiodarone concentrations after short- and long-
1989;12(7 Pt 1):1038-43. term treatment in patients with end-stage heart failure. Eur J Clin
60. Rotmensch HH, Belhassen B, Swanson BN, Shoshani D, Spielman SR, Pharmacol 1998;53(5):331-6.
Greenspon AJ, Greenspan AM, Vlasses PH, Horowitz LN. Steady- state 74. Kaplan LJ, Cappaert WE. Amiodarone-induced corneal deposits. Ann
serum amiodarone concentrations: relationships with antiarrhyth- Ophthalmol 1984;16(8):762-6.
mic efficacy and toxicity. Ann Intern Med 1984;101(4):462-9. 75. Rakita L, Sobol SM, Mostow N, Vrobel T. Amiodarone pulmonary
61. Haffajee CI, Love JC, Canada AT, Lesko LJ, Asdourian G, Alpert JS. toxicity. Am Heart J 1983;106(4 Pt 2):906-16.
Clinical pharmacokinetics and efficacy of amiodarone for refractory 76. Burton ME. Applied pharmacokinetics: principles of therapeutic
tachyarrhythmias. Circulation 1983;67(6):1347-55. drug monitoring. 4th ed. Baltimore: Lippincott Williams; 2006 p.
62. Mostow ND, Rakita L, Vrobel TR, Noon DL, Blumer J. Amiodarone: 446-57.

143

View publication stats