ARRHYTHMIAS
AND CONDUCTION DWl’lJRBANCES
Relation of Amiodarone Hepatic and Pulmonary Toxicity to Serum Drug Concentrations and Superoxide Dismutase Activity P. Timothy Pollak, MD, PhD, Arjun D. Sharma, MD, and S. George Carruthers, MD
Hepatk enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrationsanderythrocytesuperoxidedismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amiodarone. Subchkal hepatotoxkity developed in 5 patients. These patients had higher baseline ahnine transaminrse values (42.6 f 68 vs 22.9 f 1.8 U/liter) and had an imrease in serum aspartate transamlnase from 27 f 4.1 at baselins to 147 f 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. six patknts with normal baseline carbon monoxide diffusing capacity had s&clinical pulmonary toxicity develop with a mean decrease In diffudng capactty to 0.7 f 0.0s of the baseHne value, whkh correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide dittudng capacity and SOD activity remained unchanged in the othsr patients. The mechanisms of hepatk and pulmonary i*ry rsmain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatk and/or pulmonary abnormaltties develop received higher doses of amiodarone (440 f 27 VI 340 f 18 mg/day), but also had a higher amiodarone:DEA ratio sugkbletks conttlbuted to gesting that dosethe higher comentrations. Elevated baseline alanine transaminase may indkate imreased risk for hepatotoxklty while a progressive decrease in erythrocyte SOD may be an early indkatlon of pulmonary toxicity. The latter finding indkates a need to investigate the rok of free radkals in the pathogenesls of amiodarone pulmonary toxicity. (Am J Cardiol1990;65:119&1191)
From the Departments of Medicine, University Hospital, University of WesternOntario, London,Ontario, Canada,and Victoria General Hospital, Dalhousie University, Halifax, Nova Scotia, Canada. Thii study was supported by the Canadian Heart Foundation and Medical Research Council of Canada. Manuscript received October 12, 1989; revisedmanuscript receivedand acceptedJanuary 8,199O. Addressfor reprints: P. Timothy Pollak, MD, PhD, Department of Medicine, 431 MacKenzie Building, Victoria General Hospital, Halifax, Nova Scotia, Canada, B3H 2Y9.
miodarone was once consideredan almost ideal antiarrhythmic agent because of its efficacy against arrhythmias resistant to other agents,its low incidence of acute adverse effects, its once daily dosing and its lack of negative inotropic effects.’ Unfortunately, since its introduction as an experimental agent in North America, an increasing number of adverseeffects have been reported, the most serious occurring in the liver and lung.* The mechanismsof these toxicities remain unknown. Elevations of serum hepatic enzymes are reported frequently3y4and in rare casesare associated with clinical hepatitis and pathologic changessimilar to those produced by alcohol abuse.5Despite accumulating reports of amiodarone pulmonary toxicity, estimates of its incidence are highly variable and the factors predisposingto its developmentremain unclear. It has been suggestedthat amiodarone causesa druginduced lipidosis of the lungs,6 but the ultrastructural pathology would also be consistentwith the involvement of free radicals.7*8 The extremely long half-lives of amiodarone and desethylamiodarone(DEA)9 have complicated the search for correlations between adverseeffects and serum drug concentrations. Although many adverse effects occur only after several months of therapy, this may still precedethe attainment of steady-stateamiodarone and DEA serum concentrations. This makes comparisons based strictly on steady-state kinetic correlations inappropriate for many adverse effects at their time of onset.The contribution of the active metabolite, DEA, to the clinical and adverseeffects of amiodarone should also not be overlooked.1°A prospectivetrial designed in consideration of these factors was carried out to examine kinetic-dynamic relations between adverse effects,cumulative doseand increasing serum drug concentrations. Evidence for the role of free radicals in the etiology of amiodarone pulmonary toxicity was also sought using serial measurementsof superoxide dismutase (SOD) activity.
A
METHODS Subjects: Informed consent was obtained from pa-
tients in whom amiodarone therapy was indicated for cardiac arrhythmias refractory to treatment with conventional agents. Patients with hepatic or pulmonary diseaseor life-threatening extracardiac ailments which might have interfered with the identification of adverse
THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15, 1990
1185
TABLE I Patient Characteristics
and Dosing Age W)
64f3
Group A (No toxicity, n = 20) Group B (Toxicity, n = lo)* p Value+ Total (n = 30)
Weight 0%)
Men/ Women
Dose (w/day)
Dose bWk/day)
59f4 0.31
84f4 76h3
12/S 10/o
34Of18 44Of27
4.23 f 0.31 5.87 f 0.46
0.29
0.06
0.006
0.004
56f2
81*3
22/S
373 f 17
4.78 f 0.29
Values are mean f standard error of mean. * Toxicity includes 1 patient with both liver and lung changes, 4 patients with liver changes and 5 with lung changes. t Probability that difference between the means for group A and group B occurred by chance (Z-tailed unpaired t test, except chi-square
effects were excluded. Age, sex, weight and amiodarone dosing of the study patients are listed in Table I. All patients were given “loading” dosesof amiodarone 400 mg 4 times daily for 7 days. Patients with atria1 arrhythmias were generally placed on 200 mg/day while those with ventricular arrhythmias received 400 mg/ day. After adjustments for their response,4 patients continued on 200, 4 on 300, 20 on 400 and 2 on 600 mg/day. The effects of amiodarone and DEA on heart rate, QT interval and cornea1morphology in many of these patients have been reported bef0re.gThe current analysis of adverseeffects in the liver and lung was performed with data from these and additional patients who completed the study. Protocok To document changesin hepatic and pulmonary function and serum drug concentrations,assessments were scheduledbefore administration of amiodarone and at 1, 2, 3, 6, 9 and 12 months after starting therapy. During each assessment,blood was drawn for
for sex diierences).
the following measurements:routine clinical biochemistry, including serum aspartate and alanine transaminases(AST and ALT); amiodarone and DEA concentrations analyzed by high performance liquid chromatography’ I; and erythrocyte SOD activity analyzed by pyrogallol autoxidation rate-reaction.t2 Pulmonary function tests, including single breath carbon monoxide diffusing capacity of the lung (diffusing capacity), volumes, expiratory flow rates and arterialized capillary blood gases, were measured at each assessmentand chest radiographs were recorded every 3 months. The protocol defined hepatic toxicity as elevation to twice the upper limit of normal of both AST and ALT (normal X30 U/liter). Patients were to discontinue therapy if there were clinical manifestationsof hepatitis. The criteria for pulmonary toxicity were defined as the occurrence of any of the following: chest radiograph suggestiveof interstitial diseasewithout obvious cause;a sustaineddecreasein single breath diffusing capacity or
A 6.0 -
5.0 -
4.0 -
3.0 -
2.0 1.0 1.0 , 0.0 II
, 100
I 1000
1
10000
Cumulative Dose (mg/kg)
1186
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
0.5 0.0 I
, 100
.
.
. ..,..,
.
. . . ...l
1000
Cumulative Dose (mglkg)
10000
TABLE
Dose and Serum Drug Concentrations
II Cumulative
over Time
Time (months)
Group A (No toxicity, n = 20) Cumulative dose (mg/kg) Amiodarone (mg/liter) DEA (mg/liter) Group B (Toxicity, n = lo)* Cumulative dose (mg/kg) Amiodarone (mg/liter) DEA (mg/liter) Total (n = 30) Cumulative dose (mg/kg) Amiodarone (mg/liter) DEA (mg/liter)
1
2
3
6
9
12
219 l 20 1.61 f 0.23 0.79 f 0.09
345 f 27 1.96 f 0.25 0.92 f 0.09
48Of34 2.10 f 0.29 1.07f0.11
878 f 60 2.16 f 0.28 1.11 fO.ll
1238 f 85 2.05 f 0.26 1.17f0.11
1584 f 102 2.02 f 0.24 1.24f 0.12
280 f 22 1.80 f 0.23 0.68 f 0.09
456 f 34t 2.45 f 0.34 0.94f0.15
652 f 53’ 2.41 f 0.30 1.05f0.15
1171*97+ 3.18 f 0.4-6+ 1.39 f 0.20
1700 f 131+ 3.17*0.48+ 1.45 f 0.21
2236 f 179+ 3.59 f 0.43’ 1.84zk0.21+
239 rt 16 1.6811~0.17 0.75 f 0.07
382 4~ 23 2.12 f 0.20 0.92 f 0.08
538 f 32 2.20 f 0.21 1.06 f 0.09
976 f 57 2.50 f 0.25 1.20 f 0.10
1392 f 81 2.42 f 0.25 1.27 f 0.10
1801 f 106 2.54 f 0.25 1.44f0.12
Values are mean f standard error of the mean. * Toxnty ncludes 1 patient wth both liver and lung changes, 4 wth lover changes and 5 wth lung changes ’ Value for group B statlstically different from group A (p SO.05 by 2-t&d unpaired t test).
forced vital capacity to 2 consecutive follow-up visits; or cough and dyspnea not explained by congestiveheart failure or infectious diseasepersisting for >l week of investigation. Patients were to discontinue amiodarone therapy if any 2 of these criteria were met or if chest radiographs showed progressiveabnormalities. Amiodarone and DEA have similar pharmacologic activity 1@13,14 and both would be expectedto contribute to any correlations betweencumulative dose,concentration and effects. Therefore, comparisons in this study are with “total serum drug concentration” used to denote the concentration of amiodarone plus DEA (mg/ liter).
A 1000
RESULTS During 12 months of follow-up, no patients had clinical abnormalities develop that necessitatedwithdrawal of amiodarone, but 10 patients had subclinical hepatic
B
,
.
lo-, 0.0
,
,
1.0
,
,
2.0
, 3.0
Concentration FIGURE 2. A, mean sewn
embdmme)
Statistical analysis: Data are presentedas the mean f standard error of the mean. Student’s t test was used to compare parameters between groups at baseline. Two-way analysis of variance was performed to confirm changes from baseline measurementsover time. Least squares linear regression was performed to determine the degree of correlation between dose and concentrations. A p value 50.05 was considered statistically significant.
cementretbns
asp&ate
,
,
,
4.0
,
.
,
1000
,
IO-, 0.0
6.0
5.0
-
(mg/L) hnsaminase
,
,
1.0
,
,
2.0
, 3.0
,
,
,
4.0
, 5.0
,
( 6.0
Concentration (mg/L) B
over 1 year. Line -k=twmmsllnear
-~rwUncLus(*d-w~f0rcmCentrati0nsaRerbasehein
hepetktoxldtydevelop(n=25).
THE AMERICAN
JOURNAL
OF CARDIOLOGY
MAY 15, 1990
1187
and/or pulmonary toxicity developaccording to the criteria of the study design. Of these patients, 1 had both hepatic and pulmonary abnormalities, 4 had hepatic abnormalities and 5 had pulmonary abnormalities. All but 3 patients (89%) were controlled without arrhythmia recurrence by the second month. Serum drug concentrations: Total cumulative dose, amiodarone concentrationsand DEA concentrationsare listed in Table II. In both the group of 20 patients without abnormalities (group A) and the group of 10 patients with abnormalities (group B), the mean total serum drug concentrations increasedat the samerate per cumulative dose over the first 3 observations (Figure 1A). By the time a cumulative dose of 500 mg/kg was reached, mean total serum drug concentration had stopped increasing in group A while it continued to increase at the same rate per unit cumulative dose until the end of follow-up group B. Differences in concentrations between the 2 groups were statistically significant from the fourth observation (6 months) onward. The amiodarone:DEA ratio starts at infinity immediately after the first dose of amiodarone when DEA concentrations are 0. The ratio had reached 2.8 f 0.4 by the first observation in group B, which was statistically different from the 2.0 f 0.2 value (p
AND CONDUCTION DWl’lJRBANCES
Relation of Amiodarone Hepatic and Pulmonary Toxicity to Serum Drug Concentrations and Superoxide Dismutase Activity P. Timothy Pollak, MD, PhD, Arjun D. Sharma, MD, and S. George Carruthers, MD
Hepatk enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrationsanderythrocytesuperoxidedismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amiodarone. Subchkal hepatotoxkity developed in 5 patients. These patients had higher baseline ahnine transaminrse values (42.6 f 68 vs 22.9 f 1.8 U/liter) and had an imrease in serum aspartate transamlnase from 27 f 4.1 at baselins to 147 f 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. six patknts with normal baseline carbon monoxide diffusing capacity had s&clinical pulmonary toxicity develop with a mean decrease In diffudng capactty to 0.7 f 0.0s of the baseHne value, whkh correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide dittudng capacity and SOD activity remained unchanged in the othsr patients. The mechanisms of hepatk and pulmonary i*ry rsmain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatk and/or pulmonary abnormaltties develop received higher doses of amiodarone (440 f 27 VI 340 f 18 mg/day), but also had a higher amiodarone:DEA ratio sugkbletks conttlbuted to gesting that dosethe higher comentrations. Elevated baseline alanine transaminase may indkate imreased risk for hepatotoxklty while a progressive decrease in erythrocyte SOD may be an early indkatlon of pulmonary toxicity. The latter finding indkates a need to investigate the rok of free radkals in the pathogenesls of amiodarone pulmonary toxicity. (Am J Cardiol1990;65:119&1191)
From the Departments of Medicine, University Hospital, University of WesternOntario, London,Ontario, Canada,and Victoria General Hospital, Dalhousie University, Halifax, Nova Scotia, Canada. Thii study was supported by the Canadian Heart Foundation and Medical Research Council of Canada. Manuscript received October 12, 1989; revisedmanuscript receivedand acceptedJanuary 8,199O. Addressfor reprints: P. Timothy Pollak, MD, PhD, Department of Medicine, 431 MacKenzie Building, Victoria General Hospital, Halifax, Nova Scotia, Canada, B3H 2Y9.
miodarone was once consideredan almost ideal antiarrhythmic agent because of its efficacy against arrhythmias resistant to other agents,its low incidence of acute adverse effects, its once daily dosing and its lack of negative inotropic effects.’ Unfortunately, since its introduction as an experimental agent in North America, an increasing number of adverseeffects have been reported, the most serious occurring in the liver and lung.* The mechanismsof these toxicities remain unknown. Elevations of serum hepatic enzymes are reported frequently3y4and in rare casesare associated with clinical hepatitis and pathologic changessimilar to those produced by alcohol abuse.5Despite accumulating reports of amiodarone pulmonary toxicity, estimates of its incidence are highly variable and the factors predisposingto its developmentremain unclear. It has been suggestedthat amiodarone causesa druginduced lipidosis of the lungs,6 but the ultrastructural pathology would also be consistentwith the involvement of free radicals.7*8 The extremely long half-lives of amiodarone and desethylamiodarone(DEA)9 have complicated the search for correlations between adverseeffects and serum drug concentrations. Although many adverse effects occur only after several months of therapy, this may still precedethe attainment of steady-stateamiodarone and DEA serum concentrations. This makes comparisons based strictly on steady-state kinetic correlations inappropriate for many adverse effects at their time of onset.The contribution of the active metabolite, DEA, to the clinical and adverseeffects of amiodarone should also not be overlooked.1°A prospectivetrial designed in consideration of these factors was carried out to examine kinetic-dynamic relations between adverse effects,cumulative doseand increasing serum drug concentrations. Evidence for the role of free radicals in the etiology of amiodarone pulmonary toxicity was also sought using serial measurementsof superoxide dismutase (SOD) activity.
A
METHODS Subjects: Informed consent was obtained from pa-
tients in whom amiodarone therapy was indicated for cardiac arrhythmias refractory to treatment with conventional agents. Patients with hepatic or pulmonary diseaseor life-threatening extracardiac ailments which might have interfered with the identification of adverse
THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15, 1990
1185
TABLE I Patient Characteristics
and Dosing Age W)
64f3
Group A (No toxicity, n = 20) Group B (Toxicity, n = lo)* p Value+ Total (n = 30)
Weight 0%)
Men/ Women
Dose (w/day)
Dose bWk/day)
59f4 0.31
84f4 76h3
12/S 10/o
34Of18 44Of27
4.23 f 0.31 5.87 f 0.46
0.29
0.06
0.006
0.004
56f2
81*3
22/S
373 f 17
4.78 f 0.29
Values are mean f standard error of mean. * Toxicity includes 1 patient with both liver and lung changes, 4 patients with liver changes and 5 with lung changes. t Probability that difference between the means for group A and group B occurred by chance (Z-tailed unpaired t test, except chi-square
effects were excluded. Age, sex, weight and amiodarone dosing of the study patients are listed in Table I. All patients were given “loading” dosesof amiodarone 400 mg 4 times daily for 7 days. Patients with atria1 arrhythmias were generally placed on 200 mg/day while those with ventricular arrhythmias received 400 mg/ day. After adjustments for their response,4 patients continued on 200, 4 on 300, 20 on 400 and 2 on 600 mg/day. The effects of amiodarone and DEA on heart rate, QT interval and cornea1morphology in many of these patients have been reported bef0re.gThe current analysis of adverseeffects in the liver and lung was performed with data from these and additional patients who completed the study. Protocok To document changesin hepatic and pulmonary function and serum drug concentrations,assessments were scheduledbefore administration of amiodarone and at 1, 2, 3, 6, 9 and 12 months after starting therapy. During each assessment,blood was drawn for
for sex diierences).
the following measurements:routine clinical biochemistry, including serum aspartate and alanine transaminases(AST and ALT); amiodarone and DEA concentrations analyzed by high performance liquid chromatography’ I; and erythrocyte SOD activity analyzed by pyrogallol autoxidation rate-reaction.t2 Pulmonary function tests, including single breath carbon monoxide diffusing capacity of the lung (diffusing capacity), volumes, expiratory flow rates and arterialized capillary blood gases, were measured at each assessmentand chest radiographs were recorded every 3 months. The protocol defined hepatic toxicity as elevation to twice the upper limit of normal of both AST and ALT (normal X30 U/liter). Patients were to discontinue therapy if there were clinical manifestationsof hepatitis. The criteria for pulmonary toxicity were defined as the occurrence of any of the following: chest radiograph suggestiveof interstitial diseasewithout obvious cause;a sustaineddecreasein single breath diffusing capacity or
A 6.0 -
5.0 -
4.0 -
3.0 -
2.0 1.0 1.0 , 0.0 II
, 100
I 1000
1
10000
Cumulative Dose (mg/kg)
1186
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
0.5 0.0 I
, 100
.
.
. ..,..,
.
. . . ...l
1000
Cumulative Dose (mglkg)
10000
TABLE
Dose and Serum Drug Concentrations
II Cumulative
over Time
Time (months)
Group A (No toxicity, n = 20) Cumulative dose (mg/kg) Amiodarone (mg/liter) DEA (mg/liter) Group B (Toxicity, n = lo)* Cumulative dose (mg/kg) Amiodarone (mg/liter) DEA (mg/liter) Total (n = 30) Cumulative dose (mg/kg) Amiodarone (mg/liter) DEA (mg/liter)
1
2
3
6
9
12
219 l 20 1.61 f 0.23 0.79 f 0.09
345 f 27 1.96 f 0.25 0.92 f 0.09
48Of34 2.10 f 0.29 1.07f0.11
878 f 60 2.16 f 0.28 1.11 fO.ll
1238 f 85 2.05 f 0.26 1.17f0.11
1584 f 102 2.02 f 0.24 1.24f 0.12
280 f 22 1.80 f 0.23 0.68 f 0.09
456 f 34t 2.45 f 0.34 0.94f0.15
652 f 53’ 2.41 f 0.30 1.05f0.15
1171*97+ 3.18 f 0.4-6+ 1.39 f 0.20
1700 f 131+ 3.17*0.48+ 1.45 f 0.21
2236 f 179+ 3.59 f 0.43’ 1.84zk0.21+
239 rt 16 1.6811~0.17 0.75 f 0.07
382 4~ 23 2.12 f 0.20 0.92 f 0.08
538 f 32 2.20 f 0.21 1.06 f 0.09
976 f 57 2.50 f 0.25 1.20 f 0.10
1392 f 81 2.42 f 0.25 1.27 f 0.10
1801 f 106 2.54 f 0.25 1.44f0.12
Values are mean f standard error of the mean. * Toxnty ncludes 1 patient wth both liver and lung changes, 4 wth lover changes and 5 wth lung changes ’ Value for group B statlstically different from group A (p SO.05 by 2-t&d unpaired t test).
forced vital capacity to 2 consecutive follow-up visits; or cough and dyspnea not explained by congestiveheart failure or infectious diseasepersisting for >l week of investigation. Patients were to discontinue amiodarone therapy if any 2 of these criteria were met or if chest radiographs showed progressiveabnormalities. Amiodarone and DEA have similar pharmacologic activity 1@13,14 and both would be expectedto contribute to any correlations betweencumulative dose,concentration and effects. Therefore, comparisons in this study are with “total serum drug concentration” used to denote the concentration of amiodarone plus DEA (mg/ liter).
A 1000
RESULTS During 12 months of follow-up, no patients had clinical abnormalities develop that necessitatedwithdrawal of amiodarone, but 10 patients had subclinical hepatic
B
,
.
lo-, 0.0
,
,
1.0
,
,
2.0
, 3.0
Concentration FIGURE 2. A, mean sewn
embdmme)
Statistical analysis: Data are presentedas the mean f standard error of the mean. Student’s t test was used to compare parameters between groups at baseline. Two-way analysis of variance was performed to confirm changes from baseline measurementsover time. Least squares linear regression was performed to determine the degree of correlation between dose and concentrations. A p value 50.05 was considered statistically significant.
cementretbns
asp&ate
,
,
,
4.0
,
.
,
1000
,
IO-, 0.0
6.0
5.0
-
(mg/L) hnsaminase
,
,
1.0
,
,
2.0
, 3.0
,
,
,
4.0
, 5.0
,
( 6.0
Concentration (mg/L) B
over 1 year. Line -k=twmmsllnear
-~rwUncLus(*d-w~f0rcmCentrati0nsaRerbasehein
hepetktoxldtydevelop(n=25).
THE AMERICAN
JOURNAL
OF CARDIOLOGY
MAY 15, 1990
1187
and/or pulmonary toxicity developaccording to the criteria of the study design. Of these patients, 1 had both hepatic and pulmonary abnormalities, 4 had hepatic abnormalities and 5 had pulmonary abnormalities. All but 3 patients (89%) were controlled without arrhythmia recurrence by the second month. Serum drug concentrations: Total cumulative dose, amiodarone concentrationsand DEA concentrationsare listed in Table II. In both the group of 20 patients without abnormalities (group A) and the group of 10 patients with abnormalities (group B), the mean total serum drug concentrations increasedat the samerate per cumulative dose over the first 3 observations (Figure 1A). By the time a cumulative dose of 500 mg/kg was reached, mean total serum drug concentration had stopped increasing in group A while it continued to increase at the same rate per unit cumulative dose until the end of follow-up group B. Differences in concentrations between the 2 groups were statistically significant from the fourth observation (6 months) onward. The amiodarone:DEA ratio starts at infinity immediately after the first dose of amiodarone when DEA concentrations are 0. The ratio had reached 2.8 f 0.4 by the first observation in group B, which was statistically different from the 2.0 f 0.2 value (p
