J. TOXIC0L.-CLIN. TOXICOL.

, 20(2), 181-186 (1983)

ACUTE OVERDOSAGE OF AMIODARONE I N A S U I C I D E ATTEMPT

?
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M. B o n a t i , V. D'Aranno, F . G a l l e t t i , M.T. F o r t u n a t i and G.Tognoni

L a b o r a t o r y o f C l i n i c a l Pharmacology,
I s t i t u t o d i Ricerche Farmacologiche M a r i o Negri , V i a E r i t r e a 62,
Milano, I t a l y
? D i v i s i o n o f Cardiology, Ospedale Regionale, Varese, Italy
For personal use only.

ABSTRACTS

C l i n i c a l and biochemical v a r i a b l e s and b l o o d l e v e l s o f

amiodarone and i t s m e t a b o l i t e a r e r e p o r t e d a f t e r a c u t e s e l f - i n t o x -
i c a t i o n i n a young woman. D e s p i t e t h e huge amount o f d r u g i n g e s t e d
no c l i n i c a l s i d e e f f e c t s were documented o v e r t h e m o n i t o r e d p e r i o d
o f 3 months.

Amiodarone, a benzofuran d e r i v a t i v e w i t h a chemical s t r u c t u r e

resembling t h y r o x i n e , was marketed t w e n t y y e a r s ago f o r t h e t r e a t -
ment o f angina p e c t o r i s ( 1 ) . A decade a f t e r i t s i n t r o d u c t i o n i n
c l i n i c a l medicine, i t s a c t i v i t y i n s u p r a v e n t r i c u l a r and v e n t r i c u l a r
t a c h y a r r h y t h m i a s has been recoqnized ( 2 ) . Data on t h e c l i n i c a l
b e n e f i t s o f amiodarone have been accumulating r a p i d l y and c o n s i s -
t e n t l y , b u t i t s a c u t e and c h r o n i c t o x i c o l o g i c a l p r o f i l e i s f a r
from adequately understood,possibly because o f t h e l a c k o f system-
a t i c s t u d i e s and t h e wide range o f doses adopted b y v a r i o u s a u t h o r s
(400 t o 2000 mg/day l o a d i n g dose; 200-800 mg/day maintenance dose)
(3-6). I n p a r t i c u l a r , a p a r t f r o m r a r e s t u d i e s on i . v . a d m i n i s t r a t i o n

181

Copyright 0 1983 by Marcel Dekker, Inc. 073 1-3810/83/2002-0181$3.50/0

 182 BONATI ET AL.

( 7 ) , t h e acute adverse e f f e c t s of t h e d r u g have received no s p e c i f i c

a t t e n t i o n . I n t h e case reported here t h e non-therapeutic acute in-
gestion of a l a r g e amount of arniodarone represents an extreme
s i t u a t i o n with p o t e n t i a l c l i n i c a l i n t e r e s t .

CASE HISTORY
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A 20-year-old women a f t e r the evening meal and before going

t o s l e e p (about 10.00 p . m . ) a s a s u i c i d e attempt ingested 8 g of
amiodarone ( f o r t y 200 mg t a b l e t s ) which was a v a i l a b l e a t home
as maintenance therapy f o r her mother who s u f f e r e d from recur-
rent ventri cul a r tachycardia.
The s u i c i d e attempt was discovered a t 9.00 a.m. On a r r i v a l
a t t h e hospital (10.00 a.m.) the young lady was conscious and
could f u l l y describe her a c t . Profuse p e r s p i r a t i o n was t h e only
For personal use only.

abnormal finding on c l i n i c a l examination. No signs of cyanosis,

dyspnea o r decreased s e n s i t i v i t y were found. Blood pressure was
120/80 mm Hg. The ECG gave a r e g u l a r h e a r t r a t e of 90/minute
and a corresponding normal QT i n t e r v a l (0.33 s e c . ) . Based on
t h e p a t i e n t ' s apparently s a t i s f a c t o r y s t a t u s and t h e time elapsed
since drug ingestion ( 1 2 hours), no acute medical management
(e.g. g a s t r i c lavage) was undertaken; t h e p a t i e n t was kept i n
the hospital f o r observation and systematic laboratory and c l i n -
ical tests.

FOLLOW-UP CONTROLS

Taking i n t o account the spectrum of reported s i d e e f f e c t s of

long-term amiodarone therapy ( l a b o r a t o r y thyroid abnormalities,
elevated hepatic enzymes, bluish skin d i s c o l o r a t i o n , photosensi-
t i v i t y , corneal microdeposits, severe myopathy and pulmonary
f i b r o s i s ) ( 8 , 9 ) , i n t e n s i v e follow-up was assured over t h e p a t i e n t ' s
t h i r t e e n days in hospital through monitoring of hepatic f u n c t i o n ,
chest X-ray, dermatological and ophthalmological examinations.
Total blood thyroxine ( T T 4 ) and triodothyroxine (TT3) were measured
 ACUTE OVERDOSAGE OF AMIODARONE 183

by radioimunoassay (10) a t e n t r y and on t h e 4th, 7 t h , 1 1 t h and

13th days a f t e r admission. Blood concentrations of amiodarone and
of i t s desethyl metabolite were repeatedly measured by a high
pressure l i q u i d chromatographic technique previously described by
our group ( 1 1 ) . Weekly c o n t r o l s were continued u p t o t h r e e
months.
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DISCUSSION

The very favorable evolution of the case i s summarized i n

Figure 1 , which s e t s out t h e c l i n i c a l signs and t e s t s and t h e
blood p r o f i l e of amiodarone and i t s metabolite. No signs of
t o x i c i t y appeared in t h e observed c l i n i c a l and instrumental
v a r i a b l e s ; no e f f e c t s on thyroid o r hepatic function were ob-
served. No sign of pulmonary, f i b r o s i s , p h o t o s e n s i t i v i t y , skin
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pigmentation o r corneal deposits were found. After t h e s l i g h t

bradycardia observed d u r i n g t h e second and t h i r d day, QTc and
h e a r t r a t e were back t o normal remained s t a b l e t h e r e a f t e r from
t h e fourth day. Electrophysiologic parameters reported as
s p e c i f i c a l l y a f f e c t e d i n t h e r a p e u t i c s t u d i e s such a s PR i n t e r -
val and QRS w i d t h ( 1 2 ) nor signs of congestive h e a r t f a i l u r e
and a r t e r i a l hypotension from decreased myocardial c o n t r a c t -
i l i t y were observed i n our case. The elimination h a l f - l i f e
(31.5 hours) does not d i f f e r from values found i n therapeutic
s e t t i n g s a f t e r i . v . i n j e c t i o n (13-15).
Disappearance of t h e metabolite from the blood agrees w i t h
published d a t a , being longer than f o r t h e parent compound ( 1 4 ) .
This i s t h e f i r s t time t h a t desethyl amiodarone i s detected
a f t e r acute administration, possibly because of t h e unusually
l a r g e load presented t o t h e l i v e r ( i n t h e other overdosage case
reported i n t h e l i t e r a t u r e (16) the dose was only marginally
beyond t h e upper t h e r a p e u t i c loading d o s e ) .
The absence of apparent s h o r t (13 days) and medium ( 3 months)
term s i d e e f f e c t s suggests t h a t acute high-dose does not present
a worrying c l i n i c a l s i t u a t i o n possibly because of t h e very poor
Clinical Toxicology Downloaded from informahealthcare.com by UB Wuerzburg on 10/29/14

90
801 i
. . .
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LO4 , . I ' " ' " ' " " ' ' ~ " ' ' ~ ~

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3

-- 1.3
1.2
h
0
AMIODARONE
METABOLITE
-E
0
1.1
7
I
1
i 4

FIGURE I - C l i n i c a l s i g n s and t e s t s and b l o o d p r o f i l e o f

amiodarone and i t s d e s e t h y l m e t a b o l i t e o v e r 1 3
days p e r i o d a f c e r a c u t e s e l f - i n t o x i c a t i o n by
i n g e s t i o n o f 8 g. TT and TT4 l e v e l s were
3
measured i n plasma, d r u g c o n c e n t r a t i o n s i n whole
blood.
 ACUTE OVERDOSAGE OF AMIODARONE 185

b i o a v a i l a b i l i t y o f t h e compound (11,15), confirmed i n o u r case by

t h e low b l o o d l e v e l s . The wide range o f s i d e e f f e c t s seen d u r i n g
l o n g - t e r m t r e a t m e n t thus seems t o be l i n k e d t o a s t e a d y - s t a t e
s i t u a t i o n , which may r e f l e c t complete d i s t r i b u t i o n i n t a r g e t
organs and t i s s u e s (17,18), although t h e k i n e t i c p a t t e r n alone
cannot s a t i s f a c t o r i l y e x p l a i n t h e degree, frequency and mecha-
nism o f these e f f e c t s ( 1 5 ) .
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ACKNOWLEDGEMENTS

T h i s work was p a r t i a l l y funded by t h e CNR(Nationa1 Research

Council ,Rome,Italy) , program on c l i n i c a l pharmacology and r a r e
diseases.

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