European Review for Medical and Pharmacological Sciences
Use of amiodarone in emergency
A. TESTA, V. OJETTI, A. MIGNECO, M. SERRA, C. ANCONA, A. DE LORENZO*,
N. GENTILONI SILVERI
Department of Emergency Medicine, Catholic University Rome (Italy)
*Human Nutrition Unit, Tor Vergata University Rome (Italy)
Abstract. Amiodarone is one of the
most common anti-arrhythmic drugs used in the
Emergency Department. Recent guidelines on
cardiac arrest with shockable rhythm [refractory
ventricular fibrillation (VF)/pulseless ventricular
tachycardia (VT)] recommend amiodarone as an-
ti-arrhythmic of first choice. Amiodarone is also
first choice drug in the treatment of various ven-
tricular and supra-ventricular tachyarrhythmias.
This paper deals with the main therapeutical in-
dications of amiodarone in emergency medi-
cine: dosage, side effects, contraindications and
pharmacological interactions are reviewed.
Amiodarone is effective for control of hemody-
namically stable VT, polymorphic VT and wide-
complex tachycardia of uncertain origin. It is al-
so helpful for ventricular rate control of rapid
atrial arrhythmias in patients with severely im-
paired left ventricular (LV) function, when digital-
is has been ineffective, and is an adjunct to elec-
trical cardioversion. The major side effects of
amiodarone are hypotension, bradycardia and
peripheral phlebitis. Major contraindications to
the intravenous (iv) injection of amiodarone are
bradycardia, senoatrial block, severe disturbs of
conduction, second or third degree atrio-ventric-
ular blocks. Other contraindications are hy-
potension, severe respiratory failure, hepatocel-
lular failure and hyperthyroidism. Pharmacologi-
cal interactions are reported with HMG-CoA re-
ductase inhibitors, class I antiarrhythmic agents
and other drugs which contribute to prolong QT
interval, digoxin, oral anticoagulants and gener-
al anaesthesia.
Key Words:
Amiodarone, Emergency, Arrhythmias, Tachycar-
dias, Cardiac arrest, Ventricular tachycardia, Atrial fib-
rillation.
Introduction
Amiodarone, a derivative of benzofuran, is
one of the most common anti-arrhythmic
2005; 9: 183-190
drugs, frequently used in the Emergency De-
partment. In the last decade many trials and
meta-analysis described amiodarone as anti-
arrhythmic agent of first choice in the treat-
ment of hemodynamically unstable ventricu-
lar tachycardia (VT), of hemodynamically
stable wide-complex tachycardias 1, and of
many supraventricular tachyarrhythmias1,2.
The European Resuscitation Council recom-
mends its use in shockable cardiac arrest
[ventricular fibrillation (VF) and pulseless
VT]3. Finally, its use has been suggested in
post-infarction patients, either presenting fre-
quent or repetitive extra systolic beats and/or
VT4 or presenting low left ventricular ejec-
tion fraction (below 40%)5.
Up to 2% of the patients admitted to the
Emergency Department present tach-
yarrhythmias. In more than 90% these are
narrow QRS arrhythmias, such as atrial fibril-
lation (AF) (45%), paroxysmal supraventric-
ular tachycardia (35%) and atrial flutter
(8%). Around 50% of large QRS tach-
yarrhythmias are supraventricular tachycar-
dias. VT are in most cases hemodynamically
stable, while only a small part of large QRS
tachyarrhythmia are hemodynamically unsta-
ble VT or shockable cardiac arrest (VF/pulse-
less VT)6.
Often tachyarrhythmia end spontaneously
or resolve after appropriate treatment in the
Emergency Department, and around half of
the patients can be discharged after a short
period of observation.
Pharmacodynamic Properties
Electrophysiologic Effects
Amiodarone exerts a non-competitive
block of alpha and beta-adrenergic receptors
183
 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri
antagonizing tachycardia, hypertension and
oxygen consumption of the myocardium in-
duced by circulating catecholamines. These
effects contribute to the anti-arrhythmic and
anti-anginal properties of amiodarone7. After
amiodarone administration there is no signifi-
cant decrease of the myocardial contractility8.
The most relevant effects of amiodarone
on cardiac cells are the reduction of the depo-
larization (phase 4)9, the late repolarization,
caused by a prolongation of the action poten-
tial (phase 3) and the prolongation of the ef-
fective refractory period10. Therefore amio-
darone is included among class III anti-ar-
rhythmic drugs. It is known that torsades de
pointes are the classic form of proarrhythmia
observed during therapy with any drug that
prolongs repolarization. Among the class III
drugs the proarrhythmic risk appears to be
lowest for amiodarone, probably due to its
complex electrophysiologic profile that may
create significant myocardial electrical homo-
geneity.
Mechanisms of Action
Some chemical peculiarities of the drug
(high iodines content and structural analo-
gies with thyroid hormones) suggested possi-
ble influences of amiodarone on the thyroid
function 11. Furthermore, it is known that
some of the cardio-electrophysiologic effects
of the chronic administration of amiodarone
are very similar to those of hypothy-
roidism 12,13. Actually, it has been shown a
competition or an interaction between amio-
darone and the thyroid hormones at many
levels (i.e. deiodases, trans-membrane ionic
channels)14,15. Two main mechanisms concern-
ing the antiarrhythmic activity of amiodarone
have been suggested:
The T3-mediated hypothesis: amio-
darone antagonizes the thyroid hormones
on the nuclear receptor and/or on trans-
membrane carrier of T3 at cardiac lev-
el 16,17 . This T3-mediated mechanism
could explain the non-competitive adren-
ergic block of amiodarone.
The Membrane-active hypothesis: amio-
darone impairs the lipid environment of
the cell membranes where the main ionic
channels are located, directly modulating
the ionic myocardial transmembran cur-
rents18-20.
184
Pharmacokynetic Properties
Amiodarones chemical structure can be
summarised in three points: (1) presence of
aromatic rings; (2) a relatively high iodine
content; (3) presence of an aliphatic chain
with low polarity.
This chemical structure highlights some
specific pharmacological characteristics like
the high lipophylia, the low oral absorption
rate, the extended tissue distribution, the
slow elimination rate and finally the late ther-
apeutic response during oral treatment21.
After intravenous (iv) administration plas-
ma peak concentration is reached in 6-8
hours. Drug tissue distribution occurs differ-
ently after acute administration (lungs, liver,
heart and kidney) 22 and after the achieve-
ment of dynamic equilibrium (mainly in the
liver, fat tissue and in the lungs)21.
Drug clearance occurs mainly through the
liver and only 1% is excreted through the
kidneys. Amiodarone cannot be dialysed and
crosses easily the placenta (10-50%). N-de-
sethyl-amiodarone (DEA) is its main active
metabolite. After a single oral dose, amio-
darones half life is calculated to be around 24
h, during long-term therapy it increases
reaching 28 days21; while DEAs half life is
around 60 days23.
Therapeutic Indications in Emergency
Cardiac Arrest With Shockable Rhythm
(Refractory FV/Pulseless VT)
The Resuscitation 2000 Guidelines recom-
mend amiodarone as the antiarrhythmic drug
of choice in treatment of resistant VF or
pulseless VT24.
Even if the administration of amiodarone
may cause a slight delay during the resurrec-
tion procedure, evidence supports its use af-
ter epinephrine administration in the treat-
ment of shock-refractory cardiac arrest due
to VF or pulseless VT (Class of evidence
IIb)25. Some studies demonstrate that amio-
darone, like any other antiarrhythmic agent,
must be given before the fourth shock in or-
der to be effective.
In patients with out-of-hospital cardiac ar-
rest, due to refractory ventricular arrhyth-
mias, treatment with amiodarone resulted in
 Use of amiodarone in emergency
a higher rate of survival to hospital admis-
sion. Whether this benefit extends to survival
to discharge from the hospital merits further
investigation26.
In the CASCADE trial, carried out in sur-
vivors of cardiac arrest, the administration of
amiodarone in patients with an implanted au-
tomatic defibrillator significantly reduced the
number of defibrillation shocks27.
Amiodarone 300 mg (made up to 20 ml
with dextrose) should be administered into a
peripheral vein. A further dose of 150 mg
may be given for recurrent or refractory
VT/VF, followed by an infusion of 1 mg min-1
for 6 hours and then 0.5 mg min-1, to a maxi-
mum daily dose of 2 g. This maximum dose
is larger than the current European
datasheet recommendation of 1.2 g. Pre-
loaded syringes are not available because
amiodarone adheres to the plastic surface of
preloaded syringes28.
Hemodynamically Unstable VT and
Hemodynamically Stable Wide-Complex
Tachycardias
VT is considered hemodynamically sta-
ble if there are no symptoms or clinical evi-
dence of tissue hypoperfusion or shock. On
the contrary hemodynamically unstable VT
requires immediate resolution through syn-
chronized cardioversion.
In all patients with unstable hemodynam-
ics, immediate direct current (DC)-cardiover-
sion is indicated. In particular, hemodynami-
cally unstable large QRS complex tachycar-
dia should be treated with a series of three
synchronized shocks29. Pharmacological treat-
ment with amiodarone is indicated only after
failure of electrical cardioversion. Many stud-
ies evaluated amiodarone for the treatment
of hemodynamically unstable VT. Patients
with clinical congestive heart failure or de-
pressed left ventricular (LV) function should
be treated cautiously with antiarrhythmic
therapy. In these patients, many antiarrhyth-
mic agents depress LV function precipitating
or worsening congestive heart failure. Amio-
darone and lidocaine cause the least addition-
al impairment of LV function30. Because of its
broad antiarrhythmic spectrum and lesser
negative inotropic effect, amiodarone is com-
monly used in these cases.
Empirical pharmacological therapy may be
necessary for a hemodynamically stable wide-
complex tachycardia of unknown origin. Pro-
cainamide, amiodarone, and sotalol are effec-
tive in the treatment of VT and supraventric-
ular tachycardias with an accessory pathway
conduction. On the other hand, depressants
of the AV node conduction (such as adeno-
sine, beta-adrenergic receptor blockers, and
calcium channel blockers) are hazardous in
patients with preexcited atrial arrhythmias.
Therefore, the therapeutic options are re-
duced to DC cardioversion, or procainamide
or amiodarone. At presentation in the Emer-
gency Department, most of the patients with
VT are hemodynamically stable, thus allow-
ing first-line antiarrhythmic drug administra-
tion. However, in the course of the disease,
half of the patients need electrical therapy for
definitive termination of the tachycardia31.
Therefore, DC-cardioversion must be avail-
able in the Emergency Department.
When electrical cardioversion is not ap-
propriated, possible therapeutic options are:
procainamide (Class of evidence IIa), sotalol
(Class of evidence IIa), amiodarone (Class of
evidence IIb), or disopyramide (Class of evi-
dence IIb)32.
In stable and unstable large QRS tachycar-
dias, amiodarone should be administered at a
loading dose of 150 mg diluted with 5% dex-
trose for slow bolus injection (10 min) in pe-
ripheral or central vein, followed if necessary
by a second dose of 150 mg. In order to avoid
acute side effects, the second bolus should be
given after a period of 15 minutes. The thera-
peutic effects should become evident already
in the first few minutes, and decrease pro-
gressively until the next administration29,28.
The maintenance dose ranges between 10
and 20 mg/kg over 24 hours (usually 600-900
mg/24 hours and up to 1200 mg/24 hours) di-
luted in 500 ml of dextrose 5%28.
Narrow-Complex Tachycardias
(Supraventricular Arrhythmias)
Supraventricular arrhythmias include
supraventricular tachycardia, atrial extrasys-
tole, atrial flutter, AF, supraventricular
paroxysmal reciprocant tachycardias as the
Wolff-Parkinson-White syndrome.
In the supraventricular paroxysmal tachy-
cardia, amiodarone is effective because it de-
presses the conduction through the accessory
pathway (Class of evidence IIa). Amio-
darone becomes the antiarrhythmic agent of
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 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri

choice (after failure of adenosine) if cardiac
function is impaired and the ejection fraction
is < 40% or there are signs of congestive
heart failure33.
Therapeutic goals for AF include ventricu-
lar rate control, stroke prevention, conversion
to normal sinus rhythm, and maintenance of
normal sinus rhythm. In the treatment of AF,
amiodarone is commonly used34-36.
Recentely, a meta-analysis suggests that
amiodarone is an effective and relatively
rapid acting drug for the conversion of AF to
normal sinus rhythm and recommends amio-
darone as a first-line drug37. AF in young pa-
tients, with a duration of symptoms of less
than 48 h and without heart failure can be
managed in the Emergency Department with
amiodarone in order to avoid a longer hospi-
talization 38. Since amiodarone shows only
slight inotropic, dromotropic and chronotrop-
ic negative effects, it can be safely adminis-
tered in patients with organic cardiomyopa-
thy or heart failure in an Emergency Unit34-36.
Pre-treatment with amiodarone the month
before a planned electric cardioversion in pa-
tients with AF lasting more than 48 h increas-
es the percentage of conversion and reduces
the number of early recurrence of AF 35 .
Moreover, amiodarone is more effective than
propafenone and sotalol in the prevention of
AF recidives, in patients suffering from
paroxysmal and persistent AF39.
In the Wolff-Parkinson-White syndrome,
AF and atrial flutter are usually precipitat-
ed by an episode of atrioventricular re-en-
trant tachycardia. In patients with short ac-
cessory-pathway refractory periods and
rapid ventricular rates during AF, class I an-
tiarrhythmic drugs that lengthen the refrac-
tory period of the accessory pathway and
reduce ventricular rates are first choice
treatment. Class I drugs may be used alone
or in combination with an atrioventricular
nodal depressant agent. Sotalol and amio-
darone have been used in high-risk sympto-
matic patients. However, the risk of ventric-
ular arrhythmias and the occurrence of side
effects limit their usefulness 40 . Radiofre-
quency ablation should be the treatment of
choice in Wolff-Parkinson-White syndrome
and symptomatic atrioventricular re-entrant
tachycardia.
As for large QRS tachycardias, amio-
darones loading is 150 mg diluted with 5%
dextrose in slow bolus injection (10 min), fol-
lowed if necessary by a second dose of 150
mg. The maintenance dose ranges between
10 and 20 mg/kg over 24 hours28. Table I sum-
marizes the main therapeutic indication of
amiodarone in emergency.
Side Effects, Contraindications and
Pharmacological Interactions
Side Effects
Acute adverse effects of amiodarone in-
clude hypotension, bradycardia, chemical pe-
ripheral phlebitis and nausea41. Hypotension
was the most common adverse event report-
ed with amiodarone iv. The hypotension was
not dose-dependent, but related to the rate of
infusion. Therefore amiodarone should be
administered over 10 minutes42. Long-term
treatment can produce adverse effects pre-
senting several degrees of severity, frequency
and time of beginning, especially on the lung,
the thyroid, the liver or the cornea (Table II).
Lung-toxicity determines cough, dyspnoea,
fever, loss of weight, chest pain, and rarely
haemoptysis43. These symptoms often emerge
few days after treatment beginning, but
sometimes they become evident after a few
years.
Amiodarone causes large modifications of
the peripheral metabolism of thyroid hor-
mones. The most important effect is the inhi-

Table I. The main therapeutic indications of amiodarone in emergency.

Ventricular Fibrillation/pulseless Ventricular Tachycardia refractory to defibrillation (Class of evidence IIb);

Wide-Complex Tachycardia haemodynamically unstable and stable, including the polymorphic VT as well as
wide-complex tachycardia of uncertain origin (Class of evidence IIb);
Narrow-Complex Tachycardias hemodynamically stable or instable but resistant to electric cardioversion: TPSV
(Class of evidence IIa), atrial fibrillation (Class of evidence IIa), atrial tachycardia (Class of evidence IIb), atrial
tachycardia due to pre-excitation (Class of evidence IIb).

186
 Use of amiodarone in emergency

Table II. Most important side effects of amiodarone administration.

Side effects Amiodarone Frequency Method of Treatment

administration (%) diagnosis

Major effects
Proarrhythmia Short-term <1 ECG Stop amiodarone
Bradycardia Short-term 2 to 4 Physical examination, If severe, stop amiodarone
ECG and Insert pacemaker
Hypotension Short-term Unknown Physical examination, Stop/ reduce amiodarone
Blood pressure
Peripheral phlebitis Short term Unknown Physical examination Central vein cannulation
Pulmonary toxicity Long-term 2 to 17 Chest radiograph Stop amiodarone
Pulmonary function tests Corticosteroid therapy
Hyperthyroidism Long-term 1 to 23 FT3, FT4, TSH levels Antithyroid drug therapy
Stop amiodarone
Hypothyroidism Long-term 5 to 32 FT3, FT4, TSH levels Thyroid hormone therapy
Liver toxicity Long-term 1 Liver enzyme levels Stop amiodarone
(three times higher
than normal)
Optic neuropathy Long-term Unknown Ophthalmologic Stop amiodarone
examination

Minor effects
Nausea, anorexia Short-term 30 History, physical Reduce dosage
Long-term examination
Corneal microdeposits Long-term > 90 Slit-lamp examination None
Photosensitivity Long-term 4 to 9 History, physical Use sunblock
examination
Blue discoloration Long-term <9 Physical examination Reduce dosage
of skin

bition of the enzyme 5-monodeiodinase
type I that removes the iodine from the
fenolic T4 ring, forming T3, and resulting in
a relevant increase of the serum concentra-
tion of fT4 and the contemporary reduction
of fT3. Other effects are an alteration of the
reverse T3 due to a decreased clearance
and a change of serum levels of pituitary-
thyroid axis hormones with a TSH increase44.
Moreover, since amiodarone contains iodine
its administration may cause a modification
of the thyroid function, either hypothy-
roidism or thyrotoxicosis, especially at the
beginning of the treatment and on pre-exist-
ing thyroid disease (autoimmune thyroiditis
or nodular goiter)11.
Regarding liver dysfunction, some cases of
chronic hepatitis, with histopathological fea-
tures similar to alcoholic hepatitis, have been
observed. In patients with clear signs of liver
failure amiodarone is best avoided45.
After prolonged treatment it is possible
to observe corneal microstores, normally
asymptomatic which dont contraindicate
the continuation of the therapy. These mi-
crostores, formed by complex lipids, are ir-
reversible, even after treatment discontinu-
ation43.
Contraindications
Main contraindications to the iv adminis-
tration of amiodarone are synus bradycardia,
senoatrial block and severe conduction dis-
turbances like second or third degree atrio-
ventricular block. Other contraindications
are hypotension, severe respiratory failure,
thyroid disease, liver failure, cardiomyopathy
and cardiac failure. Amiodarone is best
avoided during pregnancy since it may induce
fetal thyroid diseases, and during breast-feed-
ing since significant amounts of amiodarone
are eliminated trough the breast milk during
the treatment (Table III).
Pharmacological Interactions
Administration of amiodarone in patients
taking HMG inhibitors-CoA reductase in-
hibitors, in particular simvastatin, may in-

187
 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri

Table III. Most important contraindications to acute
amiodarone administration.
Absolute contraindications
Bradycardia of the synus
Senoatrial block
Severe second or third degree atrio-ventricular
blocks (unless paced)
Pregnancy
Breast-feeding
Relative contraindications
Hypotension
Cardiomyopathy or cardiac failure
Severe respiratory failure
Thyroid disease
Hepatocellular failure
Possible drug interaction causing the risk of
torsades de point
crease the risk of myopathy. The daily intake
of simvastatin should not exceed in these cas-
es 20 mg/day46.
Potassium wasting diuretics and some class
I anti-arrhythmic agents may contribute to
prolong the QT interval and should therefore
be administrated cautiously in patients taking
amiodarone.
Amiodarone may increase the plasma level
of some anti-arrhythmic agents as chinidin,
procainamide, disopyramide and flecainide.
The interaction of amiodarone with non anti-
arrhythmic agents as vincamine, sultopride,
erythromycin iv and pentamidine iv, can raise
the risk of potentially lethal torsades de
pointes47.
Hypokaliemia may enhance the potential
pro-arrhythmic action of anti-arrhythmic
agents. Therefore, hypokaliemia should al-
ways be corrected before any amiodarone-
based treatment is started48.
Cardiopathic patients are often treated
with digoxin (whose clearance decreases
when associated with amiodarone49) and with
oral anticoagulants (whose anticoagulant ef-
fect increases after amiodarone administra-
tion48). Dose adjustment and frequent pro-
thrombin and electrocardiogram monitoring
is mandatory in these patients. Phenytoin and
cyclosporin plasma levels generally rise when
patients starts the treatment with amio-
darone. Careful clinical monitoring and
prompt dose adjustment, if needed, are indi-
cated in these patients50.
Severe adverse reactions are reported in
patients on amiodarone treatment undergo-
ing general anaesthesia: severe bradycardia
(not responsive to atropine), hypotension,
conduction disturbances and decrease of the
cardiac output. Some cases of severe respira-
tory failure were also reported, generally oc-
curring after surgery51 (Table IV).
In conclusion, amiodarone is a highly effec-
tive antiarrhythmic agent for many cardiac
arrhythmias, ranging from AF to malignant
ventricular tachyarrhythmias. It is considered
the antiarrhythmic drug of choice in treat-
ment of resistant VF or pulseless VT. It can
be safely administered in patients with organ-
ic cardiomyopathy or heart failure because it
shows only slight negative inotropic, dro-
motropic and chronotropic effects. Further-

Table IV. Most important pharmacological interactions of amiodarone.

Drug Result of interaction

Digoxin Elevated digoxin plasma concentration

Warfarin (Coumadin) Elevated prothrombin time
Simvastatin Increased incidence of myopathy if simvastatin dosage is > 20 mg per day
Sildenafil Increased sildenafil plasma concentration
Cyclosporine Increased cyclosporine plasma concentration
Antiarrhythmic drugs Additive effects: possible elevated plasma concentrations of quinidine,
disopyramide, flecainide, propafenone and dofetilide
Quinolones Additive QT effect: possible increased risk of proarrhythmia
Antidepressants Increased plasma concentration of hepatically metabolized drugs: possible
increased risk of proarrhythmia
Potassium-wasting drugs Additive QT effect: possible increased risk of proarrhytmia

188
 Use of amiodarone in emergency
more, amiodarone prevents the recurrence of
life-threatening ventricular arrhythmias and
produces a modest reduction of sudden
deaths in high-risk patients.
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