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European Review for Medical and Pharmacological Sciences
2005; 9: 183-190
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 anti-arrhythmic of first choice. Amiodarone is also
first choice drug in the treatment of various ventricular and supra-ventricular tachyarrhythmias.
This paper deals with the main therapeutical indications of amiodarone in emergency medicine: dosage, side effects, contraindications and
pharmacological interactions are reviewed.
Amiodarone is effective for control of hemodynamically stable VT, polymorphic VT and widecomplex tachycardia of uncertain origin. It is also helpful for ventricular rate control of rapid
atrial arrhythmias in patients with severely impaired left ventricular (LV) function, when digitalis has been ineffective, and is an adjunct to electrical 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-ventricular blocks. Other contraindications are hypotension, severe respiratory failure, hepatocellular failure and hyperthyroidism. Pharmacological interactions are reported with HMG-CoA reductase inhibitors, class I antiarrhythmic agents
and other drugs which contribute to prolong QT
interval, digoxin, oral anticoagulants and general anaesthesia.
Key Words:
Amiodarone, Emergency, Arrhythmias, Tachycardias, Cardiac arrest, Ventricular tachycardia, Atrial fibrillation.
drugs, frequently used in the Emergency Department. In the last decade many trials and
meta-analysis described amiodarone as antiarrhythmic agent of first choice in the treatment of hemodynamically unstable ventricular tachycardia (VT), of hemodynamically
stable wide-complex tachycardias 1, and of
many supraventricular tachyarrhythmias1,2.
The European Resuscitation Council recommends 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 frequent or repetitive extra systolic beats and/or
VT4 or presenting low left ventricular ejection fraction (below 40%)5.
Up to 2% of the patients admitted to the
Emergency Department present tachyarrhythmias. In more than 90% these are
narrow QRS arrhythmias, such as atrial fibrillation (AF) (45%), paroxysmal supraventricular tachycardia (35%) and atrial flutter
(8%). Around 50% of large QRS tachyarrhythmias are supraventricular tachycardias. VT are in most cases hemodynamically
stable, while only a small part of large QRS
tachyarrhythmia are hemodynamically unstable VT or shockable cardiac arrest (VF/pulseless 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
Introduction
Amiodarone, a derivative of benzofuran, is
one of the most common anti-arrhythmic
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 induced by circulating catecholamines. These
effects contribute to the anti-arrhythmic and
anti-anginal properties of amiodarone7. After
amiodarone administration there is no significant decrease of the myocardial contractility8.
The most relevant effects of amiodarone
on cardiac cells are the reduction of the depolarization (phase 4)9, the late repolarization,
caused by a prolongation of the action potential (phase 3) and the prolongation of the effective refractory period10. Therefore amiodarone is included among class III anti-arrhythmic 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 homogeneity.
Mechanisms of Action
Some chemical peculiarities of the drug
(high iodine’s content and structural analogies with thyroid hormones) suggested possible 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 hypothyroidism 12,13. Actually, it has been shown a
competition or an interaction between amiodarone and the thyroid hormones at many
levels (i.e. deiodases, trans-membrane ionic
channels)14,15. Two main mechanisms concerning the antiarrhythmic activity of amiodarone
have been suggested:
• The “T3-mediated” hypothesis: amiodarone antagonizes the thyroid hormones
on the nuclear receptor and/or on transmembrane carrier of T3 at cardiac level 16,17 . This T3-mediated mechanism
could explain the non-competitive adrenergic block of amiodarone.
•The “Membrane-active” hypothesis: amiodarone impairs the lipid environment of
the cell membranes where the main ionic
channels are located, directly modulating
the ionic myocardial transmembran currents18-20.
184
Pharmacokynetic Properties
Amiodarone’s 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 therapeutic response during oral treatment21.
After intravenous (iv) administration plasma peak concentration is reached in 6-8
hours. Drug tissue distribution occurs differently after acute administration (lungs, liver,
heart and kidney) 22 and after the achievement 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-desethyl-amiodarone (DEA) is its main active
metabolite. After a single oral dose, amiodarone’s half life is calculated to be around 24
h, during long-term therapy it increases
reaching 28 days21; while DEA’s half life is
around 60 days23.
Therapeutic Indications in Emergency
Cardiac Arrest With Shockable Rhythm
(Refractory FV/Pulseless VT)
The Resuscitation 2000 Guidelines recommend 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 resurrection procedure, evidence supports its use after epinephrine administration in the treatment of shock-refractory cardiac arrest due
to VF or pulseless VT (Class of evidence
IIb)25. Some studies demonstrate that amiodarone, like any other antiarrhythmic agent,
must be given before the fourth shock in order to be effective.
In patients with out-of-hospital cardiac arrest, due to refractory ventricular arrhythmias, treatment with amiodarone resulted in
Use of amiodarone in emergency
a higher rate of survival to hospital admission. Whether this benefit extends to survival
to discharge from the hospital merits further
investigation26.
In the CASCADE trial, carried out in survivors of cardiac arrest, the administration of
amiodarone in patients with an implanted automatic 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 maximum daily dose of 2 g. This maximum dose
is larger than the current European
datasheet recommendation of 1.2 g. Preloaded 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 stable” if there are no symptoms or clinical evidence of tissue hypoperfusion or shock. On
the contrary “hemodynamically unstable” VT
requires immediate resolution through synchronized cardioversion.
In all patients with unstable hemodynamics, immediate direct current (DC)-cardioversion is indicated. In particular, hemodynamically unstable large QRS complex tachycardia should be treated with a series of three
synchronized shocks29. Pharmacological treatment with amiodarone is indicated only after
failure of electrical cardioversion. Many studies evaluated amiodarone for the treatment
of hemodynamically unstable VT. Patients
with clinical congestive heart failure or depressed left ventricular (LV) function should
be treated cautiously with antiarrhythmic
therapy. In these patients, many antiarrhythmic agents depress LV function precipitating
or worsening congestive heart failure. Amiodarone and lidocaine cause the least additional impairment of LV function30. Because of its
broad antiarrhythmic spectrum and lesser
negative inotropic effect, amiodarone is commonly used in these cases.
Empirical pharmacological therapy may be
necessary for a hemodynamically stable wide-
complex tachycardia of unknown origin. Procainamide, amiodarone, and sotalol are effective in the treatment of VT and supraventricular tachycardias with an accessory pathway
conduction. On the other hand, depressants
of the AV node conduction (such as adenosine, beta-adrenergic receptor blockers, and
calcium channel blockers) are hazardous in
patients with preexcited atrial arrhythmias.
Therefore, the therapeutic options are reduced to DC cardioversion, or procainamide
or amiodarone. At presentation in the Emergency Department, most of the patients with
VT are hemodynamically stable, thus allowing first-line antiarrhythmic drug administration. 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 available in the Emergency Department.
When electrical cardioversion is not appropriated, possible therapeutic options are:
procainamide (Class of evidence IIa), sotalol
(Class of evidence IIa), amiodarone (Class of
evidence IIb), or disopyramide (Class of evidence IIb)32.
In stable and unstable large QRS tachycardias, amiodarone should be administered at a
loading dose of 150 mg diluted with 5% dextrose for slow bolus injection (10 min) in peripheral 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 therapeutic effects should become evident already
in the first few minutes, and decrease progressively 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) diluted in 500 ml of dextrose 5%28.
Narrow-Complex Tachycardias
(Supraventricular Arrhythmias)
Supraventricular arrhythmias include
supraventricular tachycardia, atrial extrasystole, atrial flutter, AF, supraventricular
paroxysmal reciprocant tachycardias as the
Wolff-Parkinson-White syndrome.
In the supraventricular paroxysmal tachycardia, amiodarone is effective because it depresses the conduction through the accessory
pathway (Class of evidence IIa). Amiodarone becomes the antiarrhythmic agent of
185
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 ventricular 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 amiodarone as a first-line drug37. AF in young patients, 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 hospitalization 38. Since amiodarone shows only
slight inotropic, dromotropic and chronotropic negative effects, it can be safely administered in patients with organic cardiomyopathy or heart failure in an Emergency Unit34-36.
Pre-treatment with amiodarone the month
before a planned electric cardioversion in patients with AF lasting more than 48 h increases 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 precipitated by an episode of atrioventricular re-entrant tachycardia. In patients with short accessory-pathway refractory periods and
rapid ventricular rates during AF, class I antiarrhythmic drugs that lengthen the refractory 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 symptomatic patients. However, the risk of ventricular arrhythmias and the occurrence of side
effects limit their usefulness 40 . Radiofrequency ablation should be the treatment of
choice in Wolff-Parkinson-White syndrome
and symptomatic atrioventricular re-entrant
tachycardia.
As for large QRS tachycardias, amiodarone’s loading is 150 mg diluted with 5%
dextrose in slow bolus injection (10 min), followed if necessary by a second dose of 150
mg. The maintenance dose ranges between
10 and 20 mg/kg over 24 hours28. Table I summarizes the main therapeutic indication of
amiodarone in emergency.
Side Effects, Contraindications and
Pharmacological Interactions
Side Effects
Acute adverse effects of amiodarone include hypotension, bradycardia, chemical peripheral phlebitis and nausea41. Hypotension
was the most common adverse event reported 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 presenting 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 hormones. 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
administration
Frequency
(%)
Major effects
Proarrhythmia
Bradycardia
Short-term
Short-term
<1
2 to 4
Hypotension
Short-term
Unknown
Peripheral phlebitis
Pulmonary toxicity
Short term
Long-term
Unknown
2 to 17
Hyperthyroidism
Long-term
1 to 23
Hypothyroidism
Liver toxicity
Long-term
Long-term
5 to 32
1
Optic neuropathy
Long-term
Unknown
Short-term
Long-term
Long-term
Long-term
30
Long-term
<9
Minor effects
Nausea, anorexia
Corneal microdeposits
Photosensitivity
Blue discoloration
of skin
> 90
4 to 9
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 concentration 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 pituitarythyroid axis hormones with a TSH increase44.
Moreover, since amiodarone contains iodine
its administration may cause a modification
of the thyroid function, either hypothyroidism or thyrotoxicosis, especially at the
beginning of the treatment and on pre-existing thyroid disease (autoimmune thyroiditis
or nodular goiter)11.
Regarding liver dysfunction, some cases of
chronic hepatitis, with histopathological features 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 don’t contraindicate
Method of
diagnosis
ECG
Physical examination,
ECG
Physical examination,
Blood pressure
Physical examination
Chest radiograph
Pulmonary function tests
FT3, FT4, TSH levels
FT3, FT4, TSH levels
Liver enzyme levels
(three times higher
than normal)
Ophthalmologic
examination
History, physical
examination
Slit-lamp examination
History, physical
examination
Physical examination
Treatment
Stop amiodarone
If severe, stop amiodarone
and Insert pacemaker
Stop/ reduce amiodarone
Central vein cannulation
Stop amiodarone
Corticosteroid therapy
Antithyroid drug therapy
Stop amiodarone
Thyroid hormone therapy
Stop amiodarone
Stop amiodarone
Reduce dosage
None
Use sunblock
Reduce dosage
the continuation of the therapy. These microstores, formed by complex lipids, are irreversible, even after treatment discontinuation43.
Contraindications
Main contraindications to the iv administration of amiodarone are synus bradycardia,
senoatrial block and severe conduction disturbances like second or third degree atrioventricular 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-feeding 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 inhibitors, in particular simvastatin, may in187
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 cases 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 antiarrhythmic 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 always be corrected before any amiodaronebased treatment is started48.
Cardiopathic patients are often treated
with digoxin (whose clearance decreases
when associated with amiodarone49) and with
oral anticoagulants (whose anticoagulant effect increases after amiodarone administration48). Dose adjustment and frequent prothrombin and electrocardiogram monitoring
is mandatory in these patients. Phenytoin and
cyclosporin plasma levels generally rise when
patients starts the treatment with amiodarone. Careful clinical monitoring and
prompt dose adjustment, if needed, are indicated in these patients50.
Severe adverse reactions are reported in
patients on amiodarone treatment undergoing general anaesthesia: severe bradycardia
(not responsive to atropine), hypotension,
conduction disturbances and decrease of the
cardiac output. Some cases of severe respiratory failure were also reported, generally occurring after surgery51 (Table IV).
In conclusion, amiodarone is a highly effective antiarrhythmic agent for many cardiac
arrhythmias, ranging from AF to malignant
ventricular tachyarrhythmias. It is considered
the antiarrhythmic drug of choice in treatment of resistant VF or pulseless VT. It can
be safely administered in patients with organic cardiomyopathy or heart failure because it
shows only slight negative inotropic, dromotropic and chronotropic effects. Further-
Table IV. Most important pharmacological interactions of amiodarone.
Drug
Digoxin
Warfarin (Coumadin)
Simvastatin
Sildenafil
Cyclosporine
Antiarrhythmic drugs
Quinolones
Antidepressants
Potassium-wasting drugs
188
Result of interaction
Elevated digoxin plasma concentration
Elevated prothrombin time
Increased incidence of myopathy if simvastatin dosage is > 20 mg per day
Increased sildenafil plasma concentration
Increased cyclosporine plasma concentration
Additive effects: possible elevated plasma concentrations of quinidine,
disopyramide, flecainide, propafenone and dofetilide
Additive QT effect: possible increased risk of proarrhythmia
Increased plasma concentration of hepatically metabolized drugs: possible
increased risk of proarrhythmia
Additive QT effect: possible increased risk of proarrhytmia
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.
13) YIN Y, VASSY R, NICOLAS P, PERRET GY, LAURENT S. Antagonism between T3 and amiodarone on the
contractility and the density of beta-adrenoceptor
on chicken cardiac myocytes. Eur J Pharmacol
1994; 261: 97-104
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