Side Effects of Amiodarone

The Essential to the Clinician

Dalmo A. R. Moreira M.D, PhD

Dante Pazzanese Institute of Cardiology
São Paulo, Brazil

Introduction
Amiodarone is an antiarrhythmic drug of the group III of the Vaughan Williams’
classification. It causes prolongation of action potential duration, specifically the
Phase 3, by blocking potassium channels, has discrete action in blocking the
sodium channels, discrete action of calcium channel blocker, and beta-blocker
effect, making it an antiarrhythmic action wider compared to other agents 1. It is
the most widely used antiarrhythmic drug for the treatment of supraventricular
and ventricular tachyarrhythmias, particularly in patients in whom
radiofrequency ablation as a means of definitive therapy, can not be employed
or is not successful, as can happen in patients with atrial fibrillation. It is an
effective drug as an adjuvant to the automatic cardioverter defibrillator (ICD) in
preventing sudden death in patients with complex ventricular arrhythmias.
Moreover, according to some meta-analysis, amiodarone is the leading
antiarrhythmic drug, and similar to what occurs with beta-blockers, is used to
reduce the risk of sudden death in selected cases, particularly in patients who
have no access to ICD therapy2.

Despite its widespread success, has side effects, cardiac and noncardiac, of
varying severity, that in some cases may limit its indication or even cause its
interruption1-4. Importantly in this regard is that such effects can be anticipated,
identified early and treated before any major damage can be caused to the
patient. Not using a drug so potent, simply on account of any potentially serious
side effects, would fail to bring benefits to patients with arrhythmias, whose
clinical significance varies with the type of heart disease present. Knowledge of
these concepts by clinicians prescribing amiodarone, increases the safety and
efficacy of treatment and provides to a larger number of patients to use this
drug.
An important concept related to antiarrhythmic treatment is that there is no cure
of an arrhythmia by the drug and that it should be used to delay or prevent the
onset of an arrhythmia, decreasing the frequency and duration of arrhythmic
recurrences, relieving symptoms and improving quality of life. In addition, many
arrhythmias such as atrial fibrillation and ventricular tachycardia, have several
extra-cardiac factors destabilizing the arrhythmogenic substrate, such as the
renin-angiotensin-aldosterone system, among others, and for this reason, drugs
without antiarrhythmic properties should be used together to improve treatment
success. This means a more extensive and modern treatment, ie not only
enhancing the action of an antiarrhythmic drug but considering the modulating
factors that facilitate the emergence of a cardiac rhythm disorder. From a
practical standpoint, when the patient needs to use amiodarone is because
other drugs have failed and a more potent and safe drug is indicated to ensure
its effective treatment. This monograph will discuss the main side effects of
amiodarone, its importance and how physicians should approach the patient
who makes use of this medicine.

Side Effects of Amiodarone

The adverse actions related to amiodarone are reported in almost all studies in
which this agent is employed, particularly with high doses (400 mg or more) at
up to 65% of patients with ventricular arrhythmias, prompting its suspension in 7
to 18% of cases3. It should be noted however, that the vast majority of these
effects is reversed with dose reduction or drug use interruption, and is rarely
associated with death.

The most severe side effects are pulmonary toxicity, liver injury and, less often,
worsening of ventricular arrhythmias. Other effects are less severe
cardiovascular, thyroid, skin, eye, neurological and gastrointestinal.

Pulmonary Toxicity
The incidence of pulmonary adverse effects caused by amiodarone is between
1% and 17% of the cases 1, 3,5. There is a pulmonary inflammatory process, with
inclusion of phospholipids in the alveoli followed by chronic pulmonary fibrosis.
This complication can be fatal if not suspected, diagnosed and treated early. An
interesting finding is that consumption of up to 200 mg daily dose usually
employed to prevent recurrent atrial fibrillation, the incidence of interstitial
pneumonitis varies between 0.1% to 0.5% and between 5% to 15% of patients
taking 500 mg or more3. For this reason in cases of clinical suspicion, the drug
should be discontinued and treatment implemented. There is still controversy
wether the chronic obstructive lung disease is a risk factor for interstitial
pneumonitis. A sub-analysis of the AFFIRM study involving elderly patients with
atrial fibrillation, Olshansky et al. demonstrated that with the dose used in that
study, the presence of pulmonary disease did not increase the risk of pulmonary
complications caused by amiodarona6. This complication usually occurs in
older people (rarely below 40 years of age) has a peak incidence during the first
year of the drug (ranging from 6 days to 60 months) and rarely with doses
below 300 mg / day.

The suspicion of this complication is raised, usually after the second month of
treatment, if the patients taking 400 mg or more (although there are reports
showing the similar effects of a dose of 200 mg a day 5) and who present with
cough, dyspnea, weight loss and sometimes fever. Wheezing, bronchospasm,
hemoptysis and respiratory failure may be other clinical findings in this
condition. Often a diagnosis is consolidated with the presence of cottony
infiltrates in the lung parenchyma on chest X-rays, and characteristic finding in
computed tomography (interstitial and alveolar infiltrate, followed by alveolar
opacification and bronchial wall thickening). The treatment is based on the
suspension of the drug and administration of corticosteroids. The clinical
remission occurs in up to 30 days with restoration of normal lung. The success
in addressing this complication is related to clinical suspicion, early diagnosis by
means of complementary examinations and the corresponding treatment with
corticosteroids.

Endocrine Changes

Thyroid
Amiodarone has a high content of iodine in its molecule, and for that reason it
would not be a surprise documentation of thyroid abnormalities caused by this
agent. These changes may occur in up to 30% of patients with or without history
of thyroid disease. Manifest themselves at any time of treatment or even after
its withdrawal. Amiodarone interferes with the conversion of T4 to T3 by
blocking the enzyme 5'deiodinase, thereby increasing plasma levels of reverse
T3, an inactive hormone.

Hypothyroidism occurs in up to 8% of patients. It is more common in areas

where the supply of iodine in the diet is normal 1, 3. This complication is more
common in women and elderly and the clinical manifestations are fatigue,
lethargy, cold intolerance, dry skin, constipation, weight gain and loss of
appetite, classical findings related to deficiency of thyroid hormone. The
treatment is based on reducing the dose of medication or even its suspension. If
no satisfactory results are obtained this will indicate hormone replacement with
levothyroxine.

Thyrotoxicosis is rarer (0.9% to 2%), most frequently in areas where there is

deficiency of iodine in the diet1, 3. There are two types: type I, which occurs in
patients with previous history of thyroid disease (Graves' disease, eg.) and type
2, which occurs in individuals without a history of tireopathy 3. In type I can occur
elevation of plasma levels of interleukin 6, the uptake of radioactive iodine by
the gland is normal or slightly elevated. Thyrotoxicosis Type 2 may be related to
an inflammation of the thyroid caused by cytotoxic effects of amiodarone and its
metabolites on the gland, resulting in tissue damage and "leakage" of the
hormone into the circulation systemically3. For this reason the levels of
interleukin 6 are very high and the uptake of radioactive iodine by the thyroid is
low. The clinical manifestations of hyperthyroidism include palpitations,
increased recurrence of atrial fibrillation in previously stable patients, weight
loss, sweating, muscle weakness, tremors and insomnia. The treatment is
based on withdrawal of amiodarone and specific therapy with corticosteroids.

Abnormal Secretion of Antidiuretic Hormone

It is a rare complication with the use of amiodarone 3. Patients affected are
usually elderly and evolving with hyponatremia. This effect can occur even in
the impregnation phase of the drug. Dose reduction and its suspension rarely
resolves the clinical picture.

Neurological effects

Tremors, ataxia and peripheral neuropathy have been reported (3% to 35% of
cases) in patients with chronic use of amiodarone, usually with doses above
400 mg daily. Less common findings include diplopia, disorientation or
confusion, paraesthesia and headache. These effects improved with dose
reduction or discontinuation of treatment1.3 .

Ophthalmologic Effects

 Crystals in the cornea are found in up to 95% of patients taking amiodarone. Its
detection does not imply a need to discontinue the drug because they rarely
compromise the vision. The use of eye drops has not proven useful in these
cases. Optic neuritis (<1% to 2% of cases) or inflammatory involvement of the
retina are rare but once diagnosed indicate the suspension of the drug 1, 3.

Dermatologic changes

The skin photosensitivity may occur in 25% to 75% of cases. A bluish

discoloration of the skin (up to 9% of cases) especially in the face, except for
cosmetic problem, rarely causes complications. When these dermatologic
changes are found, the reduction of sun exposure and use of sunscreen creams
are indicated1.3 .

Liver Side Effects

Amiodarone rarely causes liver damage however, may cause asymptomatic

elevations of plasma levels of liver enzymes in 15% to 30% of cases, hepatitis
and cirrhosis occur in <3% of patients. Periodic evaluations of liver function are
indicated, particularly whith the onset of symptoms of hepatic insufficiency or
icterícia1,3,4.

Gastrointestinal Side Effects

Anorexia, metallic taste, constipation, nausea and vomiting have been reported
in about 2% to 20% of patients using amiodarone. Are tolerated and rarely
necessitate the suspension of the drug3 .

Renal and Genitourinary Side Effects

Amiodarone can cause elevation of about 15% of serum creatinine, but not
indicating renal failure and may be related to the decrease of its tubular
secretion. No need to discontinue the drug. Epididymitis, testicular dysfunction
and impotence have been reported rarely with amiodarone, occurring in patients
with doses above 400 mg3, 4 .

Cardiac Side Effects

Amiodarone may cause bradycardia due to its effects in the sinus node or
atrioventricular block triggered by action on the atrioventricular node, especially
in patients with sinus node dysfunction and just borderline node conduction.
This effect is stronger when amiodarone is associated with digitalis, beta-
blockers or calcium channel antagonists. Oral amiodarone has no negative
inotropic effect, quite the contrary, may even improve the ejection fraction due
to the prolongation of plateau phase of action potential, which improves the
supply of calcium to the myocyte. Despite causing QT prolongation, the rate of
appearance of polymorphic ventricular tachycardia torsades de pointes-type is
low (around 0.5%), which makes amiodarone a safe drug in patients with
ventricular dysfunction. This is the only drug that can be prescribed to patients
with heart failure, manly for prevention of atrial fibrillation recurrences or
treatment of complex ventricular arrhythmia.

In conclusion, the cardiac and extra-cardiac side effects can occur in patients
taking amiodarone, usually associated with ingestion of doses above 400 mg,
but may also occur with smaller doses, but on a shorter scale. The use of
amiodarone associated with other drugs, such as a beta-blocker, an angiotensin
converting enzyme inhibitor or even an angiotensin receptor blocker, may
improve its therapeutic efficacy and reduce the risk of serious side effects by
allowing use of smaller doses. The patient should be evaluated periodically,
every six months, including a clinic visit, the performance of chest X-rays, blood
tests to investigate thyroid, liver and kidney function, which are important steps
in the clinical follow-up of patients who takes this wide spectrum and highly
efficacious drug. It is known that side effects exist but mainly the most serious
the clinician should be aware of since they are expected to happen. Doctors
must learn to make the diagnosis with the appropriate complementary
investigation and treat them as early as possible 1, 3.4. In large studies recently
published, there are no reports of deaths caused by amiodarone, just by
evaluating the patients periodically and perform its suspension when its judged
necessary7.
                                           References

1-Vassallo P, Trohman RG. Prescribing amiodarone. An evidence-based review

of clinical Indications. JAMA 2007, 298:1312-1322.
2-Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety.
Circulation 1999, 100:2025-2034.
3 - http://www.drugs.com/sfx/amiodarone-side-effects.html (accessed
28/08/2009)
4-Goldschlager N, Epstein A, Naccarelli G, Olshansky B, patients suffering from
amiodarone. Arch Intern Med 000, 160: 1741-8.
5-MC Ott, Khoor A, Leventhal JP, et al. Pulmonary toxicity in patients receiving
low-dose amiodarone. Chest. 2003, 123: 646-651
6 - Olshansky B, Sami M, Rubin A, et al. Use of amiodarone for atrial fibrillation
in patients suffering from preexisting pulmonary disease in the AFFIRM study.
Am J Cardiol 2005, 95:404-405.
7-Roy D, TalajicM, DorianP, Connolly S, EisenbergM, Greenmar et al.
Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000, 342:
913-20.