Major side effects of presently

available antiarrhythmic drugs

Samir Morcos Rafla, MD, FESC

Prof. of Cardiology. Alexandria Univ. Egypt

XIV International Symposium on Progress in Clinical Pacing

Dec 1 2010

smrafla@hotmail.com
Antiarrhythmic Drugs
Class I — Sodium channel blockers
Disopyramide (Norpace®)
Flecainide (TambocorTM)
Lidocaine (Xylocaine®)
Mexiletine (Mexitel®)
Moricizine (Ethmozine®)
Procainamide (Procan®, Procanabid®, Pronestyl®)
Propafenone (Rythmol®)
Quinidine (Cardioquin®, Quinaglute Dura-Tabs®)
Tocainide (Tonocard®)
Class II — Beta blockers

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Class III — Potassium channel blockers
Amiodarone (Cordarone®, Pacerone®)
Sotalol (Betapace)
Azimilide (StedicorTM)
Dofetilide (Tikosyn®)
Ibutilide (Corvert®)
Tedisamil (Pulsium®)
Dronedarone (Multaq)
Vernakalant (iv) (BRINAVESS) (Merck, MSD)
Nifakalant
Class IV — Calcium channel blockers
Miscellaneous
Adenosine (Adenocard®), Digoxin (Lanoxin®)
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Quinidine: ADVERSE EFFECTS
The most common adverse effects of chronic
oral quinidine therapy are gastrointestinal and
include nausea, vomiting, diarrhea. CNS
toxicity includes tinnitus, hearing loss,
psychosis (cinchonism).

Allergic reactions may be manifested as rash,

fever, immune-mediated thrombocytopenia,
hemolytic anemia. Side effects may preclude
long-term administration of quinidine in 30 to
40 % of patients.
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Quinidine can slow cardiac conduction,
sometimes to the point of block.
Quinidine can produce syncope in 0.5 to 2.0
percent of patients, most often the result of a
self-terminating episode of torsades de pointes.

Quinidine prolongs the QT interval in most

patients, whether or not ventricular arrhythmias
occur, but significant QT prolongation (QT
interval of 500 to 600 milliseconds) is often a
characteristic of patients with quinidine
syncope.
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 Amiodarone Side Effect Profile
Serious Side Effects Minor Side Effects
Pulmonary 2-17% Nausea 30%
Hyperthyroid 2% Corneal Deposits >90%
Hypothyroid 6% Photosensitivity 4-9%
Liver toxicity 1% Blue Skin <9%
Optic Neuropathy 1.8%
Proarrhythmia <1%
 Amiodarone – a breakdown…
In the United States the
37% of amiodarone’s recommended daily allowance
mass is organic iodine. (RDA) is
(that is 444mg with a infants 0-6 months is 110 mcg
loading dose of 1-8 years old, 90 mcg
amiodarone – 400mg PO 9-13 years, 120 mcg
TID) 14 and older, 150 mcg
– Of this amount 10% is The Food and Nutrition Board
free iodide (that is also sets the tolerable upper
44mg of free iodide limits of the daily iodine
daily) intake as 1.1 mg (1100 mcg) for
adults, with proportionately
lower levels for younger age
groups.
 Amiodarone-Induced Thyrotoxicosis
Type I – patients with Type II – patients with
latent thyroid disorders previously normal
– Caused by excessive, thyroid glands
uncontrolled synthesis – Direct cytotoxic
of thyroid hormone effect on thryoid
by autonomously follicles resulting in
functioning tissue in a destructive
response to iodine. inflammatory
thyroiditis
 Discerning Type I vs. II

Type I Type II
– Antimicrosomal Ab – Elevated
– Antithyroglobulin Ab Thyroglobulin
– Anti-receptor Ab – Elevated IL-6
– Normal to slightly – Color flow Doppler
elevated IL-6 reveals Pattern 0
– Color Flow Doppler (absent vascularity,
reveals pattern 1, gland destruction)
pattern 2 or pattern 3
 Medical Treatment
Type I Type II
– Treat with a – Glucocorticoids are
thionamide – since it used for anti-
is associated with inflammatory and
increased hormone membrane
synthesis (PTU or stabalizing
methimazole 30mg properties
per day) (prednisone 30-
– Can use potassium 40mg/day)
perchlorate (200mg -
1000mg per day)

Pitfalls to Treatment:
 Torsade de Pointes
Occurs in 1% of patients taking Amiodarone
Predisposing conditions
– LVH, congestive heart failure
– Bradycardia
– Hypokalemia
– Hypomagnesemia
– Digitalis therapy
– Baseline QT prolongation
– High drug concentration (except quinidine)
Patient Who Was Treated with Amiodarone
for Atrial Fibrillation
 Treatment of Torsade de Pointes

Remove offending Isoproterenol

agent – Increases rate and
Temporary ventricular decreases QT
or atrial pacing interval
Lidocaine
Mexiletine
Phenytoin
Magnesium
 Optic Neuropathy
Ocular side effects
– Corneal microdeposits – 70-100%
of patients
– Dry Eye Syndrome
– Anterior Lens opacities
– Optic Neuropathy – 1-2% of
patients
Results in optic disc swelling
Associated with visual field deficit
Can result in permanent visual loss
Blue-gray discoloration of the nose, cheeks, and
lips, sparing the deep skin folds

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Pulmonary fibrosis that can be irreversible and life
threatening - unusual at doses used for atrial
fibrillation (200 mg/day)
N Engl J Med 1997; 337:1814
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 Amiodarone: Drug Interactions of Note

Inhibits metabolism through cytochrome P450

- Inhibits metabolization of warfarin,
narcotics, several B-blockers and calcium
channel blockers
- Doubles dig level typically during co-
administration. Should reduce dig dose by
50%
Digitalis
Digitalis enhances vagal activity and thus
slows sinus node automaticity and prolongs AV
nodal conduction and refractoriness. Digitalis
inhibits the sarcolemmal Na+-K+-ATPase
leading to an increase in intracellular calcium
that may promote proarrhythmias.
Hypokalemia augments digitalis toxicity.

Tocainide (Tonocard) is a class Ib

antiarrhythmic agent. It is no longer sold in the
United States.
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Porto-marina Beach - Egypt 19
 Dronedarone - Adverse Events
DRONEDARONE PLACEBO
VARIABLE P value
N=828 N=409
Stroke 4 (0.5) 3 (0.7) 0.69
Cough 19 (2.3) 7(1.7) 0.67
Dyspnea

Hyperthyroidism 67/801 (8.4) 56/396 (14.1) 0.002

Hypothyroidism 44/801 (5.5 14/396 (3.5) 0.15

Abnormal LFTs 100/822 (12.2) 55/404(13.6) 0.52

Elev of Serum 20 (2.4) 1 (0.2) 0.004

Creatinine
Bradycardia 22 (2.7) 8 (2.2) 0.56
Heart Failure 20 (2.4) 4 (1.0) 0.12
 Dronedarone - ATHENA: Summary
Dronedarone significantly prolongs time to first CV
hospitalization or death in moderate- to high-risk AF
patients
All-cause mortality was not increased in patients
receiving dronedarone
CV mortality was lower in the dronedarone compared
to the placebo group
The reduction in CV hospitalization was mainly due to
fewer admissions for AF and acute coronary
syndromes
The application of Dronedarone may be useful in low
risk patients (NYHA Class I and II)

Hohnloser SH. Heart Rhythm Society 2008 Scientific Sessions;

May 15, 2008; San Francisco, CA.
 ATHENA Trial: Adverse Events
Increased Blood Creatinine (%)

5% 4.7% Patients treated •

with Multaq®
4% (dronedarone)
3% demonstrated
increased serum
2% creatinine more
1.0% frequently than
1%
those given
0% placebo.
Placebo Multaq®
(dronedarone)

JCE 2008; 19.1/Heart Rhythm 2008

Copyleft Clinical Trial Results. You Must Redistribute Slides
 Disopyramide (Norpace) sideffects
1. Anticholinergic side-effects
2. Induction of ventricular arrhythmias in
patients with prolonged QT interval
3. Similar to quinidine, disopyramide may
induce ventricular arrhythmia if used alone in
the treatment of fibrillation.
- Due to its negative inotropic effects,
disopyramide may reduce left ventricular out-
flow gradient and improve symptoms in
patients with obstructive hypertrophic
cardiomyopathy.
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 Procainamide - sideffects
At high levels, asystole or induction of
ventricular arrhythmias
Hypersensitivity reactions including drug fever
and rarely agranulocytosis.
Systemic lupus erythromatosus (SLE)-like
(arthralgia, fever & pleural-pericardial
inflammation)
The SLE is dose- and time-dependent, and
usually disappears upon drug stop
It is most common in patients with slow
hepatic acetylation resulting in higher plasma
level of the parent drug. 24
 Flecainide (Tambocor) & propafenone
(Rythmol®) Toxicity and Cautions for Class
IC Drugs:
 They are severe proarrhythmic drugs causing
severe worsening of a preexisting arrhythmia or
de novo occurrence of life-threatening
ventricular tachycardia
 In patients with frequent PVCs following MI,
flecainide increased mortality compared to
placebo
Notice: Class 1C drugs are particularly of
low safety and have shown even to increase
mortality when used chronically after MI.
in the Cardiac Arrhythmia Suppression
Trial (CAST), researchers found that
encainide and flecainide reduced
spontaneous ventricular arrhythmias but
were associated with a total mortality of 7.7
percent, in comparison with 3.0 percent in
the group receiving placebo.

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 Class IV ANTIARRHYTHMIC DRUGS

- Verapamil & diltiazem Both drugs are

contraindicated patients with pre-existing
depressed heart function because of their
negative inotropic activity

- Both drugs may cause bradycardia, and

asystole especially when given in combination
with β-adrenergic blockers.
 Adenosine (Adenocard)
- Adenosine activates A1-purinergic receptors
decreasing the SA nodal firing and automaticity.
- It is the drug of choice in treatment of SVT
Toxicity :
– AFib/ sinus arrest/ sinus bradycardia
– Bronchospasm
– Flushing/headache, Nausea
– The negative dromotropic effects may lead to
transient complete AV block.
Alexandria: Qaitbay Citadel. 15th century
Physicians should be cautious when selecting
AADs for treatment of AF seen in association
with WPWs. In pts with WPWs , during an
episode of AF, atrial impulses can bypass the
AV node and propagates to the ventricles
directly via accessory pathway, leading to
irregular, fast and wide complex tachycardia.
Pts suspected of having this condition should
not receive IV calcium blockers , B blockers or
digoxin.
IV propafenone is the plausible choice

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With Sotalol (Betapace) and Dofetilide
(Tikosyn), the QT interval should be monitored
carefully during drug loading. Serum potassium
levels should also be watched carefully; in fact,
one should use torsades de pointes producing
agents with caution in patients requiring
potassium-wasting diuretics.

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Sotalol (Betapace)
Sotalol is a class III agent that blocks IKr and
also a β-blocker that is useful in AF/atrial flutter
and monomorphic ventricular tachycardia.
Sotalol should preferably be initiated in-hospital
to monitor for severe bradycardia,
atrioventricular block, and QT prolongation.
Because sotalol is primarily excreted
unchanged in the urine, dose adjustment is
needed in patients with renal insufficiency.

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Dofetilide (Tikosyn) had no effect on cardiac
output, cardiac index, stroke volume index, or
systemic vascular resistance in patients with
ventricular tachycardia, mild to moderate
congestive heart failure or angina and either
normal or low left ventricular ejection fraction.

Because increase in QT interval and the risk of

ventricular arrhythmias are directly related to
plasma concentrations of dofetilide, dosage
adjustment based on calculated creatinine
clearance is critically important
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Dofetilide: Dose-Effect on TdP and VF*
Incidence of TdP or VF 12 TdP (%) 10.5
VF (%)
8

4
0.3 0.9
0
0
<250 250 500 >500
mcg mcg mcg mcg
BID BID BID BID
Dofetilide Dose
*NDA SVA Population N=1,346
FDA 7.00
Azimilide (StedicorTM) was generally well tolerated in
trials. However neutropenia was seen in 1% of pts.
Torsades de pointes occurred at a rate of 0.3%, 1.2%,
and 0.6% in pts receiving daily azimilide of 75, 100,
and 125 mg respectively.

In the A-COMET II study, 7.6 % of pts taking azimilide

developed QTc prolongation compared with only
3.5% in the sotalol group ; torsades de pointes was
reported in 2.4% of azimilide recipients.
The relatively modest efficacy of azimilide coupled
with the risk of toxicity make it unlikely to become
available for treatment of AF.
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Tedisamil (Pulsium®): Preliminary clinical data
suggest that tedisamil administration IV
effectively terminated AF but is associated with
the risk of QT prolongation and torsades de
pointes .

In multicenter study, there were 2 cases of self-

terminating V tach. observed in pts receiving
tedisamil at a dose of 0.6 mg/kg.

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Ras Sidr Beach. Egypt 38
 Atrial Specific AADs

Vernakalant: Vernakalant has a unique ion

channel-blocking profile. The agent is a sodium
channel blocker (I Na) and a potassium
channel blocker.

In ACT study, adverse events were reported in

32% of placebo recipients and 38% of
Vernakalant recipients. No deaths or torsade
de points were reported.
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Vernakalant BRINAVESS is contraindicated
in patients with severe aortic stenosis, systolic
BP<100 mm Hg, and heart failure class III and
IV.
Vernakalant is contraindicated in patients with
prolonged QT at baseline (uncorrected >440
msec), severe bradycardia, sinus node
dysfunction, or second-degree or third-degree
heart block in the absence of a pacemaker.

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Vernakalant is also contraindictated in patients
who use IV rhythm control antiarrhythmics
(class I and class III) within 4 hours prior to
administration of Vernakalant and patients with
acute coronary syndrome (including myocardial
infarction) within the last 30 days.

Adverse reactions (>5%) seen in the first 24

hours after receiving Vernakalant were taste
disturbance (20.1%), sneezing (14.6%), and
paraesthesia (9.7%).
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Nifekalant tops lidocaine for shock-resistant
ventricular arrhythmia
Administration of either nifekalant or amiodarone
before defibrillation increased the restoration of
spontaneous circulation (ROSC) and 24-h survival
rates and improved post-resuscitation cardiac
function in porcine model.
Side-effects: QT prolongation in one patient. No
other side-effects were observed in other patients,
such as deteriorated blood pressure, breath rate,
and rales. No significant changes were found in
blood test of liver and kidney functions before and 12
hours after stopping infusing NIF. Chin Med J
2010;123(15):2028
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Administrating Nifekalant
terminated sustained
ventricular tachycardia.

Maximum QT at lead V4
600 ms, minimum at lead
V5 520 ms, which were
measured between the 2
red lines
Chin Med J 2010;123(15):2028-
2033

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 Relative risk of drug-induced proarrhythmia

Drug Risk of Risk of torsades

exacerbation of de pointes
reentry
Class IA

Quinidine ++ ++
Procainamide ++ ++
Disopyramide ++ ++

Class IB

Lidocaine + 0
Mexiletine + 0
Phenytoin + 0
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 Relative risk of drug-induced proarrhythmia
Drug Risk of Risk of torsades
exacerbation of de pointes
reentry
Class IC

Flecainide +++ 0
Propafenone +++ 0
Moricizine +++ +

Class III

Amiodarone + +
Sotalol + +++
Ibutilide + +++
Dofetilide + +++ 45
 References
- Dronedarone (ERATO) Study : American Heart J. 2008; 156(3): 527.e1-
- Dronedarone : Eur Heart J. 2003;24:1481-1487
- Nifakalant. Pacing Clin Electrophysiol. 2004 Feb;27(2):212-.
- Nifekalant Chinese Medical Journal, 2010, Vol. 123 No. 15:2028-2033
- Journal of Cardiovascular Pharmacology: 2010 - Volume 55 - pp 391-398
- Pacing and Clinical Electrophysiology : 2008 ; 31, Issue 9, pages 1229–
- RxList. The internet drug index.com
- MedicineNet.com
- Side effects of antiarrhythmic drugs : in Naunyn-Schmiedeberg's
Archives of Pharmacology . Volume 269, Numbers 2-4, 282-297, DOI:
10.1007/BF01003044
- N Engl J Med 2002; 347:1834-1840
- American College of Cardiology 2010 Scientific Sessions/i2 Summit; March
15, 2010; Atlanta, GA. Abstract 903-05
- Dronedarone for Atrial Fibrillation — An Odyssey . N Engl J Med 2009;
360:1811 - 1813
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Ain Sokhna – Stella di Mare Hotel and Beach - Egypt 47