samir rafla - major side effects of presently available anti arrhythmic drugs
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Major side effects of presentlyavailable antiarrhythmic drugs
Samir Morcos Rafla, MD, FESCProf. of Cardiology. Alexandria Univ. Egypt
XIV International Symposium on Progress in Clinical Pacing
Dec 1 2010
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Antiarrhythmic DrugsClass 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 blockersAmiodarone (Cordarone®, Pacerone®)
Sotalol (Betapace)Azimilide (StedicorTM)Dofetilide (Tikosyn®)Ibutilide (Corvert®)
Tedisamil (Pulsium®)Dronedarone (Multaq)Vernakalant (iv) (BRINAVESS) (Merck, MSD)
NifakalantClass IV— Calcium channel blockersMiscellaneous
Adenosine (Adenocard®
), Digoxin (Lanoxin®)
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Quinidine: ADVERSE EFFECTSThe most common adverse effects of chronic
oral quinidine therapy are gastrointestinal andinclude nausea, vomiting, diarrhea. CNStoxicity includes tinnitus, hearing loss,
psychosis (cinchonism).
Allergic reactions may be manifested as rash,
fever, immune-mediated thrombocytopenia,hemolytic anemia. Side effects may precludelong-term administration of quinidine in 30 to40 % 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 2.0percent of patients, most often the result of aself-terminating episode of torsades de pointes.
Quinidine prolongs the QT interval in mostpatients, whether or not ventricular arrhythmiasoccur, but significant QT prolongation (QT
interval of 500 to 600 milliseconds) is often acharacteristic of patients with quinidinesyncope.
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Amiodarone Side Effect Profile
Serious Side EffectsPulmonary 2-17%
Hyperthyroid 2%
Hypothyroid 6%Liver toxicity 1%
Optic Neuropathy 1.8%
Proarrhythmia <1%
Minor Side Effects
Nausea 30%
Corneal Deposits >90%
Photosensitivity 4-9%Blue Skin <9%
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Amiodarone – a breakdown…
37% of amiodarone’smass is organic iodine.(that is 444mg with aloading dose of
amiodarone – 400mg POTID)
– Of this amount 10% isfree iodide (that is
44mg of free iodidedaily)
In the United States therecommended daily allowance(RDA) is
infants 0-6 months is 110 mcg
1-8 years old, 90 mcg
9-13 years, 120 mcg14 and older, 150 mcg
The Food and Nutrition Boardalso sets the tolerable upper
limits of the daily iodineintake as 1.1 mg (1100 mcg) foradults, with proportionatelylower levels for younger agegroups.
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Amiodarone-Induced Thyrotoxicosis
Type I – patients withlatent thyroid disorders
– Caused by excessive,uncontrolled synthesisof thyroid hormoneby autonomouslyfunctioning tissue in
response to iodine.
Type II – patients withpreviously normalthyroid glands
–Direct cytotoxiceffect on thryoidfollicles resulting ina destructive
inflammatorythyroiditis
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Discerning Type I vs. II
Type I
– Antimicrosomal Ab
– Antithyroglobulin Ab
– Anti-receptor Ab
– Normal to slightlyelevated IL-6
– Color Flow Dopplerreveals pattern 1,pattern 2 or pattern 3
Type II
– ElevatedThyroglobulin
– Elevated IL-6
– Color flow Dopplerreveals Pattern 0
(absent vascularity,gland destruction)
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Medical Treatment
Type I – Treat with athionamide – since itis associated with
increased hormonesynthesis (PTU ormethimazole 30mgper day)
– Can use potassiumperchlorate (200mg -1000mg per day)
Type II – Glucocorticoids areused for anti-inflammatory and
membranestabalizingproperties(prednisone 30-40mg/day)
Pitfalls to Treatment:
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Torsade de Pointes
Occurs in 1% of patients taking AmiodaronePredisposing conditions
– LVH, congestive heart failure
– Bradycardia
– Hypokalemia – Hypomagnesemia
– Digitalis therapy
– Baseline QT prolongation – High drug concentration (except quinidine)
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Patient Who Was Treated with Amiodaronefor Atrial Fibrillation
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Treatment of Torsade de Pointes
Remove offendingagent
Temporary ventricular
or atrial pacing
Isoproterenol
– Increases rate anddecreases QT
intervalLidocaine
Mexiletine
PhenytoinMagnesium
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Optic Neuropathy
Ocular side effects
– Corneal microdeposits – 70-100%of patients
– Dry Eye Syndrome
– Anterior Lens opacities
– Optic Neuropathy – 1-2% ofpatients
Results in optic disc swellingAssociated with visual field deficit
Can result in permanent visual loss
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Blue-gray discoloration of the nose, cheeks, andlips, sparing the deep skin folds
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Pulmonary fibrosis that can be irreversible and lifethreatening - unusual at doses used for atrialfibrillation (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%
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Digitalis
Digitalis enhances vagal activity and thus
slows sinus node automaticity and prolongs AVnodal conduction and refractoriness. Digitalisinhibits the sarcolemmal Na+-K+-ATPase
leading to an increase in intracellular calciumthat may promote proarrhythmias.Hypokalemia augments digitalis toxicity.
Tocainide (Tonocard) is a class Ibantiarrhythmic agent. It is no longer sold in theUnited States.
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19Porto-marina Beach - Egypt
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Dronedarone - Adverse Events
Stroke 4 (0.5) 3 (0.7) 0.69
Cough
Dyspnea
19 (2.3) 7(1.7) 0.67
Hyperthyroidism
Hypothyroidism
67/801 (8.4)
44/801 (5.5
56/396 (14.1)
14/396 (3.5)
0.002
0.15
Abnormal LFTs 100/822 (12.2) 55/404(13.6) 0.52
Elev of Serum
Creatinine20 (2.4) 1 (0.2) 0.004
Bradycardia
Heart Failure
22 (2.7)
20 (2.4)
8 (2.2)
4 (1.0)
0.56
0.12
VARIABLEDRONEDARONE
N=828PLACEBO
N=409P value
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Dronedarone - ATHENA: Summary
Dronedarone significantly prolongs time to first CV
hospitalization or death in moderate- to high-risk AFpatients
All-cause mortality was not increased in patientsreceiving dronedarone
CV mortality was lower in the dronedarone comparedto the placebo group
The reduction in CV hospitalization was mainly due tofewer admissions for AF and acute coronary
syndromesThe application of Dronedarone may be useful in lowrisk patients (NYHA Class I and II)
Hohnloser SH. Heart Rhythm Society 2008 Scientific Sessions;May 15, 2008; San Francisco, CA.
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1.0%
4.7%
0%
1%
2%
3%
4%
5%
Placebo Multaq®
(dronedarone)
•Patients treatedwith Multaq®
(dronedarone)demonstrated
increased serumcreatinine morefrequently thanthose given
placebo. I n c r e
a s e d B l o o d C r e a t i n i n e ( %
)
ATHENA Trial: Adverse Events
Copyleft Clinical Trial Results. You Must Redistribute Slides
JCE 2008; 19.1/Heart Rhythm 2008
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Disopyramide (Norpace) sideffects
1. Anticholinergic side-effects
2. Induction of ventricular arrhythmias inpatients with prolonged QT interval3. Similar to quinidine, disopyramide may
induce ventricular arrhythmia if used alone inthe treatment of fibrillation.- Due to its negative inotropic effects,disopyramide may reduce left ventricular out-flow gradient and improve symptoms inpatients with obstructive hypertrophiccardiomyopathy.
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Procainamide - sideffects
At high levels, asystole or induction of
ventricular arrhythmiasHypersensitivity reactions including drug feverand rarely agranulocytosis.Systemic lupus erythromatosus (SLE)-like(arthralgia, fever & pleural-pericardialinflammation)The SLE is dose- and time-dependent, and
usually disappears upon drug stopIt is most common in patients with slowhepatic acetylation resulting in higher plasma
level of the parent drug.
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Flecainide (Tambocor) & propafenone(Rythmol®) Toxicity and Cautions for ClassIC Drugs:
They are severe proarrhythmic drugs causingsevere worsening of a preexisting arrhythmia orde novo occurrence of life-threatening
ventricular tachycardia In patients with frequent PVCs following MI,
flecainide increased mortality compared to
placeboNotice: Class 1C drugs are particularly oflow safety and have shown even to increasemortality when used chronically after MI.
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in the Cardiac Arrhythmia Suppression
Trial (CAST), researchers found that
encainide and flecainide reduced
spontaneous ventricular arrhythmias butwere 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, andasystole especially when given in combination
with β-adrenergic blockers.
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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 totransient complete AV block.
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Alexandria: Qaitbay Citadel. 15th century
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Physicians should be cautious when selectingAADs for treatment of AF seen in association
with WPWs. In pts with WPWs , during anepisode of AF, atrial impulses can bypass theAV node and propagates to the ventricles
directly via accessory pathway, leading toirregular, fast and wide complex tachycardia.Pts suspected of having this condition should
not receive IV calcium blockers , B blockers ordigoxin.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 andalso a β -blocker that is useful in AF/atrial flutter and monomorphic ventricular tachycardia.
Sotalol should preferably be initiated in-hospitalto monitor for severe bradycardia,atrioventricular block, and QT prolongation.
Because sotalol is primarily excretedunchanged in the urine, dose adjustment isneeded in patients with renal insufficiency.
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Dofetilide (Tikosyn) had no effect on cardiacoutput, cardiac index, stroke volume index, or
systemic vascular resistance in patients withventricular tachycardia, mild to moderatecongestive 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 toplasma concentrations of dofetilide, dosageadjustment based on calculated creatinineclearance is critically important
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FDA 7.00
Dofetilide: Dose-Effect on TdP and VF*
0 0.3 0.9
10.5
0
4
8
12
<250
mcg
BID
250
mcg
BID
500
mcg
BID
>500
mcg
BID
Dofetilide Dose
I n c i d e n c e
o f T d P o
r V
F
TdP (%)VF (%)
*NDA SVA Population N=1,346
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Azimilide (StedicorTM) was generally well tolerated intrials. 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 azimilidedeveloped QTc prolongation compared with only3.5% in the sotalol group ; torsades de pointes was
reported in 2.4% of azimilide recipients.The relatively modest efficacy of azimilide coupledwith the risk of toxicity make it unlikely to becomeavailable for treatment of AF.
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Tedisamil (Pulsium
®
): Preliminary clinical datasuggest that tedisamil administration IVeffectively terminated AF but is associated withthe risk of QT prolongation and torsades de
pointes .
In multicenter study, there were 2 cases of self-
terminating V tach. observed in pts receivingtedisamil at a dose of 0.6 mg/kg.
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38Ras Sidr Beach. Egypt
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Vernakalant: Vernakalant has a unique ionchannel-blocking profile. The agent is a sodiumchannel blocker (I Na) and a potassium
channel blocker.
In ACT study, adverse events were reported in
32% of placebo recipients and 38% ofVernakalant recipients. No deaths or torsadede points were reported.
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Atrial Specific AADs
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Vernakalant BRINAVESS is contraindicated
in patients with severe aortic stenosis, systolicBP<100 mm Hg, and heart failure class III andIV.
Vernakalant is contraindicated in patients withprolonged QT at baseline (uncorrected >440msec), severe bradycardia, sinus node
dysfunction, or second-degree or third-degreeheart block in the absence of a pacemaker.
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Vernakalant is also contraindictated in patientswho use IV rhythm control antiarrhythmics
(class I and class III) within 4 hours prior toadministration of Vernakalant and patients withacute coronary syndrome (including myocardial
infarction) within the last 30 days.
Adverse reactions (>5%) seen in the first 24
hours after receiving Vernakalant were tastedisturbance (20.1%), sneezing (14.6%), andparaesthesia (9.7%).
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Nifekalant tops lidocaine for shock-resistantventricular arrhythmia
Administration of either nifekalant or amiodaronebefore defibrillation increased the restoration ofspontaneous circulation (ROSC) and 24-h survivalrates and improved post-resuscitation cardiac
function in porcine model.Side-effects: QT prolongation in one patient. Noother side-effects were observed in other patients,
such as deteriorated blood pressure, breath rate,and rales. No significant changes were found inblood test of liver and kidney functions before and 12hours after stopping infusing NIF. Chin Med J
2010;123(15):2028 42
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Administrating Nifekalantterminated sustained
ventricular tachycardia.
Maximum QT at lead V4600 ms, minimum at lead
V5 520 ms, which weremeasured between the 2red linesChin Med J 2010;123(15):2028-
2033
Relative risk of drug induced proarrhythmia
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Relative risk of drug-induced proarrhythmia
Drug Risk of
exacerbation ofreentry
Risk of torsades
de pointes
Class IA
QuinidineProcainamideDisopyramide
++++++
++++++
Class IB
LidocaineMexiletinePhenytoin
+++
000
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Relative risk of drug-induced proarrhythmia
Drug Risk of
exacerbation ofreentry
Risk of torsades
de pointes
Class IC
FlecainidePropafenoneMoricizine
+++++++++
00+
Class III
AmiodaroneSotalolIbutilide
Dofetilide
+++
+
+++++++
+++ 45
R f
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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'sArchives 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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