Samir Rafla - Major Side Effects of Presently Available Anti Arrhythmic Drugs

8/8/2019 Samir Rafla - Major Side Effects of Presently Available Anti Arrhythmic Drugs

http://slidepdf.com/reader/full/samir-rafla-major-side-effects-of-presently-available-anti-arrhythmic-drugs 1/47

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

[email protected]



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

2



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®)

3



4

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.



5

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.



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%



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.



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



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)



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:



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)



Patient Who Was Treated with Amiodaronefor Atrial Fibrillation



Treatment of Torsade de Pointes

Remove offendingagent

Temporary ventricular

or atrial pacing

Isoproterenol

– Increases rate anddecreases QT

intervalLidocaine

Mexiletine

PhenytoinMagnesium



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



Blue-gray discoloration of the nose, cheeks, andlips, sparing the deep skin folds

15



16

Pulmonary fibrosis that can be irreversible and lifethreatening - unusual at doses used for atrialfibrillation (200 mg/day)N Engl J Med 1997; 337:1814



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 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.

18

http://en.wikipedia.org/wiki/Antiarrhythmic_agent






19Porto-marina Beach - Egypt



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



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.



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



23

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.



24

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.



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.



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.

26



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.



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.



Alexandria: Qaitbay Citadel. 15th century



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

31



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.

32



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.

33



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

34

http://www.drugs.com/pro/tikosyn.html

http://www.drugs.com/pro/tikosyn.html



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



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.

36



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.

37



38Ras Sidr Beach. Egypt



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.

39

Atrial Specific AADs



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.

40



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%).

41



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



43

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



Relative risk of drug-induced proarrhythmia

Drug Risk of

exacerbation ofreentry

Risk of torsades

de pointes

Class IA

QuinidineProcainamideDisopyramide

++++++

++++++

Class IB

LidocaineMexiletinePhenytoin

+++

000

44



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



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

46

http://www.cmj.org/periodical/IssueList.asp?pyear=2010&pissue=15&pvol=123&pjournal=Chinese%20Medical%20Journal

http://onlinelibrary.wiley.com/doi/10.1111/pace.2008.31.issue-9/issuetoc

http://www.springerlink.com/content/0028-1298/


http://www.springerlink.com/content/0028-1298/269/2-4/

http://www.nejm.org/doi/full/10.1056/NEJMp0902248

































Samir Rafla - Major Side Effects of Presently Available Anti Arrhythmic Drugs

Documents

Transcript of Samir Rafla - Major Side Effects of Presently Available Anti Arrhythmic Drugs