A Practical Overview of A Practical Overview of Antiarrhythmic Drugs Antiarrhythmic Drugs Commonly Used in Atrial Commonly Used in Atrial Fibrillation Fibrillation RESOURCE SESSION RESOURCE SESSION Olavo Fernandes, Pharm.D. Olavo Fernandes, Pharm.D. Pharmacy Practice Leader, Pharmacy Practice Leader, Toronto General Hospital, Toronto General Hospital, UHN UHN Assistant Professor, University of Toronto Assistant Professor, University of Toronto October 2002 October 2002
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A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial Fibrillation RESOURCE SESSION A Practical Overview of Antiarrhythmic Drugs Commonly.
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A Practical Overview of A Practical Overview of Antiarrhythmic Drugs Commonly Antiarrhythmic Drugs Commonly
Used in Atrial FibrillationUsed in Atrial Fibrillation
– QRS > 0.12 secs: QRS > 0.12 secs: conduction from ventricle or conduction from ventricle or supraventricularsupraventricular
T waveT wave– repolarization of ventriclerepolarization of ventricle
U waveU wave– uncertainuncertain
PR intervalPR interval– < 0.2 seconds< 0.2 seconds– conduction velocityconduction velocity– beginning of P wave to onset of beginning of P wave to onset of
QRSQRS
QTQTcc interval interval– < 0.4 seconds< 0.4 seconds– refractory periodrefractory period– beginning of Q to end of Tbeginning of Q to end of T
Sodium-dependent Fibres/ Fast FibresSodium-dependent Fibres/ Fast Fibres– atrial and ventricular tissueatrial and ventricular tissue– Phase O, 1, 2, 3, 4Phase O, 1, 2, 3, 4
Calcium-dependent FibresCalcium-dependent Fibres– SA and AV nodesSA and AV nodes– only 3 phasesonly 3 phases– Ca enters instead of Na in Phase OCa enters instead of Na in Phase O– higher resting membrane potentialhigher resting membrane potential– increase in slope of phase 4increase in slope of phase 4
Refractory PeriodRefractory Period
AutomaticityAutomaticity– intrinsic property of spontaneous impulse generationintrinsic property of spontaneous impulse generation
Atrial Fibrillation- Rate ControlAtrial Fibrillation- Rate Control
Why use an agent for rate control?Why use an agent for rate control?» better filling time, better diastolic functionbetter filling time, better diastolic function» consider risks of conversion, embolic risks, drug side effectsconsider risks of conversion, embolic risks, drug side effects
OPTIONSOPTIONS– DigoxinDigoxin
» increase vagal tone (decrease AV node conduction), inhibit Na/K increase vagal tone (decrease AV node conduction), inhibit Na/K PumpPump
– Beta Blockers ( metoprolol, esmolol, atenolol)Beta Blockers ( metoprolol, esmolol, atenolol)» slow SA node, slow AV node conduction, effect on refractory slow SA node, slow AV node conduction, effect on refractory
– directly effect on AV node directly effect on AV node (effective during stress)(effective during stress)
– negative inotrope (concern negative inotrope (concern in in CHF)CHF)
– may be useful with may be useful with concurrent CAD/Post MI concurrent CAD/Post MI patientspatients
– bronchospasm (asthma)bronchospasm (asthma)
– effect on blood sugar (DM)effect on blood sugar (DM)
– main SE: hypotensionmain SE: hypotension
CALCIUM CHANNEL CALCIUM CHANNEL BLOCKERSBLOCKERS– faster onset (minutes)faster onset (minutes)– directly effect on AV node directly effect on AV node
(effective during stress)(effective during stress)– negative inotrope (concern in negative inotrope (concern in
CHF) verapamil > diltiazemCHF) verapamil > diltiazem– may be useful with may be useful with
concurrent CAD/Post MI concurrent CAD/Post MI patientspatients
– main side effect:hypotensionmain side effect:hypotension– cost diltiazem > verapamilcost diltiazem > verapamil
Conversion of Atrial Conversion of Atrial FibrillationFibrillation ConsiderationsConsiderations
– better cardiac function, more times in A Fib harder to convert to NSR, better cardiac function, more times in A Fib harder to convert to NSR, emboli and anticoagulation, may need rate control during conversionemboli and anticoagulation, may need rate control during conversion
Direct Current ConversionDirect Current Conversion– 100J, 200J, 300J, 360J 100J, 200J, 300J, 360J – burns, relapse, sedation, worsened arrhythmiasburns, relapse, sedation, worsened arrhythmias
Pharmacological OptionsPharmacological Options– Amiodarone (least proarrhythmic, some AVN block, least negative Amiodarone (least proarrhythmic, some AVN block, least negative
inotropy, very costly IV)inotropy, very costly IV)– Procainamide, SotalolProcainamide, Sotalol– QuinidineQuinidine– IbutilideIbutilide
Management of newly discovered AFManagement of newly discovered AF(Circulation 2001; 104: 2118-2150)(Circulation 2001; 104: 2118-2150)
Pharmacologic cardioversion of AF<7 daysPharmacologic cardioversion of AF<7 days (Circulation 2001; 104: 2118-2150) (Circulation 2001; 104: 2118-2150)
Pharmacologic cardioversion of AF>7 daysPharmacologic cardioversion of AF>7 days(Circulation 2001; 104: 2118-2150(Circulation 2001; 104: 2118-2150
Pharmacological management of patients with Pharmacological management of patients with recurrent AF recurrent AF (Circulation 2001;1104: 2118-2150) (Circulation 2001;1104: 2118-2150)
Anticoa gula tion a nd ra te contro la s needed
Minim a l or no sym ptom s
D isopyra m ideProca ina m ide
Q uinid ine
non pclg
Am ioda rone
Fleca inidePropa fenone
Sota lo l
N o (or m inim a l)*
Am ioda rone
H F
D isoprya m ideProca ina m ide
Q uinid ine
Am ioda rone
Sota lo l
C AD
Am ioda rone
Yes
D isoprya m ideProca ina m ide
Q uinid ine
Am ioda roneSota lo l
F leca inidePropa fenone
N o
LVH >1.4 cm
H ypertension
Yes
H ea rt D isea se
Anticoa gula tion a nd ra te contro l a s needed
D isa bling sym ptom s
R ecurrent pa roxysm a lAF
Drug Profile: DigoxinDrug Profile: Digoxin MechanismMechanism
– binds and inhibits Na/K binds and inhibits Na/K ATPaseATPase
– slows AV node conduction slows AV node conduction (vagus nerve)(vagus nerve)
– more prone to toxicity with more prone to toxicity with hypokalemia (sensitizes hypokalemia (sensitizes myocardium to digoxin effect)myocardium to digoxin effect)
confirmationconfirmation– initiation or change in therapyinitiation or change in therapy– changes in renal functionchanges in renal function– clinical deteriorationclinical deterioration– addition of interacting addition of interacting
Decreased levelsDecreased levels– hyperthyroidism, binding drug hyperthyroidism, binding drug
interactionsinteractions
Drug Profile: DigoxinDrug Profile: Digoxin
ADVANTAGESADVANTAGES Positive inotropePositive inotrope Maybe useful in Maybe useful in
patients with patients with concurrent AF / CHFconcurrent AF / CHF
LIMITATIONSLIMITATIONS Limited to atrial Limited to atrial
arrhythmiasarrhythmias Limited efficacyLimited efficacy Pro-arrhythmicPro-arrhythmic Narrow therapeutic rangeNarrow therapeutic range Limited efficacy during Limited efficacy during
high sympathetic tonehigh sympathetic tone Caution with adverse Caution with adverse
effects/ drug interactionseffects/ drug interactions
Drug Profile: DiltiazemDrug Profile: Diltiazem Mechanism:Mechanism:
– blocks slow calcium channelsblocks slow calcium channels– slows AV node conductionslows AV node conduction– vasodilatationvasodilatation
Administration/DosingAdministration/Dosing– bolus and continuous infusionbolus and continuous infusion– 0.25 mg/kg over 2 minutes, 0.25 mg/kg over 2 minutes,
after 15 minutes can give 0.35 after 15 minutes can give 0.35 mg/kg over 2 minutesmg/kg over 2 minutes
– continuous infusion 10mg/hr continuous infusion 10mg/hr (up to 15mg/hr) x 24 hr(up to 15mg/hr) x 24 hr
– D5W, NSS, 2/3-1/3D5W, NSS, 2/3-1/3– refrigerated for storagerefrigerated for storage
period (class III)period (class III)– AVN conduction slowing (IV)AVN conduction slowing (IV)– blocks cellular K channelsblocks cellular K channels
KineticsKinetics– bioavailability: 35-65%bioavailability: 35-65%– half life: mean 52 dayshalf life: mean 52 days– volume of distribution: 5000Lvolume of distribution: 5000L
– active metabolite: desethyl-active metabolite: desethyl-amiodaroneamiodarone
Kinetic ImplicationsKinetic Implications» loading dosesloading doses» delayed AA effectdelayed AA effect» delayed elimination if drug delayed elimination if drug
stoppedstopped» compliancecompliance» role of levelsrole of levels
Drug Profile: AmiodaroneDrug Profile: Amiodarone
IndicationsIndications IVIV
– suppression of recurrent suppression of recurrent sustained VT, ongoing sustained VT, ongoing VT/VF, acute conversion of VT/VF, acute conversion of AFAF
Atrial Fibrillation/FlutterAtrial Fibrillation/Flutter– slow VRR (AVN block)slow VRR (AVN block)– convert to NSRconvert to NSR– maintain NSR after maintain NSR after
conversionconversion– dose lower in atrial dose lower in atrial
arrhythmiasarrhythmias
Post MIPost MI– CAMIAT and EMIATCAMIAT and EMIAT– showed amio. - low incidence showed amio. - low incidence
of proarrhythmia; safe in LV of proarrhythmia; safe in LV dysfunctiondysfunction
Primary prevention of SCDPrimary prevention of SCD– RFs for SCD: LV dysfunction, RFs for SCD: LV dysfunction,
frequent or complex ectopicsfrequent or complex ectopics– GESICSA and CHF STATGESICSA and CHF STAT– MADIT (ICD)MADIT (ICD)
Secondary prevention -SCDSecondary prevention -SCD– CASCADE, AVIDCASCADE, AVID– ICD preferredICD preferred– amio. second line amio. second line
Drug Profile: AmiodaroneDrug Profile: Amiodarone Administration/DosingAdministration/Dosing
– 150-300 mg IV over 10 minutes 150-300 mg IV over 10 minutes followed by 0.5 - 2 mg/kg followed by 0.5 - 2 mg/kg minute infusion (1000mg / 24 minute infusion (1000mg / 24 hrs)hrs)
– See handoutSee handout– continue oral load over several continue oral load over several
» 1200-1800 mg/d x 1-2 wks; 1200-1800 mg/d x 1-2 wks; 800mg/d x 2 wks; 600mg/d x 4 800mg/d x 2 wks; 600mg/d x 4 wks; then 200-400mg/dwks; then 200-400mg/d
– Atrial arrhythmiasAtrial arrhythmias» 600-800 mg/d x 4wks; 400 mg/d 600-800 mg/d x 4wks; 400 mg/d
MonitorMonitor– vitals, ECG, BP, HRvitals, ECG, BP, HR– vein site for phlebitisvein site for phlebitis
Amiodarone :Adverse EffectsAmiodarone :Adverse Effects Long term oral therapyLong term oral therapy
– 80% report side effects, in trials 80% report side effects, in trials only 10-20% have side effects only 10-20% have side effects necessitating withdrawalnecessitating withdrawal
– SE appear to be dose relatedSE appear to be dose related– minimize doses/ reduce dose is sx minimize doses/ reduce dose is sx
occuroccur– regular monitoring in preventing regular monitoring in preventing
and managing SEsand managing SEs
CVCV– sinus bradycardia (0-10%), AV sinus bradycardia (0-10%), AV
conduction disturbances and heart conduction disturbances and heart block (2-5%), rare TdPblock (2-5%), rare TdP
– type 1:type 1: hypersensitivityhypersensitivity (after (after first few weeks) with first few weeks) with development of fever, SOB, development of fever, SOB, cough; tx : stop amio.cough; tx : stop amio.
– type 2type 2: : interstitial / alveolar interstitial / alveolar pneumonitispneumonitis (7 mos - 2 yrs); (7 mos - 2 yrs); insidious onset of non-insidious onset of non-productive cough, fatigue, productive cough, fatigue, SOB, pleuritic CP, fever; SOB, pleuritic CP, fever; infiltrates and pulmonary infiltrates and pulmonary fibrosis on CXR; tx: stop fibrosis on CXR; tx: stop amioamio
GIGI– increase in AST/ALT/ ALP (25%)increase in AST/ALT/ ALP (25%)– hepatitis, hepatic failurehepatitis, hepatic failure– N, V, A commonN, V, A common
ThyroidThyroid– inhibits conversion T4 to T3inhibits conversion T4 to T3– hypo (3%) or hyperthyroidism hypo (3%) or hyperthyroidism
(2%)(2%)– hypothyroidism:hypothyroidism:
» rare after first 18 monthsrare after first 18 months» responds to thyroid replacementresponds to thyroid replacement
– hyperthyroidismhyperthyroidism» occur at any time, difficult to occur at any time, difficult to