clinical pharmacology of antiarrhythmic medications
DESCRIPTION
CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS. Vincent F. Mauro, PharmD, FCCP. Professor of Clinical Pharmacy and Adjunct Professor of Medicine The University of Toledo. GOALS. To have a better understanding of: - PowerPoint PPT PresentationTRANSCRIPT
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CLINICAL PHARMACOLOGY CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC OF ANTIARRHYTHMIC
MEDICATIONSMEDICATIONS
CLINICAL PHARMACOLOGY CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC OF ANTIARRHYTHMIC
MEDICATIONSMEDICATIONS
Vincent F. Mauro, PharmD, FCCPVincent F. Mauro, PharmD, FCCPProfessor of Clinical Pharmacy
andAdjunct Professor of Medicine
The University of Toledo
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GOALSGOALSGOALSGOALS
To have a better understanding of:To have a better understanding of: The EPS properties of antiarrhythmics according The EPS properties of antiarrhythmics according
to their Vaughan-Williams classificationto their Vaughan-Williams classification Important pharmacotherapeutic issues related to Important pharmacotherapeutic issues related to
antiarrhythmic useantiarrhythmic use The causes & treatment of torsade de pointesThe causes & treatment of torsade de pointes
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AutomaticityAutomaticity
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Reentry-induced dysrhythmia
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Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
IAIA QuinidineQuinidine ICIC FlecainideFlecainide
ProcainamideProcainamide PropafenonePropafenone
DisopyramideDisopyramide EncainideEncainide
IBIB LidocaineLidocaine I?I? MoricizineMoricizine
MexiletineMexiletine
TocainideTocainide
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Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
IIII Beta-adrenergic blockersBeta-adrenergic blockers
IIIIII AmiodaroneAmiodarone IbutilideIbutilide
Dronedarone Dronedarone DofetilideDofetilide
SotalolSotalol BretyliumBretylium
IVIV Calcium channel blockersCalcium channel blockers
Diltiazem & VerapamilDiltiazem & Verapamil
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Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
DigoxinDigoxin
AdenosineAdenosine
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GenericGeneric BrandnameBrandnameDisopyramideDisopyramide NorpaceNorpace
MexiletineMexiletine MexitilMexitil
FlecainideFlecainide TambocorTambocor
PropafenonePropafenone RythmolRythmol
AmiodaroneAmiodarone Cordarone, PaceroneCordarone, Pacerone
DronedaroneDronedarone MultaqMultaq
EsmololEsmolol BreviblocBrevibloc
SotalolSotalol Betapace, SorineBetapace, Sorine
IbutilideIbutilide CorvertCorvert
DofetilideDofetilide TikosynTikosyn
DigoxinDigoxin Lanoxin, Digitek Lanoxin, Digitek
AdenosineAdenosine AdenocardAdenocard
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Type IxType Ix
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Type IaType Ia
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Type IbType Ib
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Type IcType Ic
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Ia’s create a double block
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Ib’s take away the block
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What about Ic’s?- They have no effect on action
potential duration
What about Ic’s?- They have no effect on action
potential duration
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Type II & IVType II & IV
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Type IIIType III
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CLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONSMedicationMedication Ventricular Ventricular
AtrialAtrialQuinidineQuinidinePO,SR,IVPO,SR,IV XX X XProcainamideProcainamide IVIV XX X XDisopyramideDisopyramidePO,SRPO,SR XX X X
LidocaineLidocaineIVIV XX - -MexiletineMexiletinePOPO XX - -
FlecainideFlecainidePOPO X!!X!! X XPropafenonePropafenonePO,SRPO,SR XX X X
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CLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONSMedicationMedication Ventricular Ventricular
AtrialAtrialBeta-blockersBeta-blockersPO,SR,IVPO,SR,IV E E AV AV AmiodaroneAmiodaronePO,IVPO,IV XX X XDronedaroneDronedaronePOPO - - XXSotalolSotalolPO,IVPO,IV X X X/AV X/AVDofetilideDofetilidePOPO ? ? X XIbutilideIbutilideIVIV ? ? AF/Fl AF/Fl
Calcium channel blockersCalcium channel blockersPO,SR,IVPO,SR,IV E? E? AV AV
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CLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONS
MedicationMedication Ventricular VentricularAtrialAtrial
DigoxinDigoxinPO,IVPO,IV -- AV AV
AdenosineAdenosineIVIV -- PSVTPSVT
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QuinidineQuinidine
• Type IA antiarrhythmicType IA antiarrhythmic• Indicated for atrial fibrillation and Indicated for atrial fibrillation and
ventricular tachycardiasventricular tachycardias
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QuinidineQuinidineAdverse EffectsAdverse Effects• GI irritationGI irritation• Bitter tasteBitter taste• Hepatitis & other hepatic conditionsHepatitis & other hepatic conditions• Rash & drug feverRash & drug fever• ThrombocytopeniaThrombocytopenia• CinchonismCinchonism
• TinnitusTinnitus• Blurred visionBlurred vision• HeadachesHeadaches• DizzinessDizziness
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QuinidineQuinidine
• Different salts Different salts • Sulfate (83%)Sulfate (83%)PO,SRPO,SR
• Gluconate (62%)Gluconate (62%)SR,IVSR,IV
• Hepatically eliminated Hepatically eliminated (t(t1/21/2 ~6-8 hr) ~6-8 hr)
• Increases digoxin & warfarin levelsIncreases digoxin & warfarin levels• IV dosage form – hemodynamic instabilityIV dosage form – hemodynamic instability• Some concern when IV verapamil or Some concern when IV verapamil or
diltiazem is given to a patient on quinidinediltiazem is given to a patient on quinidine
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ProcainamideProcainamideProcainamideProcainamide Type IA antiarrhythmicType IA antiarrhythmic Indicated for acute conversion of Indicated for acute conversion of
ventricular & atrial dysrhythmiasventricular & atrial dysrhythmias
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ProcainamideProcainamide
• Short half-life (~3 hours)Short half-life (~3 hours)• 6-h & 12-h SR dosage forms once existed6-h & 12-h SR dosage forms once existed• 50% hepatically metabolized, mostly to 50% hepatically metabolized, mostly to
NAPA NAPA (fast/slow acetylators)(fast/slow acetylators)
• NAPA (as w/ 50% of PA) is renally NAPA (as w/ 50% of PA) is renally eliminatedeliminated
• Causes drug-induced SLECauses drug-induced SLE
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ProcainamideProcainamideAdverse EffectsAdverse Effects• GastrointestinalGastrointestinal• CNSCNS• FeverFever• RashRash• Blood dyscrasias Blood dyscrasias • Some negative inotropic propertiesSome negative inotropic properties• Hypotension w/ rapid IV infusionsHypotension w/ rapid IV infusions
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ProcainamideProcainamideProcainamideProcainamide DosingDosing
Acute: 17 mg/kg @ 20 mg/min (50 mg/min, if Acute: 17 mg/kg @ 20 mg/min (50 mg/min, if urgent)urgent)
Infusion: 1-4 mg/min (depends on renal fxn)Infusion: 1-4 mg/min (depends on renal fxn) MetabolismMetabolism
NAPA produced NAPA produced (a renally eliminated active (a renally eliminated active metabolite of procainamide)metabolite of procainamide)
Toxicity if NAPA levels exceed 20 mg/LToxicity if NAPA levels exceed 20 mg/L
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DisopyramideDisopyramide
• Type IA antiarrhythmicType IA antiarrhythmic• Indicated in atrial and ventricular Indicated in atrial and ventricular
arrhythmiasarrhythmias
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DisopyramideDisopyramide
• Concentration-dependent plasma protein Concentration-dependent plasma protein bindingbinding
• An increase in dosage rate results in an increase An increase in dosage rate results in an increase in the percentage of disopyramide that is in the percentage of disopyramide that is unboundunbound
• Increased unbound drug allows for enhanced Increased unbound drug allows for enhanced clearanceclearance
• As a result, increasing the dosage rate results in a As a result, increasing the dosage rate results in a less than proportional increase in total drug less than proportional increase in total drug concentrationconcentration
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Dosage Rate
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DisopyramideDisopyramide
• Therefore, total drug concentrations have a Therefore, total drug concentrations have a limited role in assisting on how much to limited role in assisting on how much to adjust the dosage of disopyramide due to adjust the dosage of disopyramide due to its concentration-dependent plasma its concentration-dependent plasma protein bindingprotein binding
• Total drug concentrations can be used to Total drug concentrations can be used to document a patient’s “effective” drug document a patient’s “effective” drug concentration once efficacy has been concentration once efficacy has been demonstrateddemonstrated
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DisopyramideDisopyramide
Adverse EffectsAdverse Effects• GastrointestinalGastrointestinal• Negative inotropeNegative inotrope• Anticholinergic adverse effectsAnticholinergic adverse effects
• Dry mouthDry mouth• Blurred visionBlurred vision• ConstipationConstipation• Urinary hesitationUrinary hesitation
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DisopyramideDisopyramide
• EliminationElimination• ~50% hepatic~50% hepatic• ~50% renal~50% renal
• Half-lifeHalf-life• ~7 hours~7 hours
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DisopyramideDisopyramide
• Used in neurocardiogenic syncope & Used in neurocardiogenic syncope & hypertrophic heartshypertrophic hearts• Anticholinergic propertiesAnticholinergic properties• Negative inotropic propertiesNegative inotropic properties
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LidocaineLidocaine
• Type IB antiarrhythmicType IB antiarrhythmic• Indicated in acute treatment and Indicated in acute treatment and
prevention of ventricular dysrhythmiasprevention of ventricular dysrhythmias
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LidocaineLidocaineLidocaineLidocaine Half LifeHalf Life
Initially, Initially, 1.51.5 hours; but increases hours; but increases to to 3.03.0 hours 2-3 days into therapy hours 2-3 days into therapyLLidocaine reduces its own rate of idocaine reduces its own rate of
metabolismmetabolism
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LidocaineLidocaineLidocaineLidocaine
Toxicity most often manifested by:Toxicity most often manifested by:
NauseaNausea DizzinessDizziness
DrowsinessDrowsiness ConfusionConfusion
TremorsTremors Facial numbnessFacial numbness
ParesthesiasParesthesias Peripheral Peripheral numbnessnumbness
Altered speechAltered speech SeizuresSeizures
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LidocaineLidocaine DosingDosing
1.0-1.5 mg/kg IVP over 1-2 min; repeat 1.0-1.5 mg/kg IVP over 1-2 min; repeat every 5-10 min with 0.5-0.75 mg/kg, as every 5-10 min with 0.5-0.75 mg/kg, as needed, until 3 mg/kg total doseneeded, until 3 mg/kg total dose
Typical maintenance dose: 1.0-4.0 Typical maintenance dose: 1.0-4.0 mg/minmg/minUse lower rate with Use lower rate with CHFCHF
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MexiletineMexiletine
• Type IB antiarrhythmicType IB antiarrhythmic• Only indicated to prevent ventricular Only indicated to prevent ventricular
arrhythmiasarrhythmias
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MexiletineMexiletine
Adverse EffectsAdverse Effects• ExtremelyExtremely GI irritatingGI irritating• Altered CNS functioningAltered CNS functioning
• Hepatically metabolizedHepatically metabolized• Half-life: 6-12 hoursHalf-life: 6-12 hours
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FlecainideFlecainide
• Type IC antiarrhythmicType IC antiarrhythmic
• Since it is very proarrhythmic:Since it is very proarrhythmic:• Generally used only for atrial dysrhythmiasGenerally used only for atrial dysrhythmias
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FlecainideFlecainide• Very proarrhythmic in patients with:Very proarrhythmic in patients with:• CADCAD• CHFCHF• Ventricular dysrhythmiasVentricular dysrhythmias
• Used primarily in atrial fibrillation when Used primarily in atrial fibrillation when concerns for proarrhythmias are not concerns for proarrhythmias are not presentpresent
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FlecainideFlecainide
Adverse EffectsAdverse Effects• GastrointestinalGastrointestinal• CNSCNS• Negative inotropeNegative inotrope
PharmacokineticsPharmacokinetics• Mostly hepatic clearance Mostly hepatic clearance (60%)(60%); some renal ; some renal (30%)(30%)
• Half-life: ~20 hoursHalf-life: ~20 hours
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PropafenonePropafenone
• Type IC with some beta-blocking Type IC with some beta-blocking propertiesproperties
• Primarily used for atrial dysrhythmiasPrimarily used for atrial dysrhythmias• Rarely, ventricularRarely, ventricular
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PropafenonePropafenone
Adverse EffectsAdverse Effects• GastrointestinalGastrointestinal• CNSCNS• Negative inotropeNegative inotrope• Metallic tasteMetallic taste
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PropafenonePropafenone
• Non-linear absorption & eliminationNon-linear absorption & elimination• Bioavailability increases w/ higher dosesBioavailability increases w/ higher doses
• IR and SR dosages are NOT bioequivalentIR and SR dosages are NOT bioequivalent• SR has reduced bioavailabilitySR has reduced bioavailability
• Clearance decreases w/ higher dosesClearance decreases w/ higher doses• Hepatic eliminationHepatic elimination
• Active metabolitesActive metabolites• Extensive (90%) & Slow (10%) metabolizersExtensive (90%) & Slow (10%) metabolizers
• Increases digoxin levelsIncreases digoxin levels
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SotalolSotalol
• Non-selective beta-blocker with type III Non-selective beta-blocker with type III antiarrhythmic activityantiarrhythmic activity
• Used to acutely treat and prevent atrial Used to acutely treat and prevent atrial & ventricular dysrhythmias& ventricular dysrhythmias
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SotalolSotalol
• Renally eliminatedRenally eliminated• Negative inotropeNegative inotrope• Beta-blocker concernsBeta-blocker concerns
• Torsade de pointesTorsade de pointes
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SotalolSotalol
• Renally eliminatedRenally eliminated• Negative inotropeNegative inotrope• Beta-blocker concernsBeta-blocker concerns
• Torsade de pointesTorsade de pointes• Do not initiate if QT > 450 msecDo not initiate if QT > 450 msec• Desire QT < 500 msec for first 3 daysDesire QT < 500 msec for first 3 days• Desire QT < 520 msec thereafterDesire QT < 520 msec thereafter
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SotalolSotalol
Now available parenterallyNow available parenterally• IndicationsIndications
• Ventricular tachyarrhythmiasVentricular tachyarrhythmias• Atrial fibrillation/flutterAtrial fibrillation/flutter
• 75 mg IV = 80 mg po75 mg IV = 80 mg po• Give dose over 5 hoursGive dose over 5 hours
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AmiodaroneAmiodarone
Type III antiarrhythmic agentType III antiarrhythmic agent Contains alpha- & beta-receptor Contains alpha- & beta-receptor
blocking properties as well as blocking properties as well as sodium-, potassium-, & calcium- sodium-, potassium-, & calcium- channel blocking propertieschannel blocking properties
Indicated for ventricular & atrial Indicated for ventricular & atrial dysrhythmiasdysrhythmias
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AmiodaroneAmiodarone Large volume of distributionLarge volume of distribution Half-life: 30 - 100 daysHalf-life: 30 - 100 days Metabolized primarily by CYP 3A4Metabolized primarily by CYP 3A4 Active metabolite: N-desethylamiodaroneActive metabolite: N-desethylamiodarone
Half-life: ~60 daysHalf-life: ~60 days
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AmiodaroneAmiodarone ToxicitiesToxicities
CNSCNS LiverLiver Cornea depositsCornea depositsGIGI ThyroidThyroid Optic neuropathyOptic neuropathySkinSkin BradycardiaBradycardia Photosensitivity Photosensitivity
Pulmonary Pulmonary fibrosisfibrosis
Baseline labsBaseline labs Thyroid Thyroid (recheck every 6 mths)(recheck every 6 mths) LiverLiver (recheck every 6 mths)(recheck every 6 mths) PulmonaryPulmonary (annual CXR)(annual CXR)
Arch Intern Med 2000;160:1741-8Arch Intern Med 2000;160:1741-8
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AmiodaroneAmiodarone An allergy to iodine (but not contrast dye) An allergy to iodine (but not contrast dye)
is a contraindication to using amiodaroneis a contraindication to using amiodarone
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AmiodaroneAmiodarone An oral dosing protocolAn oral dosing protocol
15 mg/kg/day x 1 week (~400 mg TID)15 mg/kg/day x 1 week (~400 mg TID) 10 mg/kg/day x 2 weeks (~400 mg BID)10 mg/kg/day x 2 weeks (~400 mg BID) 5 mg/kg/day (~400 mg QD)5 mg/kg/day (~400 mg QD) Eventually reduce to 100-200 mg dailyEventually reduce to 100-200 mg daily
Oral bioavailability:Oral bioavailability: ~50% ~50%
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AmiodaroneAmiodarone General IV loadGeneral IV load
150 mg over 10 minutes150 mg over 10 minutes 1 mg/min x 6 hours1 mg/min x 6 hours 0.5 mg/min x 18 hours or longer0.5 mg/min x 18 hours or longer Monitor heart rate & blood pressureMonitor heart rate & blood pressure
Ventricular fibrillationVentricular fibrillation 300 mg IVP; may repeat w/ 150 mg IVP300 mg IVP; may repeat w/ 150 mg IVP
Ventricular tachycardiaVentricular tachycardia 150 mg over 10 min; repeat as needed to a total of 150 mg over 10 min; repeat as needed to a total of
2.2 gm in 24 hours2.2 gm in 24 hours
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A Sampling of Drug InteractionsA Sampling of Drug Interactions
WarfarinWarfarin DigoxinDigoxin MetoprololMetoprolol QuinidineQuinidine ProcainamideProcainamide DisopyramideDisopyramide
FlecainideFlecainide TheophyllineTheophylline PhenytoinPhenytoin SimvastatinSimvastatin CyclosporineCyclosporine MethotrexateMethotrexate
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DronedaroneDronedarone A “less toxic” amiodaroneA “less toxic” amiodarone
Half-life: 13-19 hoursHalf-life: 13-19 hours
Only FDA-approved for atrial Only FDA-approved for atrial fibrillation/flutterfibrillation/flutter Not as effective as amiodaroneNot as effective as amiodarone
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DronedaroneDronedarone GI irritationGI irritation Prolongs QT interval Prolongs QT interval Negative inotropeNegative inotrope
Contraindicated in:Contraindicated in: NYHA IVNYHA IV Acute CHF exacerbationsAcute CHF exacerbations
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DronedaroneDronedarone Metabolized by CYP 3A4Metabolized by CYP 3A4
Inhibits CYPs 3A4 & 2D6 and P-gpInhibits CYPs 3A4 & 2D6 and P-gp Increases digoxin levelsIncreases digoxin levels
Dosing: 400 mg BIDDosing: 400 mg BID
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IbutilideIbutilide PharmacologyPharmacology
Type III antiarrhythmicType III antiarrhythmic Indicated for acute conversion of atrial Indicated for acute conversion of atrial
flutter a/o fibrillationflutter a/o fibrillation
ProarrhythmicProarrhythmic More so in patients w/ CHFMore so in patients w/ CHF
If ibutilide fails to convert, it may at least If ibutilide fails to convert, it may at least enhance the response to electrocardioversionenhance the response to electrocardioversion
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IbutilideIbutilide Monitor for proarrhythmias, Monitor for proarrhythmias,
including torsade de pointes, for 4-6 including torsade de pointes, for 4-6 hours after dosing and until QT is hours after dosing and until QT is not prolongednot prolonged
Hepatically clearedHepatically cleared Half-life: ~6 hoursHalf-life: ~6 hours
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IbutilideIbutilide Approved DosingApproved Dosing
1 mg (0.01 mg/kg < 60 kg) over 10 min; 1 mg (0.01 mg/kg < 60 kg) over 10 min; repeat, if needed, after 10 minrepeat, if needed, after 10 min
Preload with magnesium (?)Preload with magnesium (?)
Alternative Method of DosingAlternative Method of Dosing 2 mg (placed in 50 cc D5W) over 30 minutes2 mg (placed in 50 cc D5W) over 30 minutes StopStop infusion when patient converts infusion when patient converts Preload with magnesium (?)Preload with magnesium (?)
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DofetilideDofetilide
Oral “relative” to ibutilideOral “relative” to ibutilide Indicated for atrial fibrillation/flutterIndicated for atrial fibrillation/flutter
ConversionConversion MaintenanceMaintenance
ProarrhythmicProarrhythmic Torsade de pointesTorsade de pointes
Need Need “certification”“certification” to prescribe & to prescribe & dispensedispense
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DofetilideDofetilide To become To become “certified”“certified” to dispense to dispense
dofetilide, visit:dofetilide, visit:
www.TIKOSYN.com www.TIKOSYN.com
Click on the prompt that allows you to become aClick on the prompt that allows you to become a Confirmed PrescriberConfirmed Prescriber
and follow the instructionsand follow the instructions
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DofetilideDofetilide ClearanceClearance
HepaticHepatic CYP 3A4CYP 3A4
RenalRenal Renal tubular secretionRenal tubular secretion
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DofetilideDofetilide
Drug Interaction Precautions Drug Interaction Precautions CYP 3A4 inhibitorsCYP 3A4 inhibitors
Erythro, Clarithro, Grapefruit, Conazoles, SSRIsErythro, Clarithro, Grapefruit, Conazoles, SSRIs
Cationic renal secretion inhibitorsCationic renal secretion inhibitors Triamterene, Metformin, AmilorideTriamterene, Metformin, Amiloride
QT-prolonging medicationsQT-prolonging medications
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DofetilideDofetilide ContraindicationsContraindications
QTc > 440 msec (> 500 msec w/ VCD)QTc > 440 msec (> 500 msec w/ VCD) CrCl < 20 mL/minCrCl < 20 mL/min DrugsDrugs
CimetidineCimetidine Trimethoprim (incl. Bactrim)Trimethoprim (incl. Bactrim) VerapamilVerapamil KetoconazoleKetoconazole ProchlorperazineProchlorperazine MegestrolMegestrol HCTZHCTZ
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DofetilideDofetilide
Generally, wait Generally, wait threethree half-lives after stopping half-lives after stopping previous antiarrhythmic before starting previous antiarrhythmic before starting dofetilidedofetilide With amiodarone, waitWith amiodarone, wait threethree months (or until months (or until
amiodarone concentrationamiodarone concentration < 0.3< 0.3 mcg/mL)mcg/mL) Wait Wait 48 hours48 hours after stopping dofetilide before after stopping dofetilide before
starting another antiarrhythmicstarting another antiarrhythmic
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Dofetilide Dofetilide Considerations when initiating therapy:Considerations when initiating therapy: Hospitalization for Hospitalization for 33 days days Continuous EKG monitoringContinuous EKG monitoring Determine baseline CrCl & QTcDetermine baseline CrCl & QTc Confirm that patient has method of obtaining Confirm that patient has method of obtaining
medication from a medication from a “certified” “certified” pharmacy upon pharmacy upon dischargedischarge If patient cannot immediately obtain dofetilide upon If patient cannot immediately obtain dofetilide upon
discharge, assure that patient can obtain 7-day “bridge” discharge, assure that patient can obtain 7-day “bridge” therapy from the hospitaltherapy from the hospital
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Dofetilide Dofetilide
Starting dosesStarting doses
CrClCrCl DoseDose> 60 mL/min> 60 mL/min 500 mcg BID500 mcg BID
40 - 60 mL/min40 - 60 mL/min 250 mcg BID250 mcg BID
20 - 39 mL/min20 - 39 mL/min 125 mcg BID125 mcg BID
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DofetilideDofetilide
Check QTc Check QTc 2-32-3 hours after 1st dose hours after 1st dose
Decrease future doses by 50% if:Decrease future doses by 50% if: QTc increased by QTc increased by 15%15% from baseline from baseline QTc QTc > 500> 500 msec (> 550 msec if VCD) msec (> 550 msec if VCD)
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DofetilideDofetilide
With each subsequent dose, check QTc With each subsequent dose, check QTc
2-32-3 hours after administration hours after administration
Discontinue dofetilide if QTc Discontinue dofetilide if QTc > 500> 500 msec msec
((> 550> 550 msec if VCD) msec if VCD)
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Digoxin in CHFDigoxin in CHF
• Loading dose not essential for CHFLoading dose not essential for CHF• Improves CHF morbidity, but not Improves CHF morbidity, but not
mortalitymortality• Drug levels for CHF: 0.7-0.9 ng/mLDrug levels for CHF: 0.7-0.9 ng/mL
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DigoxinDigoxin
• Vagolytic effects slow heart rate and Vagolytic effects slow heart rate and conduction through AV nodeconduction through AV node
• Used to slow the ventricular rate of atrial Used to slow the ventricular rate of atrial fibrillationfibrillation
• Used to interrupt reentry in PSVTUsed to interrupt reentry in PSVT
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DigoxinDigoxin
• Loading dose Loading dose • About 0.0125 mg/kg of LBWAbout 0.0125 mg/kg of LBW• Give 50% now, then two doses of 25%; each Give 50% now, then two doses of 25%; each
separated by 4-6 hoursseparated by 4-6 hours
• Severe renal failure reduces the VSevere renal failure reduces the Vdd; thus, ; thus, a smaller loading dose is requireda smaller loading dose is required
• Therapeutic range: 1–2 mcg/LTherapeutic range: 1–2 mcg/L
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Digoxin – General FactsDigoxin – General Facts
• Half-life: 36 hours or longerHalf-life: 36 hours or longer• Long distribution phase (6-12 hours)Long distribution phase (6-12 hours)• Primarily renal eliminationPrimarily renal elimination• Important Drug interactionsImportant Drug interactions
• VerapamilVerapamil• Quinidine Quinidine • AmiodaroneAmiodarone• PropafenonePropafenone
• Effects reversed with Digibind & DigifabEffects reversed with Digibind & Digifab• Digibind/fab use impacts digoxin levelsDigibind/fab use impacts digoxin levels
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Drug DistributionDrug DistributionDrug DistributionDrug Distribution
Cp
Time
12 h
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DigoxinDigoxinAdverse EffectsDigoxinDigoxinAdverse Effects
GastrointestinalGastrointestinal
DysrhythmiasDysrhythmias
Central nervous system Central nervous system
VisualVisual
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DIGOXIN TOXICITYDIGOXIN TOXICITYPrecipitating FactorsDIGOXIN TOXICITYDIGOXIN TOXICITYPrecipitating Factors
HypokalemiaHypokalemia
HypomagnesemiaHypomagnesemia
HypercalcemiaHypercalcemia
HypothyroidismHypothyroidism
AmyloidosisAmyloidosis
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DIGOXIN DRUG INTERACTIONSDIGOXIN DRUG INTERACTIONSDIGOXIN DRUG INTERACTIONSDIGOXIN DRUG INTERACTIONS
Increased concentrationsIncreased concentrationsQuinidine RanolazineVerapamil CarvedilolAmiodarone CyclosporineDronedarone PPI’sPropafenone Macrolides
Decreased concentrationsDecreased concentrationsAcarbose/MiglitolBile acid sequestrants
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AdenosineAdenosineAdenosineAdenosine Rapid IV push (6 mg over 1-2 sec) Rapid IV push (6 mg over 1-2 sec) When using IV line, flush with salineWhen using IV line, flush with saline If no effect after 1-2 min, give 12 mg; may If no effect after 1-2 min, give 12 mg; may
repeat 12 mg dose oncerepeat 12 mg dose once Short-term adverse effects:Short-term adverse effects:
FlushingFlushing Chest discomfortChest discomfortShortness of breathShortness of breath AsystoleAsystole
Effects potentiated by dipyridamole & CBZEffects potentiated by dipyridamole & CBZ DO NOTDO NOT use in heart transplant patients use in heart transplant patients
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AdenosineAdenosineAdenosineAdenosine
The effects of adenosine are The effects of adenosine are antagonized by methylxanthinesantagonized by methylxanthines
TheophyllineTheophyllineCaffeineCaffeine
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MEDICATION COMPARISONMEDICATION COMPARISONMEDICATION COMPARISONMEDICATION COMPARISONMedicationMedication Efficacy Side Effects Toxicity Efficacy Side Effects ToxicityQuinidineQuinidine 22 ModMod ModModDisopyramide*Disopyramide* 1.51.5 HighHigh LowLowMexiletineMexiletine 11 ModMod LowLowFlecainide*Flecainide* 22oo V. LowV. Low LowLowPropafenone*Propafenone* 22?? Low-ModLow-Mod LowLowAmiodaroneAmiodarone 44 HighHigh V. HighV. HighSotalol*Sotalol* 2.52.5 Low-ModLow-Mod LowLow
**Negative Inotrope Negative Inotrope ooProarrhythmia risk Proarrhythmia risk ??Has potential for proarrhythmia?Has potential for proarrhythmia?
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TORSADE DE POINTESTORSADE DE POINTES Cardiovascular AgentsTORSADE DE POINTESTORSADE DE POINTES Cardiovascular AgentsType IAType IA
QuinidineQuinidine ProcainamideProcainamide DisopyramideDisopyramide
Type IIIType III SotalolSotalol DronedaroneDronedarone IbutilideIbutilide DofetilideDofetilide
RanolazineRanolazine
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TORSADE DE POINTESTORSADE DE POINTESAntimicrobialsTORSADE DE POINTESTORSADE DE POINTESAntimicrobials
PentamidinePentamidine
MacrolidesMacrolides Erythromycin & ClarithromycinErythromycin & Clarithromycin
KetolidesKetolides TelithromycinTelithromycin
FluoroquinolonesFluoroquinolones MoxifloxacinMoxifloxacin
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TORSADE DE POINTESTORSADE DE POINTESNon-Cardiovascular AgentsTORSADE DE POINTESTORSADE DE POINTESNon-Cardiovascular Agents
AntipsychoticsAntipsychotics
AntidepressantsAntidepressants
VasopressinVasopressin
TacrolimusTacrolimus
DroperidolDroperidol
TamoxifenTamoxifen
MethadoneMethadone
Chloral hydrateChloral hydrate
TriptansTriptans
CyclobenzaprineCyclobenzaprine
ApomorphineApomorphine
VardenafilVardenafil
PosaconazolePosaconazole
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TORSADE DE POINTESTORSADE DE POINTESDiscontinued AgentsTORSADE DE POINTESTORSADE DE POINTESDiscontinued Agents
Terfenadine/AstemizoleTerfenadine/Astemizole
CisaprideCisapride
Gatifloxacin/Grepafloxacin/SparfloxacinGatifloxacin/Grepafloxacin/Sparfloxacin
ProbucolProbucol
BepridilBepridil
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TORSADE DE POINTESTORSADE DE POINTES TreatmentTORSADE DE POINTESTORSADE DE POINTES Treatment Discontinue causative medicationDiscontinue causative medication Correct hypokalemia & hypomagnesemiaCorrect hypokalemia & hypomagnesemia Give magnesium 1-2 grams IVGive magnesium 1-2 grams IV To prevent subsequent episodes, increase To prevent subsequent episodes, increase
heart rate until cause of TdP is corrected heart rate until cause of TdP is corrected and/or cleared from the bodyand/or cleared from the body Temporary pacemakerTemporary pacemaker IsoproterenolIsoproterenol
Cardioversion is only indicated when patient Cardioversion is only indicated when patient becomes hemodynamically compromisedbecomes hemodynamically compromised