CLINICAL PHARMACOLOGY OF CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC ANTIARRHYTHMIC MEDICATIONS MEDICATIONS Vincent F. Mauro, PharmD, Vincent F. Mauro, PharmD, FCCP FCCP Professor of Clinical Pharmacy and Adjunct Professor of Medicine The University of Toledo
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CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS
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 Presentation
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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
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
AutomaticityAutomaticity
Reentry-induced dysrhythmia
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
Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
Classification of Classification of Antiarrhythmic AgentsAntiarrhythmic Agents
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
• 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
ProcainamideProcainamideProcainamideProcainamide Type IA antiarrhythmicType IA antiarrhythmic Indicated for acute conversion of Indicated for acute conversion of
• 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
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
DisopyramideDisopyramide
• Type IA antiarrhythmicType IA antiarrhythmic• Indicated in atrial and ventricular Indicated in atrial and ventricular
arrhythmiasarrhythmias
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
Dosage Rate
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
• Used in neurocardiogenic syncope & Used in neurocardiogenic syncope & hypertrophic heartshypertrophic hearts• Anticholinergic propertiesAnticholinergic properties• Negative inotropic propertiesNegative inotropic properties
LidocaineLidocaine
• Type IB antiarrhythmicType IB antiarrhythmic• Indicated in acute treatment and Indicated in acute treatment and
prevention of ventricular dysrhythmiasprevention of ventricular dysrhythmias
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
LidocaineLidocaineLidocaineLidocaine
Toxicity most often manifested by:Toxicity most often manifested by:
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
MexiletineMexiletine
• Type IB antiarrhythmicType IB antiarrhythmic• Only indicated to prevent ventricular Only indicated to prevent ventricular
• Since it is very proarrhythmic:Since it is very proarrhythmic:• Generally used only for atrial dysrhythmiasGenerally used only for atrial dysrhythmias
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
• 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
SotalolSotalol
Now available parenterallyNow available parenterally• IndicationsIndications
• 75 mg IV = 80 mg po75 mg IV = 80 mg po• Give dose over 5 hoursGive dose over 5 hours
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
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
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
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
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
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
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 (?)
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
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
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
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
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
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)
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)
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
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
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
• 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
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
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
AdenosineAdenosineAdenosineAdenosine
The effects of adenosine are The effects of adenosine are antagonized by methylxanthinesantagonized by methylxanthines
TheophyllineTheophyllineCaffeineCaffeine
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?
TORSADE DE POINTESTORSADE DE POINTES Cardiovascular AgentsTORSADE DE POINTESTORSADE DE POINTES Cardiovascular AgentsType IAType IA
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