CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS

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


IAIA QuinidineQuinidine ICIC FlecainideFlecainide

ProcainamideProcainamide PropafenonePropafenone

DisopyramideDisopyramide EncainideEncainide

IBIB LidocaineLidocaine I?I? MoricizineMoricizine

MexiletineMexiletine

TocainideTocainide



IIII Beta-adrenergic blockersBeta-adrenergic blockers

IIIIII AmiodaroneAmiodarone IbutilideIbutilide

Dronedarone Dronedarone DofetilideDofetilide

SotalolSotalol BretyliumBretylium

IVIV Calcium channel blockersCalcium channel blockers

Diltiazem & VerapamilDiltiazem & Verapamil



DigoxinDigoxin

AdenosineAdenosine

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

Type IxType Ix

Type IaType Ia

Type IbType Ib

Type IcType Ic

Ia’s create a double block

Ib’s take away the block

What about Ic’s?- They have no effect on action

potential duration

What about Ic’s?- They have no effect on action

potential duration

Type II & IVType II & IV

Type IIIType III

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

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

CLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONSCLINICAL INDICATIONS

MedicationMedication Ventricular VentricularAtrialAtrial

DigoxinDigoxinPO,IVPO,IV -- AV AV

AdenosineAdenosineIVIV -- PSVTPSVT

QuinidineQuinidine

• Type IA antiarrhythmicType IA antiarrhythmic• Indicated for atrial fibrillation and Indicated for atrial fibrillation and

ventricular tachycardiasventricular tachycardias

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

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

ProcainamideProcainamideProcainamideProcainamide Type IA antiarrhythmicType IA antiarrhythmic Indicated for acute conversion of Indicated for acute conversion of

ventricular & atrial dysrhythmiasventricular & atrial dysrhythmias

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

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

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

DisopyramideDisopyramide

• Type IA antiarrhythmicType IA antiarrhythmic• Indicated in atrial and ventricular Indicated in atrial and ventricular

arrhythmiasarrhythmias


• 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


• 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


Adverse EffectsAdverse Effects• GastrointestinalGastrointestinal• Negative inotropeNegative inotrope• Anticholinergic adverse effectsAnticholinergic adverse effects

• Dry mouthDry mouth• Blurred visionBlurred vision• ConstipationConstipation• Urinary hesitationUrinary hesitation


• EliminationElimination• ~50% hepatic~50% hepatic• ~50% renal~50% renal

• Half-lifeHalf-life• ~7 hours~7 hours


• 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:

NauseaNausea DizzinessDizziness

DrowsinessDrowsiness ConfusionConfusion

TremorsTremors Facial numbnessFacial numbness

ParesthesiasParesthesias Peripheral Peripheral numbnessnumbness

Altered speechAltered speech SeizuresSeizures

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


• Type IB antiarrhythmicType IB antiarrhythmic• Only indicated to prevent ventricular Only indicated to prevent ventricular

arrhythmiasarrhythmias


Adverse EffectsAdverse Effects• ExtremelyExtremely GI irritatingGI irritating• Altered CNS functioningAltered CNS functioning

• Hepatically metabolizedHepatically metabolized• Half-life: 6-12 hoursHalf-life: 6-12 hours

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

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

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

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


Adverse EffectsAdverse Effects• GastrointestinalGastrointestinal• CNSCNS• Negative inotropeNegative inotrope• Metallic tasteMetallic taste


• 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

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

SotalolSotalol

• Renally eliminatedRenally eliminated• Negative inotropeNegative inotrope• Beta-blocker concernsBeta-blocker concerns

• Torsade de pointesTorsade de pointes

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

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

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

Half-life: ~60 daysHalf-life: ~60 days

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

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

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%

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

A Sampling of Drug InteractionsA Sampling of Drug Interactions

WarfarinWarfarin DigoxinDigoxin MetoprololMetoprolol QuinidineQuinidine ProcainamideProcainamide DisopyramideDisopyramide

FlecainideFlecainide TheophyllineTheophylline PhenytoinPhenytoin SimvastatinSimvastatin CyclosporineCyclosporine MethotrexateMethotrexate

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 GI irritationGI irritation Prolongs QT interval Prolongs QT interval Negative inotropeNegative inotrope

Contraindicated in:Contraindicated in: NYHA IVNYHA IV Acute CHF exacerbationsAcute CHF exacerbations

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

Hepatically clearedHepatically cleared Half-life: ~6 hoursHalf-life: ~6 hours

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 (?)

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

DofetilideDofetilide ClearanceClearance

HepaticHepatic CYP 3A4CYP 3A4

RenalRenal Renal tubular secretionRenal tubular secretion


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

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


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


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)


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

• Therapeutic range: 1–2 mcg/LTherapeutic range: 1–2 mcg/L

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

Drug DistributionDrug DistributionDrug DistributionDrug Distribution

Cp

Time

12 h

DigoxinDigoxinAdverse EffectsDigoxinDigoxinAdverse Effects

GastrointestinalGastrointestinal

DysrhythmiasDysrhythmias

Central nervous system Central nervous system

VisualVisual

DIGOXIN TOXICITYDIGOXIN TOXICITYPrecipitating FactorsDIGOXIN TOXICITYDIGOXIN TOXICITYPrecipitating Factors

HypokalemiaHypokalemia

HypomagnesemiaHypomagnesemia

HypercalcemiaHypercalcemia

HypothyroidismHypothyroidism

AmyloidosisAmyloidosis

DIGOXIN DRUG INTERACTIONSDIGOXIN DRUG INTERACTIONSDIGOXIN DRUG INTERACTIONSDIGOXIN DRUG INTERACTIONS

Increased concentrationsIncreased concentrationsQuinidine RanolazineVerapamil CarvedilolAmiodarone CyclosporineDronedarone PPI’sPropafenone Macrolides

Decreased concentrationsDecreased concentrationsAcarbose/MiglitolBile acid sequestrants

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

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

QuinidineQuinidine ProcainamideProcainamide DisopyramideDisopyramide

Type IIIType III SotalolSotalol DronedaroneDronedarone IbutilideIbutilide DofetilideDofetilide

RanolazineRanolazine

TORSADE DE POINTESTORSADE DE POINTESAntimicrobialsTORSADE DE POINTESTORSADE DE POINTESAntimicrobials

PentamidinePentamidine

MacrolidesMacrolides Erythromycin & ClarithromycinErythromycin & Clarithromycin

KetolidesKetolides TelithromycinTelithromycin

FluoroquinolonesFluoroquinolones MoxifloxacinMoxifloxacin

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

TORSADE DE POINTESTORSADE DE POINTESDiscontinued AgentsTORSADE DE POINTESTORSADE DE POINTESDiscontinued Agents

Terfenadine/AstemizoleTerfenadine/Astemizole

CisaprideCisapride

Gatifloxacin/Grepafloxacin/SparfloxacinGatifloxacin/Grepafloxacin/Sparfloxacin

ProbucolProbucol

BepridilBepridil

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

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CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS