A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial Fibrillation RESOURCE SESSION A Practical Overview of Antiarrhythmic Drugs Commonly.

A Practical Overview of A Practical Overview of Antiarrhythmic Drugs Commonly Antiarrhythmic Drugs Commonly

Used in Atrial FibrillationUsed in Atrial Fibrillation

RESOURCE SESSIONRESOURCE SESSION

Olavo Fernandes, Pharm.D. Olavo Fernandes, Pharm.D.

Pharmacy Practice Leader, Pharmacy Practice Leader, Toronto General Hospital, UHNToronto General Hospital, UHN

Assistant Professor, University of TorontoAssistant Professor, University of Toronto

October 2002October 2002

Cardiac Conduction SystemCardiac Conduction System

SA nodeSA node– primary pacemaker (60-100 primary pacemaker (60-100

bpm)bpm)– autonomic nervous systemautonomic nervous system– vagus nerve (parasym.)vagus nerve (parasym.)– catacholamines (sym)catacholamines (sym)

AV nodeAV node– filter (40-60 bpm)filter (40-60 bpm)– controls number of controls number of

impulses reaching the impulses reaching the ventricle from atriaventricle from atria

Bundle of HisBundle of His– conducts impulses to conducts impulses to

bundle branchesbundle branches

Perkinje systemPerkinje system– < 40 bpm< 40 bpm– bifarcates into several bifarcates into several

bundle brunches bundle brunches

Electrocardiogram (ECG)Electrocardiogram (ECG)

P waveP wave– depolarization of atriadepolarization of atria

QRS ComplexQRS Complex– depolarization of ventricledepolarization of ventricle

– QRS interval normally < 0.12 QRS interval normally < 0.12 secs.secs.

– widened QRS: prolonged widened QRS: prolonged conductionconduction

– 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

Cardiac Action PotentialsCardiac Action Potentials

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

ClassificationClassification (Circulation 2001; 104: 2118-2150)(Circulation 2001; 104: 2118-2150)

Atrial ArrhythmiasAtrial Arrhythmias

Goals of TherapyGoals of Therapy convert to sinus rhythmconvert to sinus rhythm control ventricular response ratecontrol ventricular response rate relieve associated symptoms (palpitations, relieve associated symptoms (palpitations,

fatigue, dyspnea, syncope, angina, heart fatigue, dyspnea, syncope, angina, heart failure)failure)

prevent recurrenceprevent recurrence prevent complications: life threatening prevent complications: life threatening

arrhythmias, stroke, MI, tachycardiaarrhythmias, stroke, MI, tachycardia

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

periodperiod

– Calcium Channel Blockers (diltiazem, verapamil)Calcium Channel Blockers (diltiazem, verapamil)» block slow calcium channels, slow AV node conductionblock slow calcium channels, slow AV node conduction

Rate Control Agent Rate Control Agent ConsiderationsConsiderationsDIGOXINDIGOXIN

– vagally mediatedvagally mediated– slow onset- 4hrs (large slow onset- 4hrs (large

VD)VD)– poor effectiveness poor effectiveness

during high sympathetic during high sympathetic tone (stress)tone (stress)

– positive inotrope (benefit positive inotrope (benefit with concurrent CHF)with concurrent CHF)

– proarrhythmic, side proarrhythmic, side effectseffects

Rate Control Agent Rate Control Agent ConsiderationsConsiderations

BETA BLOCKERSBETA BLOCKERS– 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 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)

KineticsKinetics– dist: wide 7-8 L/kg (skeletal dist: wide 7-8 L/kg (skeletal

muscle, myocardium, kidneys)muscle, myocardium, kidneys)– ptn binding : 20-40%ptn binding : 20-40%– elimination: renal 70-80%; elimination: renal 70-80%;

hepatic (up to 30%)hepatic (up to 30%)– time to peak: 1-4 hr (IV); 2-6 hr time to peak: 1-4 hr (IV); 2-6 hr

(po)(po)

– time to steady state: 5-7 days time to steady state: 5-7 days (2-3 wks in RF)(2-3 wks in RF)

– elimination half life: 35-40 hrs elimination half life: 35-40 hrs (2-5 days in RF)(2-5 days in RF)

IndicationsIndications– CHF, AF- rate controlCHF, AF- rate control

DosingDosing– load: 0.250mg IV over 15 min load: 0.250mg IV over 15 min

repeat in 6hr; 0.250 mg po q6h repeat in 6hr; 0.250 mg po q6h x 4 (total 1 mg)x 4 (total 1 mg)

– renal dysfunction load 0.125mg renal dysfunction load 0.125mg q6h (total 0.5-0.75 mg)q6h (total 0.5-0.75 mg)

– initial mx dose: 0.125 - 0.250 initial mx dose: 0.125 - 0.250 mg pomg po

Drug Profile: DigoxinDrug Profile: Digoxin Adverse EffectsAdverse Effects

– GIGI: N, V, A, D: N, V, A, D– CNS:CNS: disorientation, confusion disorientation, confusion– Ocular:Ocular: colour vision colour vision

disturbances (yellow-green), disturbances (yellow-green), halos, photophobiahalos, photophobia

– CV:CV: bradycardia, heart block, bradycardia, heart block, VTVT

– more prone to toxicity with more prone to toxicity with hypokalemia (sensitizes hypokalemia (sensitizes myocardium to digoxin effect)myocardium to digoxin effect)

– toxicity: hyperkalemia, toxicity: hyperkalemia, ventricular arrhythmias, visual ventricular arrhythmias, visual disturbancesdisturbances

– DIGIBINDDIGIBIND

Drug InteractionsDrug Interactions– physically adsorption physically adsorption

(antacids, sucralfate, resins)(antacids, sucralfate, resins)

– antibiotics (digoxin antibiotics (digoxin metabolized by gut bacteria)metabolized by gut bacteria)

– increased serum level increased serum level (quinidine, amiodarone, (quinidine, amiodarone, verapamil)verapamil)

– assay interference assay interference (spironolactone)(spironolactone)

MonitoringMonitoring– ECG, HR, renal function, ECG, HR, renal function,

potassium, digoxin levelspotassium, digoxin levels

Digoxin: serum levelsDigoxin: serum levels Therapeutic RangeTherapeutic Range

– 1.2- 2.5 nmol/L 1.2- 2.5 nmol/L – AFib at higher end of targetAFib at higher end of target

Indications Indications – suspected toxicity/ suspected toxicity/

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

medicationsmedications– routine monitoring - yearlyroutine monitoring - yearly– subtherapeutic responsesubtherapeutic response

Sample Collection TimeSample Collection Time– not < 8 hrs and preferably not < 8 hrs and preferably

trough level before next dosetrough level before next dose– at least 5 days after starting tx at least 5 days after starting tx

or changing doseor changing dose– Increased levelsIncreased levels

Increased LevelsIncreased Levels– advanced age, renal disease, advanced age, renal disease,

hepatic disease, amiodarone, hepatic disease, amiodarone, verapamil, CsA, quinidineverapamil, CsA, quinidine

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

Adverse Effects Adverse Effects – IV: hypotension, bradycardiaIV: hypotension, bradycardia– worsening CHF symptomsworsening CHF symptoms– heart blockheart block

Drug InteractionsDrug Interactions– AV node blocking agents (BB, AV node blocking agents (BB,

CCB, digoxin)CCB, digoxin)– hypotensive agentshypotensive agents– negative inotropesnegative inotropes

MonitorMonitor– ECG, BP, HRECG, BP, HR– CHF symptomsCHF symptoms

Drug Profile: MetoprololDrug Profile: Metoprolol Mechanism:Mechanism:

– competitive block agonist competitive block agonist effect of sympathetic effect of sympathetic neurotransmitters neurotransmitters

– block adrenergic stimulation block adrenergic stimulation of cardiac action potentialsof cardiac action potentials

– Beta-1 selective agentBeta-1 selective agent– slows AV node conductionslows AV node conduction

Administration/DosingAdministration/Dosing– 12.5 - 100 mg po bid12.5 - 100 mg po bid– 5mg IV push for acute 5mg IV push for acute

management ( if necessary management ( if necessary 10-15 mg IV q 6h)10-15 mg IV q 6h)

Adverse Effects Adverse Effects – IV: hypotension, bradycardiaIV: hypotension, bradycardia– worsening CHF symptomsworsening CHF symptoms– bronchospasm in asthmabronchospasm in asthma– heart blockheart block

Drug InteractionsDrug Interactions– AV node blocking agents AV node blocking agents

( CCB, digoxin)( CCB, digoxin)– hypotensive agentshypotensive agents– negative inotropesnegative inotropes

MonitorMonitor– ECG, BP, HRECG, BP, HR– CHF symptomsCHF symptoms

Drug Profile: AmiodaroneDrug Profile: Amiodarone Mechanism:Mechanism:

– complex pcl profile: actions of complex pcl profile: actions of all classes all classes

– conduction slowing (class I)conduction slowing (class I)– BB activity (class II)BB activity (class II)– prolong APD and refractory prolong APD and refractory

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

– elimination: primarily elimination: primarily hepatic metabolism / biliary hepatic metabolism / biliary excretionexcretion

– 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

weeksweeks– Ventricular arrhythmiasVentricular arrhythmias

» 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

x 2-4 wks; 200 mg/d thereafterx 2-4 wks; 200 mg/d thereafter

Adverse Effects (IV)Adverse Effects (IV)– hypotension (related to hypotension (related to

vehicle)vehicle)– peripheral vein phlebitis (run peripheral vein phlebitis (run

at < 2mg/ml)at < 2mg/ml)– IV infusions > 2 hrs IV infusions > 2 hrs

administer in glass bottles of administer in glass bottles of D5WD5W

– proarrhythmia : rareproarrhythmia : rare– 100% liver metabolism100% liver metabolism

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

– increase plasma cholesterolincrease plasma cholesterol

PulmonaryPulmonary– most feared adverse effectmost feared adverse effect

– pulmonary fibrosis (2-7%) pulmonary fibrosis (2-7%) can be fatal in 10% of casescan be fatal in 10% of cases

– appears in pts with > 400mg/ appears in pts with > 400mg/ dayday

– CXR: bilateral and diffuse CXR: bilateral and diffuse changes/ interstitial infiltrateschanges/ interstitial infiltrates

– Sx: dyspnea, cough, chest Sx: dyspnea, cough, chest pain, pleural rubpain, pleural rub

Amiodarone : Adverse EffectsAmiodarone : Adverse EffectsPulmonaryPulmonary

– 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

manage (thyroidectomy)manage (thyroidectomy)

Amiodarone: Adverse EffectsAmiodarone: Adverse Effects DermatolgicialDermatolgicial

– skin reaction (15%)skin reaction (15%)

– photosensitivity (10%)- limit sun photosensitivity (10%)- limit sun exposure and sunscreenexposure and sunscreen

– long term blue-gray discoloration long term blue-gray discoloration (1-7%)(1-7%)

CNSCNS– 40% have CNS effects (fatigue, 40% have CNS effects (fatigue,

tremor, ataxia, peripheral tremor, ataxia, peripheral neuropathy)neuropathy)

Optho. Optho. – corneal depositscorneal deposits

– rare: visual disturbancesrare: visual disturbances

– sx: photophobia, blurred vision, sx: photophobia, blurred vision, blue-green halosblue-green halos

MonitoringMonitoring– labs (renal function, CBC, labs (renal function, CBC,

LFTs, thyroid function), ECG, LFTs, thyroid function), ECG, CXR CXR

» baseline, as sx occur and baseline, as sx occur and every 4-6 monthsevery 4-6 months

– PFTs, eye exam: baseline and PFTs, eye exam: baseline and as symptoms occuras symptoms occur

– ECG, HR, BP at regular ECG, HR, BP at regular intervalsintervals

Drug InteractionsDrug Interactions– warfarin, digoxin, BB, CCB, warfarin, digoxin, BB, CCB,

procainamide, quinidineprocainamide, quinidine– (see handout)(see handout)

Drug Profile: AmiodaroneDrug Profile: Amiodarone

ADVANTAGESADVANTAGES effective in a wide range effective in a wide range

of arrhythmiasof arrhythmias neutral effects on neutral effects on

inotropy (CHF patients)inotropy (CHF patients) safety in CAD and LV safety in CAD and LV

dysfunctiondysfunction low incidence of low incidence of

proarrhythmiaproarrhythmia some rate control some rate control

properties in AFproperties in AF

LIMITATIONSLIMITATIONS many chronic side many chronic side

effects effects drug interactionsdrug interactions IV amiodarone - very IV amiodarone - very

expensiveexpensive

Drug Profile: ProcainamideDrug Profile: Procainamide Mechanism:Mechanism:

– Class 1a AA- blocks Na Class 1a AA- blocks Na channelschannels

– prolongs refractory period and prolongs refractory period and decreases conduction velocitydecreases conduction velocity

Administration/DosingAdministration/Dosing– IV and PO regimensIV and PO regimens– depends on indication and depends on indication and

renal functionrenal function– paradoxical initial increase in paradoxical initial increase in

HRHR

Kinetic ImplicationsKinetic Implications– active metabolite- NAPAactive metabolite- NAPA

– levels to prevent toxicity (drug levels to prevent toxicity (drug and NAPA)and NAPA)

Adverse EffectsAdverse Effects– hypotension, bradycardia hypotension, bradycardia – proarrhythmic (TdP)proarrhythmic (TdP)– drug-induced lupus (SLE)drug-induced lupus (SLE)– GI: nausea, vomitingGI: nausea, vomiting– CNS: disorientationCNS: disorientation

Drug InteractionsDrug Interactions– amiodarone, Septra (TMP/SMX)amiodarone, Septra (TMP/SMX)

MonitorMonitor– ECG, BP, HRECG, BP, HR