Intravenous Amiodarone for Intravenous Amiodarone for Supraventricular TachycardiasSupraventricular Tachycardias

Jerrold H Levy, MDJerrold H Levy, MDEmory University School of MedicineEmory University School of Medicine

Atlanta, GeorgiaAtlanta, Georgia

Supraventricular Tachycardias: Supraventricular Tachycardias: Therapeutic ObjectivesTherapeutic Objectives

• Determine the mechanism of the Determine the mechanism of the arrhythmia arrhythmia

• Restore sinus rhythm with the simplest Restore sinus rhythm with the simplest technique and approach as possibletechnique and approach as possible

• Eliminate or significantly reduce Eliminate or significantly reduce arrhythmia recurrences and underlying arrhythmia recurrences and underlying causecause

Singh 2002.

RARA LALA

LVLVRVRV

Types of Supraventricular Types of Supraventricular TachyarrhythmiasTachyarrhythmias

Sinus Node ReentrySinus Node Reentry

Atrial FlutterAtrial Flutter

Automatic Atrial TachycardiaAutomatic Atrial Tachycardia

Reentrant Atrial TachycardiaReentrant Atrial Tachycardia

Atrioventricular NodalAtrioventricular NodalReentry (AVNRT)Reentry (AVNRT)

AV Reentry via an AccessoryAV Reentry via an AccessoryAV Connection (AVRT)AV Connection (AVRT)

Atrial Fibrillation (Not Shown)Atrial Fibrillation (Not Shown)

Singh 2002.

Types of Paroxysmal Types of Paroxysmal Supraventricular TachycardiaSupraventricular Tachycardia

AV NodalReentry

AV ReciprocatingTachycardia Sinus Nodal Reentry

Intra-atrial Reentry

Automatic AtrialTachycardia

Mechanisms of Paroxysmal Mechanisms of Paroxysmal Supraventricular TachycardiasSupraventricular Tachycardias

Enhanced Automaticity:Enhanced Automaticity:• Paroxysmal and AcuteParoxysmal and Acute

• ChronicChronic

Re-entry without Bypass Tracts:Re-entry without Bypass Tracts:• AV Nodal Re-entry: Slow – Fast/Fast – SlowAV Nodal Re-entry: Slow – Fast/Fast – Slow

• Sinoatrial Nodal Re-entrySinoatrial Nodal Re-entry

• Intra-atrial Re-entryIntra-atrial Re-entry

Re-entry in Association with Bypass Tracts:Re-entry in Association with Bypass Tracts:• Re-entry with Anterograde AV Conduction (Orthodromic)Re-entry with Anterograde AV Conduction (Orthodromic)

– With Evidence of Pre-excitation of 12-Lead ECGWith Evidence of Pre-excitation of 12-Lead ECG– Concealed WPW (Bypass Tract ConductingConcealed WPW (Bypass Tract Conducting

Only Retrogradely)Only Retrogradely)

• Re-entry with Anterograde Conduction Over BypassRe-entry with Anterograde Conduction Over BypassTract (Antidromic) During TachycardiaTract (Antidromic) During Tachycardia

Accessory Pathways: Concealed Accessory Pathways: Concealed Bypass Tract AV Reentrant TachycardiaBypass Tract AV Reentrant Tachycardia

AV NodeAV Node

Bundle of HisBundle of His

Left Bundle BranchLeft Bundle Branch

PP

Right Bundle BranchRight Bundle Branch

Concealed BypassConcealed BypassTractTract

Singh 2002.

AV NodeAV Node

Electrical Conduction in Electrical Conduction in Atrial FlutterAtrial Flutter

Ventricular Rate 150-160 (Most Often 2:1 AV Block)Ventricular Rate 150-160 (Most Often 2:1 AV Block)

ECG of FlutterECG of Flutter

Baseline Coarsely or Finely Irregular; P Waves Absent.Baseline Coarsely or Finely Irregular; P Waves Absent.Ventricular Response (QRS) Irregular, Slow or RapidVentricular Response (QRS) Irregular, Slow or Rapid

Coarse Fibrillation Fine Fibrillation

Atrial FibrillationAtrial Fibrillation

Scheidt S, Erlebacher JA, Netter FH. Basic Electrocardiography ECG. Ciba-Geigy: First Printing, 1986, p23.

ElectrocardiogramElectrocardiogram

AF is Associated WithAF is Associated WithCV DiseasesCV Diseases

• CT surgeryCT surgery

• Valvular orValvular orcongential diseasecongential disease

• HypertensionHypertension

• CardiomyopathyCardiomyopathy

• Heart failureHeart failure

• Myocardial ischemia/MIMyocardial ischemia/MI

• Peri/myocarditisPeri/myocarditis

• Infiltrative heart Infiltrative heart diseasedisease

• Cardiac traumaCardiac trauma

Systemic DiseasesSystemic Diseases

• AgeAge

• DTs, sympathetic stormDTs, sympathetic storm

• Electrolyte disordersElectrolyte disorders

• ThyrotoxicosisThyrotoxicosis

• Fever/hypothermiaFever/hypothermia

• HypovolemiaHypovolemia

• DiabetesDiabetes

• AnemiaAnemia

• Pulmonary diseasePulmonary disease

• Cerebrovascular diseaseCerebrovascular disease

Antiarrhythmic Drugs Antiarrhythmic Drugs vs. Therapeutic Goalvs. Therapeutic Goal

AtriumAtrium

His PurkinjeHis Purkinje

VentricleVentricle

APAP

AV NodeAV Node

IbutilideIbutilide

QuinidineQuinidineProcainamideProcainamideDisopyramideDisopyramide

FlecainideFlecainidePropafenonePropafenoneSotalolSotalolAmiodaroneAmiodarone

Vagal StimulationVagal StimulationDigoxinDigoxin-Blocking Drugs-Blocking DrugsVerapamilVerapamilDiltiazemDiltiazemAdenosineAdenosine

Singh 2002.

Simulated Drug Level CurvesSimulated Drug Level Curves= “Full” loading dose

Time (Half-life)

0 1 2 3 4 5 6

TherapeuticConcentration

Range

Pla

sma

Dru

g L

evel

= Half loading dose and infusion

= Infusion without loading dose

Levy 2002.

Agents Used in the Treatment of SVT Agents Used in the Treatment of SVT Tachycardias by Vaughan Williams ClassTachycardias by Vaughan Williams Class

1A:1A: Quinidine, procainamide, disopyramideQuinidine, procainamide, disopyramide

1C:1C: Flecainide, propafenoneFlecainide, propafenone

2: 2: Esmolol, propranolol, metoprolol,Esmolol, propranolol, metoprolol,atenolol, (et al)atenolol, (et al)

3: 3: Amiodarone, sotalolAmiodarone, sotalol

4:4: Diltiazem, verapamilDiltiazem, verapamil

– Glycosides: digoxin Glycosides: digoxin

– Purinergic: adenosinePurinergic: adenosine

Singh 2002.

Amiodarone Historical Amiodarone Historical Landmarks (1)Landmarks (1)

1962:1962: Synthesized as an anti-anginal Synthesized as an anti-anginal compound (Charlier)compound (Charlier)

1968:1968: Novel action with new biological Novel action with new biological profile (Charlier)profile (Charlier)

1970:1970: Unusual electrophysiology profile Unusual electrophysiology profile (Singh & Vaughan Williams)(Singh & Vaughan Williams)

74/76:74/76: Unusual clinical potency as an Unusual clinical potency as an antiarrhythmic drug (Rosenbaum M)antiarrhythmic drug (Rosenbaum M)

Amiodarone Historical Amiodarone Historical Landmarks (2)Landmarks (2)

1983:1983: First US Symposium on Amiodarone First US Symposium on Amiodarone (Singh & Zipes)(Singh & Zipes)

1984:1984: FDA ApprovalFDA Approval

1993:1993: Efficacy Unparalleled; Mode ofEfficacy Unparalleled; Mode ofAction UnknownAction Unknown

1995:1995: Amiodarone IV approvedAmiodarone IV approved

1999:1999: Symposium, the last 15 yearsSymposium, the last 15 years(Singh, AJC (Suppl))(Singh, AJC (Suppl))

Singh 2002.

Unique Features of Amiodarone Unique Features of Amiodarone as an Anti-arrhythmic Drugas an Anti-arrhythmic Drug

• Long elimination half-lifeLong elimination half-life

• Can be administered to anephric patientsCan be administered to anephric patientson dialysison dialysis

• Well tolerated in advanced CHFWell tolerated in advanced CHF

• Manageable drug-drug interactionsManageable drug-drug interactions(ie, digoxin, coumadin)(ie, digoxin, coumadin)

• Very low incidence of torsades de pointes Very low incidence of torsades de pointes even with diuretic therapyeven with diuretic therapy

Singh 2002.

Unique Features of Amiodarone Unique Features of Amiodarone as an Anti-arrhythmic Drug (Cont’d.)as an Anti-arrhythmic Drug (Cont’d.)

• Has Class 1 properties without the Has Class 1 properties without the associated proarrhythmic actions or associated proarrhythmic actions or negative impact on mortalitynegative impact on mortality

• Has antisympathetic actions withoutHas antisympathetic actions withoutbeta-blocker side effectsbeta-blocker side effects

• Increases LVEF and improves CHFIncreases LVEF and improves CHF

• Antifibrillatory actions in the ventricles may Antifibrillatory actions in the ventricles may be augmented by addition of beta-blockadebe augmented by addition of beta-blockade

Singh 2002.

Intravenous Amiodarone Intravenous Amiodarone PharmacokineticsPharmacokinetics

• Peak levels after single 5 mg/kgPeak levels after single 5 mg/kg15 min infusions: 5-41 mg/L 15 min infusions: 5-41 mg/L

• After 10 min 150 mg load for VF/VT:After 10 min 150 mg load for VF/VT:7-26 mg/L7-26 mg/L

• Levels decline to 10% of peak withinLevels decline to 10% of peak within30-45 min at the end of the infusion30-45 min at the end of the infusion

• After 48 hrs of continued infusions,After 48 hrs of continued infusions,levels 0.7 to 1.4 mg/Llevels 0.7 to 1.4 mg/L

Singh 2002.

Pharmacokinetics of Pharmacokinetics of Oral AmiodaroneOral Amiodarone

• Absorption: TAbsorption: Tmaxmax:2-12 h (lab 0.4-3 h):2-12 h (lab 0.4-3 h)

• Extent of absorption: Poor and slowExtent of absorption: Poor and slow

• Bioavailability: Variable (22-86%)Bioavailability: Variable (22-86%)

• Protein binding: 96.3 ± 0.6%Protein binding: 96.3 ± 0.6%

• Volume of distribution: 1.3-65.8 l/kgVolume of distribution: 1.3-65.8 l/kg

• Negligible renal excretionNegligible renal excretion

• Biotransformation: Hepatic and intestinalBiotransformation: Hepatic and intestinal

• Elimination half-life: 3.2-20.7 h (acute),Elimination half-life: 3.2-20.7 h (acute),13.7-52.6 day (chronic)13.7-52.6 day (chronic)

Singh 2002.

Pharmacokinetics of Pharmacokinetics of Oral AmiodaroneOral Amiodarone

• Total body clearance: 0.10-0.77 l/minTotal body clearance: 0.10-0.77 l/min

• Pattern of elimination: First orderPattern of elimination: First order

• Metabolites: Major: mono N-Metabolites: Major: mono N-desethylamiodarone, Minor: bis-N-desethylamiodarone, Minor: bis-N-desethylamiodarone, deiodinated metabolitesdesethylamiodarone, deiodinated metabolites

• Therapeutic levels: 1.0-2.5 µg/mL rangeTherapeutic levels: 1.0-2.5 µg/mL range

• Special factors: Slow onset and offsetSpecial factors: Slow onset and offsetof actionof action

Singh 2002.

Actions of IV Amiodarone vs Actions of IV Amiodarone vs Chronic AmiodaroneChronic Amiodarone

ActionsActions IV AmioIV Amio Chronic AmioChronic Amio

Repolarization (QT Repolarization (QT interval) prolongation interval) prolongation (atria & ventricles)(atria & ventricles)

±± ++++++++

Conduction velocityConduction velocity(atria & vent) reduced(atria & vent) reduced

++++ ++++(function of rate)(function of rate)

Sinus rates reducedSinus rates reduced ++ ++++++

AV nodalAV nodalconduction slowedconduction slowed

++ ++++

Actions of IV Amiodarone vs Actions of IV Amiodarone vs Chronic AmiodaroneChronic Amiodarone

ActionsActions IV AmioIV Amio Chronic AmioChronic Amio

AV nodal refactoriness AV nodal refactoriness increasedincreased

++++ ++++++++

Atrial refactoriness Atrial refactoriness increasedincreased

±± ++++++

Ventricular refactoriness Ventricular refactoriness increasedincreased

±± ++++++

Noncompetitive alpha Noncompetitive alpha and beta blocking activityand beta blocking activity

++ ++

Singh 2002.

Pharmacokinetics of Pharmacokinetics of IV AmiodaroneIV Amiodarone

Summary: More rapid onset and offsetSummary: More rapid onset and offsetof action with IV versus oralof action with IV versus oral

Comparison of Oral vs. IV Amiodarone:Comparison of Oral vs. IV Amiodarone:Conversion of Atrial FibrillationConversion of Atrial Fibrillation

• N=52 patients with atrial fibrillationN=52 patients with atrial fibrillation

– 86 episodes of attempted cardioversion with 86 episodes of attempted cardioversion with oral, intravenous, or DC cardioversionoral, intravenous, or DC cardioversion

• Conversion to sinus rhythm achievedConversion to sinus rhythm achieved

– 29% of pts treated with oral amiodarone29% of pts treated with oral amiodarone

– 42% of pts treated with DC cardioversion42% of pts treated with DC cardioversion

– 64% of pts treated with intravenous 64% of pts treated with intravenous amiodaroneamiodarone

– Overall statistical significance: Overall statistical significance: PP == 0.0320.032

Horner SM. Acta Cardiol. 1992;47:473.

Efficacy of IV Amiodarone for the Efficacy of IV Amiodarone for the Conversion of Atrial arrhythmiaConversion of Atrial arrhythmia

Vietti-RamusVietti-Ramuset al. 1992et al. 1992

44 pts44 pts 86% w/ SVT reverted to SR <24 h86% w/ SVT reverted to SR <24 h100% w/ PSVT reverted to SR <24 h100% w/ PSVT reverted to SR <24 h75% w/ AFL reverted to SR <24 h75% w/ AFL reverted to SR <24 h85.7% w/ AF reverted to SR <24 h85.7% w/ AF reverted to SR <24 h

StrasbergStrasberget al. 1985et al. 1985

26 pts26 pts 100% reverted to SR (100% reverted to SR (PP<0.001)<0.001)46% reverted <30 min46% reverted <30 min23% converted 2-8 h23% converted 2-8 h27% no conversion27% no conversion4% reverted to AFL < 10 min; to SR 40 min later4% reverted to AFL < 10 min; to SR 40 min later

Faniel and Faniel and SchoenfeldSchoenfeld19831983

26 pts26 pts 80.8% reverted to SR <24 h and maintained >48 h80.8% reverted to SR <24 h and maintained >48 hMean time from treatment to SSR = 171 minMean time from treatment to SSR = 171 minTotal dose = 6.9 ± 2.3 mg/kgTotal dose = 6.9 ± 2.3 mg/kg

Management of Atrial Tachyarrhythmias in the Management of Atrial Tachyarrhythmias in the Critically Ill: a Comparison of Intravenous Critically Ill: a Comparison of Intravenous

Procainamide and AmiodaroneProcainamide and Amiodarone

24 pts atrial fibrillation more than 1 h evaluated – 10 Amiodarone,24 pts atrial fibrillation more than 1 h evaluated – 10 Amiodarone,14 Procainamide 14 Procainamide

Methods:Methods:

• Amiodarone IV 3 mg/kg then 10 mg/kg/24 h with repeat dose of 3 Amiodarone IV 3 mg/kg then 10 mg/kg/24 h with repeat dose of 3 mg/kg at 1 h if no response or Procainamide IV 10 mg/kg at 1 mg/kg at 1 h if no response or Procainamide IV 10 mg/kg at 1 mg/kg/min then 2-4 mg/min for 24 h with repeat dose of 5mg/kg mg/kg/min then 2-4 mg/min for 24 h with repeat dose of 5mg/kg at 1 h if no response at 1 h if no response

Results:Results:

• 7/10 Amiodarone-treated patients, 10/14 Procainamide-treated 7/10 Amiodarone-treated patients, 10/14 Procainamide-treated patients converted to sinus rhythm by 12 hourspatients converted to sinus rhythm by 12 hours

• No significant change in SBP from baselineNo significant change in SBP from baseline

Chapman MJ et al Intensive Care Med 1993;19:48-52.

Amiodarone Versus Propafenone for Conversion Amiodarone Versus Propafenone for Conversion of Chronic Atrial Fibrillation: Results of a of Chronic Atrial Fibrillation: Results of a

Randomized, Controlled StudyRandomized, Controlled Study

118 pts with atrial fibrillation lasting more than 3 weeks, 118 pts with atrial fibrillation lasting more than 3 weeks, 34 amiodarone, 32 propafenone, 35 control 34 amiodarone, 32 propafenone, 35 control

Methods:Methods:

• IV amiodarone 300 mg over 1 h, then 20 mg/kg over 24 hours plus 600 IV amiodarone 300 mg over 1 h, then 20 mg/kg over 24 hours plus 600 mg orally, in 3 doses for 1 week, then 400 mg/day orally for 3 weeks. mg orally, in 3 doses for 1 week, then 400 mg/day orally for 3 weeks. IV propafenone 2 mg/kg over 15 minutes, then 10 mg/kg over 24 h IV propafenone 2 mg/kg over 15 minutes, then 10 mg/kg over 24 h and then 450 mg/day orally for 1 month. All patients received digoxin and then 450 mg/day orally for 1 month. All patients received digoxin and anticoagulation and anticoagulation (INR 2-3) (INR 2-3)

Results:Results:

• 16/34 (47.05%) amiodarone-treated patients vs. 13/32 (40.62%) 16/34 (47.05%) amiodarone-treated patients vs. 13/32 (40.62%) propafenone-treated propafenone-treated

• Patients converted to sinus rhythm, P<0.001Patients converted to sinus rhythm, P<0.001

• 1 propafenone-treated patient discontinued treatment because of 1 propafenone-treated patient discontinued treatment because of QRS wideningQRS widening

Kochiadakis GE et al J Am Coll Cardiol 1993;33:966-71.

PIAF TrialPIAF Trial

Rhythm or Rate Control in Atrial Fibrillation Rhythm or Rate Control in Atrial Fibrillation PPharmacologicalharmacologicalIIntervention in ntervention in AAtrial trial FFibrillation (PIAF): a Randomized Trialibrillation (PIAF): a Randomized Trial

• 252 pts enrolled, 125 diltiazem, 127 amiodarone252 pts enrolled, 125 diltiazem, 127 amiodarone

Methods:Methods:

Pts randomized to diltiazem or amiodaronePts randomized to diltiazem or amiodarone

Results:Results:

• 76 pts on diltiazem, 70 on amiodarone reported76 pts on diltiazem, 70 on amiodarone reportedimproved symptoms, improved symptoms, PP=0.317=0.317

• 23% of amiodarone pts returned to sinus rhythm23% of amiodarone pts returned to sinus rhythm

• amiodarone-treated pts did better on 6 min walk test than diltiazemamiodarone-treated pts did better on 6 min walk test than diltiazem

Conclusion: Conclusion: In patients with atrial fibrillation, the therapeutic strategies of rate In patients with atrial fibrillation, the therapeutic strategies of rate versus rhythm control yielded similar clinical results overallversus rhythm control yielded similar clinical results overall

1. Hohnloser et al. Lancet. 2000;356:1789-94.

IV Amiodarone Treatment for Acute Heart IV Amiodarone Treatment for Acute Heart Rate Control in Critically Ill PatientsRate Control in Critically Ill Patients

MethodsMethods

• Retrospective study of 38 ICU patientsRetrospective study of 38 ICU patients

– Pts received IV amiodarone for resistant Pts received IV amiodarone for resistant atrial tachyarrhythmiasatrial tachyarrhythmias

• Onset of rapid heart rate (mean 149 ± 13 Onset of rapid heart rate (mean 149 ± 13 beats/min was associated with decrease in beats/min was associated with decrease in systolic blood pressure of 20 ± 5 mm Hg systolic blood pressure of 20 ± 5 mm Hg ((PP<0.05)<0.05)

Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Am J Cardiol. 1998;81:594-8.

IV Amiodarone Treatment for Acute Heart IV Amiodarone Treatment for Acute Heart Rate Control in Critically Ill PatientsRate Control in Critically Ill Patients

• Intravenous diltiazem (n=34), esmololIntravenous diltiazem (n=34), esmolol(n=4), and digoxin (n=24) had no effect,(n=4), and digoxin (n=24) had no effect,while reducing systolic blood pressurewhile reducing systolic blood pressureof 6 ± 4 mm Hg (of 6 ± 4 mm Hg (PP<0.05)<0.05)

• Infusion of amiodarone (242 ± 137 mgInfusion of amiodarone (242 ± 137 mgover 1 hr decreased heart rate by 37 ± 8 over 1 hr decreased heart rate by 37 ± 8 beats/min and increased systolic blood pressure beats/min and increased systolic blood pressure by 24 ± 6 mm Hg (by 24 ± 6 mm Hg (PP<0.05)<0.05)

– Beneficial outcomes noted inBeneficial outcomes noted inpulmonary artery occlusive pressurepulmonary artery occlusive pressureand cardiac outputand cardiac output

Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Am J Cardiol. 1998;81:594-8.

Caveats RegardingCaveats RegardingAmiodarone DosingAmiodarone Dosing

• Complex PK/PD with extremely longComplex PK/PD with extremely longhalf lifehalf life

• Different efficacy rates with studies dueDifferent efficacy rates with studies dueto dosing issues, and different patient to dosing issues, and different patient populationspopulations

Amiodarone IV for Atrial Amiodarone IV for Atrial Arrhythymias: SummaryArrhythymias: Summary

• Effective in SVT, but best studied in AFEffective in SVT, but best studied in AF

• Acute IV therapy is different than Acute IV therapy is different than chronic oral administration: dosing and chronic oral administration: dosing and PK needsPK needsto be considered to be considered

• In critically ill patients, IV therapyIn critically ill patients, IV therapyis requiredis required

Questions and AnswersQuestions and Answers