Intravenous Amiodarone for Supraventricular Tachycardias

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Intravenous Amiodarone for Supraventricular
Tachycardias

• Jerrold H Levy, MD
• Emory University School of Medicine
• Atlanta, Georgia

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Supraventricular Tachycardias Therapeutic
Objectives

• Determine the mechanism of the arrhythmia
• Restore sinus rhythm with the simplest technique
  and approach as possible
• Eliminate or significantly reduce arrhythmia
  recurrences and underlying cause

Singh 2002.
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Types of Supraventricular Tachyarrhythmias
Sinus Node Reentry Atrial Flutter Automatic
Atrial Tachycardia Reentrant Atrial
Tachycardia Atrioventricular NodalReentry
(AVNRT) AV Reentry via an AccessoryAV Connection
(AVRT) Atrial Fibrillation (Not Shown)
RA
LA
LV
RV
Singh 2002.
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Types of Paroxysmal Supraventricular Tachycardia
AV ReciprocatingTachycardia
Sinus Nodal Reentry
Intra-atrial Reentry
Automatic AtrialTachycardia
AV NodalReentry
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Mechanisms of Paroxysmal Supraventricular
Tachycardias

• Enhanced Automaticity
• Paroxysmal and Acute
• Chronic
• Re-entry without Bypass Tracts
• AV Nodal Re-entry Slow Fast/Fast Slow
• Sinoatrial Nodal Re-entry
• Intra-atrial Re-entry
• Re-entry in Association with Bypass Tracts
• Re-entry with Anterograde AV Conduction
  (Orthodromic)
• With Evidence of Pre-excitation of 12-Lead ECG
• Concealed WPW (Bypass Tract ConductingOnly
  Retrogradely)
• Re-entry with Anterograde Conduction Over
  BypassTract (Antidromic) During Tachycardia

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Accessory Pathways Concealed Bypass Tract AV
Reentrant Tachycardia
Concealed BypassTract
AV Node
Bundle of His
Left Bundle Branch
Right Bundle Branch
P
Singh 2002.
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Electrical Conduction in Atrial Flutter
AV Node
ECG of Flutter
Ventricular Rate 150-160 (Most Often 21 AV Block)
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Atrial Fibrillation
Electrocardiogram
Coarse Fibrillation
Fine Fibrillation
Baseline Coarsely or Finely Irregular P Waves
Absent. Ventricular Response (QRS) Irregular,
Slow or Rapid
Scheidt S, Erlebacher JA, Netter FH. Basic
Electrocardiography ECG. Ciba-Geigy First
Printing, 1986, p23.
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AF is Associated With

• Systemic Diseases
• Age
• DTs, sympathetic storm
• Electrolyte disorders
• Thyrotoxicosis
• Fever/hypothermia
• Hypovolemia
• Diabetes
• Anemia
• Pulmonary disease
• Cerebrovascular disease

• CV Diseases
• CT surgery
• Valvular orcongential disease
• Hypertension
• Cardiomyopathy
• Heart failure
• Myocardial ischemia/MI
• Peri/myocarditis
• Infiltrative heart disease
• Cardiac trauma

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Antiarrhythmic Drugs vs. Therapeutic Goal
Vagal StimulationDigoxinb-Blocking
DrugsVerapamilDiltiazemAdenosine
Ibutilide
Atrium
AV Node
QuinidineProcainamideDisopyramide
FlecainidePropafenoneSotalolAmiodarone
His Purkinje
AP
Ventricle
Singh 2002.
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Simulated Drug Level Curves
Full loading dose
Half loading dose and infusion
Therapeutic Concentration Range
Plasma Drug Level
0
1
2
3
4
5
6
Time (Half-life)
Levy 2002.
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Agents Used in the Treatment of SVT Tachycardias
by Vaughan Williams Class

• 1A Quinidine, procainamide, disopyramide
• 1C Flecainide, propafenone
• 2 Esmolol, propranolol, metoprolol, atenolol,
  (et al)
• 3 Amiodarone, sotalol
• 4 Diltiazem, verapamil
• Glycosides digoxin
• Purinergic adenosine

Singh 2002.
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Amiodarone Historical Landmarks (1)

• 1962 Synthesized as an anti-anginal
  compound (Charlier)
• 1968 Novel action with new biological
  profile (Charlier)
• 1970 Unusual electrophysiology profile
  (Singh Vaughan Williams)
• 74/76 Unusual clinical potency as an
  antiarrhythmic drug (Rosenbaum M)

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Amiodarone Historical Landmarks (2)

• 1983 First US Symposium on Amiodarone (Singh
  Zipes)
• 1984 FDA Approval
• 1993 Efficacy Unparalleled Mode of Action
  Unknown
• 1995 Amiodarone IV approved
• 1999 Symposium, the last 15 years (Singh, AJC
  (Suppl))

Singh 2002.
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Unique Features of Amiodarone as an
Anti-arrhythmic Drug

• Long elimination half-life
• Can be administered to anephric patientson
  dialysis
• Well tolerated in advanced CHF
• Manageable drug-drug interactions(ie, digoxin,
  coumadin)
• Very low incidence of torsades de pointes even
  with diuretic therapy

Singh 2002.
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Unique Features of Amiodarone as an
Anti-arrhythmic Drug (Contd.)

• Has Class 1 properties without the associated
  proarrhythmic actions or negative impact on
  mortality
• Has antisympathetic actions withoutbeta-blocker
  side effects
• Increases LVEF and improves CHF
• Antifibrillatory actions in the ventricles may be
  augmented by addition of beta-blockade

Singh 2002.
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Intravenous Amiodarone Pharmacokinetics

• Peak levels after single 5 mg/kg15 min
  infusions 5-41 mg/L
• After 10 min 150 mg load for VF/VT7-26 mg/L
• Levels decline to 10 of peak within30-45 min at
  the end of the infusion
• After 48 hrs of continued infusions,levels 0.7
  to 1.4 mg/L

Singh 2002.
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Pharmacokinetics of Oral Amiodarone

• Absorption Tmax2-12 h (lab 0.4-3 h)
• Extent of absorption Poor and slow
• Bioavailability Variable (22-86)
• Protein binding 96.3 0.6
• Volume of distribution 1.3-65.8 l/kg
• Negligible renal excretion
• Biotransformation Hepatic and intestinal
• Elimination half-life 3.2-20.7 h
  (acute),13.7-52.6 day (chronic)

Singh 2002.
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Pharmacokinetics of Oral Amiodarone

• Total body clearance 0.10-0.77 l/min
• Pattern of elimination First order
• Metabolites Major mono N-desethylamiodarone,
  Minor bis-N-desethylamiodarone, deiodinated
  metabolites
• Therapeutic levels 1.0-2.5 µg/mL range
• Special factors Slow onset and offsetof action

Singh 2002.
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Actions of IV Amiodarone vs Chronic Amiodarone
Actions IV Amio Chronic Amio
Repolarization (QT interval) prolongation (atria ventricles)
Conduction velocity(atria vent) reduced (function of rate)
Sinus rates reduced
AV nodalconduction slowed
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Actions of IV Amiodarone vs Chronic Amiodarone
Actions IV Amio Chronic Amio
AV nodal refactoriness increased
Atrial refactoriness increased
Ventricular refactoriness increased
Noncompetitive alpha and beta blocking activity
Singh 2002.
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Pharmacokinetics of IV Amiodarone

• Summary More rapid onset and offsetof action
  with IV versus oral

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Comparison of Oral vs. IV AmiodaroneConversion
of Atrial Fibrillation

• N52 patients with atrial fibrillation
• 86 episodes of attempted cardioversion with oral,
  intravenous, or DC cardioversion
• Conversion to sinus rhythm achieved
• 29 of pts treated with oral amiodarone
• 42 of pts treated with DC cardioversion
• 64 of pts treated with intravenous amiodarone
• Overall statistical significance P 0.032

Horner SM. Acta Cardiol. 199247473.
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Efficacy of IV Amiodarone for the Conversion of
Atrial arrhythmia
Vietti-Ramuset al. 1992 44 pts 86 w/ SVT reverted to SR lt24 h 100 w/ PSVT reverted to SR lt24 h 75 w/ AFL reverted to SR lt24 h 85.7 w/ AF reverted to SR lt24 h
Strasberget al. 1985 26 pts 100 reverted to SR (Plt0.001) 46 reverted lt30 min 23 converted 2-8 h 27 no conversion 4 reverted to AFL lt 10 min to SR 40 min later
Faniel and Schoenfeld 1983 26 pts 80.8 reverted to SR lt24 h and maintained gt48 h Mean time from treatment to SSR 171 min Total dose 6.9 2.3 mg/kg
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Management of Atrial Tachyarrhythmias in the
Critically Ill a Comparison of Intravenous
Procainamide and Amiodarone

• 24 pts atrial fibrillation more than 1 h
  evaluated 10 Amiodarone,
• 14 Procainamide
• Methods
• 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/min then 2-4
  mg/min for 24 h with repeat dose of 5mg/kg at 1 h
  if no response
• Results
• 7/10 Amiodarone-treated patients, 10/14
  Procainamide-treated patients converted to sinus
  rhythm by 12 hours
• No significant change in SBP from baseline

Chapman MJ et al Intensive Care Med
19931948-52.
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Amiodarone Versus Propafenone for Conversion of
Chronic Atrial Fibrillation Results of a
Randomized, Controlled Study

• 118 pts with atrial fibrillation lasting more
  than 3 weeks,
• 34 amiodarone, 32 propafenone, 35 control
• Methods
• 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. 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
  anticoagulation (INR 2-3)
• Results
• 16/34 (47.05) amiodarone-treated patients vs.
  13/32 (40.62) propafenone-treated
• Patients converted to sinus rhythm, Plt0.001
• 1 propafenone-treated patient discontinued
  treatment because of QRS widening

Kochiadakis GE et al J Am Coll Cardiol
199333966-71.
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PIAF Trial

• Rhythm or Rate Control in Atrial Fibrillation
  Pharmacological
• Intervention in Atrial Fibrillation (PIAF) a
  Randomized Trial
• 252 pts enrolled, 125 diltiazem, 127 amiodarone
• Methods
• Pts randomized to diltiazem or amiodarone
• Results
• 76 pts on diltiazem, 70 on amiodarone
  reportedimproved symptoms, P0.317
• 23 of amiodarone pts returned to sinus rhythm
• amiodarone-treated pts did better on 6 min walk
  test than diltiazem
• Conclusion
• In patients with atrial fibrillation, the
  therapeutic strategies of rate
• versus rhythm control yielded similar clinical
  results overall

1. Hohnloser et al. Lancet. 20003561789-94.

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

• Methods
• Retrospective study of 38 ICU patients
• Pts received IV amiodarone for resistant atrial
  tachyarrhythmias
• Onset of rapid heart rate (mean 149 13
  beats/min was associated with decrease in
  systolic blood pressure of 20 5 mm Hg (Plt0.05)

Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Am
J Cardiol. 199881594-8.
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IV Amiodarone Treatment for Acute Heart Rate
Control in Critically Ill Patients

• Intravenous diltiazem (n34), esmolol(n4), and
  digoxin (n24) had no effect,while reducing
  systolic blood pressureof 6 4 mm Hg (Plt0.05)
• Infusion of amiodarone (242 137 mgover 1 hr
  decreased heart rate by 37 8 beats/min and
  increased systolic blood pressure by 24 6 mm Hg
  (Plt0.05)
• Beneficial outcomes noted inpulmonary artery
  occlusive pressureand cardiac output

Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Am
J Cardiol. 199881594-8.
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Caveats RegardingAmiodarone Dosing

• Complex PK/PD with extremely longhalf life
• Different efficacy rates with studies dueto
  dosing issues, and different patient populations

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Amiodarone IV for Atrial Arrhythymias Summary

• Effective in SVT, but best studied in AF
• Acute IV therapy is different than chronic oral
  administration dosing and PK needsto be
  considered
• In critically ill patients, IV therapyis required

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Questions and Answers