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

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A Practical Overview of Antiarrhythmic Drugs
Commonly Used in Atrial FibrillationRESOURCE
SESSION

• Olavo Fernandes, Pharm.D.
• Pharmacy Practice Leader, Toronto General
  Hospital, UHN
• Assistant Professor, University of Toronto
• October 2002

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Cardiac Conduction System

• SA node
• primary pacemaker (60-100 bpm)
• autonomic nervous system
• vagus nerve (parasym.)
• catacholamines (sym)
• AV node
• filter (40-60 bpm)
• controls number of impulses reaching the
  ventricle from atria

• Bundle of His
• conducts impulses to bundle branches
• Perkinje system
• lt 40 bpm
• bifarcates into several bundle brunches

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Electrocardiogram (ECG)

• P wave
• depolarization of atria
• QRS Complex
• depolarization of ventricle
• QRS interval normally lt 0.12 secs.
• widened QRS prolonged conduction
• QRS gt 0.12 secs conduction from ventricle or
  supraventricular

• T wave
• repolarization of ventricle
• U wave
• uncertain
• PR interval
• lt 0.2 seconds
• conduction velocity
• beginning of P wave to onset of QRS
• QTc interval
• lt 0.4 seconds
• refractory period
• beginning of Q to end of T

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Cardiac Action Potentials

• Sodium-dependent Fibres/ Fast Fibres
• atrial and ventricular tissue
• Phase O, 1, 2, 3, 4
• Calcium-dependent Fibres
• SA and AV nodes
• only 3 phases
• Ca enters instead of Na in Phase O
• higher resting membrane potential
• increase in slope of phase 4
• Refractory Period
• Automaticity
• intrinsic property of spontaneous impulse
  generation

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Classification (Circulation 2001 104 2118-2150)
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Atrial Arrhythmias

• Goals of Therapy
• convert to sinus rhythm
• control ventricular response rate
• relieve associated symptoms (palpitations,
  fatigue, dyspnea, syncope, angina, heart failure)
• prevent recurrence
• prevent complications life threatening
  arrhythmias, stroke, MI, tachycardia

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Atrial Fibrillation- Rate Control

• Why use an agent for rate control?
• better filling time, better diastolic function
• consider risks of conversion, embolic risks, drug
  side effects
• OPTIONS
• Digoxin
• increase vagal tone (decrease AV node
  conduction), inhibit Na/K Pump
• Beta Blockers ( metoprolol, esmolol, atenolol)
• slow SA node, slow AV node conduction, effect on
  refractory period
• Calcium Channel Blockers (diltiazem, verapamil)
• block slow calcium channels, slow AV node
  conduction

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Rate Control Agent Considerations

• DIGOXIN
• vagally mediated
• slow onset- 4hrs (large VD)
• poor effectiveness during high sympathetic tone
  (stress)
• positive inotrope (benefit with concurrent CHF)
• proarrhythmic, side effects

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Rate Control Agent Considerations

• BETA BLOCKERS
• faster onset (minutes)
• directly effect on AV node (effective during
  stress)
• negative inotrope (concern in CHF)
• may be useful with concurrent CAD/Post MI
  patients
• bronchospasm (asthma)
• effect on blood sugar (DM)
• main SE hypotension

• CALCIUM CHANNEL BLOCKERS
• faster onset (minutes)
• directly effect on AV node (effective during
  stress)
• negative inotrope (concern in CHF) verapamil gt
  diltiazem
• may be useful with concurrent CAD/Post MI
  patients
• main side effecthypotension
• cost diltiazem gt verapamil

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Conversion of Atrial Fibrillation

• Considerations
• better cardiac function, more times in A Fib
  harder to convert to NSR, emboli and
  anticoagulation, may need rate control during
  conversion
• Direct Current Conversion
• 100J, 200J, 300J, 360J
• burns, relapse, sedation, worsened arrhythmias
• Pharmacological Options
• Amiodarone (least proarrhythmic, some AVN block,
  least negative inotropy, very costly IV)
• Procainamide, Sotalol
• Quinidine
• Ibutilide

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Management of newly discovered AF(Circulation
2001 104 2118-2150)
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Pharmacologic cardioversion of AFlt7 days
(Circulation 2001 104 2118-2150)
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Pharmacologic cardioversion of AFgt7
days(Circulation 2001 104 2118-2150
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Pharmacological management of patients with
recurrent AF (Circulation 20011104 2118-2150)
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Drug Profile Digoxin

• Mechanism
• binds and inhibits Na/K ATPase
• slows AV node conduction (vagus nerve)
• Kinetics
• dist wide 7-8 L/kg (skeletal muscle, myocardium,
  kidneys)
• ptn binding 20-40
• elimination renal 70-80 hepatic (up to 30)
• time to peak 1-4 hr (IV) 2-6 hr (po)

• time to steady state 5-7 days (2-3 wks in RF)
• elimination half life 35-40 hrs (2-5 days in RF)
• Indications
• CHF, AF- rate control
• Dosing
• load 0.250mg IV over 15 min repeat in 6hr 0.250
  mg po q6h x 4 (total 1 mg)
• renal dysfunction load 0.125mg q6h (total
  0.5-0.75 mg)
• initial mx dose 0.125 - 0.250 mg po

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Drug Profile Digoxin

• Adverse Effects
• GI N, V, A, D
• CNS disorientation, confusion
• Ocular colour vision disturbances
  (yellow-green), halos, photophobia
• CV bradycardia, heart block, VT
• more prone to toxicity with hypokalemia
  (sensitizes myocardium to digoxin effect)
• toxicity hyperkalemia, ventricular arrhythmias,
  visual disturbances
• DIGIBIND

• Drug Interactions
• physically adsorption (antacids, sucralfate,
  resins)
• antibiotics (digoxin metabolized by gut bacteria)
• increased serum level (quinidine, amiodarone,
  verapamil)
• assay interference (spironolactone)
• Monitoring
• ECG, HR, renal function, potassium, digoxin levels

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Digoxin serum levels

• Therapeutic Range
• 1.2- 2.5 nmol/L
• AFib at higher end of target
• Indications
• suspected toxicity/ confirmation
• initiation or change in therapy
• changes in renal function
• clinical deterioration
• addition of interacting medications
• routine monitoring - yearly
• subtherapeutic response

• Sample Collection Time
• not lt 8 hrs and preferably trough level before
  next dose
• at least 5 days after starting tx or changing
  dose
• Increased levels
• Increased Levels
• advanced age, renal disease, hepatic disease,
  amiodarone, verapamil, CsA, quinidine
• Decreased levels
• hyperthyroidism, binding drug interactions

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Drug Profile Digoxin

• ADVANTAGES
• Positive inotrope
• Maybe useful in patients with concurrent AF / CHF

• LIMITATIONS
• Limited to atrial arrhythmias
• Limited efficacy
• Pro-arrhythmic
• Narrow therapeutic range
• Limited efficacy during high sympathetic tone
• Caution with adverse effects/ drug interactions

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Drug Profile Diltiazem

• Mechanism
• blocks slow calcium channels
• slows AV node conduction
• vasodilatation
• Administration/Dosing
• bolus and continuous infusion
• 0.25 mg/kg over 2 minutes, after 15 minutes can
  give 0.35 mg/kg over 2 minutes
• continuous infusion 10mg/hr (up to 15mg/hr) x 24
  hr
• D5W, NSS, 2/3-1/3
• refrigerated for storage

• Adverse Effects
• IV hypotension, bradycardia
• worsening CHF symptoms
• heart block
• Drug Interactions
• AV node blocking agents (BB, CCB, digoxin)
• hypotensive agents
• negative inotropes
• Monitor
• ECG, BP, HR
• CHF symptoms

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Drug Profile Metoprolol

• Mechanism
• competitive block agonist effect of sympathetic
  neurotransmitters
• block adrenergic stimulation of cardiac action
  potentials
• Beta-1 selective agent
• slows AV node conduction
• Administration/Dosing
• 12.5 - 100 mg po bid
• 5mg IV push for acute management ( if necessary
  10-15 mg IV q 6h)

• Adverse Effects
• IV hypotension, bradycardia
• worsening CHF symptoms
• bronchospasm in asthma
• heart block
• Drug Interactions
• AV node blocking agents ( CCB, digoxin)
• hypotensive agents
• negative inotropes
• Monitor
• ECG, BP, HR
• CHF symptoms

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Drug Profile Amiodarone

• Mechanism
• complex pcl profile actions of all classes
• conduction slowing (class I)
• BB activity (class II)
• prolong APD and refractory period (class III)
• AVN conduction slowing (IV)
• blocks cellular K channels
• Kinetics
• bioavailability 35-65
• half life mean 52 days
• volume of distribution 5000L

• elimination primarily hepatic metabolism /
  biliary excretion
• active metabolite desethyl-amiodarone
• Kinetic Implications
• loading doses
• delayed AA effect
• delayed elimination if drug stopped
• compliance
• role of levels

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Drug Profile Amiodarone

• Indications
• IV
• suppression of recurrent sustained VT, ongoing
  VT/VF, acute conversion of AF
• Atrial Fibrillation/Flutter
• slow VRR (AVN block)
• convert to NSR
• maintain NSR after conversion
• dose lower in atrial arrhythmias

• Post MI
• CAMIAT and EMIAT
• showed amio. - low incidence of proarrhythmia
  safe in LV dysfunction
• Primary prevention of SCD
• RFs for SCD LV dysfunction, frequent or complex
  ectopics
• GESICSA and CHF STAT
• MADIT (ICD)
• Secondary prevention -SCD
• CASCADE, AVID
• ICD preferred
• amio. second line

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Drug Profile Amiodarone

• Administration/Dosing
• 150-300 mg IV over 10 minutes followed by 0.5 - 2
  mg/kg minute infusion (1000mg / 24 hrs)
• See handout
• continue oral load over several weeks
• Ventricular arrhythmias
• 1200-1800 mg/d x 1-2 wks 800mg/d x 2 wks
  600mg/d x 4 wks then 200-400mg/d
• Atrial arrhythmias
• 600-800 mg/d x 4wks 400 mg/d x 2-4 wks 200 mg/d
  thereafter

• Adverse Effects (IV)
• hypotension (related to vehicle)
• peripheral vein phlebitis (run at lt 2mg/ml)
• IV infusions gt 2 hrs administer in glass bottles
  of D5W
• proarrhythmia rare
• 100 liver metabolism
• Monitor
• vitals, ECG, BP, HR
• vein site for phlebitis

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Amiodarone Adverse Effects

• Long term oral therapy
• 80 report side effects, in trials only 10-20
  have side effects necessitating withdrawal
• SE appear to be dose related
• minimize doses/ reduce dose is sx occur
• regular monitoring in preventing and managing SEs
• CV
• sinus bradycardia (0-10), AV conduction
  disturbances and heart block (2-5), rare TdP
• increase plasma cholesterol

• Pulmonary
• most feared adverse effect
• pulmonary fibrosis (2-7) can be fatal in 10 of
  cases
• appears in pts with gt 400mg/ day
• CXR bilateral and diffuse changes/ interstitial
  infiltrates
• Sx dyspnea, cough, chest pain, pleural rub

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Amiodarone Adverse Effects

• GI
• increase in AST/ALT/ ALP (25)
• hepatitis, hepatic failure
• N, V, A common
• Thyroid
• inhibits conversion T4 to T3
• hypo (3) or hyperthyroidism (2)
• hypothyroidism
• rare after first 18 months
• responds to thyroid replacement
• hyperthyroidism
• occur at any time, difficult to manage
  (thyroidectomy)

• Pulmonary
• type 1 hypersensitivity (after first few weeks)
  with development of fever, SOB, cough tx stop
  amio.
• type 2 interstitial / alveolar pneumonitis (7
  mos - 2 yrs) insidious onset of non-productive
  cough, fatigue, SOB, pleuritic CP, fever
  infiltrates and pulmonary fibrosis on CXR tx
  stop amio

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Amiodarone Adverse Effects

• Dermatolgicial
• skin reaction (15)
• photosensitivity (10)- limit sun exposure and
  sunscreen
• long term blue-gray discoloration (1-7)
• CNS
• 40 have CNS effects (fatigue, tremor, ataxia,
  peripheral neuropathy)
• Optho.
• corneal deposits
• rare visual disturbances
• sx photophobia, blurred vision, blue-green halos

• Monitoring
• labs (renal function, CBC, LFTs, thyroid
  function), ECG, CXR
• baseline, as sx occur and every 4-6 months
• PFTs, eye exam baseline and as symptoms occur
• ECG, HR, BP at regular intervals
• Drug Interactions
• warfarin, digoxin, BB, CCB, procainamide,
  quinidine
• (see handout)

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Drug Profile Amiodarone

• ADVANTAGES
• effective in a wide range of arrhythmias
• neutral effects on inotropy (CHF patients)
• safety in CAD and LV dysfunction
• low incidence of proarrhythmia
• some rate control properties in AF

• LIMITATIONS
• many chronic side effects
• drug interactions
• IV amiodarone - very expensive

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Drug Profile Procainamide

• Mechanism
• Class 1a AA- blocks Na channels
• prolongs refractory period and decreases
  conduction velocity
• Administration/Dosing
• IV and PO regimens
• depends on indication and renal function
• paradoxical initial increase in HR
• Kinetic Implications
• active metabolite- NAPA

• levels to prevent toxicity (drug and NAPA)
• Adverse Effects
• hypotension, bradycardia
• proarrhythmic (TdP)
• drug-induced lupus (SLE)
• GI nausea, vomiting
• CNS disorientation
• Drug Interactions
• amiodarone, Septra (TMP/SMX)
• Monitor
• ECG, BP, HR