Title: A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial Fibrillation RESOURCE SESSION
1 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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3Cardiac 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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5Electrocardiogram (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
6Cardiac 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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8Classification (Circulation 2001 104 2118-2150)
9Atrial 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
10Atrial 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
11Rate 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
12Rate 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
13Conversion 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
14Management of newly discovered AF(Circulation
2001 104 2118-2150)
15Pharmacologic cardioversion of AFlt7 days
(Circulation 2001 104 2118-2150)
16Pharmacologic cardioversion of AFgt7
days(Circulation 2001 104 2118-2150
17Pharmacological management of patients with
recurrent AF (Circulation 20011104 2118-2150)
18Drug 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
19Drug 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
20Digoxin 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
21Drug 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
22Drug 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
23Drug 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
24Drug 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
25Drug 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
26Drug 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
27Amiodarone 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
28Amiodarone 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
29Amiodarone 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)
30Drug 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
31Drug 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