Download A Practical Overview of Antiarrhythmic Drugs Commonly Used in

A Practical Overview of
Antiarrhythmic Drugs Commonly
Used in Atrial Fibrillation
RESOURCE SESSION
Olavo Fernandes, Pharm.D.
Pharmacy Practice Leader, Toronto General Hospital, UHN
Assistant Professor, University of Toronto
October 2002
Cardiac Conduction System
SA node
– primary pacemaker (60100 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
– < 40 bpm
– bifarcates into several
bundle brunches
Electrocardiogram (ECG)
P
wave

– repolarization of ventricle
– depolarization of atria

QRS Complex
– depolarization of ventricle
– QRS interval normally < 0.12
secs.
– widened QRS: prolonged
conduction
– QRS > 0.12 secs:
conduction from ventricle or
supraventricular
T wave

U wave
– uncertain

PR interval
– < 0.2 seconds
– conduction velocity
– beginning of P wave to
onset of QRS

QTc interval
– < 0.4 seconds
– refractory period
– beginning of Q to end of T
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
Classification
(Circulation 2001; 104: 2118-2150)
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
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
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
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 > diltiazem
– may be useful with
concurrent CAD/Post MI
patients
– main side
effect:hypotension
– cost diltiazem > verapamil
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
Management of newly discovered AF
(Circulation 2001; 104: 2118-2150)
Pharmacologic cardioversion of AF<7 days
(Circulation 2001; 104: 2118-2150)
Pharmacologic cardioversion of AF>7 days
(Circulation 2001; 104: 2118-2150
Pharmacological management of patients with
recurrent AF (Circulation 2001;1104: 2118-2150)
Recurrent paroxysmal
AF
Minimal or no symptoms
Anticoagulation and rate control
as needed
Disabling symptoms
Anticoagulation and rate control as needed
Heart Disease
No (or minimal)*
Yes
Flecainide
Propafenone
Sotalol
HF
CAD
Hypertension
Amiodarone
Amiodarone
Sotalol
LVH>1.4 cm
Disopyramide
Procainamide
Quinidine
non pclg
Amiodarone
Yes
No
Disopryamide
Procainamide
Quinidine
Amiodarone
Flecainide
Propafenone
Amiodarone
Sotalol
Disopryamide
Procainamide
Quinidine
Drug Profile: Digoxin

– binds and inhibits Na/K
ATPase
– slows AV node conduction
(vagus nerve)

– time to steady state: 5-7
days (2-3 wks in RF)
– elimination half life: 35-40
hrs (2-5 days in RF)
Mechanism

– CHF, AF- rate control
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)
Indications

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
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
Digoxin: serum levels

Therapeutic Range

– 1.2- 2.5 nmol/L
– AFib at higher end of target

– not < 8 hrs and preferably
trough level before next
dose
– at least 5 days after starting
tx or changing dose
– Increased levels
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

Increased Levels
– advanced age, renal
disease, hepatic disease,
amiodarone, verapamil,
CsA, quinidine

Decreased levels
– hyperthyroidism, binding
drug interactions
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
Drug Profile: Diltiazem

Mechanism:

– blocks slow calcium
channels
– slows AV node conduction
– vasodilatation

Adverse Effects
– IV: hypotension,
bradycardia
– worsening CHF symptoms
– heart block
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

Drug Interactions
– AV node blocking agents
(BB, CCB, digoxin)
– hypotensive agents
– negative inotropes

Monitor
– ECG, BP, HR
– CHF symptoms
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


– IV: hypotension,
bradycardia
– worsening CHF symptoms
– bronchospasm in asthma
– heart block

Drug Interactions
– AV node blocking agents (
CCB, digoxin)
– hypotensive agents
– negative inotropes
Administration/Dosing
– 12.5 - 100 mg po bid
– 5mg IV push for acute
management ( if necessary
10-15 mg IV q 6h)
Adverse Effects

Monitor
– ECG, BP, HR
– CHF symptoms
Drug Profile: Amiodarone

– 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

– elimination: primarily
hepatic metabolism / biliary
excretion
– active metabolite: desethylamiodarone
Mechanism:
Kinetics
– bioavailability: 35-65%
– half life: mean 52 days
– volume of distribution:
5000L

Kinetic Implications
» loading doses
» delayed AA effect
» delayed elimination if drug
stopped
» compliance
» role of levels
Drug Profile: Amiodarone
Indications
 IV
– suppression of recurrent
sustained VT, ongoing
VT/VF, acute conversion of
AF


– 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)
Atrial Fibrillation/Flutter
– slow VRR (AVN block)
– convert to NSR
– maintain NSR after
conversion
– dose lower in atrial
arrhythmias
Post MI

Secondary prevention -SCD
– CASCADE, AVID
– ICD preferred
– amio. second line
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 < 2mg/ml)
– IV infusions > 2 hrs
administer in glass bottles
of D5W
– proarrhythmia : rare
– 100% liver metabolism

Monitor
– vitals, ECG, BP, HR
– vein site for phlebitis
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 > 400mg/
day
– CXR: bilateral and diffuse
changes/ interstitial infiltrates
– Sx: dyspnea, cough, chest
pain, pleural rub
Amiodarone : Adverse Effects
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 nonproductive cough, fatigue,
SOB, pleuritic CP, fever;
infiltrates and pulmonary
fibrosis on CXR; tx: stop
amio

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)
Amiodarone: Adverse Effects

Dermatolgicial

– skin reaction (15%)
– photosensitivity (10%)- limit
sun exposure and
sunscreen
– long term blue-gray
discoloration (1-7%)


– 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
CNS
– 40% have CNS effects
(fatigue, tremor, ataxia,
peripheral neuropathy)
Optho.
– corneal deposits
– rare: visual disturbances
– sx: photophobia, blurred
vision, blue-green halos
Monitoring

Drug Interactions
– warfarin, digoxin, BB, CCB,
procainamide, quinidine
– (see handout)
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
Drug Profile: Procainamide

– Class 1a AA- blocks Na
channels
– prolongs refractory period
and decreases conduction
velocity


Kinetic Implications
– active metabolite- NAPA
Adverse Effects
–
–
–
–
–
Administration/Dosing
– IV and PO regimens
– depends on indication and
renal function
– paradoxical initial increase
in HR

– levels to prevent toxicity
(drug and NAPA)
Mechanism:

hypotension, bradycardia
proarrhythmic (TdP)
drug-induced lupus (SLE)
GI: nausea, vomiting
CNS: disorientation
Drug Interactions
– amiodarone, Septra
(TMP/SMX)

Monitor
– ECG, BP, HR