Transcript Anti arrhythmic Drugs

TOPICS COVERED
 Electrophysiology of the heart
 Arrhythmia: definition, mechanisms, types
 Drugs :class I, II, III, IV
 Guide to treat some types of arrhythmia
Resting membrane potential
• Retention of many intracellular
anions.
• The resting cell membrane is almost
100 times more permeable to
potassium than to sodium,
• Na+K+ATPase pump.
- 90mV
Non-Pacemaker potential
+ 20 mV
N.B. The slope of
phase 0 =
conduction
velocity
Also the peak of
phase 0 = Vmax
Phase 0: fast upstroke
Due to Na+ influx
Na
Na
Na
- 90 mV
Non-Pacemaker potential
threshold
M
M
Closed
Open
Gate Opens
Open
Na/K/ATPase pump active
3 Na out/2 K in helps
repolarization
-50 mv M gate closes
-85 mv h gate opens
Slowly
Closed
Depolarization
tissue
h
Repolarization
h
M
h
Open
Closed
Closed
threshold
M
M
Open
Gate Opens
h
Open
Na/K/ATPase pump active
3 Na out/2 K in helps
repolarization
-50 mv M gate closes
-85 mv h gate opens
Slowly
Closed
Depolarization
tissue
h
Repolarization
h
M
Class
IC
Class
IB
Open
Closed
+ 20 mV
- 90 mV
Phase 1: partial
repolarization
Due to rapid efflux of K+
Non-Pacemaker potential
+ 20 mV
Phase 2:
plateau
Due to Ca++ influx
- 90 mV
Non-Pacemaker potential
+ 20 mV
Phase 3:
repolarization
Due to K+ efflux
- 90 mV
Non-Pacemaker potential
+ 20 mV
Phase 4: Resting
Membrane
Potential
- 90 mV
Non-Pacemaker potential
Phase 4: pacemaker potential
Na influx and K efflux and Ca
influx until the cell reaches
threshold and then turns into
phase 0
- 40 mV
Pacemaker cells (automatic cells) have
unstable membrane potential so they can
generate AP spontaneously
- 60 mV
Pacemaker potential
Phase 0:
upstroke:
Due to Ca++
influx
- 40 mV
- 60 mV
Depolarization due to calcium NOT sodium!
Pacemaker potential
Phase 3:
repolarization
Due to K+
efflux
- 40 mV
- 60 mV
Pacemaker potential
Slow Ca++
Channels Open
K+ Channels
Open more
- 40 mV
- 60 mV
Na+ Leak
And less leaky to potassium
Pacemaker potential
• Sympathetic – speeds heart rate by  Ca++ & I-f
channel flow
• Parasympathetic – slows rate by  K+ efflux & 
Ca++ influx
Cardiac action potentials have long refractory periods (RP). No stimulus
can produce another action potential during the effective refractory
period.
• Transmembrane action
potential occurring in
an automatic cardiac
cell and the relationship
of this action potential
to events depicted on
the electrocardiogram
(ECG).
Arrhythmia: Definition,
Mechanisms, Types
Arrhythmia /dysrhythmia: abnormality in the
site of origin of impulse, rate, or conduction
If the arrhythmia arises
from atria, SA node, or
AV node it is called
supraventricular
arrhythmia
If the arrhythmia
arises from the
ventricles it is called
ventricular
arrhythmia
1. Ischemia
• pH & electrolyte abnormalities
• 80% – 90% asstd with MI
2. Excessive myocardial fiber stretch/ scarred/
diseased cardiac tissue
3. Excessive discharge or sensitivity to autonomic
transmitters
4. Excessive exposure to foreign chemicals & toxic
substances
• 20% - 50% asstd with General Anesthesia
• 10% - 20% asstd with Digitalis toxicity
Abnormal heart pulse formation
• Sinus pulse
• Ectopic pulse
• Triggered activity
Abnormal heart pulse conduction
• Reentry
• Conduct block
Triggered activity
• Early afterdepolarizations
associated with QT
prolongation (torsades de
pointes)
• Delayed
afterdepolarizations
associated with Ca2+
overload (e.g. digoxin)
The “Re-Entry” Mechanism of
Ectopic Beats & Rhythms
• Most common
mechanism
• Requires two separate
paths of conduction
• Requires an area of
slow conduction
• Requires unidirectional
block
Re-entry Circuits as Ectopic Foci and Arrhythmia Generators
Atrio-Ventricular Nodal Re-entry
• supraventricular tachycardia
Atrial Re-entry
• atrial tachycardia
• atrial fibrillation
• atrial flutter
Atrio-Ventricular Re-entry
• Wolf Parkinson White
• supraventricular tachycardia
Ventricular Re-entry
• ventricular tachycardia
Antiarrhythmic
drugs
The ultimate goal of antiarrhythmic drug therapy:
o Restore normal sinus rhythm and conduction
o Prevent more serious and possibly lethal
arrhythmias from occurring.
Antiarrhythmic drugs are used to:
 Suppressing automaticity in pacemaker
 Prolonging the effective refractory period
 Facilitating impulse conduction along normal
conduction pathways
Class I: Sodium channel blockers (membranestabilizing agents)
1 a: Block Na+ channel and prolong action potential
1 b: Block Na+ channel and shorten action potential
1 c: Block Na + channel with no effect on action
potential
Class II: β- blockers
Class III: Potassium channel blockers (main effect is
to prolong the action potential)
Class IV: Slow (L-type) calcium channel blockers
CLASS IA
• Procainamide,
• Quinidine,
• Disopyramide
prolong AP
duration, amplitude of AP,
Vmax
They make the
slope more
horizontal
CLASS IB
•
•
•
•
Lidocaine
Mexiletine
Phenytoin
Tocainide
no change Vmax
shortened AP duration,
CLASS IC
• Flecainide,
• Propafenone,
• Moricizine
Vmax
slow conduction
but minimal prolongation
of refractoriness.
CLASS II
•
•
•
•
•
Propranolol
Atenolol
Metoprolol
Timolol,
Esmolol
CLASS III
•
•
•
•
•
Amiodarone
Sotalol,
Bretylium
Dofetilide
Ibutilide
CLASS IV
• Verapamil
• Diltiazem
modification of the Sicilian Gambit
drug classification system
• Ia, Ic class: Prolong QT interval, will cause VT
or VF in coronary artery disease and heart
failure patients
• III class: Like Ia, Ic class agents
• II, IV class: Bradycardia
Class I
Procainamide
• Mechanism of Action
• INa (primary) and IKr
(secondary)blockade.
• Slowed conduction
velocity and pacemaker
activity.
• Prolonged action
potential duration and
refractory period.
prolong AP
duration, amplitude of AP,
Vmax
Procainamide
Clinical Applications
• Most atrial and
ventricular arrhythmias
• Drug of second choice
for most sustained
ventricular arrhythmias
associated with acute
myocardial infarction
Procainamide
Pharmacokinetics
• Oral and parenteral; oral
slow-release forms
available Duration: 2–3 h
• eliminated by hepatic
metabolism to (NAPA)
and renal elimination
• NAPA implicated in
torsades de pointes in
patients with renal failure
Procainamide
Toxicities, Interactions
• Increased arrhythmias, hypotension, lupus-like
syndrome
Dose
• For stable wide-QRS tachycardia
• IV dose: 20-50 mg/min slowly until
• Arrhythmia suppressed, hypotension ensues, QRS duration
increases 50%, or maximum dose 17 mg/kg given
• Maintenance infusion: 1-4 mg/min
• Avoid if prolonged QT or CHF
Quinidine
• Similar to procainamide but more toxic
(cinchonism, torsades); rarely used in
arrhythmias
Disopyramide
• Similar to procainamide but significant
antimuscarinic effects; may precipitate heart
failure; not commonly used
Lidocaine
Mechanism of Action
• Sodium channel (INa)
blockade
• Blocks activated and
inactivated channels
with fast kinetics
• Does not prolong and
may shorten action
potential
Lidocaine
Clinical Applications
• Terminate ventricular
tachycardias and prevent
ventricular fibrillation
after cardioversion
• Dosage:
1.5 mg/kg IV, then
1– 4 mg/min; repeat
1/2 initial dose after
10 min
Lidocaine
Pharmacokinetics
• IV
• first-pass hepatic
metabolism
• Reduce dose in patients
with heart failure or
liver disease
Toxicities
• Neurologic symptoms
Mexiletine
• Orally active congener of lidocaine; used in
ventricular
arrhythmias,
chronic
pain
syndromes
Flecainide
Mechanism of Action:
• Sodium channel (INa)
blockade
• Dissociates from
channel with slow
kinetics
• no change in action
potential duration
Flecainide
Clinical Applications:
• Supraventricular
arrhythmias in patients
with normal heart
• do not use in ischemic
conditions (postmyocardial infarction)
Flecainide
Pharmacokinetics:
• Oral
• hepatic and kidney
metabolism
• half life ∼ 20 h
Toxicities:
• Proarrhythmic
Notice: Class 1C drugs are particularly of low safety and have shown even
increase mortality when used chronically after MI
Propafenone
• Orally active, weak bblocking activity;
supraventricular
arrhythmias; hepatic
metabolism.
Moricizine
• Phenothiazine derivative, orally active;
ventricular arrhythmias, proarrhythmic.
Withdrawn in USA.
Class II
Propranolol
Mechanism of Action:
• Direct membrane
effects (sodium channel
block) and prolongation
of action potential
duration
• slows SA node
automaticity and
• AV nodal conduction
velocity
Propranolol
Clinical Applications:
• Atrial arrhythmias and
prevention of recurrent
infarction and sudden
death
Pharmacokinetics:
• Oral, parenteral
• duration 4–6 h
Propranolol
Dose:
1 mg over 1 min (total 1012 mg; 0.15 mg/kg).
onset:5 min
Toxicities:
• Asthma, AV blockade,
acute heart failure
• Interactions: With other
cardiac depressants and
hypotensive drugs
Esmolol
• Short-acting, IV only;
used for intraoperative
and other acute
arrhythmias
• Loading dose of 200-500
mcg/kg IV over 1 min,
then 50-100 mcg/kg/min;
titrate by 50 mcg/kg/min
q 15-20 min. up to 200
mcg/kg/min
• Onset: 2-3 min.
Class III
Amiodarone
Mechanism of Action:
• Blocks IKr, INa, ICa-L
channels,β adrenoceptors
• Prolongs action potential
duration and QT interval
• slows heart rate and AV
node conduction
• Low incidence of torsades
de pointes
Amiodarone
Clinical Applications:
• Serious ventricular
arrhythmias and
supraventricular
arrhythmias
Amiodarone
Pharmacokinetics:
• Oral, IV
• variable absorption and
tissue accumulation
• hepatic metabolism,
elimination complex and
slow
Dose
• First dose: IV 300 mg over 10
minutes
• Repeat as needed if VT recurs
• Follow by maintenance infusion of
900 mg over 24 hrs
Amiodarone
Toxicities:
• Bradycardia and heart block
in diseased heart,
peripheral vasodilation,
pulmonary and hepatic
toxicity
• hyper- or hypothyroidism.
Interactions:
• Many, based on CYP
metabolism
Sotalol
• B-Adrenergic and IKr
blocker, direct action
potential prolongation
properties, use for
ventricular arrhythmias,
atrial fibrillation
• Dose:
 Sotalol IV dose:
 100 mg (1.5 mg/kg) over 5
minutes
 Avoid if prolonged QT
Dofetilide
Mechanism of Action:
• IKr block
• Prolongs action
potential, effective
refractory period
Dofetilide
Clinical Applications:
• Maintenance or
restoration of sinus
rhythm in atrial
fibrillation
Dofetilide
Pharmacokinetics:
• Oral
• renal excretion
Toxicities:
• Torsades de pointes
(initiate in hospital)
Interactions:
• Additive with other QTprolonging drugs
Ibutilide
• Potassium channel blocker, may activate
inward current; IV use for conversion in atrial
flutter and fibrillation
Dronedarone
• Amiodarone derivative; multichannel actions,
reduces mortality in patients with atrial
fibrillation
Class IV
Verapamil
• Mechanism of Action:
• blocks both activated
and inactivated L-type
calcium (SA & AV node)
• AV nodal conduction
time and ERP
• Extracardiac Effects:
Peripheral vasodilation
(Less than nifedipine)
Verapamil
Clinical Applications:
• Supraventricular
tachycardia. Atrial
fibrillation and flutter
.
Verapamil
Toxicities:
• constipation, sinus arrest,
hypotension, headache,
nervousness
Dose:
• 5-10 mg (0.075-0.15
mg/kg) over 2 min; if no
response, additional 5-10
mg after 15-30 min; 3-10
mg every 4-6 h for rate
control. Onset:3-5 min.
Unclassified
Adenosine
• Endogenous chemical
Mechanism of Action:
•
•
Increase in potassium efflux
decreases calcium influx.
This hyperpolarizes cardiac cells
Clinical Applications:
• PSVT
• Rapid IV injection
• t 1/2: (2 - 10 sec)
• S: flushing, chest pain, and
dyspnea
• Caution in patients (AV)
block, bronchial asthma
Adenosine
Dose:
• Adenosine IV dose:
• First dose: 6 mg rapid IV
push; follow with NS flush.
• Second dose: 12 mg if
required.
Magnesium
Mechanism of Action:
• unknown
Clinical Applications:
• Used for treatment of
torsades de pointes
Toxicities:
– Bradycardia
– Respiratory paralysis
– Flushing
– Headache
– Given in 2 gm over 10 min
Compare??
class
ECG QT
Conduction
velocity
Refractory
period
IA
++
↓
↑
IB
0
no
↓
IC
+
↓
no
II
0
↓In SAN and
AVN
↑ in SAN and
AVN
III
++
No
↑
IV
0
↓ in SAN and
AVN
↑ in SAN and
AVN
WPW
AF
2010 American Heart Association Guidelines for Cardiopulm
Resuscitation and Emergency Cardiovascular Care