Transcript Antiarrhythmic drugs

Electrophysiology of the heart
Arrhythmia: definition, mechanisms,
types
Drugs :class I, II, III, IV, others
Guide to treat some types of
arrhythmia
Normal conduction pathway:
1- SA node generates
action potential and
delivers it to the
atria and the AV
node
2- The AV node
delivers the impulse
to purkinje fibers
3- purkinje fibers
conduct the impulse
to the ventricles
Other types of
conduction that
occurs between
myocardial cells:
When a cell is
depolarized 
adjacent cell
depolarizes
along
Action potential of the heart:
In the atria, and
ventricles the AP curve
consists of 5 phases
In the SA node , AV
node and purkinje AP
curve consists of 3
phases
Non-pacemaker action potential
Phase 1: partial
repolarization
Due to rapid efflux
of K+
Phase 0: fast
upstroke
Due to Na+
influx
Phase 2: plateu
Due to Ca++
influx
Phase 3:
repolarization
Due to K+
efflux
Phase 4: resting
membrane
potential
N.B. The slope of phase 0 = conduction velocity
Also the peak of phase 0 = Vmax
Pacemaker Action Potential
Phase 0:
upstroke:
Due to Ca++
influx
Phase 4:
pacemaker
potential
Na influx and K
efflux and Ca
influx until the
cell reaches
threshold and
then turns into
phase 0
Pacemaker cells (automatic cells) have
unstable membrane potential so they can
generate AP spontaneously
Phase 3:
repolarization:
Due to K+ efflux
Effective refractory period (ERP)
It is also called absolute refractory period
(ARP) :
•In this period the cell can’t be excited
•Takes place between phase 0 and 3
If the arrhythmia
arises from atria,
SA node, or AV
node it is called
supraventricular
arrhythmia
Causes of arrhythmia
arteriosclerosis
Coronary
artery spasm
If the arrhythmia
arises from the
ventricles it is
called ventricular
arrhythmia
Heart
block
Myocardial
ischemia
1- Abnormal impulse
generation
Altered normal Automatic
rhythms
Rate of
impulse
generation
Site of impulse
generation(Ectopic
focus)
AP arises from sites
other than SA node
↑AP from SA node
Triggered
rhythms
Delayed
Early
afterdepolarization afterdepolarization
 Refers to the accelerated generation of an action
potential by either normal pacemaker tissue
(enhanced normal automaticity) or by abnormal tissue
within the myocardium (abnormal automaticity).
 The discharge rate of normal or abnormal pacemakers
may be accelerated by drugs, various forms of cardiac
disease, reduction in extracellular potassium, or
alterations of autonomic nervous system tone
arrhythmias that arise as a result of afterdepolarizations (abnormal depolarizations
that interrupt phase 2, phase 3, or phase 4 ) which on depends of the prior impulse (or
series of impulses)
 DAD –AP occurs once
 AED –AP occurs during
repolarization
 Causes
 Congenital defective of K
channel
 Prolong QT syndrome
 Abn Na Channel- fast
recovery to resting state
 K channel blockers drug
 Hypokalemia eg: use of
diuretic
 Bradycardia prolong
Action potential duration
repolarization complete
 caused by intracellular Ca / Na
overload
 Adrenergic stimulation (Ca &
Na overload)
 Digitalis (- Na K APTase, red
Na effux, >NA intra cellular,
+ Na Ca exchanger ,
 Miocardia Ischaemia/
infaction( reduce O2, reduce
ATP production, reduce Na K
ATPase activity
2-Abnormal conduction
Conduction block
1st
degree
2nd
degree
Reentry
3rd
degree
Anatomical
determine
Funtional
determine
1-This pathway is
blocked
This is when the
impulse is not
conducted from the
atria to the
ventricles
3-So the cells here
will be reexcited
(first by the original
pathway and the
other from the
retrograde)
2-The impulse
from this
pathway travels
in a retrograde
fashion
(backward)
 Reexcitation of cardiac
tissue by return of the
same cardiac impulse
using a circuitous
pathway
 Due to imbalance of
conduction and
refractories
 Mech of PVCVT and
VFSVT,AF,flutter
Abnormal anatomic
conduction
Here is an accessory
pathway in the
heart called Bundle
of Kent
•Present only in small populations
•Lead to reexcitation  WolfParkinson-White Syndrome
(WPW)
In case of abnormal
generation:
Decrease of phase 4
slope (in pacemaker
cells)
Before drug
after
phase4
In case of abnormal
conduction:
↓conduction velocity
(remember phase 0)
Raises the threshold
↑ERP
(so the cell won’t be
reexcited again)
Tachydysrhythmias
Regular
Irregular
Narrow complex
Wide complex
Narrow complex
Wide complex
Sinus Tachycardia
Atrial Tachycardia
Atrial Flutter
AVNRT/AVRT
Ventricular tachycardia
Pacer-mediated
tachycardia
SVT with pre-existing BBB
SVT with rate-dependent BBB
MAT
Atrial Fibrillation
Atrial Flutter with
variable block
Torsade des Pointes
Ventricular fibrillation
 The ultimate goal of antiarrhythmic drug therapy:
 Restore normal sinus rhythm and conduction
 Prevent more serious and possibly lethal arrhythmias




from occurring.
Antiarrhythmic drugs are used to:
decrease conduction velocity
change the duration of the effective refractory period
(ERP)
suppress abnormal automaticity
•Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia)
•They are classified according to Vaughan William into four classes according to their
effects on the cardiac action potential
class
mechanism
action
notes
I
Na+ channel blocker
Change the slope of
phase 0
Can abolish
tachyarrhythmia
caused by reentry
circuit
II
β blocker
↓heart rate and
conduction velocity
Can indirectly alter K
and Ca conductance
K+ channel blocker
1. ↑action potential
duration (APD) or
effective refractory
period (ERP).
2. Delay repolarization.
Inhibit reentry
tachycardia
Ca++ channel blocker
Slowing the rate of rise
in phase 4 of SA node &
conduction velocity
↓conduction velocity
in SA and AV node
III
IV
Class I
Have moderate K+ channel
blockade
IA
They act on open Na+
channels or
inactivated only
IB
IC
They ↓ conduction velocity in non-nodal
tissues (atria, ventricles, and purkinje fibers)
So they are used
when many Na+
channels are opened
or inactivated (in
tachycardia only)
because in normal
rhythm the channels
will be at rest state so
the drugs won’t work
Class IA
Quinidine
Procainamide
Dysopyramide
 Slowing of the rate of rise in phase 0
 ↓conduction velocity
 ↓of Vmax of the cardiac action
potential
 prolong muscle action potential &
ventricular (ERP)
 ↓ the slope of Phase 4 spontaneous
depolarization (SA node)
Decreased pacemaker activity
They make the
slope more
horizontal
 Intermidiate interection with sodium channel blocker
Pharmacokinetics:
quinidine
procainamide
Good oral
bioavailability
80% protein
binding
Metabolized in the
liver (P4 50)
active metabolite
(50 % has anti
arrythmic effect)
Good oral
bioavailability
15 % protein binding .
Concentrate @heart &
other tissue > plasma
loadingIV
12mg/kg,0.3mg/kg/min
maintenance 2-5
mg/min
Dysopyramide
Oral
administration
Extensive protein
binding
50 % excreted unchanged in
urine 20 % to dealkylated
metabolite (1/10 antiarrythmic
effect )
Dose 150mg qid up
to 1gm/day
Oral 0.2-0.6 gm 2-4x
a day
Procainamide metabolized into N-acetylprocainamide (NAPA) (active class III)major metabolite which is cleared by the kidney (avoid in renal failure)
 Supraventricular and ventricular arrhythmias
 Quinidine –prevent recurrent supraventricular
tachydysrhythmias & suppress ventricular premature
contraction
 Oral quinidine/procainamide are used with class III drugs in
refractory ventricular tachycardia patients with implantable
defibrillator
 IV procainamide used
 for hemodynamically stable ventricular tachycardia
 for acute conversion of atrial fibrillation including Wolff-
Parkinson-White Syndrome (WPWS)
Quinidine
myocardial depression
Hypotension( a adrenoreceptor
blockade)
Torsades de pointes arrhythmia
because it ↑ ERP (QT interval)
Shortens A-V nodal refractoriness
(↑AV conduction) by
antimuscarinic like effect
↑digoxin concentration by :
1- displace from tissue binding
sites
2- ↓renal clearance
SA dysfunction & AV block esp pt
with sick sinus syndrome
Procainamide
Reduce CO
&Hypotensive-rapid IV
Cardiac conduction
abnormalityAsystole or
ventricular arrhythmia
Hypersensitivity : fever,
agranulocytosis
Systemic lupus erythromatosus (SLE)-like
symptoms: arthralgia, fever, pleuralpericardial inflammation.
Symptoms are dose and time dependent
Common in patients with slow hepatic
acetylation
Notes:
Torsades de pointes: twisting of the point . Type of
tachycardia that gives special characteristics on ECG
At large doses of quinidine  cinchonism occurs:blurred vision,
tinnitus, headache, psychosis and gastrointestinal upset
Quinidine has anti vagal action accelerate AVN conduction
Digoxin is administered before quinidine to prevent the conversion
of atrial fibrillation or flutter into paradoxical ventricular
tachycardia
Adverse effect of Disopyramide-Negetive inotropic effect , CI in Cardiac failure or AV block
-Urinary retension,dry mouth,blurred vision & precipitated glaucoma
(anticholinergic activity)
-Sinus Node depression& Prolong QTVentricular reentry arrythmia, VF, TDP
Class IB
lidocaine
mexiletine tocainide
 They shorten Phase 3 repolarization
 ↓ the duration of the cardiac action
potential
 Suppress arrhythmias caused by
abnormal automaticity
 Show rapid association &
dissociation (weak effect) with Na+
channels with appreciable degree of
use-dependence
 Min change on conduction velocity
Lidocaine

Used IV because of extensive 1st
pass metabolism

Clearence is related to hepatic
blood flow, liver fx,microsomal
activity-prolong in liver dis,
heart failure, elderly

Propanolol , cimetidine,
halothane  dec hepatic
clearence of lignocaine
Mexiletine

Oral analogs of lidocaine

Used for chronic treatment of
ventricular arrhythmias
associated with previous
myocardial infarction
Adverse effects:
1- neurological effects
2- negative inotropic activity
Uses
They are used in the treatment of ventricular arrhythmias arising during
myocardial ischemia or due to digoxin toxicity
They have little effect on atrial or AV junction arrhythmias (because they have
min effect on conduction velocity)
Death
26
Ventricular Arrest
24
22
Respiratory arrest
20
Cardiac Arrhythmia
18
Coma
16
Myocardial depression
14
Loss of conciousness
CNS
excitation
12
Convulsion
10
Muscle twitching
8
Visual disturbances
6
Lightheadness, tinnitus,
circumoral & tongue numbness
4
2
Positive inotropy,
anticonvulsant, antiarrythmic
0
Plasma lidocaine concentration µg/ml
Class IC
flecainide
propafenone
 Markedly slow Phase 0 fast
depolarization
 Markedly slow conduction in the
myocardial tissue
 They possess slow rate of association
and dissociation (strong effect) with
sodium channels
 Have only minor effects on the
duration of action potential and
refractoriness
 Reduce automaticity by increasing
the threshold potential rather than
decreasing the slope of Phase 4
spontaneous depolarization.
 Clinical use
 Pharmacokinetics
 Refractory ventricular
 Rapid and complete absorbed
arrhythmias.
after oral: bioavailability-90%
 particularly potent
suppressant of premature
 40-50% protein binding
ventricular contractions (beats)  Vd: 5-10 L/kg
 Dosage :
 Orally :100 – 200 mg bd
 IV :2 mg/kg up to 150 mg
 Metabolized in liver
 25% excreted unchanged by
the kidneys
 Elimination half life: 7-15 h
 Elimination decrease in ;
over 10-30 mins
Infusion :
 CCF , renal failure
1.5 mg/kg/h for 1 hour,
 Drugs interaction
Then 0.1 – 0.25 mg/kg/h
 Flecainide increase the plasma
concentrations of digoxin and
 Therapeutic plasma con. :
propanolol
0.2-1.0 ug/ml
Toxicity and Cautions for Class IC Drugs:
 Potentially serious proarrhythmogenic effect causing:
 severe worsening of a preexisting arrhythmia (ventricular
arrhythmia aggravated in 5-12 % patient)
 In patients with frequent premature ventricular contraction
(PVC) following MI, flecainide increased mortality
compared to placebo.
 CNS effect comman- diziness, visual disturbance, GIT upset
Notice: Class 1C drugs are particularly of low safety and have shown
even increase mortality when used chronically after MI
Compare between class IA, IB, and IC drugs as
regards effect on Na+ channel & ERP


Sodium channel blockade:
IC > IA > IB
Increasing the ERP:
IA>IC>IB (lowered)
Because of
K+ blockade
Mechanism of action
 Negative inotropic and
chronotropic action.
Clinical Uses
 Treatment of increased
sympathetic activity-induced
arrhythmias such as stress- and
exercise-induced arrhythmias
 Prolong AV conduction
(delay)- prolong PR
interval
 Diminish phase 4
depolarization 
suppressing
automaticity(of ectopic
focus)
 Atrial flutter and fibrillation.
 AV nodal tachycardia.
Reduce mortality in postmyocardial infarction patients
Protection against sudden cardiac
death
Pharmacokinetic 
Protein bound – 60%
Rapid metabolized by red blood cell esterase to inactive acid metabolism
and methyl alcohol
Half-life 10 minute
 Clinical use
 Short term management
of tachycardia and
hypertension in perioperative period, acute
SVT
 No intrinsic
sympathomimetic activity
or membrane stabilizing
properties
 Adverse effect
 Cardiac
 precipitate heart failure
 Non cardiac
 act B2- adrenoreceptor
antagonism at high
dose – caution in
asthmatics
 Irritant to veins and
extravasations - tissue
necrosis
 Oral dose:
Adverse effects
 Bradycardia,hypotension,
( Chronic suppression of
ventricular dysrhythmia)
myocardial suppression and
bronchospasm, acccentuate CCF
 IV:
 1 mg per minute,
 cross placenta readily. Fetal
total dose3 to 6mg
bradycardia, hypoglycaemia,
(emergency suppression
hyperbilirubinaemia and
of cardiac dysrythmia)
intrauterine growth retardation
(IUGR) are concerns.
Propranolol
 Most reports have not shown
was proved to reduce the
incidence of sudden
significant adverse fetal effects
arrhythmatic death &
reinfact after myocardial
but beta-blockers are probably
infarction
best avoided in known IUGR
 10 to 80mg every 6-8 hr
 Prolongation of phase 3 repolarization
without altering phase 0 upstroke or
the resting membrane potential
 prolong both the duration of the
action potential and ERP
Class III
sotalol

amiodarone
ibutilide
Clinical Uses:
Wide spectrum activity against refractory
supraventricular and ventricular tachyarrhythmia

Pulseless ventricular tachycardia and fibrillation resistant
to defibrillation

Effective for suppression of tachyarrhythmia a/w WPWS
Sotalol (Sotacor)
 non selective B adrenergic blockade
 prolongs the duration of action potential and refractoriness in
all cardiac tissues (by action of K+ blockade) – class 111
action
 suppresses Phase 4 spontaneous depolarization
 possibly producing severe sinus bradycardia (by β blockade
action)
 β-adrenergic blockade combined with prolonged action
potential duration may be of special efficacy in prevention of
sustained ventricular tachycardia
 Most dangerous S/ E:
 the polymorphic torsades de pointes ventricular tachycardia
because it increases ERP, prolong QT interval
Ibutilide
 Used in atrial fibrillation or flutter
 Only drug in class three that possess pure K+ blockade
 Slow repolarization
 Prolong cardiac action potensials
 IV administration
 May lead to torsade de pointes
by enhance influx Na, blocked
K channel
 A Benzoflurance derivative, resembles thyrosine
 Amiodarone is a drug of multiple actions ,complex comprising
class I, II, III, and IV actions
 Dominant effect: Prolongation of action potential duration and
refractoriness
 It slows cardiac conduction, works as Ca2+ channel blocker,
and as a weak β-adrenergic blocker
Dose and administration
 VF/VT unresponsive to CPR, shock and vasopressor
 IV: 300 mg (5mg/kg) bolus
 Life threatening arrhythmias
 Max dose: 2.2 g IV over 24H
 Rapid Infusion 150 mg over 10 minutes , Slow infusion: 360 mg
over 6H, Maintenance Infusion: 540 mg over 18H
 Therapeutic blood level: 1.0 – 3.5 mcg/ml
Pharmacokinetics
 Poorly absorbed from gut,oral bioav. 50-70%
 Highly protein-bound >95%
 Vd 2-70 l/kg
 Elimination half-life 20-100 days
 Hepatic metabolism produces desmethylamiodarone –
antiarrhythmic activity
 Not removed by hemodialysis
 Drug interaction
 effect of other highly protein bound drugs
(phenytoin, warfarin) are increase – dose should
adjust
 Plasma level of digoxin may rise when amiodarone
added
Toxicity
 Common with patient chronic treatment
 Most common include GI intolerance, tremors, ataxia, dizziness, and
hyper-or hypothyrodism (2-4 %)
 Cardiac – bradycardia and hypotension. Prolonged QT interval (inc
ventricular tachyarrrythmia including Torsade de points)
 Corneal microdeposits may be accompanied with disturbed night
vision
 Others: liver toxicity, photosensitivity & rash (10 %) , gray facial
discoloration, neuropathy, prox muscle weakness, and weight loss
 The most dangerous side effect is pulmonary fibrosis which occurs
in 2-5% of the patients
 can be irreversible and life threatening -unusual at doses used for
atrial fibrillation (200 mg/day)
 10% fatal, most reversible
 Calcium channel blockers decrease inward
Ca2+ currents resulting in a decrease of
phase 4 spontaneous depolarization (SA
node)
 They slow conductance in Ca2+ current-
dependent tissues like AV node.
 Examples: verapamil & diltiazem
 Because they act on the heart only and
not on blood vessels.
 Dihydropyridine family are not used
because they only act on blood vessels
Verapamil
 Prevents influx of Ca through slow (L) channel in SA and
AV node – reduce their automaticity
 They prolong ERP of AV node  ↓conduction of impulses
from the atria to the ventricles
 Coronary artery dilatation
Clinical Uses
More effective in treatment of atrial than ventricular
arrhythmias.
Treatment of supra-ventricular tachycardia preventing the
occurrence of ventricular arrhythmias
Treatment of atrial flutter and fibrillation
Dose
5 – 10 mg IV bolus over 1-3 min
Infusion 5 mcg/kg
Phamacokinetic
 Orally and IV
 90% absorbed from gut,





oral bioav.25% d/t high
first-pass metabolism
90% bound to plasma
protein
Metabolized in liver
Excreted in urine
Vd 3-5 l/kg
Elimination half-life 3-7
hrs
CI- Sick sinus
syndrome. heart
block, poor left
ventricular failure
Adverse effect
 Cardiac
 SVT with WPW syndrome
 verapamil precipitate VT
 Pt with poor LV function
 precipitate cardiac failure
 With agent that slow AV
conduction (digoxin,B-blocker,
halothane)
 precipitate serious bradycardia
and AV block
 Increase serum level of digoxin
 Non cardiac
 cerebral artery dilatation,
constipation
Adenosine
 Endogenous nucleoside
 slows conduction of cardiac impulses through
the AVN and accessory pathways
 uses
 Effective for stable narrow complex SVT
 Effective in terminating those due to reentry
involving AV node or sinus node
 Regular and monomorphic wide-complex
 Not effective in AF, flutter or VT
 Mechanism of action
 Its stimulates cardiac
adenosine 1 receptors to
increase K+ currents
 shorten the action
potential duration
 hyperpolarize cardiac cell
membranes.
 In addition, Adenosine
decrease cAMP
concentration
 Phamacokinetic
 Its short-lived cardiac
effects
 Elimination half time : 10
seconds by carriermediated cellular uptake
 Dosage
 IV : 6mg iv rapid bolus
(over 1-3 second
followed by NS bolus) ,
followed by a dose of
12mg if necessary
 Drug interaction
 Inhibit by theophylline
 Potentiated by
adenosine uptake
inhibitors such as
dipyridamole
 Side effects
 Facial flushing , Headache
 Dyspnea, Chest discomfort
 Nausea
 Transient atrioventricular
heart block, asystole
 Rare – bronchospasm
 Pharmacologic effects of
adenosine are antagonized
by methyxanthines
(theophylline, caffeine)
and potentiated by
dipyridamole
 Contraindication
 2nd or 3rd degree heart block
& Sick sinus syndrome
 Mode of action
 Co-factor for membrane
enzyme Na+/K+ ATPase
 Lack of magnesium may
lead to intracellular K+
depletion
 Slow the conduction
 Dose:
 1-2 g (2-4 ml of 50%
solution) dilute in 50 ml
D5 over 1h ( poorly
absorbed from gut)
trough AV node and
 Mg is excreted by kidneys
prolong the refractory
and accumulate in renal
period in atria &
ventricles– similar class 111 failure
 Clinical use
 Adverse effect
 Torsade de pointes
 Hypotension
 Ventricular arrhythmias
ass with digitalis toxicity
 Multifocal atrial
tachycardia
 Mode of action
 Direct –
 bind and inhibit cardiac Na+/K+ ATPase  increase
intracellular Na+ and decrease intracellular K+
 Raised intracellular Na+ increased exchanged with
extracellular Ca2+ resulting increase availability of
intracellular Ca2+  positive inotopic effect, increasing
excitability and force of contraction
 Indirect release of Ach at cardiac muscarinic receptors – slow
conduction and prolong refractory period in AV node and
bundle of HIS
 Clinical use
 Treatment of atrial
fibrilation or flutter
 Dose
 Loading dose 1 – 1.5 mg,
divided dose over 24h
 Maintenance dose 125 –
500 mcg/day
 Therapeutic range 1-2
mcg/l
 Adverse effect
 Cardiac
 PVC, bigemini, all form of
AV block
 ECG – prolonged PR
interval, ST segment
depression, T wave
flattening and short QT
interval
 Non cardiac
 Anorexia, nausea and
vomiting, diarrhoe and
lethargy,
 visual disturbance,
headache and gynecosmatia
 Toxicity – plasma conc >2.5
mcg/l
 Treatment of digoxin toxicity
 Stop digoxin adm. Gastric lavage, actvated
charchoal
 Correct precipitating factor – K+
 SVT – propanolol
 AV blockade – pacing, atropine, isoprenaline
 Ventricular arrhythmias – phenytoin, lignocaine,
pacing
 Digoxin – specific Fab a/body fragments
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
1st: Reduce thrombus formation by using anticoagulant warfarin
2nd: Prevent the arrhythmia from converting to ventricular arrhythmia:
First choice: class II drugs:
•After MI or surgery
•Avoid in case of heart failure
Second choice: class IV
digoxin
•Only in heart failure of left ventricular dysfunction
Address precipitating
factors : hyperthyroidism,
heart failure & etc
3rd: Conversion of the arrhythmia into normal sinus rhythm:
Class III:
IV ibutilide, IV/oral amiodarone, or oral sotalol
Class IA: ( no longer recommended except vagally mediated AF coz More effective drug
available , extra cardiac side effect & proarrythmia effect)
Use direct current in case
Oral quinidine + digoxin (or any drug from the 2nd step)
of unstable hemodynamic
patient
Class IC:
Oral propaphenone or IV/oral flecainide