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LECTURES OUTLINE:
Electrophysiology of the heart
Arrhythmia: definition, mechanisms,
types
Drugs :class I, II, III, IV
Guide to treat some types of
arrhythmia
Questions
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Normal conduction pathway:
1 !A node generates
action potential and
deli"ers it to the atria
and the AV node
# $he AV node
deli"ers the impulse
to pur%in&e fi'ers
( pur%in&e fi'ers
conduct the impulse
to the "entricles
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Action potential of the heart:
In the atria,
pur%in&e, and
"entricles the A)
cur"e consists of
* phases
In the !A node
and AV node, A)
cur"e consists of
( phases
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Nonpacema%er action potential
)hase +: fast
upstro%e
Due to Na
influ-
)hase (:
repolari.ation
Due to /efflu-
)hase 0: resting
mem'rane potential
)hase #: plateuDue to a
influ-
)hase 1: partial
repolari.ation
Due to rapid efflu- of /
N232 $he slope of phase + 4 conduction "elocity
Also the pea% of phase + 4 Vma-
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)acema%er A)
)hase 0: pacema%erpotential
Na influ- and / efflu-
and a influ- until the
cell reaches threshold
and then turns into
phase +
)hase +: upstro%e:Due to a influ-
)hase (:repolari.ation:
Due to / efflu-
)acema%er cells 5automatic cells6 ha"e
unsta'le mem'rane potential so they can
generate A) spontaneously
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Effecti"e refractory period 5E7)6
It is also called a'solute refractory period
5A7)6 :8In this period the cell can9t 'e e-cited8$a%es place 'etween phase + and (
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Arrhythmia
If the arrhythmia
arises from the
"entricles it is
called "entriculararrhythmia
If the arrhythmia
arises from atria,
!A node, or AVnode it is called
supra"entricular
arrhythmia
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Mechnisms of Arrhythmogenesis
Delayed
afterdepolari.ation
Early
afterdepolari.ation
A) from !A node
A) arises from sites
other than !A node
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$his is when the
impulse is not
conducted from
the atria to the
"entricles
1$his
pathway is
'loc%ed
#$he impulse
from this pathway
tra"els in a
retrograde fashion5'ac%ward6
(!o the cells here will
'e ree-cited 5first 'y theoriginal pathway and the
other from the
retrograde6
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;ere is an
accessory
pathway in the
heart called3undle of /ent
8)resent only in small populations
8
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Action of drugs
In case of a'normal generation:
Decrease of phase 0
slope 5in pacema%ercells6
3efore drug
after
phase0
7aises the threshold
In case of a'normal conduction:
>conduction
"elocity 5remem'erphase +6
E7)
5so the cellwon9t 'e
ree-cited
again6
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Supraventricular Arrhythmias !inus $achycardia: high sinus rate of 1++1?+'eats@min, occurs during e-ercise or other conditions
that lead to increased !A nodal firing rate Atrial $achycardia: a series of ( or more consecuti"eatrial premature 'eats occurring at a freuency B1++@min
)aro-ysmal Atrial $achycardia 5)A$6: tachycardia which'egins and ends in acute manner
Atrial Clutter: sinus rate of #*+(*+ 'eats@min2 Atrial Ci'rillation: uncoordinated atrial depolari.ations2
AV 'loc%sA conduction 'loc% within the AV node , occasionally in the
'undle of ;is, that impairs impulse conduction from theatria to the "entricles2
Types of Arrhythmia
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Ventricular Premature Beats (VPBs): caused 'y
ectopic "entricular foci characteri.ed 'y widened Q7!2
Ventricular Tachycardia (VT): high "entricular rate
caused 'y a'normal "entricular automaticity or 'y
intra"entricular reentry can 'e sustained or non
sustained 5paro-ysmal6 characteri.ed 'y widened Q7!
rates of 1++ to #++ 'eats@min lifethreatening2
Ventricular Flutter "entricular depolari.ations
B#++@min2
Ventricular Fibrillation uncoordinated "entricular
depolari.ations
ventricular Arrhythmias
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Pharmacologic Rationale &Goals $he ultimate goal of antiarrhythmic drug
therapy:o 7estore normal sinus rhythm and conductiono )re"ent more serious and possi'ly lethal
arrhythmias from occurring2 Antiarrhythmic drugs are used to:
decrease conduction "elocity change the duration of the effecti"e refractory
period 5E7)6 suppress a'normal automaticity
A t h th i d
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Antyarrhythmic drugs
class mechanism action notes
I Na channel 'loc%erhange the slope of
phase +
an a'olishtachyarrhythmia
caused 'y reentrycircuit
II 'loc%er >heart rate and
conduction "elocityan indirectly alter /and a conductance
III /channel 'loc%er
12 action potentialduration 5A)D6 or
effecti"e refractoryperiod 5E7)62#2 Delay
repolari.ation2
Inhi'it reentrytachycardia
IV achannel 'loc%er!lowing the rate of rise
in phase 0 of !A
node5slide 1#6
>conduction "elocityin !A and AV node
8Fost antiarrhythmic drugs are proarrhythmic 5promote arrhythmia68$hey are classified according to Vaughan Williaminto four classes according to their
effects on the cardiac action potential
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$hey > conduction "elocity in nonnodaltissues 5atria, "entricles, and pur%in&e
fi'ers6$hey act on open
Nachannels or
inacti"ated only
;a"e moderate /
channel 'loc%ade
!o they are used
when many Na
channels are openedor inacti"ated 5in
tachycardia only6'ecause in normal
rhythm the channels
will 'e at rest state
so the drugs won9twor%
Class I drugs
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Slowing of the rate of risein phase 0 conduction
velocity of Vmaof the cardiac action
potential $hey prolong muscle action
potential "entricular 5E7)6 $hey > the slope of )hase 0
spontaneous depolari.ation5!A node6 decreaseenhanced normalautomaticity
$hey ma%e the
slope more
hori.ontal
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Class IA Drugs
$hey possess intermediate rate of association and
dissociation 5moderate effect6 with sodium channels2
!harmaco"inetics#
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Class IA DrugsUses !upra"entricular and "entricular arrhythmias
Quinidine is rarely used for supra"entriculararrhythmias Hral uinidine@procainamide are used with class III
drugs in refractory "entricular tachycardia patients
with implanta'le defi'rillator IV procainamide used for hemodynamically sta'le
"entricular tachycardia IV procainamide is used for acute con"ersion of
atrial fi'rillation including =olff)ar%inson=hite!yndrome 5=)=!6
defi'rillator
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Class IA Drugs Toxicity
!ystemic lupus erythromatosus 5!
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Notes:
$orsades de pointes: twisting of the point 2 $ype of
tachycardia that gi"es special characteristics on EG
At large dosesof uinidine cinchonism occurs:'lurred "ision, tinnitus, headache,
psychosis and gastrointestinal upset
Digo-in is administered 'efore uinidine to pre"ent the con"ersion of atrial fi'rillation or
flutter into parado-ical "entricular tachycardia
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Class IB Drugs
$hey shorten )hase (repolari.ation
> the duration of the cardiacaction potential
$hey suppress arrhythmiascaused 'y a'normalautomaticity
$hey show rapid association $dissociation5wea% effect6 with
Na,channels with apprecia'ledegree of usedependence
No effect on conduction "elocity
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Agents of Class IB
%idocaine
Used IV because o e!tensive"stpass metabolism
#idocaine is the dru$ o choice
in emer$ency treatment o
ventricular arrhythmias
%as &'S eects: drosiness
numbness convulstion andnysta$mus
Meiletine
These are the oral analo$s o lidocaine
*e!iletine is used or chronic
treatment o ventricular arrhythmias
associated ith previous myocardial
inarction
&ses$hey are used in the treatment of "entricular arrhythmias arising during myocardial
ischemia or due to digo-in to-icity
$hey ha"e little effect on atrial or AV &unction arrhythmias 5'ecause they don9t act onconduction "elocity6
Ad"erse effects:
1neurological effects #negati"e inotropic acti"ity
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Class IC Drugs
$hey mar"edly slow !hase 0fastdepolari.ation $hey mar%edly slow conduction in
the myocardial tissue $hey possess slow rate of
association and dissociation'strong effect( with sodiumchannels
$hey only ha"e minor eects onthe duration o action potential
and reractoriness $hey reduce automaticity 'y
increasing the threshold potentialrather than decreasing the slope of)hase 0 spontaneous
depolari.ation2
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Uses:
7efractory "entricular arrhythmias2 Clecainide is a particularly potent suppressant of premature
"entricular contractions 5'eats6
Toicity and Cautions for Class IC )rugs# $hey are severe proarrhythmogenic drugscausing:
12 se"ere worsening of a pree-isting arrhythmia
#2 de no"o occurrence of lifethreatening "entricular tachycardia In patients with freuent premature "entricular contraction 5)V6
following FI, flecainide increased mortality compared to placebo.
*otice# Class +C drugs are particularly of low safety and have
shown even increase mortality when used chronically after MI
&ompare beteen class IA IB and I& dru$s as
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&ompare beteen class IA IB and I& dru$s as
re$ards eect on 'a+ channel , -.P
Sodium channel bloc/ade:
I& 0 IA 0 IB Increasin$ the -.P:
IA0I&0IB (loered) 3ecause of/ 'loc%ade
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DRUGS
(-are!ergic "loc#ers$
Uses $reatment of increased
sympathetic acti"ityinducedarrhythmias such as stressand e-erciseinduced
arrhythmias Atrial flutter and fi'rillation2 AV nodal tachycardia2 7educe mortality in post
myocardial infarction patients )rotection against suddencardiac death
Fechanism of action Negati"e inotropic
and chronotropicaction2
)rolong AVconduction 5delay6
Diminish phase 0depolari.ation
suppressingautomaticity5ofectopic focus6
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Class II ANTIARRHYTHMICDRUGS
Propranolol (nonselective): was pro"ed toreduce the incidence of sudden arrhythmaticdeath after myocardial infarction
*etoprolol reduce the ris% of 'ronchospasm ,smolol# Esmolol is a "ery shortacting 1adrenergic
'loc%er that is used 'y intra"enous route in acutearrhythmias occurring during surgery oremergencies
selecti"e
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DRUGS
%& "loc#ers
)rolongation of phase (repolari.ation without alteringphase + upstro%e or the restingmem'rane potential
$hey prolong 'oth the durationof the action potential and E7)
$heir mechanism of action isstill not clear 'ut it is thoughtthat they 'loc% potassiumchannels
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Uses: Ventricular arrhythmias, especially "entricular
fi'rillation or tachycardia !upra"entricular tachycardia
Amiodarone usage is limited due to its widerange of side effects
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Sotalol 'Sotacor( !otalol also prolongs the duration of action potential and
refractoriness in all cardiac tissues 5'y action of /, 'loc%ade6 !otalol suppresses )hase 0 spontaneous depolari.ation and
possi'ly producing se"ere sinus 'radycardia 5'y 'loc%adeaction6
$he adrenergic 'loc%ade com'ined with prolonged actionpotential duration may 'e of special efficacy in pre"ention ofsustained "entricular tachycardia
It may induce the polymorphic torsades de pointes "entriculartachycardia 5'ecause it increases E7)6
I'utilidesed in atrial fi'rillation or flutterIV administrationFay lead to torsade de pointesHnly drug in class three that possess pure / 'loc%ade
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Amiodarone (Cordarone) Amiodarone is a drug of multiple actions and is still not well understood
It is e-tensi"ely ta%en up 'y tissues, especially fatty tissues 5e-tensi"edistri'ution6
t1@#4 J+ days )otent )0*+ inhi'itor Amiodarone antiarrhythmic effect is comple- comprising class I II III
and IV actions8 Dominant effect: )rolongation of action potential duration and refractoriness8 It slows cardiac conduction, wor%s as a#channel 'loc%er, and as a wea%
adrenergic 'loc%er
Toicity Fost common include GI intolerance, tremors, ata-ia, di..iness, and hyper
or hypothyrodism orneal microdeposits may 'e accompanied with distur'ed night "ision Hthers: li"er to-icity, photosensiti"ity, gray facial discoloration, neuropathy,
muscle wea%ness, and weight loss $he most dangerous side effect ispulmonary fi-rosiswhich occurs in
#*K of the patients
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DRUGS
(Calciu C)a!!el Bloc#ers$
alcium channel 'loc%ers decreaseinward a#,currents resulting in adecrease of phase 0 spontaneousdepolari.ation 5!A node6
$hey slow conductance in a#,currentdependent tissues li%e AVnode2
E-amples: "erapamil diltia.em3ecause they act on the heart only
and not on 'lood "essels2 Dihydropyridine family are not used
'ecause they only act on 'lood "essels
Mec)a!is o*
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Mec)a!is o*actio!
$hey 'ind only to depolari.ed 5open6 channels pre"ention of repolari.ation
$hey prolong E7) of AV node >conduction of impulses from the atria to the"entricles
!o they act only in cases of arrhythmia 'ecause many a#
channels are depolari.ed while in normal rhythm many of them
are at rest
Fore effecti"e in treatment of atrial than "entricular arrhythmias2$reatment of supra"entricular tachycardia pre"enting theoccurrence of "entricular arrhythmias$reatment of atrial flutter and fi'rillation
Uses
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contraindication ontraindicated in patients with pree-isting
depressed heart function 'ecause of their negati"einotropic acti"ity
Ad"erse effects
ause 'radycardia, and asystole especially whengi"en in com'ination with adrenergic 'loc%ers
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Miscella!eous A!tiarr)yt)icDrugs
Adenosine
o Adenosine activatesA1purinergic receptorsdecreasing the !A nodal firing and automaticity,reducing conduction "elocity, prolonging effecti"erefractory period, and depressing AV nodalconducti"ity
o It is the drug of choice in the treatment ofparo-ysmal supra"entricular tachycardia
o It is used only 'y slow intra"enous 'oluso It only has a lowprofile to-icity 5lead to
'ronchospasm6 'eing e-tremly short acting for 1*seconds only
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class -&1 2T &onductionvelocity .eractoryperiod
IA >
I3 + no >
I > no
II + >In !AN andAVN
in !AN andAVN
III No
IV + > in !AN andAVN
in !AN andAVN
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1st: 7educe throm'us formation 'y using anticoagulant warfarin
#nd
: )re"ent the arrhythmia from con"erting to "entricular arrhythmia:Cirst choice: class II drugs:8After FI or surgery8A"oid in case of heart failure
!econd choice: class IV
$hird choice: digo-in8Hnly in heart failure of left "entricular dysfunction
(rd: on"ersion of the arrhythmia into normal sinus rhythm:
lass III:
IV i'utilide, IV@oral amiodarone, or oral sotalol
lass IA:
Hral uinidine digo-in 5or any drug from the #ndstep6
lass I:
Hral propaphenone or IV@oral flecainide
se direct current in case
of unsta'le hemodynamic
patient
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Cirst choice: class II8IV followed 'y oral
8Early after FI
!econd choice: amiodarone
A"oid using
class I after
FI
mortality
Cirst choice:
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:LMOPR5IA, I, class III6 torsades de pointes2
lasses II and IV 'radycardia 5don9t com'ine the two6
In atrial flutter use 51st>impulses from atria to "entricular to pre"ent
"entricular tachycardia612lass II
#2lass IV
(2Digo-in25 6
#ndcon"ert atrial flutter to normal sinus rhythm use:
12I'utilide
#2!otalol
(2IA or I25 6
If you use uinidine com'ine it with digo-in or 'loc%er 5'ecause of its anti
muscarinic effect6
A"oid I in myocardial infarction 'ecause it mortality
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1 In "entricular tachycardia and sta'le hemodynamic which drug to 'e usedS
A propranolol3 procainamide
uinidine
D "erapamil
# Fr2Green de"loped an arrhythmia and was treated2 A month later, he has arthralgia,
fe"er, pleural inflammation2 =hat was the treatment of arrhythmiaS
A esmolol
3 class III
procainamide
D propafenone
( inchonism occurs with digo-in
A pulmonary fi'rosis diltia.em
3 'radycardia amiodarone
5C6
Recommended