2._antiarrhythmic_drugs_ (1).ppt

7/26/2019 2._antiarrhythmic_drugs_ (1).ppt

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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

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2._antiarrhythmic_drugs_ (1).ppt