ARRHYTHMIA & ANTIARRHYTHMIC DRUGS
Slide no:1Pharmacology
Presented by
S.Lakshmi Sravanthi
11AB1R0051
Vignan pharmacy college (Approved by AICTE , PCI & Affiliated to JNTU kakinada)
Vadlamudi , Guntur (Dt)-522213
Electrophysiology of the heart
Arrhythmia: definition, mechanisms, types
Drugs :class I, II, III, IV
Guide to treat some types of arrhythmia
Date:26-07-2014 Pharmacology Slide no:2
Cardiac arrythmias results from alterations in the orderly
sequence of depolarisation followed by repolarization in the heart.
Cardiac arrythmias may result in alterations in heart rate or rhythm
and arise from alterations in simple generation or conduction.
CARDIAC ARRYTHMIAS
Definition
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ELECTROPHYSIOLOGY – CARDIAC RHYTHM
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Conducting tissue
• SA node,AV node,bundle of his & purkije fibers.
Contractile tissue
• Atria and ventricles.
IMPULSE GENERATION AND CONDUCTION
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CARDIAC ACTION POTENTIAL
Divided into five phases (0,1,2,3,4)
• Phase 0 – rapid depolarization
• Phase 1 – early repolarization
• Phase 2 – plateau phase
• Phase 3 – rapid repolarization
• Phase 4 – resting phase, diastolic depolarization
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Action Potential
Phase 0
Phase 4
Phase 3
Phase 2
Phase 1
- 90 mV
0 mV
30 mV
Non nodal tissues
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0 1 2 3 4
• Effective refractory period
• Absolute refractory period
• Relative refractory period
1
0
2
3
4
ARP RRP
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Pacemaker
AP
Phase 4: pacemaker potential
Na+ influx and K+ efflux and Ca++ influx until the cell reaches threshold and then turns into phase 0
Phase 0: upstroke:Due to Ca++ influx
Phase 3: repolarization:
Due to K+ efflux
Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP
spontaneously
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ECG showing wave
segments
Contraction of atria
Contraction of ventricles
Repolarization of ventricles
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Pharmacology
Slide no:10
ARRHYTHMIA
Abnormal impulse generation
Triggered activity
Abnormal impulse conduction
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Depressed automaticity of SA node
Enhanced automaticity of SA node
Impulse from ectopic loci
Ischemia, digitalis, catecholamine's, acidosis, hypokalaemia
Less (-) resting membrane potential
More (-) TP
Abnormal impulse generation
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Extra abnormal depolarisation
- Due to abnormal intracellular Ca2+ regulation
- During or immediately after phase 3
- After depolarisation may be categorized in to
- Early after depolarisation
- Delay after depolarisation
Triggered Activity
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After depolarizations
EADs prolonged APD
Clinical arrhythmia:
e.g., torsades de pointesdue to: long QT syndrome
genetic defects
DADs HR or [Ca2+]i
Clinical arrhythmia:
e.g., Ca2+ overloaddue to: digoxin or PDE inhibitor toxicity
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Conduction block
Reentry phenomenon
Accessory tract pathway
Abnormal impulse conduction
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Due to depression of impulse conduction at AV node & bundle of
His, due to vagal influence or ischemia.
Types :
1st degree heart block – slowed conduction
2nd degree block – some supraventricular complex not conducted
3rd degree block – no supraventricular complex are conducted
Conduction Block
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Due to abnormality of conduction , an impulse may recirculate
in the heart and causes repetitive activation without the need
for any new impulse to be generated. These are called
reentrant arrythmias.
Circus movement type:
A premature impulse temporarily blocked in one direction by
refractory tissue, makes a one-way transit around an obstacle
finds the original spot in an advanced state of recovery and
rexicites it, setting up recurrent activation of adjacent myocardium.
Re-entry phenomenon
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ACCESSORY TRACT PATHWAY Accessory
pathway in the heart called
Bundle of Kent
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IMPORTANT CARDIAC ARRHYTHMIAS
Extra systole – premature beats
Due to abnormal automaticity or impulse arising from ectopic focus.
PSVT – Sudden onset of AT 150-200/min
Due to circus movement type of Re-entry or accessory pathway
AFL – 200-300 / min
Due to re entry circuit in right atrium
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ATRIAL FIBRILLATION
• 350-550/min
• Due to electrophysiological inhomogenesity
of atrial fibers.
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pharmacology
Slide no:21
VT – 4 or more consecutive ventricular extrasystoles
Due to either discharge from ectopic focus or reentry
circuits
Torsades de points
Polymorphic VT with rapid asynchronous complex, twisting
along the baseline on ECG with long QT interval
VF
Grossly irregular, rapid & fractionated action of ventrcles –
resulting in incoordinated contraction of ventricles with loss of
pumping function.
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POSSIBLE MECHANISMS OF ANTIARRHYTHMIC DRUGS
1. Suppressing the Automaticity
↓ Rate of phase 0
↓ Slope of phase 0
Duration ERP ↑
TP less negative
Resting membrane potential more negative
2. Abolishing reentry
Slow conduction
↑ ERP
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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:
o Decrease conduction velocity
o Change the duration of the effective refractory period (ERP)
o Suppress abnormal automaticity
Pharmacological goals
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VAUGHAN-WILLIAMS CLASSIFICATION
CLASS MECHANISM
I Na+ channel blocker
II β blocker
III K+ channel blocker
IV Ca++ channel blocker
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class mechanism action notes
I Na+ channel blockerChange 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
III K+ channel blocker
1. ↑action potential duration (APD) or effective refractory
period (ERP).2. Delay repolarization.
Inhibit reentry tachycardia
IV Ca++ channel blockerSlowing the rate of rise in phase 4 of SA node.
↓conduction velocity in SA and AV node
Anti arrythmic drugs
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Class I
IA IB IC
They ↓ automaticity in non-nodal tissues (atria, ventricles, and purkinje
fibers)
They act on open Na+ channels or
inactivated only
Use dependence
Have moderate K+ channel blockade
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IAQuinidin
eProcaina
mideDisopyra
mideMoricizi
ne
Slowing the rate of rise in phase 0
They prolong action potential & ERP
↓ the slope of Phase 4 spontaneous depolarization
↑ QRS & QT interval
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Antimalarial, antipyretic, skeletal muscle relaxant and atropine like action.
• Quinidine binds to open and inactivated sodium channels
and prevents sodium influx, slowing the rapid upstroke during
phase o.
• It also decreases the slope of phase 4 spontaneous
depolarization and inhibits potassium channels.
QUINIDINE
Mechanism of action
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Diarrhoea
“Cinchonism” – tinnitus, vertigo,
headache, nausea & blurred vision.
200-400 mg orally tds
C/I
AV block
QT prolongation- Torsades de
pointes
Digoxin, enzyme inducer
Myasthenia gravis
A/E
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• Ventricular tachyarrythmias
• Used in the termination of ventricular tachycardia
• Quinidine can interact the plasma concentration of digoxin,
which may in turn lead to signs and symptoms of digitalis
toxicity.
• Cimitidine increases hepatic metabolism of quinidine
Uses
Drug interactions
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Procaine derivative, quinidine like action
Procainamide binds to open and inactivated Na+ channels and
prevents sodium influx, slowing the rapid upstroke during
phase 0
Hypotension Hypersensitivity reaction
PROCAINAMIDE
Mechanism of action
A/E
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Paroxysmal atrial tachycardia
Premature atrial contractions
Dose:1-1.5g rate of 20-50mg/min
• Procainamide
hypersensitivity
• Bronchial asthma
• Cimitidine inhibits the
metabolism of procainamide
Uses
Drug InteractionsC/I
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DISOPYRAMIDE
Disopyramide produces a negative ionotropic effects
that is greater than weak effect exerted by quinidine and
procainamide, and unlike the latter drugs, disopyramide
causes peripheral vasoconstriction.
• Myocardial depression
• Urinary retention
• Constipation
Mechanism of action
A/E
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Disopyramide
• ventricular tachycardia
• AF & AFI
- CHF
In the presence of phenytoin, the metabolism of disopyramide
is increased and the accumulation of its metabolite is also
increased, there by increasing the probability of
anticholinergic properties.
Uses
C/I
Drug Interactions
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A/E Nausea Dizziness A-V block
Uses Ventricular
tachycardia
C/I A-V block
Drug hypersensitivity
MORICIZINE
Drug interactions
No significant interactions
Mechanism of action
Moricizine reduces the maximal
upstroke of phase 0 and shortens
the cardiac transmembrane action
potential.
The phenomenon may explain
the efficacy of moricizine in
suppressing rapid ecotopic
activity.
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They shorten Phase 3 repolarization
↓ the duration of the cardiac action potential
Prolong phase 4
IBLidocaine Mexiletine Phenytoin
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the duration of action potential decreases
LIDOCAINE
It shorten phase 3 repolarization and decreases the
duration of action potential
• Drowsiness
• Slurred speech
• Confusion and convulsions
• VA
• Digitalis toxicity
A/E Uses
Mechanism of action
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C/I
Lidocaine is contraindicated
in the presence of second and
third degree heart block, since it
may increase the degree of block
and can abolish the
idioventricular Pacemaker
responsible for maintaining the
cardiac rhythm.
• Proponolol increases its
toxicity.
• The myocardial depressant
effect of lidocaine is enhanced
by phenytoin administration.
Drug interactions
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Phenytoin was originally introduced for the control of
convulsive disorders but now also been shown to be
effective in the treatment of cardiac arrythmias.
Anaesthesia
Open heart surgery
Digitalized induced and ventricular arrythmia in children
PHENYTOIN
Uses
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Respiratory arrest Severe bradycardia
Hypotension Severe heart failure
AF & AFI
Plasma phenytoin concentrations are increased in
the presence of chloramphenicol, disulfiram, and
isoniazid, since the later drugs inhibit the hepatic
metabolism of phenytoin
A/E C/I
Drug Interactions
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It is a local anaesthatic and an active antiarrythmic by the
oral route; chemically and pharmacologically similar to lidocaine.
It reduces automaticity in PF, both by decreasing phase 4 slow
and by increasing threshold voltage.
By reducing the rate of 0 phase depolarization in ischemic
PF it may convert one-way block to two-way block.
MEXELETINE
Mechanism of action
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Tremor
Hypotension
Bradycardia
• Cardiogenic shock
• Second or third-degree
heart block
• VA
• Congenital long
QT syndrome
• When mexiletine is administered with phenytoin
or rifampin, since these drugs stimulate the hepatic
metabolism of mexiletine, reducing its plasma
concentration.
A/E C/I
Uses Drug Interactions
Date:26-07-2 014 Pharmacology Slide no:43
markedly slow Phase 0 depolarization
slow conduction in the myocardial tissue
minor effects on the duration of action potential
and ERP
reduce automaticity by increasing threshold potential
rather than decreasing slope of Phase 4 depolarization.
flecainide
Encainide
Propafenone
moricizine
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Flecainide suppresses phase 0 upstroke in purkinje
and myocardial fibers.
This causes marked slowing of conduction in all cardiac
tissues, with a minor effect on the duration of the action
potential and refractoriness.
Automaticity is reduced by an increase in the threshold
potential rather than a decrease in the slope of phase
4 depolarization
FLECAINIDE & ENCAINIDE
Mechanism of action
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Proarrhythmogenic efffect on
patients with coronary artery
disease
Use- ventricular arrhythmia
A/E – torsades de point, visual
disturbances & headache
Digoxin toxicity
C/I- cardiogenic shock
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Structural similarities with
propranolol
C/I – Heart failure
A/E – proarrhythmogenic effect,
metallic taste & constipation
150-200mg at 8 hourly
Uses – VT & supra ventricular
arrhythmias.
PROPAFENONE
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Has all three subclass properties
Less proarrhythmogenic effect
Used in ventricular arrhythmias
200-400mg orally at 8hourly
MORICIZINE
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CLASS II DRUGS – PROPRANOLOL, METOPROLOL, ESMOLOL, ACEBUTOLOL
Depress phase 4 depolarization
depress automaticity
prolong AV conduction
↑ ERP
Prolong PR interval
HR
contractility
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Hypoglycemia(infants)Asthma
Branchospasm
Asthma
Bradycardia
Severe CHF
C/I
PROPANOLOL
Mechanism of action
Propanolol decreases the slope of
phase 4 depolarization and
other ectopic foci.
Prolong the ERP of A-V node.
Uses
AF
Digitalis-induced arrythmias
A/E
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Acebutolol is a cardioselective
β1-adrenoreceptor blocking agent
that also has some minor membrane
stabilizing effect on the action
potential.
Mechanism of action
Acebutolol reduces blood pressure in
patients with essential hypotension
primarily through its negative
ionotropic and chronotropic effects.
Acebutolol
A/EBradycardia
GI upset
C/ICardiogenic shockSevere bradycardia
Uses• VA• Angina pectoris
ACEBUTOLOL
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ESOMOLOL
Esomolol is a short-acting i.v administered β1-selective
adrenoreceptor blocking agent.
It doesn’t posses membrane-stabilizing activity.
A/E
Hypotension
Nausea
Headache
Dyspnea
Uses
Supraventricular
tachyarrythmias
C/I
Asthma
Sinus bradycardia
A-V block
Severe CHF
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USES
Sympathetically mediated arrhythmia Sinus tachycardia
Supraventricular arrhythmia – AF / PSVT Ventricular arrhythmia – QT
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• K+ channel blockers
• AP / ERP without affecting
phase 0 / 4
• Prolong QT & PR
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pharmacology
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Amiodarone Bretylium Sotalol
Amiodarone
Iodine – containing
Block K+ Na+ , Ca++
& β
HR & AV nodal
conduction
QT prolongatio
n
Uses =VF, VT & AF
Arrhythmic death in post MI LD-150mg
slow IVMD-
1mg/min for 6hrs
A/E – heart block,
pulmonary, hepatitis,
dermatitis, corneal
deposits & thyroidism
Interaction – digoxin, diltiazem
& quinidine
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Bretylium
Antihypertensive
Uses-VF & VT
A/E – postural hypotension
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Non cardioselective blocker Has both class II & class III
actions Oral dose 80mg twice daily Proarrhythmic effect C/I - hypokalaemia
Sotalol
Like – Amiodarone
Arrhythmic death in post MI
Uses =VF, VT & AF
A/E= fatigue,
Headache, chest pain
Drug interactionsDrug with inherent
QT-Interval prolonging activity may enhance the class 3 effects of sotalol.
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NEWER CLASS III
DronedaroneTedisamil
Vernakalant
Azimilide
Without iodine, short t1/2, AFOral 400mg twice daily
Na+ & K+, atrial ERP, AF
Block both rapid & slow k+ channel
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Mechanism
• Block L-type calcium channels.
• Rate of phase 4 in SA / AV node
• Slow conduction – prolong ERP
• Phase 0 upstroke
Class IVVerapamil Diltiazem
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Stronger action on heart than smooth muscle
Used in supraventricular arrhythmia
80-120mg three times a day
A/E – ankle oedema, constipation
C/I – AV block, LVF, hypotention & WPW
It digoxin toxicity
Mixed action Oral dose 30-90mg 6hourly
Verapamil
Diltiazem
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WHICH OTHER DRUGS……
Naturally occurring nucleoside
Adenosine receptors – open GP-K+ & inhibits nodal conduction
Used in Reentry circuit, PSVTs & SVT
Ultra short t1/2 (10-20 sec)
A/E – facial flushing, short breath, bronchospasm, metallic taste
Dipyridamole it’s action
3mg IV bolus
Adenosine
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Magnesium
Na+/K+ATPase, Na+, K+ & Ca++
VT, digitalis-induced & torsades de point
Normal – conduction, ERP & automaticity
Hypokalaemia – EAD & DAD
Potassium
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ARRHYTHMIAS ACUTE THERAPY CHRONIC THERAPY
FIRST CHOICE ALTERNATIVES FIRST CHOICE ALTERNATIVES
1 AF/AFL ESMOLOL VERAPAMILE DIGOXINPROPRANOLOL
2 PSVT ADENOSINE ESMOLOLDILTIZEM
VERAPAMIL
DIGOXINVERAPAMILE
PROPRANOLOL
PROPAFENONE
3 VT LIDOCAINECARDIOVERSION
PROCAINAMIDEMEXILETINE
AMIODARONE
AMIODARONEDOFETILIDE
MEXILETINEPROPRANOLOLPROPAFENONE
4 TORSADES DE POINT
PACING ISOPRENALINEMAGNESIUM
PROPRANOLOL PACING
5 VF ELECTRICAL DEFIBRILLATION
LIDOCAINEAMIODARONE
AMIODARONE PROCAINAMIDEDOFETILIDE
6 WPW CARDIOVERSION AMIODARONEPROPAFENONE
PROCAINAMIDE
AMIODARONEPROPRANOLOL
QUINIDINEPROPAFENONE
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Antiarrhythimcs QuinidineProcainamideDisopyramidePropafenoneAmiodarone
Antimicrobials QuinineMefloquineArtemisininSparfloxacin & gatifloxacin
Antihistaminics Terfenadine AstemizoleEbastine
Antidepressants Amitryptylline
Antipsychotics ThioridazineRisperidone
Prokinetics Cisapride
Drugs that prolong QT interval
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pharmacology
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REFERENCESPharmacology - IV edition , Pg.no:196-207
- Lippincotts
Illustrated reviews
Clinical pharmacology - IX edition , Pg.no:497-519
- P.N.Bennett
- M.J.Brown
Essentials of medical pharmacology – K .D. Tripathi Pg.no:508-520
Pharmacology – Rang/ dale
- fifth edition , Pg no:277-280
Modern pharmacology with clinical Applications.
- Sixth edition
- Charles R.Ciaig. Robert E. StitzelDate:26-07-2 014 pharmacology Slide no:66
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