ARRHYTHMIA & ANTIARRHYTHMIC DRUGS

Presented by

S.Lakshmi Sravanthi11AB1R0051

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

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

ELECTROPHYSIOLOGY – CARDIAC RHYTHM

Conducting tissue

• SA node,AV node,bundle of his & purkije fibers.

Contractile tissue

• Atria and ventricles.

IMPULSE GENERATION AND CONDUCTION

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

Action Potential

Phase 0

Phase 4

Phase 3

Phase 2

Phase 1

- 90 mV

0 mV

30 mV

Non nodal tissues

0 1 2 3 4

• Effective refractory period

• Absolute refractory period

• Relative refractory period

1

0

2

3

4

ARP RRP

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

ECG showing wave

segments

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

ARRHYTHMIA

Abnormal impulse generation

Triggered activity

Abnormal impulse conduction

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

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

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

Conduction block

Reentry phenomenon

Accessory tract pathway

Abnormal impulse conduction

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

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

ACCESSORY TRACT PATHWAY Accessory

pathway in the heart called

Bundle of Kent

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

ATRIAL FIBRILLATION

o 350-550/min

o Due to electrophysiological inhomogenesity

of atrial fibers.

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.

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

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

VAUGHAN-WILLIAMS CLASSIFICATION

CLASS MECHANISM

I Na+ channel blocker

II β blocker

III K+ channel blocker

IV Ca++ channel blocker

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

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

IAQuinidin

eProcaina

mideDisopyra

mideMoricizin

e

Slowing the rate of rise in phase 0

They prolong action potential & ERP

↓ the slope of Phase 4 spontaneous depolarization

↑ QRS & QT interval

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

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

• 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

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

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

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

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

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.

They shorten Phase 3 repolarization

↓ the duration of the cardiac action potential

Prolong phase 4

IB

Lidocaine Mexiletine Phenytoin

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

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

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

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

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

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

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.

IC

flecainide Encainide Propafenone moricizine

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

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

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

Has all three subclass properties

Less proarrhythmogenic effect

Used in ventricular arrhythmias

200-400mg orally at 8hourly

MORICIZINE

CLASS II DRUGS – PROPRANOLOL, METOPROLOL, ESMOLOL, ACEBUTOLOL

Depress phase 4 depolarization

depress automaticity

prolong AV conduction

↑ ERP

Prolong PR interval

HR

contractility

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

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/E

Bradycardia

GI upset

C/I

Cardiogenic shock

Severe bradycardia

Uses• VA• Angina pectoris

ACEBUTOLOL

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

USESSympathetically

mediated arrhythmia Sinus tachycardia

Supraventricular arrhythmia – AF /

PSVT

Ventricular arrhythmia – QT

WPW

• K+ channel blockers

• AP / ERP without affecting

phase 0 / 4

• Prolong QT & PR

Class III

Amiodarone Bretylium Sotalol

Amiodarone

Iodine – containing

Block K+ Na+ , Ca++ & β

HR & AV nodal

conductionQT prolongation

Uses =VF, VT & AF

Arrhythmic death in post MI

LD-150mg slow IV

MD-1mg/min for 6hrs

A/E – heart block, pulmonary,

hepatitis, dermatitis, corneal deposits &

thyroidism

Interaction – digoxin,

diltiazem & quinidine

Bretylium

Antihypertensive

Uses-VF & VT A/E – postural hypotension

C/I – digitalis induced, shock

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.

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

Mechanism

• Block L-type calcium channels.

• Rate of phase 4 in SA / AV node

• Slow conduction – prolong ERP

• Phase 0 upstroke

Class IV

Verapamil Diltiazem

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

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

Magnesium

Na+/K+ATPase, Na+, K+ & Ca++

VT, digitalis-induced & torsades de point

Normal – conduction, ERP & automaticity

Hypokalaemia – EAD & DAD

Potassium

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

Antiarrhythimcs QuinidineProcainamideDisopyramidePropafenoneAmiodarone

Antimicrobials QuinineMefloquineArtemisininSparfloxacin & gatifloxacin

Antihistaminics Terfenadine AstemizoleEbastine

Antidepressants Amitryptylline

Antipsychotics ThioridazineRisperidone

Prokinetics Cisapride

Drugs that prolong QT interval

REFERENCES

o Lippincotts,Pharmacology-IV Edition,Pg.no:196-207

o P.N.Bennet,M.J.Brown,Clinical Pharmacology-IX Edition,Pg no:497-519

o K .D. Tripathi,Essentials Of Medical Pharmacology, Pg.no:508-520

oRang/ dale,Pharmacology, V Edition , Pg no:277-280

o Charles R.Ciaig,Robert E. Stitzel,Modern Pharmacology With Clinical

Applications

I thank principal sir Dr. P. Srinivasa Babu for giving me this opportunity.

I Also thankful to my guide Mrs.B.DEEPTI M.Pharm(Ph.D)

for her constant guidance.

ACKNOWLEDGEMENT