This document discusses antiarrhythmic drugs used to treat irregular heart rhythms. It begins by defining different types of arrhythmias including bradyarrhythmias, tachyarrhythmias, and heart block. The causes of arrhythmias are then explained as enhanced automaticity, triggered activity, reentry, and fractionation of impulses. Common arrhythmia conditions seen clinically are also outlined. The document then discusses the Vaughan-Williams classification system for antiarrhythmic drugs and provides details on representative drugs from each class, including their mechanisms of action and uses.

1. Antiarrhythmic Drugs
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. Introduction
• Irregularity in Cardiac Rhythm
• Bradyarrhythmia: Failure of impulse generation
resulting in slow heart rates
• Heart Block: Results from failure of impulse to
propagate normally from atrium to ventricle –
usually defect in AV node or His-Purkinje system
• Tachyarrhythmias: Abnormally rapid heart
rhythms
– Common clinical condition
– Treated by Antiarrhythmic Drugs - Drugs used to
prevent or treat irregularities of Cardiac Rhythm

3. Causes of Arrhythmia
• Root causes: When the normal sequence of impulse
generation and propagation is perturbed

4. Arrhythmias –
pacemaker acticity
• Enhanced Automaticity: Pacemaker cells or
ordinary fibres
– Results due to patholgical increase in phase 4 slope -
accelerated pacemaker rate
– May result from current of Injury
– Physiology: ACh reduces such pacemaker rate – by
decreasing phase 4 and hyperpolarization
– Ventricular wall cells (WMCs) may also show such
pace maker activity – due to ischaemia

5. Triggered
Activity
• A normal AP interrupted/followed by a abnormal
depolarization (a triggering rhythm)
Delayed After Depolarization: Caused by Digoxin
toxicity, Myocardial Ischaemia or Adrenergic stress or
Heart failure – due to Ca++ overload
Early After Depolarization: Due to interruption in
phase 3 repolarization
Causes: Slow heart rate, Hypokalaemia and drugs prolonging
QT interval – quinidine, sotalol, procainamide etc. (block IK
channel)
Torsades de pointes: due to marked prolongation of
APD – polymorphic ventricular tachycardia – long QT
interval and frequent changing of QRS

6. Reentry
• One of the causes of the most arrhythmias
• Normally, impulses propagate in synchronized
manners
• But, here one impulse reenters and re-excites
areas of heart more than once – no need for new
impulse generation
• Re-entering of impulses may be
1. Anatomically defined reentry – Circus movement
type
2. Functionally defined reentry - Microentry circuit

7. Functionally defined reentry
Ventricular fibrilation
Atrial fibrillation

8. Anatomically defined reentry – Accessory
pathway (WPW syndrome)
Wolf-Parkinson-White Syndrome
AV nodal reentry, Atrial flutter and PSVT

9. Fractionation of Impulse
• Increased Vagal activity – Atrial ERP brief and
inhomogenous
• Premature impulses get conducted by fibres
having short ERP – then to the fibres with
longer ERP and so on
• Asynchronous activation of atrial fibres –
inhomogenicity – Atrial fibrilation etc.

10. Arrhythmia Conditions - Clinically
• Extrasystole: premature beats due to abnormal automaticity/after
depolarization – AES, VES or AV nodal ES
• Paroxysmal Supraventricular Tachycardia (PSVT): Sudden onset of
atrial tachycardia 150-200/minute (1:1), reentry phenomenon (AV
node)
• Atrial Flutter: 200-350/minute (2:1 to 4:1 AV block), reentrant
circuit in right atrium
• Atrial Fibrillation: Asynchronous activation of atrial fibres 350-
550/min with irregular 100 to 160 ventricular beats – due to
electrophysiological inhomogenicity of atrial muscles (bag of
worms)
• Ventricular tachycardia: 4 or more consecutive extrasystole of
ventricles – monomorphic or polymorphic
• Ventricular Fibrillation: rapid irregular contractions – fatal (MI,
electrocution)
• Torsades de pointes: polymorphic ventricular tachycardia, rapid
asynchronous complexes, rise and fall in baseline of ECG
• Atrio-ventricular Block (A-V Block): vagal influence or ischaemia -
1st, 2nd and 3rd degree – slowed conduction, drop beat and no

11. Atria and Ventricular arrhythmia -
Animation
Ventricular arrhythmia Atrial arrhythmia

12. Vaugham-Williams
classification
• Class I – Na+ Channel Blockers
– 1a: quinidine, procainamide, disopyramide
– 1b: lignocaine, mexilitine, phenytoin, propafenone
– 1c: Propafenone, Flecainide, Encainide, Moricizine
• Class II – Beta-adrenergic Blockers - Propranolol,
Sotalol, Esmolol and Acebutalol
• Class III – K+ channel blockers: Amiodarone,
Ibutilide, Dofetilide, Sotalol (II + III action) and
bretylium
• Class IV – Ca++ channel blockers: Verapamil,
diltiazem and bepridil

13. Ionic Basis of Action Potential in Heart

14. Class I - antiarrhythmics
Class I antiarrhythmics: are further classified to
Ia, Ib and Ic – based on repolarization and potency of Na+
blockade – state dependant manner
Lidocaine
Phenytoin
Flecainide
Propafenone
Na+ blockade: Ic>1a>1b ERP: 1a>2c>1b

15. Subclass – I A - quinidine,
procainamide, disopyramide
• Binds to Na+ channels in open state and prevent conduction of
ions (Refractory – Rest – Open – Refractory) - Moderate sodium
channel blockade in open state
• Prolong refractoriness by blocking several types of potassium
channel
• Delayed Na channel recovery
• Delayed AV conduction
• Useful in conditions where Na+ channels open frequently –
ectopic beats - atrial tachycardia and atrial fibrillation and
ventricular arrhythmias
• Abolish reentry – unidirectional block to bidirectional block
• Electrophysiology changes: Lengthen action potential, slow rate
of rise of phase 0, Prolong repolarization ---------------- also prolong
AV node ERP - ECG changes: Prolong PR, QRS, QT

16. Subclass - IB
• Lowest potency for Na+ channel blocker -
inactivated state
• Do not delay channel recovery
• EP changes: Shorten action potential, Limited
effect on rate of rise of phase 0, Shorten
repolarization ------------- no ERP effect on AV
node (shorten)
• ECG: Shorten QT
• Used in Treatment and prevention of ventricular
tachycardia and fibrillation after Myocardial
Infarction – lignocaine IV , e.g, lignocaine,
mexilitine, phenytoin, propafenone

17. Subclass IC
• Propafenone, Flecainide, Encainide, Moricizine
• Marked Na+ channel blockade in open state – with longest recovery
time
• Refractory period of AV node is increased – marked delay in
conduction
• Electrophysiology changes: No effect on length of action potential,
Markedly reduces rate of rise of phase 0 and ---------- marked delay
in AV conduction with little effect on repolarization
• ECG: markedly prolong PR and QRS complex
• Prolong refractoriness by blocking outward-rectifying potassium
channels
• General reduction in excitability
• Used in life threatening ventricular fibrillation since they have
highest affinity to Na+ channels involving AV node - WPW syndrome
and Paroxysmal atrial fibrillation

18. Individual Drugs

19. Antiarrhythmic -
Quinidine
• Dextroisomer of Quinine: N+ channel blocking and antivagal
action
• Actions:
 Inhibition of Na channel – slanted O phase and Decreases phase 4
 Prolongation of APD – due to K+ channel block
 Increase in ERP – due to delay in Na+ and K+ channel recovery
 Net result is delay in conductivity and increase in refractoriness
 Fall in BP – direct cardiac depression
 Other actions include – alpha blockade, decreased skeletal muscle contractility,
uterine contractions, vomiting and diarrhoea etc.
 Kinetics: well absorbed orally, half life – 10 Hrs
 Uses:
 Broad spectrum antiarrhythmic
 Atrial fibrillation and flutter, prevention of PSVT and prevention of ventricular
tachycardia
 Adverse effects: Not used now for adverse effects like
Proarrhythmia (torsades de pointes), sudden cardiac arrest or VF,
cinchonism, angioedema, vascular collapse etc.
 Available as 200, 300 mg tabs. And 300 mg/ml Injections

20. Procainamide
• Procaine derivative (amide)
• Identical action with quinidine except:
– Minimal antivagal action
– Lesser suppression of ectopic automaticity
– Lesser depression of contractility and AV conduction
– No alpha blocking action
• Kinetics:
– Absorbed orally and bioavailability is 80%
– Metabolized in liver to N-acetyl-procainamide (NAPA) – blocks K
channel and prolongs repolarization
• Dosage – 250 mg tabs and 1gm/ml injections
– Antiarrhythmic – 0.5 to 1 gm oral followed by 0.25-0.50 mg
every 2 Hrs
• Uses: Mainly for monomorphic VTs and to prevent
recurrences
• ADRs: Hypersensitivity, flushing, hypertension, torsedes de
pointes and CNS symptoms – mental confusion,
hallucinations and weakness

21. Antiarrhythmic – Lidocaine
(Lignocaine)
• Popular antiarrhythmic and also local anaesthetic (membrane
stabilizing action)
• Lowest potency for Na+ channel inactivated state – ECTOPIC Foci
– Enhance phase – 4 depolarization in partially depolarized or stretched PF –
After depolarization antagonized – no effect on SAN
– Practically no action on Atrial fibres
– Rate of 0 phase in AVN and ventricles – not affected
– Reduction in APD in PF and ventricular myocardium
• Actions:
– Selective action on partially depolarized and cells with long APD – normal
ventricular and conducting fibres – not affected
– Suppression of automaticity in ectopic foci (reentry) – one way or two way
block
– Enhanced phase-4 depolarization in partially depolarized or stretched PF
(APD long)
– Little effects on cardiac contractility and arterial BP

22. Lidocaine – contd.
• Kinetics: Ineffective orally, given IV lasts for 10-20 minutes.
Therefore given as IV bolus 50-100 mg followed by 20-40 mg
every 10-20 minutes. Half-life prolonged in CHF (coz. Vd
decreases) and 70-80% metabolized by liver
• Adverse effects: Neurological – drowsiness, paresthesia,
blurred vision, nystagmus and fits etc.
– No proarrhythmic effects – no cardiotoxicity
• Uses: 50-100 mg bolus and 10-20 mg every 20 minutes
– 1st line of drug in Arrhythmia following acute MI and cardiac
surgery
– Prevention of ventricular tachycardia
– Digitalis toxicity – no AV block
• LA lignocaine Vs Antiarrhythmic lignocaine ?

23. Beta blockers
• Drugs used are beta-blockers: Propranolol, Sotalol, Esmolol
and Acebutlol
• Suppression of adrenergically mediated activity
• Propranolol - Membrane stabilizing effect like quinidine on
heart – high doses – clinical dose: cardiac adrenergic
blockade
• Clinical doses (antiarrhythmic effect) - Block beta-1
receptor in heart and decreases heart rate
1. Decrease in phase 4 depolarization and automaticity in SA
node, AVN, PF and other ectopic foci (Adrenaline causes
ventricular ES and fibrilation by increasing the phase 4
depolarization !!!)
2. Prolongation of ERP of AVN – impede AV conduction

24. Uses of Propranolol
• Arrhythmias associated with increased sympathetic
activity – sinus tachycardia, atrial extrasystoles
provoked by emotion and exercise
• Less effective in PSVT than adenosine and verapamil
• Propranolol is used to treat sympathetically mediated
arrhythmias - phaeochromocytoma and halothane
anaesthesia
– Sinus tachycardia, atrial and nodal extrasystole and nodal
extrasystole provoked by exercise
Does not abolish AF or Afl but decreases ventriculsar rate
• Reduce mortality after MI – anti-ischaemic action
• Esmolol IV – quickly terminates AF and fluttter and
used in emergency control of arrhythmia due to
anaesthetics

25. Class-III
Antiarrhythmics
• Class III drugs K channel blockers prolong
repolarization (increase refractoriness) by blocking
outward potassium conductance
– Prolongation of Cardiac action potential
– Increased ERP
• Drugs – Amiodarone Ibutilide, dofetilide,
sotalol (II + III action) and bretylium
• Bretylium is used only in life threatening
arrhythmias

26. Amiodarone
Long acting and highly lipophillic and Iodine containing
compound
MOA: - multiple actions
1. Blocking of delayed rectifier K+ channel – prolongs APD
2. Weak class I (lidocaine like) – depresses conducton in
partially depolarized and long APD
3. II (beta- blocker) – NC alpha and beta; and class IV actions
4. Also direct coronaray and peripheral vasodilator
• Overall – Slowed conduction and supressed automaticity
Kinetics: Incompletely and slowly absorbed – daily oral dose is
given for several days for actions to develop, t1/2 = 3-8
weeks
Dose: 400-600 mg/day p.o for many days followed by 100-200
mg/day as maintenance (100-300 mg slow IV)

27. Amiodarone
Uses:
• Most tachyarrhythmic conditions – ventricular and supraventricular
• Recurrent VT and VF
• WPW syndrome
Adverse effects:
• Photosensitization – skin pigmentation
• Peripheral neuropathy – weak shoulder and pelvic muscles
• Myocardial depression – bradycardia
• Pulmonary alveolitis and fibrosis – kept below 200 mg
• Corneal micro deposits – on long term use
• Hypothyroidism, goitre – inhibition of T4 to T3
Drug Interactions: Digoxin and warfarin (reduced renal clearance)

28. Class IV -
Antiarrhythmics
• Three important classes:
– Phenylalkylamines – hydrophillic Verapamil
– Dihydropyridines – lipophilic Nifedepine
– Benzothiazepines – hydrophilic Diltiazem
• Verapamil and diltiazem: are useful in
Arrhythmia
• Relatively selective AV nodal L-type calcium
channel blockers – depression of Ca++ mediated
depolarization and delay recovery
– Slows SA node automaticity
– reduced phase 4 depolarization in SAN and PF –
extinction of latent pacemakers and DAD
– Prolongation of AVN ERP – reentry terminated
– Negative ionotropic action

29. Class IV – contd.
• Uses: Verapamil
1. PSVT:
• For termination of attack – 5 mg IV over 2-3 minutes
(reflex bradycardia)
• For prevention of attack 60-120 mg orally tds
2. Reduce ventricular rate in Atrial fibrillation (AF)
and Atrial flutter – with digitalis

30. Miscellaneous Agents
Adenosine:
• Endogenously produced important chemical mediator used in
PSVT
• MOA:
– Activation of ACh sensitive K+ channel - membrane hyperpolarization
of SA node (G-protein coupled adenosine receptor A1)
– depression of SA node and also slowing of AV conduction
– shortening of action potential in atrium and reduced excitability
– Also indirectly reduces Ca++ current in AV node – depression of
reentry in PSVT

31. Adenosine – contd.
• Very short half life – 20-30 sec. - Uptake by RBCs
and endothelial cells (5-AMP and inosine)
• Administered intravenously – available as free
base or ATP
– 6 - 12 mg/ATP 10 - 20 mg given as a rapid intravenous
bolus (administered over a 1-2 second period)
– If the first dose does not result in elimination of the
supraventricular tachycardia within 1-2 minutes - 12
mg should be given as a rapid intravenous bolus
• ADR: chest tightness, dyspnoea, fall in BP and
flushing etc.

32. When Antiarrhythmics ?
• Asymptomatic and those which do not interfere
haemodynamics – AES, VES, 1st degree block and
bundle branch block – no need of treatment
• Therapy needed:
– Life threatening VT, TdP and VF
– Causing breathlessness, hypotension and cardiac
failure
– Marked palpitation – PSVT, VT, AF and TdP
– Myocardial infarction

33. Non-pharmacological treatment
• Acute
– Vagal manoeuvres
– DC cardioversion
• Prophylaxis
– Radiofrequency ablation
– Implantable defibrillator
• Pacing (external, temporary, permanent)

34. The Pacemaker
• Surgical implantation of electrical
leads attached to a pulse generator
1) Leads via subclavian vein and
advanced to the chambers on the
vena cava (right) side of the heart
2) 2 leads - right atrium, and right
ventricle
3) Pulse generator containing
microcircuitry and battery are
attached to leads and placed into a
“pocket” under the skin near the
clavicle
4) Pulse generator sends signal - to
contract atria, then ventricles
• Pulse generator - sense electrical
activity - only deliver electrical
impulses when needed.
• Pacemakers : can only speed up a
heart experiencing bradycardia,
cannot alter a condition of
tachycardia

35. Expected Questions ??
• Classification of anttiarrhythmic drugs
• Lidocaine as antiarrhythmic agent
• Amiodarone as antiarrhythmic agent
• Role of Beta blockers (Propranolol) and Ca++
channel blockers (Verapamil) in Arrhythmia
• Short Note: Adenosine