A Power point presentation on "Antiarrhythmic drugs" suitable for UG MBBS level students

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