Scope: This subject is intended to impart the fundamental knowledge on various aspects (classification, mechanism of action, therapeutic effects, clinical uses, side effects and contraindications) of drugs acting on different systems of body and in addition,emphasis on the basic concepts of bioassay. Objectives: Upon completion of this course the student should be able to 1. Understand the mechanism of drug action and its relevance in the treatment of different diseases 2. Demonstrate isolation of different organs/tissues from the laboratory animals by simulated experiments 3. Demonstrate the various receptor actions using isolated tissue preparation

1. Course: Pharmacology II
Unit 1: Pharmacology of Drugs Acting on
Cardiovascular System
Topic: Anti- Arrhythmic Drugs
CO - 503T.1: Explain pharmacology of the drugs acting on
various Cardiac complications
BY
Mr. Bhagwat H. Garje (M.Pharm).
Asst. Professor
Department of Pharmacology
SCOPER, Kopergaon
Date: 25/07/2022
Lecture No.:

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 --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)

6. Re-entry
• 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. Atria and Ventricular arrhythmia - Animation
Ventricular arrhythmia Atrial arrhythmia

10. 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 nifedipine

11. 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 Flecainide
Phenytoin Propafenone
Na+ blockade: Ic>1a>1b ERP: 1a>2c>1b

12. 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

13. 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

14. 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

15. Individual Drugs

16. 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,

17. ▪ 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

18. 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

19. 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

20. Lidocaine – cont.…
• 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 ?

21. 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

22. 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

23. 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

24. 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)

25. 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)

26. 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

27. Class IV – cont...
• 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

28. 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

29. Adenosine – cont...
• 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.

30. 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

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

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