Anti arrhythmic drugs

1. Anti Arrhythmic Drugs

2. What is an Arrhythmia ?
 Irregular rhythm
 Abnormal Rate
 Conduction abnormality

3. What causes an arrhythmia?
 Changes in automaticity of the pacemaker
 Ectopic foci causing abnormal APs
 Reentry tachycardias
 Block of conduction pathways
 Abnormal conduction pathways (WPW)
 Electrolyte disturbances & Drugs
 Hypoxic/ Ischemic tissue can undergo spontaneous
depolarization & become an ectopic pacemaker

4. Important cardiac arrhythmias
 Extra systoles
 PSVT
 Atrial flutter
 Atrial fibrillation
 Ventricular tachycardia
 Torsade's de pointes
 Ventricular fibrillation
 AV block

5. Normal Sinus Rhythm
 Heart rhythm is determined by
SA node = Cardiac Pacemaker
 Called Sinus Rhythm
 Specialised pacemaker cells
spontaneously generate APs
 APs spread through the
conducting pathways
 Normal sinus rate 60-100
beats/min

6. Conducting System
 SAN AP triggers atrial
depolarisation
 AVN  Only pathway for AP to
enter ventricles
 Conducts slowly: Complete
atrial systole appear before
ventricular systole
 Conducts rapidly  through
Bundles of His & Purkinje 
Ventricular depolarization &
contraction

7. Conducting System
 Permits rapid organized
depolarization of ventricular
myocytes
 Necessary for the efficient
generation of pressure during
systole
 Atrial activation complete 0.09s
after SAN firing
 Delay at AVN
 Septum activated 0.16s
 Whole ventricle activated by
0.23s

8. Cardiac Action Potential
Phase 4: RMP
 AP depolarizes cells to
threshold -70mV
Phase 0: Rapid depolarization
 Caused by a transient opening
of fast Na channels
 Increases inward directed
depolarizing Na+ currents
 Generate "fast-response" APs

9. Cardiac Action Potential
Phase 1: Initial repolarization
 Open K channel: transient
outward hyperpolarizing K+
current
 Large increase in slow inward
gCa++ occurs at the same
time
 L-type CaCh open
 Repolarization delayed
Phase 2: Plateau phase
 Plateau phase prolongs AP
duration vs APs in nerves &
skeletal muscle

10. Cardiac Action Potential
Phase 3: Repolarization
 K channels open
 Inactivation of Ca++
channels
 Action potential in non-
pacemaker cells is primarily
determined by relative
changes in fast Na+, slow
Ca++ and K+ conductances
and currents

11. Refractory Periods
 Once an AP is initiated, there is a
period (phase 0,1,2, part 3) that a
new AP cannot be initiated.
 Effective or Absolute refractory
period (ERP or ARP)
 Stimulation of cell by adjacent cell
depolarizing does not produce
new propagated APs
 Prevents compounded APs from
occurring & limits frequency of
depolarization and HR

12. Regulation of Cardiac APs
SNS - Increased with concurrent
inhibition vagal tone:
 NA binds to B1 Rec
 Increases cAMP
 Increases Ca & Na in
 Decreases K out
 Increases slope phase 0
Non-Nodal tissue:
 More rapid depolarization
 More forceful contraction
 Pacemaker current enhanced
 Increase slope phase 4
 Pacemaker potential more rapidly
reaches threshold
 Rate increased

13. Regulation of Cardiac APs
PSNS (Vagal N)
 Ach binds M2 rec
 Increases gK+
 Decreases inward Ca & Na
Non-Nodal tissue:
 More rapid depolarization
 More forceful contraction
 Pacemaker current suppressed
 Decreases pacemaker rate
 Decrease slope of Phase 4
 Hyperpolarizes in Phase 4
 Longer time to reach threshold
voltage

14. Atrial Fibrillation & Flutter
• Normally, the top chambers (atria) contract & push blood into
the bottom chambers (ventricles).
• In atrial fibrillation  the atria beat irregularly.
• In atrial flutter  the atria beat regularly, but faster than usual &
more often than the ventricles  so, you may have 4 atrial beats
to every 1 ventricular beat.

15. Atrial Fibrillation & Flutter
• Atrial flutter is less common than atrial fibrillation
• Atrial flutter is less common, but has similar symptoms (feeling
faint, tiredness, palpitations, shortness of breath or dizziness).
• Some people have mild symptoms, others have none at all.

16. Torsade's de pointes (TdP)
 French for “twisting of the points” is one of several types of life-
threatening heart rhythm disturbances.
 In the case of TdP  the heart's 2 lower chambers (ventricles) beat
faster than the upper chambers (atria)
 TdP is associated with a prolonged QT interval which may be
congenital or acquired.
 Torsade usually terminates spontaneously but frequently recurs &
may degenerate into ventricular fibrillation.

17.  70% of acute MI, 50% of those given GA  irregularity
in cardiac rhythm
 Ventricular fibrillation (VF)  sudden cardiac death
 Currently focus on usage of electrical devices
 Drugs - treatment of AF & prevention of VF
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7 October 2021
In General

18. Rationale for Antiarrhythmic Drugs
 Restore normal rhythm, rate & conduction or prevent more
dangerous arrhythmias
 Alter conduction velocity (SAN or AVN)
 Alter slope 0 depolarization
 Alter excitability of cardiac cells by changing duration of ERP
 ERP  Interrupts tachy caused by reentry
 Suppress abnormal automaticity

19. 19
Vaughan William & Singh Classification
Classes 1, 2, 3, 4 – 1970’s
Sub classified by Harrison for clinical utility
7 October 2021
DR. BRAMAH N SINGH
DR. VAUGHAN WILLIAM

20. Vaughan Williams & Singh Classification
I
• Membrane stabilizing agents (Na+ channel blockers)
• Ia-Quinidine, Procainamide, Disopyramide
• Ib- Lidocaine, Mexiletine, Phenytoin, Tocainide
• Ic- Propafenone, Flecainide, Encainide
II
• β blockers
• Propranolol, Esmolol, Sotalol
III
• Agents widening Action Potential (K+ channel blockers)
• Amiodarone, Dronedarone, Dofetilide, Ibutilide,
Bretylium
IV
• Ca2+ channel blockers
• Verapamil, Diltiazem
20
7 October 2021

21. Class Ia similar to Class III
Propranolol (of class II) has also class I action
Sotalol & Bretylium has both class II & class III actions
NOTE:
Drugs for Paroxysmal Supraventricular Tachycardia (PSVT)
Adenosine
Digoxin
Others
Atropine
MgSo4

22. Phases of AP

23. Phases of AP

24. Re-entry
In normal tissue, if a single Purkinje fibre forms two
branches (1 & 2), the AP will travel down each
branch.
An electrode (*) in a side branch off of branch 1
would record single, normal AP as they are
conducted down branch 1 and & into the side
branch.
If branches 1 & 2 are connected together by a
common, connecting pathway (branch 3), the AP
that travel into branch 3 will cancel each other out.

25. PURKINJE JUNCTION
Reentry can occur if branch 2, for e.g., has a
unidirectional block.
In such a block, impulses can travel retrograde
(from branch 3 into branch 2).
When this condition exists, an AP will travel down
the branch 1, into branch 3, and then travel
retrograde through the unidirectional block in
branch 2 (blue line).
Within the block (gray area), the conduction
velocity is reduced because of depolarization.
When the AP exits the block, if it finds the tissue
excitable, then the AP will continue by travelling
down (i.e., reenter) the branch 1.
If the AP exits the block in branch 2 & finds the
tissue unexcitable, then the AP will die.

26. Principles in Treatment of Arrhythmias
• Do not treat all arrhythmias
• Treatment with antiarrhythmics needed if
– Uncomfortable palpitations
– Risk to life
– Causing hypotension, breathlessness, cardiac failure
– Can progress to more serious arrhythmias
Restore to sinus rhythm, control ventricular
rate, or change to a more desirable pattern
of electrical/ mechanical activity

27. Phases of AP
Reduce rate of
Phase 0
depolarization
Decrease slope
of phase 4
Widens APD or
ERP increased
Shorten action
potential and
reduce
automaticity

28. Class -I Drugs
Class IA – Quinidine, Procainamide, Disopyramide &
Class IC – Propafenone, Flecainide
 Block Na+ channel in open state
 Delay AV conduction
 Delay recovery of channel
Class IB – Lignocaine, Mexiletine
 Block Na+ channels in inactivated state
 No effect on AV conduction or recovery
Although similar, class IC actions more potent than IA

29. Quinidine- D- isomer of quinine
 Na block  Reduce automaticity
 K block  Prolong refractoriness
 Alpha block  Hypotension
 Antivagal action

30. Quinidine- D- isomer of quinine
ADR
Torsade de pointes,
 VF,
Angioedema,
 Thrombocytopenia,
Cinchonism: ringing in ears, deafness, vertigo, visual disturbances

31. Quinidine- D- isomer of quinine
Interactions:
Increase digoxin levels,
 Torsade de points in Hypokalemia,
Cardiac depression with Beta blockers.
Uses:
Maintain sinus rhythm after control of AF or Afl,
Rarely in ventricular arrhythmias  Not preferred due to ADRs
Dose: 100 – 200 mg TDS

32. Procainamide
 Similar to quinidine, except that
 Less effective for ectopics
 Less depression of AV conduction
 Less antivagal action; No Alpha blocking action
Metabolism: Acetylation  metabolite is K blocker & prolong
repolarization.
Fast and slow acetylators based on metabolism

33. Procainamide
ADR
GI disturbance
Confusion
Flushing
Hypotension
Torsades de pointes
Hypersensitivity
SLE (in slow acetylators)
Uses: Monomorphic VT, WPW VT (Not suitable for long term treatment)
Dose: 0.5 to 1 gram oral or im

34. Disopyramide
 Similar to quinidine, except that
 No alpha blocking action
 Prominent anti cholinergic action
 Negative inotropic effect on ventricle
ADR
Dry mouth
Constipation
 Urinary retention
 Decrease cardiac output

35. Disopyramide
Uses:
Prevention of Ventricular Arrhythmias
Maintenance after cardioversion for AF & AFl
C/I  Sick sinus, Cardiac failure, Prostate hypertrophy
Dose: 100 – 150 mg QID or TDS.

36. Propafenone
Potent Na channel blocker also block beta receptors
ADR  Nausea, vomiting, bitter taste, constipation, blurred
vision
Caution  Can precipitate CHF & Bronchospasm
Uses Reserve drug for ventricular arrhythmia, re-entry
tachycardia, to maintain sinus rhythm in AF
Dose: 150 mg BD to 300 mg TDS

37. Flecainide
Potent Na channel blocker  More proarrhythmic
Caution  CAST study showed increase mortality in MI patients
Uses Resistant recurrent AF, WPW without CHF
Moricizine  Withdrawn from market

38. Proarrhythmic Drugs
 Class I C
Propafenone
 Beta blocker
Sotalol
 Class III antiarrhythmic drugs
Amiodarone
Dronedarone
Dofetilide
Ibutilide

39. Lignocaine/ Lidocaine
 Na block in inactive state  reduce automaticity in ectopics
 No effect on atria; do not affect SA node
 Suppress re-entrant ventricular arrhythmia
 Orally Inactive – parenteral action lasts 10 – 20 min

40. Lignocaine/ Lidocaine
ADR  Paresthesia, twitching, fits, disorientation, drowsiness
Interactions Propranolol reduce hepatic blood flow & prolong
duration of action
Uses  Ventricular tachyarrhythmias following MI, surgery, digitalis
toxicity
Dose  50 – 100 mg bolus iv followed by 1 – 3 mg/ min infusion

41. Mexiletine
 Also local anesthetic
 Active orally as antiarrhythmic.
 Activity similar to ligoncaine
ADR  Bradycardia, hypotension, AV block, tremor, neurological
symptoms
Uses  Ventricular tachyarrhythmias following MI; orally used to
suppress VT for long term

42. Propranolol
 Suppress adrenergically mediated ectopic activity
 Direct membrane stabilizing action at high dose only
 Reduce automaticity  if it is high due to adrenergic effect
Uses: Sinus tachycardia, Atrial or Nodal Extra Systoles, PSVT,
Arrhythmias due to Pheochromocytoma, Halothane anesthesia
Caution: Can cause bradycardia in WPW

43. Sotalol
 Beta blocker with K channel blocking action (Class III action too)
 Prolong ERP, delay AV conduction
 Suppress adrenergically mediated ectopic activity
 Direct membrane stabilizing action at high dose only
 Reduce automaticity  if it is high due to adrenergic effect
Uses: Polymorphic VT & for maintaining sinus rhythm in AF/ AFl
Caution: Risk of Torsade De Pointes; C/I – Patients with long QT interval

44. Esmolol
Short acting Beta blocker given as i.v.
Uses:
Supraventricular tachycardia
Anesthesia associated arrhythmias

45. Amiodarone
 Blocks  inactive Na channel, delayed rectifier K channel,
myocardial Ca channels & beta receptors
 Reduce ectopic automaticity
 Very long duration of action: 3- 8 weeks half life

46. Amiodarone
ADR
GIT symptoms
Photosensitization
Pigmentation
Corneal microdeposits
Pulmonary alveolitis & fibrosis
Peripheral neuropathy
Hypothyroidism & Hyperthroidism

47. Amiodarone
Interactions: Increase digoxin & warfarin levels.
AV block with beta blockers
Uses: Ventricular & supraventricular arrhythmias, VT and VF

48. Dofetilide, Ibutilide
 Newer anti-arrhythmic drugs (Pure Class III drugs)
 Block delayed rectifier K channels  prolong APD & ERP
Uses: Maintain sinus rhythm post conversion from AF or AFl
Bretylium
 K channel block; adrenergic neurone blocker
 Rarely used for reversal of VF

49. Verapamil & Diltiazem
 Block L type calcium channel and delay their recovery
 Suppress automaticity
 Prolong AV node ERP Suppress re-entry based on AV node
 Poor efficacy in ventricular arrhythmias

50. Verapamil & Diltiazem
Uses: PSVT without hypotension or CHF, AF or Afl to control
ventricular rate.
Caution:
 Avoid in re-entry arrhythmia.
 Avoid in patients with heart block, with digitalis toxicity and VT

51. Adenosine
 SA node, AV node and atria  A1 adenosine receptor (GPCR)
 Activation of A1 - membrane hyperpolarization by Ach sensitive K
channels
 Bradycardia, slowing of conduction, reduced excitability
 Depress re-entry circuit; Transient coronary dilatation
 Very short acting (10 sec). Uptake by RBC and endothelial cells
 Dipyridamole inhibits uptake & Theophylline antagonize A1 R

52. Adenosine
Uses: PSVT, coronary dilatation in procedures, controlled
hypotension in surgery
ADR: Dyspnea, chest pain, hypotension, flushing, bronchospasm
Dose: Adenosine base 6 – 12 mg; ATP 10 – 20 mg