1. ANTI ARRHYTHMIC
DRUG THERAPY

2. Contents
• Electrophysiology of Heart
• Arrhythmia: Definition, Types,
Mechanisms
• Antiarrhythmic drugs: Class I, II , III ,
IV
• Treatment of arrhythmia : Guidelines

3. Introduction
Electrophysiology of Heart

4. Normal conduction pathway
SA node
Generates action
potential
AV node
Delivers the
impulse to purkinje
fibers
Purkinje fibers
Conduct the
impulse to the
ventricles

5. NormaIml cpounlsdeu ccotniodnu cptaiotnhway
SAN
AVN
 Impulses originate
regularly at a
frequency of
60-100 beat/ min

6. Cardiac Action Potential
 Divided into five phases (0,1,2,3,4)
 Phase 4 - Resting phase (resting membrane potential)
 Associated with diastole portion of heart cycle
 Addition of current into cardiac muscle (stimulation)
causes
 Phase 0 –Opening of fast Na channels
 Drives Na+ into cell, changing membrane potential
 Transient outward current due to movement of Cl-and
K+
 Phase 1 – Initial rapid repolarization
 Closure of the fast Na+ channels
Phase 0 and 1 together correspond to the R and S
Keating MT, Sanguinetti MC: Molecular & Cellular Mechanisms of cardiac arrhythmia. Cell
2001;104;569

7. Cardiac Action Potential (contd)
 Phase 2 - Plateau phase
 Sustained by the balance between the inward
movement of Ca+ and outward movement of K +
 Long duration compared to other nerve and muscle
tissue
 Corresponds to ST segment of the ECG
 Phase 3 – Repolarization
 K+ channels remain open,
 Outward K+ movement, repolarization of cell
 Closure of K + channels when membrane potential
reaches certain level
 Corresponds to T wave on the ECG

8. mv 20
Cardiac Action
0
-20
-40
-60
-80
-100
Phase 1
(Plateau Phase)
Phase 0
Phase 2
Phase 3
Phase 4
Na+
Na+ ca++
ATPase
Potential
Resting
membrane
Potential
Na+
Na+
NNaa++
m
Na+
h
K+
ca++
K+K
K++
ccaa++++
KK+K++ Na+
K+
Depolarization

9. mv 20
Cardiac Action
0
-20
-40
-60
-80
-100
Phase 1
(Plateau Phase)
Phase 0
Phase 2
Phase 3
Phase 4
Na+
Na+ ca++
ATPase
Potential
R.M.P
Na+
Na+
NNaa++
m
Na+
h
K+
ca++
K+K
K++
ccaa++++
KK+K++ Na+
K+
Depolarization
AP curve in
pacemaker Cells

10. Effective refractory period
(ERP)
 Also called Absolute Refractory Period (ARP)
 Period in which cells can’t be excited
 Takes place between phase 0 and 3
Duan D et al; Functtional role of ion channels in cardiac disease; Acta Pharmacol Sin 2005; 26;265

11. Arrhythmias
 Variation in either the site or rate of cardiac
impulse formation, and/or a variation in the
sequence of cardiac impulse propagation
 Causes:
 Arteriosclerosis
Coronary artery Spasm
Heart block
Myocardial ischemia
Hume RJ, Grant AO, Cardiac arrhythimia ; Katzung Basic & clinical pharmacology, Lange Medical
Publishers,12th ed,2012,pg227-250

12. Normal heartbeat & Arrhythmia
Normal
rhythm
Arrhythmia
AV septum

13. Mechanisms of
Arrhythmogenesis
1- Abnormal Impulse Generation
Automatic
rhythms
Triggered
rhythms
Enhanced
normal
automaticity
Ectopic focus
Delayed after
daepolarization
Early after
depolarization
↑AP from
SA node
AP arises from
sites other
than SA node

14. Mechanisms of
Arrhythmogenesis
2-Abnormal
conduction
Conduction
block
Reentry
1st degree 2nd
degree
3rd degree
Circus
movemen
t
Reflectio
n
When impulse is
not conducted
from the atria to
the ventricles

15. Mechanisms of
Arrhythmogenesis
 Mechanisms of bradycardias:
 Sinus bradycardia: D/t abnormally slow
automaticity
 Bradycardia due to AV block: Abnormal
conduction within the AV node or the distal AV
conduction system
 Mechanisms of tachycardias :
 - Accelerated automaticity.
 - Triggered activity
 - Re-entry (or circus movements)

16. Mechanisms of
Arrhythmogenesis
 ACCELERATED AUYOMATICITY
 D/t increase in rate of diastolic depolarization or
changing threshold potential
 Can occur in virtually all cardiac tissues and
may initiate arrhythmias
 Thought to produce sinus tachycardia, escape
rhythms and accelerated AV nodal (junctional)
rhythms

17. Mechanisms of
Arrhythmogenesis
 TRIGGERED ACTIVITY
 Myocardial damage → oscillations of
transmembrane potential → 'after
depolarizations’ → threshold potential →
Arrhythmia
 Can be exaggerated by pacing, catecholamines,
electrolyte disturbances, and some medications
 Examples : Digoxin toxicity → causes
 Atrial tachycardias
Ventricular arrhythmia in the long QT syndrome

18. Mechanisms of
Arrhythmogenesis
 RE-ENTRY (OR CIRCUS MOVEMENT)
 Occurs when 'ring' of cardiac tissue surrounds
inexcitable core
 Tachycardia initiated if an ectopic beat finds one
limb refractory (α) resulting in unidirectional block
and the other limb excitable
 Circus movement will be maintained If:
Time to conduct around the ring > Recovery
times (refractory periods) of the tissue within
the ring
 Majority of regular paroxysmal tachycardias are
produced by this mechanism

19. Reentry Arrhythmias
Normal
Re-enterant
Tachycardia

20. Mechanisms of
Arrhythmogenesis
 ABNORMAL ANATOMIC CONDUCTION
Bundle of Kent
•Present only in small
populations
•Lead to reexcitation 
Wolf-Parkinson-White
Syndrome (WPW)

21. Types of Arrhythmia
 Sinus Tachycardia:
High sinus rate of 100-180 beats/min
Occurs during exercise or other conditions that
lead to increased SA nodal firing rate
 Atrial Tachycardia:
 Series of 3 or more consecutive atrial
premature beats occurring at a frequency
>100/min
 Paroxysmal Atrial Tachycardia (PAT):
Tachycardia which begins and ends in acute

22. Types of Arrhythmia
 Atrial Flutter:
Sinus rate of 250-350 beats/min.
 Atrial Fibrillation:
Uncoordinated atrial depolarizations.
 AV blocks
Conduction block within the AV node ,
occasionally in the bundle of His → impairs
impulse conduction from the atria to the
ventricles.

23. Types of Arrhythmia
 Ventricular Premature Beats (VPBs):
 Ectopic ventricular foci; characterized by
widened QRS.
 Ventricular Tachycardia (VT):
High ventricular rate caused by abnormal
ventricular automaticity or by intraventricular
reentry
Can be sustained or non-sustained
(paroxysmal);
Characterized by widened QRS; rates of 100

24. Types of Arrhythmia
 Ventricular Flutter:
Ventricular depolarizations >200/min.
 Ventricular Fibrillation:
Uncoordinated ventricular depolarizations

25. Management of Arrhythmia

26. Management of Arrhythmia
 Pharmacological therapy (Antiarrhythmic
Drugs)
 Cardioversion
 Pacemaker therapy
 Surgical therapy e.g. aneurysmal excision
 Interventional therapy “ablation”

27. Antiarrhythmic Drugs

28. Pharmacologic rationale & Goal
 The ultimate goal of antiarrhythmic drug
therapy:
 Restore normal sinus rhythm and conduction
 Prevent more serious and possibly lethal
arrhythmias from occurring.
 Antiarrhythmic drugs are used to:
 Decrease conduction velocity
 Change the duration of the effective refractory
period (ERP)
 Suppress abnormal automaticity Shrivatsa U, Wadhani M, Singh AB; Mechanisms of antiarrhythmic drug action & their clinical relevance for
controlling disorders of cardiac rhythm; Curr Cardiol Rep 2002;4;401

29. Classification of Antiarrhythmic
Drugs
Classified a/c to Vaughan William into four
Class clMaescsheansism Action Notes
I
Na+ channel
blocker
Change 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
Slowing the rate of rise in phase
↓conduction
velocity in SA and

30. Classification of Antiarrhythmic
Drugs

31. Classification of Anti-Arrhythmic
Phase 0
-
Phase 1
Phase 2
Phase 3
Phase 4
R.M.P
(Plateau Phase)
Class I:
Na + channel blockers.
-
-
- Pacemaker potential
-
Class III:
K + channel blockers
Class IV:
Ca ++ channel blockers
Class II:
Beta blockers
Drugs

32. Treatment of tachyarrhythmias:
 Class I drugs (Membrane stabilizing drugs) :
Mechanism:
Class I drugs block fast Na+ channels, thereby
Reducing the rate of phase 0
depolarization
Prolonging the effective refractory period
Increasing the threshold of excitability
Reducing phase 4 depolarization
These drugs also have local anesthetic
properties
Woosely RL. Antiarrhythmic drugs. Hurst’s The Heart (Ed. Fuster V, Alexander RW, O’Rourke RA,
et al.) 10th edition.2001;1:899–924

33. Class IA
1. Quinidine
 Alkaloid – cinchona , dextro isomer of quinine.
 Blocks sodium channel & potassium channel
also
 Anti-muscarinic and Alpha blocking action
 Administered orally & is rapidly absorbed from
gastrointestinal tract
 Hydroxylated in the liver
 t1/2 of approximately 5—12 hours, longer in
hepatic or renal disease & in heart failure
 Bitter and irritant
 Inhibitor of CYP P450 system.

34. 1. Quinidine
 ↑↑ plasma conc of digoxin by displacing it from
tissue binding sites & decreasing its renal &
biliary clearance.
 Uses:
 Atrial fibrillation
Ventricular tachycardia
 Adverse effects :
GIT : Diarrhea, nausea, vomiting and
cinchonism
Thrombocytopenia
 Precipitate torsade de pointes by prolonging

35. 1. Quinidine
 Drug interactions
 Increases digoxin plasma levels &risk of
digitalis toxicity
 t1/2 reduced by agents that induce drug-metabolizing
enzymes (phenobarbital,
phenytoin)
May enhance the activity of coumarin
anticoagulants & other drugs metabolized by
hepatic microsomal enzymes
Cardiotoxic effects exacerbated by
hyperkalemia

36. 2. Procainamide
 Like quinidine, but
 Safer to use intravenously
 Produces fewer adverse GI effects
 Acetylated in liver to N-acetylprocainamide
(NAPA)
 Eliminated by the kidney (t ½ -3 – 5 hrs)
 More likely than quinidine to produce severe or
irreversible heart failure
 Adverse effects
SLE like syndrome consisting of arthralgia and
arthritis specially in slow acetylators

37. 3. Disopyramide
 Prominent anti-cholinergic activity
 Eliminated by the kidney (t ½ - 4 – 10 hrs)
 Approved only for ventricular arrhythmia & Atrial
fibrilllation (not a first line)
 Adverse Events:
Proarrhythmic
 Urinary retention, Blurred vision, Dry mouth (
Parasympatholytic)
 Mild negative ionotrophy

38. Class IB
1. Lidocaine:
 Least cardiotoxic : (t ½ - 1.5 - 2 hrs)
 Block inactivated Na channels : preferred for
partially depolarized cells in ischemic area
 High first pass metabolism – not given orally
 Used in:
 Ventricular arrhythmia
 Digoxin induced arrhythmia
 Main toxicity:
Neurological – drowsiness, nystagmus &
seizures

39. 2. Mexiletine and Tocainide
 Similar in action to lidocaine
 Can be administered orally
 T ½ - Mexiletine – 10-12 hrs
- Tocanide – 11-23 hrs
 Used for long-term treatment of ventricular
arrhythmias associated with previous
Myocardial Infarction
 Adverse events:
 Mexiletine : Ataxia, dizziness, tremors
 Tocainide : Blood dyscrasias, pulmonary
fibrosis, GI and neurological symptoms

40. Moricizine
 Phenothiazine
 Has properties of class IB, IA, and IC
antiarrhythmics,
 Use should be limited to life-threatening
ventricular arrhythmias

41. Class IC
 Class of potent Na channel blocker
 Drugs of this class have negative inotropic effect
 High pro-arrhythmogenic potential – sudden
death

42. Class IC
1.Flecainide
 Orally active antiarrhythmic
Metabolized by microsomal enzymes (t ½ - 20
hrs)
Used for ventricular tachyarrhythmias &
maintenance of sinus rhythm in patients with
paroxysmal atrial fibrillation and/or atrial flutter
& WPW
 C/I in pts with structural heart disease
 Adverse events :
Heart failure, dizziness, headache , Blurred

43. 2. Propafenone
Spectrum of action similar to that of quinidine
 Possesses β-adrenoceptor antagonist activity
Metabolized by hepatic microsomal enzymes
T ½ - 2 – 10 hrs
Approved for treatment of supraventricular
arrhythmias and suppression of life-threatening
ventricular arrhythmias
 C/I in structural heart disease
 Adverse events:
Nausea, Vomitting, altered taste

45. Class II
 They Are β-adrenoceptor antagonists,
including propranolol
 Act by reducing sympathetic stimulation
 Inhibit phase 4 depolarization
 Depress automaticity
 Prolong AV conduction
 Decrease
Heart rate
Contractility

46. Class II
 Major drugs
Propranolol, a nonselective β-adrenoceptor
antagonist
Acebutolol & esmolol, more selective β1-
adrenoceptor antagonists
Used to treat ventricular arrhythmias
Propranolol, metoprolol, nadolol, and
timolol frequently used to prevent recurrent
MI

47. Class II
 Absorption and elimination:
Propranolol: oral, iv
Esmolol: iv only (very short acting T½, 9 min)
 Cardiac effects
  APD and refractory period in AV node to
slow AV conduction velocity
  decrease phase 4 depolarization
(catecholamine dependent)

48. Class II
 Uses:
Treating sinus and catecholamine dependent
tachyarrhythmias
Converting reentrant arrhythmias in AV
 Protecting the ventricles from high atrial rates
 Side effects:
Bronchospasm
 Hypotension
 Don’t use in partial AV block or ventricular
failure

49. Class III
 Class III drugs:
Prolong action potential duration
Prolong effective refractory period
 Act by:
interfering with outward K+ currents or
slow inward Na+ currents

50. Class III

51. 1. Amiodarone
 Structurally related to thyroxine.
 Net effect:
Increases refractoriness
Depresses sinus node automaticity
Slows conduction.
 Long half-life (14—100 days) ↑ risk of toxicity
 Plasma conc not well correlated with its effects
 After parenteral administration:
 Electrophysiologic effects →within hours
 Effects on abnormal rhythms may not be seen
for several days

52. 1. Amiodarone
 Antiarrhythmic effects may last for weeks or
months after the drug is discontinued
 Uses:
Refractory life-threatening ventricular
arrhythmias in preference to lidocaine
T/t of atrial and/or ventricular arrhythmias
 Adverse effects
Pulmonary fibrosis
 Skin pigmentation
Corneal deposits
 Interferes with the thyroid function

53. 2. Ibutilide
 Administered by intravenous infusion
 Pure Ikr channel blocker
 Also activates inward Na+ current
 Net result in  APD
 Causes  QT
 Uses :
Conversion of atrial fibrillation and flutter
 Side effects :
Torsades de pointes

54. 3. Sotalol
 Prolongs the cardiac action potential
 Increases the duration of the refractory period
 Has nonselective β-adrenoceptor antagonist
activity
 Uses:
 Atrial arrhythmias or life-threatening ventricular
arrhythmias
Treatment of sustained ventricular tachycardia
Adverse effects:
Proarrhythmic actions, dyspnea, and
dizziness

55. 4. Dofetilide
Administered orally
  APD and refractory period
 Potent inhibitor of K+-channels
Used in T/t of atrial fibrillation or atrial flutter
Adverse effects:
Serious arrhythmias, Torsades de pointes
5.Bretylium
 Also has some direct antiarrhythmic action.
Has properties of class II drugs
Used for T/t of Ventricular arrhythmia after
lidocaine failure

56. Class IV
 Mechanism
 Class IV drugs selectively block L-type calcium
channels.
 These drugs prolong nodal conduction and effective
refractory period and have predominate actions in
nodal tissues

57. Class IV

58. Verapamil
 Phenylalkylamine that blocks both activated and
inactivated slow calcium channels.
 Tissues that depend on L-type calcium channels
are most affected
 Has equipotent activity on the AV and SA nodes
and in cardiac and vascular muscle tissues
 Useful in:
Supraventricular tachycardia
 Atrial flutter and fibrillation

59. Verapamil
 Adverse effects:
Negative inotropic action that limits its use
in damaged hearts;
Can lead to AV block when given in large
doses or in patients with partial blockage.
Can precipitate sinus arrest in diseased
patients
Causes peripheral vasodilation.

60. Miscellaneous Antiarrhythmic
Drugs
 Adenosine
 Acts through specific purinergic (P1)
receptors.
Causes an increase in potassium efflux and
decreases calcium influx.
 This hyperpolarizes cardiac cells and
decreases the calcium-dependent portion of
the action potential.
Drug of choice for the treatment of
paroxysmal supraventricular tachycardia,
including those associated with Wolff-

61. Digoxin
 Mode of action:
Na-K ATPase inhibition
Positive inotrope
Vagotonic
 T ½ - Premature (61hrs), Neonate (35hrs), Infant
(18hrs), Child (37hrs), Adult (35-48hrs )
 Uses:
Supraventricular Tachycardia

62. Digoxin
 Interactions:
Coumadin- ↑ PT
 ↑ Digoxin level
 Quinidine, amiodarone, verapamil
 ↓ renal function/renal tubular excretion
(Spironolactone)
Worse with ↓ K+, ↓ Ca++

63. Digoxin Toxicity
 Proarrhythmic
 Causes nausea/vomiting, lethargy, visual
changes
 Metabolic
Hyper K+, Ca++
Hypo K+, Mg++
Hypoxemia
Hypothyroidism

64. Investigational Drugs
 Analogs of Amiodarone are being developed
such as:
 ATI-2001
 Dronedarone
 SR-33589
 Dronedarone:
 Resonable safety profile
Well characterized pharmacokinetic &
pharmacodynamic profile
 Effective in doses lower than 2000 mg/day Wolbrette D et al ; Dronedarone for the treatment of atrial fibrillation and atrial flutter: Approval and
efficacy ; Vasc Health Risk Manage 2010;6;517

65. Investigational Drugs
 Azimilide :
 Potassium-channel blocking properties
 Prolongs cardiac AP & refractory periods
Found to be effective in patients with
symptomatic tachyarrhythmias and ICDs
therapies in recent studies
Other drugs, such as Ambasilide, are also in
clinical development
Chromanol 293B is in preclinical testing
Reynolds RM, Josephson ME. Sustained ventricular tachycardiain ischemic cardiomyopathy : current
management. ACC Current Journal Review 2005;14:63-71

66. Treatment of bradyarrhythmias
 Atropine
Blocks the effects of acetylcholine.
Elevates sinus rate and AV nodal and sinoatrial
(SA) conduction velocity, & decreases
refractory period
Used to treat bradyarrhythmias that
accompany MI
 Adverse effects:
Dry mouth, mydriasis, and cycloplegia;
May induce arrhythmias.

67. Treatment of bradyarrhythmias
 Isoproterenol
Stimulates β-adrenoceptors
 Increases heart rate and contractility.
Uses:
Maintain adequate heart rate and cardiac
output in patients with AV block
 Adverse effects:
Tachycardia, Anginal attacks
Headaches, Dizziness
 Flushing, and tremors

68. T/t of Atrial Flutter/Fibrillation
1. Reduce thrombus formation by using
anticoagulant warfarin
2. Prevent the arrhythmia from converting to
ventricular arrhythmia
 First choice: class II drugs:
 After MI or surgery
 Avoid in case of heart failure
 Second choice: class IV drugs
 Third choice: digoxin
 Only in heart failure of left ventricular
dysfunction

69. T/t of Atrial Flutter/Fibrillation
3. Conversion of the arrhythmia into normal sinus
rhythm
 Class III:
 IV ibutilide, IV/oral amiodarone, or oral sotalol
 Class IA:
 Oral quinidine + digoxin (or any drug from the 2nd
step)
 Class IC:
 Oral propaphenone or IV/oral flecainide
 Use direct current in case of unstable
hemodynamic patient
Fuster V et al; ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. Circulation
2006;114;700

70. T/t of Ventricular Arrhythmia
 Premature ventricular beat (PVB)
 First choice: class II
 IV followed by oral
 Early after MI
 Second choice: amiodarone
 Avoid using class IC after MI  ↑ mortality

71. T/t of Ventricular Tachycardia
 First choice: Lidocaine IV
Repeat injection if needed
 Second choice: procainamide IV
Adjust the dose in case of renal failure
 Third choice: class III drugs
Especially amiodarone and sotalol
Grant AO, Recent advances in the treatment of arrhythmia. Circ J 2003;67;651

72. Thank You