2. Contents
• Electrophysiology of Heart
• Arrhythmia: Definition, Types,
Mechanisms
• Antiarrhythmic drugs: Class I, II , III ,
IV
• Treatment of arrhythmia : Guidelines
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
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
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
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
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
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
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
44.
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
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
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-
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
