DRUG USED IN THE TREATMENT OF

ARRHYTHMIAS

Copperbelt University School of Medicine

MBChB Pharmacology
February 2015
(Dr Sindwa Kanyimba)
Physiology of the normal heart

• SA node generates action potential and delivers it to the atria

and the AV node
• The AV node delivers the impulse to Purkinje fibers
• Purkinje fibres conduct the impulse to the ventricles
• The passage of ions across the myocyte cell membrane is
regulated through specific ion channels that produce cyclical
depolarisation and repolarisation of the cell, call an action
potential
• The electrophysiological events can be divided into 5 phases:
0, 1, 2, 3 and 4

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 Electrophysiology of cardiac cells

Phase 0 – Upstroke (Rapid Depolarisation)

• Rapid depolarisation of the cell membrane in response to fast inflow of
sodium ions
• Speed of Phase 0 depolarisation determines the velocity of impulse
conduction
Phase 1 – Partial Repolarisation
Short period of repolarisation due to rapid efflux of potassium ions
Phase 2 - Plateau
• Slow influx of calcium (a depolarising event) balances the efflux of
potassium (a repolarising event) resulting in a plateau phase of the
action potential
• Calcium entering the cell is responsible for myocyte contraction
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Electrophysiology of cardiac cells …. cont’d

Phase 3 - Repolarisation
• Calcium influx stops and potassium efflux increases
• Potassium efflux results in rapid repolarisation
Phase 4 – Resting membrane potential (diastole)
• Fully repolarised state with a trans-membrane potential of
-90mv
• Cells that possess automaticity depolarise (due to sodium and
calcium influx) till threshold potential (-50mv) when they
depolarise rapidly & generate an impulse (Phase 0)

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Refractory period

• While depolarized, the cell is resistant (refractory) to a

subsequent depolarization event
• Absolute (effective) refractory period: period of time during
which a new action potential cannot be initiated once an
action potential is initiated (i.e. period during which a
subsequent depolarization is not possible when an action
potential has been initiated)
• Relative refractory period: after partial (but incomplete
repolarization), a subsequent depolarization is possible but
occurs slowly

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Types of cardiac tissue

Fast-channel tissues: atrial and ventricular myocytes, and the His-

Purkinje system
• Have a high density of fast sodium channels
• Their action potentials are characterized by little or no spontaneous
diastolic depolarization
• Have very rapid initial depolarization rates (and thus rapid
conduction velocity)
• Their loss of refractoriness is coincident with repolarization
• Have short refractory periods
• Are able to conduct repetitive impulses at high frequencies

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Types of cardiac tissue …. cont’d

Slow-channel tissues (SA and AV nodes)

• Have low density of fast sodium channels
• Their action potentials are characterized by more rapid
spontaneous diastolic depolarization (and thus pacemaker
activity)
• Have slow initial depolarization rates (and thus slow
conduction velocity)
• Their loss of refractoriness is delayed after repolarization
(thus long refractory periods)
• They are not able to conduct repetitive impulses at high
frequencies
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Pacemaker activity

• Normally the SA node has the most rapid rate of spontaneous

diastolic depolarization so its cells produce spontaneous
action potentials at a higher frequency than other tissues
• Thus the SA node is the dominant automatic (pacemaker)
tissue in the normal heart
• If the SA node does not produce impulses, tissue with the
next highest automaticity rate (typically the AV node)
functions as the pacemaker
• Sympathetic stimulation increases the discharge frequency of
pacemaker tissue and parasympathetic stimulation decreases
it
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 Phase 1: partial
Non-pacemaker action repolarization
potential Due to rapid efflux of K+

Phase 2: plateu
Phase 0: fast
Due to Ca++ influx
upstroke
Due to Na+
influx
Phase 3:
repolarization
Due to K+ efflux

Phase 4: resting
membrane potential

N.B. The slope of phase 0 = conduction velocity

Also the peak of phase 0 = Vmax

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Pacemaker action
potential

Phase 0: upstroke: Phase 3:

Due to Ca++ influx repolarization:
Due to K+ efflux

Phase 4: pacemaker
potential
Na influx and K efflux and
Ca influx until the cell
reaches threshold and
then turns into phase 0

Pacemaker cells (automatic cells) have

unstable membrane potential so they can
generate AP spontaneously 10
Arrhythmia (dysrhythmia)

• Definition: Abnormality in the site of origin of impulse, rate or

conduction
• Causes of arrhythmias: congenital structural abnormalities,
rheumatic heart disease, hypoxia, hypercapnia, electrolyte
imbalances, hormonal imbalances, drugs, toxins, arteriosclerosis,
coronary artery spasm, myocardial ischaemia
• If the arrhythmia arises from atria, SA node, or AV node it is
called supraventricular arrhythmia
• If the arrhythmia arises from the ventricles it is called ventricular
arrhythmia

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 Pathophysiology of arrhythmias: (1) Abnormal impulse
generation (2) Abnormal conduction
Abnormal -1
impulse
generation

Automatic Triggered
rhythms rhythms

Enhanced
normal Ectopic focus Delayed Early
automaticity afterdepolarization afterdepolarization

AP arises from sites

other than SA node
↑AP from SA node

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 2-Abnormal
conduction

Conduction
Reentry
block

Circus
1st degree 2nd degree 3rd degree Reflection
movement

This is when the 1-This

impulse is not pathway is
conducted from the blocked
atria to the
ventricles
3-So the cells here will be
re-excited (first by the
original pathway and the
2-The impulse from
other from the retrograde)
this pathway travels
in a retrograde
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fashion (backward)
Abnormal anatomic conduction
Here is an
accessory
pathway in the
heart called
Bundle of Kent

• Present only in small populations

• Lead to re-excitation  Wolf-Parkinson-
White Syndrome (WPW)

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Clinical classification of arrhythmias

Site of origin of the abnormality

• Atrial
• Junctional
• Ventricular

Whether rate is increased or decreased

• Tachyarrhythmias
• Bradyarrhythmias

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Supraventricular arrhythmias

• 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: a 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 manner
• Atrial flutter: sinus rate of 250-350 beats/min
• Atrial fibrillation (AF): uncoordinated atrial depolarizations
• AV blocks: A conduction block within the AV node ,
occasionally in the bundle of His, that impairs impulse
conduction from the atria to the ventricles
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 Ventricular arrhythmias
• Ventricular premature beats (VPBs): caused by ectopic ventricular foci;
characterized by widened QRS
• Ventricular tachycardia (VT): high ventricular rate caused by abnormal
ventricular automaticity or by intra-ventricular reentry; can be sustained or
non-sustained (paroxysmal); characterized by widened QRS; rates of 100 to
200 beats/min; life-threatening
• Ventricular flutter: ventricular depolarizations >200/min
• Ventricular fibrillation (VF): uncoordinated ventricular depolarizations
• Torsade de pointes: a polymorphic ventricular tachycardia with a
characteristic illusion of a twisting of the QRS complex around the
isoelectric baseline. Torsades de pointes can degenerate into ventricular
fibrillation which will lead to sudden death in the absence of medical
intervention.
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Pharmacologic rationale & goals in treatment of
arrhythmias

The ultimate goal of anti-arrhythmic 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
• Suppress abnormal automaticity

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 Anti-arrhythmic drugs
• Most anti-arrhythmic drugs are pro-arrhythmic (promote arrhythmia)
• They are classified according to Vaughan William into four classes according to their effects
on the cardiac action potential
Class Mechanism Action Notes
Can abolish
Na+ channel blocker Reduce maximum rate of tachyarrhythmia
I (membrane depolarisation therefore reduce
caused by reentry
stabilising agents) conduction velocity
circuit
Can indirectly alter
↓heart rate and conduction
II β blocker velocity K and Ca
conductance
1. ↑action potential duration
(APD) or effective refractory Inhibit reentry
III K+ channel blocker
period (ERP) tachycardia
2. Delay repolarization
Suppress automatic activity of ↓conduction
IV Ca channel blocker
++
pacemaker cells velocity in SA and
AV node

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 Class IA drugs – Na+ channel blockers

Prolong action potential (due to K+ channel blockade)

Examples: quinidine, procainamide, disopyramide
Quinidine & disopyramide can cause Torsades de pointes
Uses
• Atrial and ventricular tachyarrhythmias
• All types of supraventricular tachycardia
Adverse effects
• Quinidine: GI upset, myocardial depression, anti-muscarinic effects,
ventricular tachycardia, haemolytic anaemia, thrombocytopaenia,
rash, potentiates digoxin & warfarin
• Disopyramide: anti-muscarinic effects, myocardial depression,
tachydysrhythmia, agranulocytosis, rash, GI effects
• Procainamide: drug-induced SLE
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 Class 1B drugs – Na+ channel blockers
Shorten action potential and therefore decrease the effective refractory period
Examples: lignocaine, mexiletine, phenytoin
Uses
• Lignocaine: ventricular tachycardia (VT) and ventricular fibrillation (VF),
especially during acute ischemia and myocardial infarction
• Mexiletine: ventricular tachyarrhythmias
• Phenytoin: digitalis-induced supraventricular arrhythmias, polymorphic VT
associated with increased QT interval
Adverse effects
• Lignocaine: confusion, convulsions, hypotension, blurred vision, numbness,
dizziness
• Mexiletine: GI irritation, confusion, dizziness, tremor, nystagmus, ataxia,
drowsiness
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Class 1C – Na+ channel blockers

No effect on action potential

Examples: flecainide and propafenone
Uses
• Supraventricular tachyarrhythmias including atrial fibrillation and
flutter; and ventricular arrhythmias refractory to other
medications or radiofrequency ablation
Adverse effects
• Flecainide & propafenone: myocardial depression, dizziness,
ventricular tachycardia, worsen cardiac failure
• Class 1C drugs have low safety and have shown an increase in
mortality when used chronically after myocardial infarction

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 Class II – Beta adrenergic blockers
Examples: propranolol, metoprolol, esmolol
Esmolol is a very short-acting β1 blocker that is used by intravenous route in acute
arrhythmias occurring during surgery or emergencies
Mechanism of action
• Negative inotropic and chronotropic action
• Prolong AV conduction
• Diminish phase 4 depolarization suppressing automaticity of ectopic focus
Uses
• Supraventricular tachycardia
• Treatment of increased sympathetic activity-induced tachyarrhythmias such as
stress- and exercise-induced arrhythmias; and arrhythmias due to
hyperthyroidism
• Ventricular rate control in atrial flutter and atrial fibrillation
• AV nodal tachycardia
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 Class III – K+ channel blockers

Block potassium channels

Delay repolarization (prolong action potential) thereby prolonging effective
refractory period
Examples: amiodarone, sotalol, ibutilide, dofetilide and bretylium
Can all cause Torsade de pointes
Uses
• Sotalol: atrial and ventricular tachyarrhythmias
• Ibutilide: atrial fibrillation and atrial flutter and other supraventricular
tachycardias
• Dofetilide: conversion and maintenance of normal sinus rhythm in atrial
fibrillation and atrial flutter
• Bretylium: refractory VT and VF, especially due to acute ischemia
• Amiodarone: sustained VT and VF
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 Amiodarone

• Also has noncompetitive beta-blockade actions

• Amiodarone is broad spectrum and can be used in the treatment of
paroxysmal supraventricular, nodal and ventricular tachycardias, atrial
fibrillation and flutter, WPW syndrome tachyarrhythmias, and
ventricular fibrillation
• Does not cause myocardial depression
• Can be given orally or IV. Acts rapidly when given IV.
• Has a long half-life (60 days) therefore given once daily
• Amiodarone usage is limited due to its wide range of adverse effects
• Adverse effects: pulmonary fibrosis, photosensitivity, skin discoloration,
corneal deposits, thyroid dysfunction, hepatotoxicity, peripheral
neuropathy, potentiates digoxin & warfarin.
• Beta-blockers & verapamil augment its depressant effect on SA & AV
node

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Class III drugs – K+ channel blockers …. cont’d

Sotalol
• A competitive beta-blocker with K+ channel blocking effects
• The β-adrenergic blockade combined with prolonged action
potential duration may be of special efficacy in prevention of
sustained ventricular tachycardia

Ibutilide: Only drug in class three that possess pure K+ blockade

Bretylium: Adverse effects include nausea, vomiting, hypotension,

bradycardia

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 Class IV drugs: calcium channel blockers

• Examples: verapamil and diltiazem

• Ca2+ channel blockers decrease inward Ca2+ currents resulting
in a decrease of phase 4 spontaneous depolarization (SA node)
• They slow conductance in Ca2+ current-dependent tissues like
AV node
• Effects: suppress automatic activity of pacemaker cells and
reduce conduction velocity in the SA & AV nodes
Uses
• Treatment of supraventricular tachycardias
• Ventricular rate control in atrial flutter and atrial fibrillation
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Calcium channel blockers …. cont’d

Adverse effects
• Hypotension, myocardial depression, constipation and cause
bradycardia, and asystole especially when given in combination
with β-adrenergic blockers
• Contraindicated in patients with pre-existing depressed heart
function because of their negative inotropic activity
Contra-indications
• Broad complex tachycardia (where QRS complex is wide)
• Concurrent administration with a beta-blocker (risk of bradycardia
and asystole)

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Digitalis: digoxin & digitoxin

Enhances vagal activity (stimulates central vagal nuclei)

Through this action, digitalis:
• Decreases automaticity of SA node
• Slows AV conduction
• Increases refractoriness of the AV node
• Shortens refractory period of atrial muscle cells
• Decreases myocardial excitability
Uses
• Ventricular rate control in atrial fibrillation
Contra-indication
• Supraventricular arrhythmias associated with accessory conducting pathways
(e.g. Wolf-Parkinson-White syndrome)

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Digitalis: adverse effects

• Cardiac: ectopic dysrhythmias (ventricular ectopic beats),

ventricular tachydysrhythmias, paroxysmal supraventricular
tachycardia, bradycardia & heart block, and ventricular
fibrillation
• CNS: confusion, restlessness, agitation, nightmares, acute
psychosis
• GIT: anorexia, nausea, vomiting, diarrhoea
• Visual: disturbances of colour vision, photophobia, blurring
• Others: gynaecomastia

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Management of digitalis-induced arrhythmias

Digitalis-induced tachyarrhythmias
•  Intravenous magnesium sulphate
• Phenytoin and lignocaine - depress the enhanced ventricular
automaticity without significantly slowing AV conduction
• In addition, phenytoin can terminate supraventricular
dysrhythmias induced by digitalis
Digitalis-induced bradyarrhythmias
• Atropine is recommended for improving AV nodal conduction

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Digitalis …. cont’d

Contra-Indicated drugs in digoxin-induced arrhythmias

• Quinidine, procainamide, and bretylium
• Both quinidine and procainamide slow down AV, SA, and His-
Purkinje conductivity further
• Quinidine reduces digoxin tissue binding and renal clearance,
thereby increasing digoxin levels
• Bretylium can precipitate ventricular dysrhythmia
Immunotherapy in digitalis overdosage
•  The antidote is digitalis-specific antibody fragments (Fab)
which bind and inactivate digitalis

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Adenosine

• Activates adenosine A1 adenosine receptor resulting in activation

of the acetylcholine-sensitive K+ channels in the atrium, sinus
and AV node, thereby causing hyperpolarisation
• Effects: decreases action potential duration, reduces SA node
firing and automaticity and depresses AV node conduction
• It is the drug of choice in the treatment of paroxysmal supra-
ventricular tachycardia
• Short acting (15 seconds) and given by slow IV bolus injection
• Adverse effects: bronchospasm, flushing, chest pain, dizziness,
nausea
• Avoid in bronchial asthma
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Magnesium sulphate

• Inhibits calcium channels

• Has an influence on sodium/potassium ATPase, sodium
channels & potassium channels
• Uses: Torsade de pointes and digitalis-induced
tachyarrhythmias

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Management of atrial fibrillation (AF)

Initial goal: rate control & anti-coagulation

• Rate control: beta-blockers, calcium channel blockers, digoxin
• Anti-coagulation: IV heparin, warfarin (target INR 2 - 3) - reduces risk
of stroke x3

Eventual goal: restoration & maintenance of sinus rhythm

• To improve cardiac hemodynamics & quality of life & reduce the risk of
thromboembolic complications
• Restoration of sinus rhythm: DC cardioversion
• Maintenance of sinus rhythm: quinidine, flecainide, propafenone,
sotalol and amiodarone 
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Proposed anti-arrhythmic drugs of choice for long
term treatment of AF

Selection is based on underlying heart disease:

• Structurally normal heart and young age - propafenone,
flecainide, sotalol
• Coronary artery disease - sotalol, amiodarone
• Congestive heart failure - amiodarone
• Left ventricular hypertrophy - sotalol

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Atrial flutter

Treatment of symptomatic atrial flutter:

• Ventricular rate control - drugs that block the AV node: IV
calcium channel blockers or beta-blockers can be used,
followed by initiation of oral agents
• Termination of sustained episodes - (1) Electrical
cardioversion: 50 - 100 J (2) Pharmacological cardioversion:
procainamide, flecainide, propafenone, amiodarone (3) Atrial
overdrive pacing (4) Combination therapy of above

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Wolff-Parkinson-White Syndrome

Drug therapy is only indicated in symptomatic patients

Aims of treatment
• To slow conduction rate
• To prolong the refractory period of the bypass tract
Drugs
• Disopyramide, amiodarone, sotalol - increase the refractory
period in the accessory pathway
• Avoid digoxin & verapamil (increase conduction in the bypass
tract)
NB:Treatment of choice for most patients is radiofrequency
ablation of the bypass tract 

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ENDE