Drug management of cardiac dysrhythmias

PREPARED BY:
DR SITANIMEZI MWEENDA-CHIKUTA
 INTRODUCTION
• Antiarrhythmic Drugs:
– are drugs used to prevent or treat irregularities of cardiac rhythm.
• Arrhythmias are the most important cause of sudden cardiac
death.
– not all need treatment with antiarrhythmic drugs.
• Abnormal automaticity or impaired conduction or both underlie
cardiac arrhythmias.
• arrhythmias can be caused by (altering electrophysiological properties of cardiac fibres):
– Ischaemia, electrolyte and pH imbalance, mechanical injury, stretching,
neurogenic and drug influences, including antiarrhythmics.
 IMPULSE CONDUCTION IN NORMAL HEART
Normal conduction
pathway
• 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
 Action potential of the heart

In the atria, In the SA node and

purkinje, and AV node, AP curve
ventricles the AP consists of 3 phases
curve consists of 5
phases

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 Electrophysiology of cardiac cells

• The passage of ions across the myocyte cell membrane is

regulated through specific ion channels that produce cyclical
depolarisation and repolarisation of the cell, called an action
potential.
• The electrophysiological events can be divided into 5 phases:
0, 1, 2, 3 and 4

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

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Electrophysiology of cardiac cells …. cont’d

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 transmembrane
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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There are two types of cardiac tissue:

1. 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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2. 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 13
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
1- Abnormal
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
fashion (backward) 16
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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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:

1. Restore normal sinus rhythm and conduction
2. Prevent more serious and possibly lethal
arrhythmias from occurring

Antiarrhythmic drugs are used to:

1. Decrease conduction velocity
2. Change the duration of the effective refractory
period
3. Suppress abnormal automaticity

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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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 PHARMACOLOGY OF THE ANTIARRHYTHMIC AGENTS
• The most widely used scheme for the classification of
antiarrhythmic drug actions recognizes four classes:
• Class I:
– Drugs that block voltage-sensitive Sodium channels.
• They are subdivided into I A, I B, and I C.
• Class II
– Beta adrenoceptor antagonists
• Class III
– Drugs that substantially prolong the cardiac action potential
• Class IV
– Calcium antagonists
 Anti-arrhythmic drugs
•Most antiarrhythmic 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 K and Ca
velocity
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 Systemic Lupus erythromatous (SLE) = an inflammatory
connective tissue disease with variable features, frequently including fever, weakness and fatigability, joint
pains or arthritis resembling rheumatoid arthritis, diffuse erythematous skin lesions on the face, neck, or
upper extremities, with liquefaction degeneration of the basal layer and epidermal atrophy, lymphadenopathy,
pleurisy or pericarditis, glomerular lesions, anemia, hyperglobulinemia, and a positive LE cell test, with serum
antibodies to nuclear protein and sometimes to double-stranded DNA and other substances.

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 Class 1B drugs – Na+ channel blockers

• Mode of Action: Shorten action potential and therefore ↓ 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

• Markedly inhibit conduction through the His-Purkinje system
• 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
1. Negative inotropic and chronotropic action
2. Prolong AV conduction
3. Diminish phase 4 depolarization suppressing
automaticity of ectopic focus

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Class II – Beta adrenergic blockers …. cont’d

Uses
1. Supraventricular tachycardia
2. Treatment of increased sympathetic activity-induced
tachyarrhythmias:
– E.g. stress- and exercise-induced arrhythmias; and
– arrhythmias due to hyperthyroidism
3. Ventricular rate control in atrial flutter and atrial fibrillation
4. AV nodal tachycardia

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 Class III – K+ channel blockers
• Mode of Action:
– 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
1. Sotalol: atrial and ventricular tachyarrhythmias
2. Ibutilide: atrial fibrillation and atrial flutter and other supraventricular
tachycardias
3. Dofetilide: conversion and maintenance of normal sinus rhythm in
atrial fibrillation and atrial flutter
4. Bretylium: refractory VT and VF, especially due to acute ischemia
5. Amiodarone: sustained VT and VF

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 Amiodarone

• Mode of action:
– Interferes with cardiac repolarization by blocking the K+
channels;
– it also has noncompetitive beta-blockade actions
• Amiodarone is broad spectrum and can be used:
– treatment of paroxysmal supraventricular,
– nodal and ventricular tachycardias,
– atrial fibrillation and flutter,
– WPW syndrome tachyarrhythmias
– 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
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Amiodarone …. cont’d

• Amiodarone has limited use: 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
• Mode of Action: 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: nausea, vomiting, hypotension, bradycardia
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Calcium channel blockers

• Examples: verapamil and diltiazem

• Mechanism of action:
– ↓ inward Ca2+ currents →↓ phase 4 spontaneous depolarization (SA
node)
– They slow conductance in Ca2+ current-dependent tissues like AV
node
– They prolong effective refractory period of AV node → ↓conduction
of impulses from the atria to the ventricles
• Effects:
1. suppress automatic activity of pacemaker cells
2. ↓ conduction velocity in the SA & AV nodes
Uses
1. Treatment of supraventricular tachycardias
2. 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 (esp. in combination
with β-adrenergic blockers)
• Contraindicated: pre-existing depressed heart function
(because of their negative inotropic activity)
Contra-indications
1. Broad complex tachycardia (where QRS complex
is wide)
2. Concurrent administration with a beta-blocker
(risk of bradycardia and asystole)
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Digitalis: digoxin & digitoxin
Mechanism of action:
• Enhances vagal activity (stimulates central vagal nuclei)
– Through this action, digitalis:
• ↓automaticity of SA node
• Slows AV conduction
• ↑ refractoriness of the AV node
• Shortens refractory period of atrial muscle cells
• ↓ 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
• 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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Cardiac manifestations of digitalis toxicity

• Bradycardia
• Heart block
• Multiple ventricular ectopics
• Ventricular bigeminy (alternate ventricular ectopics)
• Paroxysmal atrial tachycardia
• Ventricular tachycardia
• Ventricular fibrillation

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Management of digitalis-induced arrhythmias

Digitalis-induced tachyarrhythmias
1. i.v. magnesium sulphate
2. Phenytoin and lignocaine:
▪ Depress the enhanced ventricular automaticity without significantly
slowing AV conduction
▪ Phenytoin also 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: ↓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

• Mode of Action:
– Activates adenosine A1 adenosine receptor resulting in
activation of the acetylcholine-sensitive K+ channels in the
atrium, sinus and AV node, causing hyperpolarisation
• Effects: ↓action potential duration,
– reduces SA node firing and automaticity and depresses AV node
conduction
• Use:
– 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
• Caution: Avoid in bronchial asthma
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Magnesium sulphate

• Mode of Action: 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

1. To improve cardiac hemodynamics and quality of life and;
2. ↓ risk of thromboembolic complications
– Restoration of sinus rhythm: Direct Current (DC) cardioversion (a
procedure using defibrillator to deliver a controlled electric shock to your heart so as to try and
return your heart rhythm (beat) to normal)
– 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:

1. Structurally normal heart and young age
▪ propafenone, flecainide, sotalol
2. Coronary artery disease - sotalol, amiodarone
3. Congestive heart failure - amiodarone
4. 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
• (high energy shock given to reset normal rhythm)
2. Pharmacological cardioversion
• (procedure for returning an abnormal heart to normal rhythm): procainamide, flecainide,
propafenone, amiodarone
3. Atrial overdrive pacing
• (a pacemaker mode designed to increase the atrial pacing rate to a level slightly higher than patient’s
intrinsic rate)
4. Combination therapy of above

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Wolff-Parkinson-White Syndrome

• Drug therapy is only indicated in symptomatic patients

Aims of treatment
1. To slow conduction rate
2. 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)

NOTE: Treatment of choice for most patients is radiofrequency ablation of the

bypass tract

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THE END!!