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CARDIAC ARRHYTHMIAS &
ANTI-ARRHYTHMIC DRUGS
Or
Cardiac Dysrhythmias
& Anti-dysrhythmic Drugs
16th Feb 2017
1
Drugs Affecting the Heart:
Overview
• To understand this topic revise on the following: the anatomy of the heart
 physiology of the cardiac function in terms of
electrophysiology, of contraction, of oxygen
consumption and coronary blood flow, of
autonomic control and as a source of peptide
hormones.
This provides a basis for understanding effects of
drugs on the heart and their place in treating cardiac
disease.
The main drugs considered are drugs that act directly
on the heart, namely anti-dysrhythmic drugs; drugs
that increase the force of contraction of the heart
(esp. digoxin), and anti- angina drugs.
2
Drugs Affecting the Heart:
Overview…
• The commonest forms of heart disease are
caused by atheroma in the coronary arteries,
and thrombosis on ruptured atheromatous
plaques;
• drugs to treat and prevent these will be
discussed in the following topics i.e. Lipid
lowering drugs and anti-platelet agents,
anticoagulants and anti thrombolytic agents.
• Heart failure is mainly treated indirectly by
drugs that work on vascular smooth muscle, by
diuretics and -adrenoceptor antagonists
3
Drugs Affecting the Heart:
Overview…
NB:
• Atheroma= fatty degeneration or thickening of
the walls of the larger arteries occurring in
atherosclerosis
• Atherosclerosis=the most common form of
arteriosclerosis, marked by cholesterol-lipidcalcium deposits in the walls of arteries
4
Drugs Affecting the Heart:
Introduction
•
This topic will consider effects of drugs on the heart
under three main headings:
1) Rate and rhythm
2) Myocardial contraction
3) Metabolism and blood flow
• The effects of drugs on these aspects of cardiac
function are not independent of each other.
• For e.g., if a drug affects the electrical properties of
the myocardial cell membrane, it is likely to influence
both cardiac rhythm and myocardial contraction.
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Drugs Affecting the Heart:
Introduction…
•
•
Similarly, a drug that affects contraction will
inevitably alter metabolism and blood flow as
well.
Nevertheless, from a therapeutic point of view,
these three classes of effect represent distinct
clinical objectives in relation to the treatment,
respectively, of cardiac dysrhythmias,
cardiac failure and coronary insufficiency
(as occurs during angina pectoris or myocardial
infarction)
6
Physiology of Cardiac Function:
Cardiac Rate and Rhythm
• The chambers of the heart normally
contract in coordinated manner, pumping
blood efficiently by a route determined by
the valves.
• Coordination of contraction is achieved by
a specialized conducting system
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The Ionic Basis of Normal Cardiac
Action Potential
• In the normal heart the site (focus) for the
generation of the heart beat is the sinoatrial
(SA) node.
• From here electrical impulses are conducted in
sequence through the atrial muscle to the
atrioventricular (AV) node and thus, via the
bundle of His and the Purkinje fibres, to the
ventricular muscle cells. (SA node-Atrium-AV
node-Purkinje fibres-Ventricle)
8
The Ionic Basis of Normal Cardiac
Action Potential…
• The contractile cells of the atria and ventricles
show a characteristic form of action potential
associated with the movement of Na+, Ca2+
and K+ through specific ion channels.
• The opening and closing of these channels
(their gating) is variously influenced by
membrane potential, intracellular ionic
concentrations and ligands, such as
noradrenaline, acetylcholine and adenosine.
• Gating processes are usually time dependent.9
The Ionic Basis of Normal Cardiac
Action Potential…
•
1)
2)
3)
4)
Electrophysiological features of cardiac
muscle that distinguish it from other excitable
tissues include:
Pacemaker activity
Absence of fast Na+ current in SA and AV
nodes, where slow inward Ca2+ current
initiates action potentials
Long action potential (‘plateau’) and refractory
period
Influx of Ca2+ during the plateau
10
The Ionic Basis of Normal Cardiac
Action Potential…
• Thus several of the special features of cardiac
rhythm relate to Ca2+ currents.
• The heart contains intracellular calcium
channels, which are important in controlling
cardiac rate and rhythm.
• The main type of voltage-dependent calcium
channel in adult working myocardium is the Ltype channel, which is also important in
vascular smooth muscle; L-type channels are
important in specialized conducting regions as
11
well as in working myocardium.
The Ionic Basis of Normal Cardiac
Action Potential…
•
1)
2)
3)
4)
5)
•
The cardiac action potential is conventionally
divided for descriptive purposes into five
phases, (refer fig. 1next slide) which are:Phase 0 (fast/rapid depolarisation)
Phase 1 (partial repolarisation)
Phase 2 (plateau)
Phase 3 (repolarisation)
Phase 4 (pacemaker)
These broadly correlate with the opening
and/or closing of different ion channel types12
Fig.1. Cardiac muscle cell AP
13
Phase 0= Rapid Depolarization:
• The main upstroke of the cardiac action
potential is primarily due to influx of Na+
through voltage sensitive Na+ channels
• Caused by a transient opening of fast Na
channels
• Increases inward directed depolarizing
Na+ currents
• Generate "fast-response" APs
14
Phase 1= Partial Repolarization:
• appears to be secondary to outward K+
flux plus inactivation of Na+ influx.
• The rapid inactivation of the Na+ channels
produces a short lived repolarization of
membrane potential.
• This generates the notch/peak, which is
especially prominent in ventricular cells.
• There may also be a transient voltage
sensitive outward current
15
Phase 2= The Plateau
• is primarily due to Ca2+ influx. The depolarization
generated during phase 0 initiates the relatively
slow action of L-type voltage-sensitive Ca
channels.
• The influx of Ca2+ through these maintains the
depolarized state of the cardiac muscle cell and
gives rise to the plateau phase, which is very
prominent in the ventricle.
• Plateau phase prolongs AP duration vs APs in
nerves and skeletal muscle
16
Phase 2= The Plateau…
• Entry of Ca2+ during this phase is of critical
importance in generating cardiac force.
• Additionally, the maintained depolarization
causes voltage-sensitive Na+ channels to
remain inactivated and inwardly rectifying
K+ channels to remain closed.
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Phase 3= Rapid Repolarization
• due to K+ efflux.
• This phase terminates the AP
• Occurs as the Ca2+ current inactivates and
a delayed outwardly rectifying K + current
activates, causing outward K + current.
18
Phase 4= The Pacemaker
Potential
• Resting membrane potential;
• is a gradual depolarization during
diastole. Pacemaker activity is normally
found only in nodal and conducting tissue.
• The pacemaker potential is caused by a
combination of increasing inward
currents and reduced outward currents
during diastole
19
The Ionic Basis of Normal Cardiac
Action Potential…
• Three types of ion channels are responsible
for the generation and propagation of cardiac
action potential:
(1)The fast Na+ - channels:
- open very fast and inactivate very fast
- activated at membrane potentials
between –70 and –50 mV
-responsible for the rapid upstroke of action
potential (AP) in the atria, bundle of His,
Purkinje fibers & ventricles
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(2) Slow Ca2+ - Na+ channels:
- open slowly and take a long time to
inactivate
-responsible for the plateau in the
ventricular AP
(3) Slow K+ channels:
responsible for the repolarization
phase of cardiac action potential
21
Cardiac muscle can be divided into 3
main types
1) Tissue with spontaneous pacemaker
activity:(a) SA node
(b) The AV node
(2) Specialized high velocity conducting
tissue.
(a) bundle of His (b) the Purkinje fibres
(3) Atrial & Ventricular myocardium
22
Cardiac muscle can be divided into 3
main types…
(1)Tissue with spontaneous pacemaker
activity
(a) SA node:
-this is the pacemaker
- generates heart beats (70 – 80
beats/min)
- has no fast Na+ - channels
- low permeability to K+
- AP rises slowly & falls slowly
23
24
(b) The AV node: (40 – 60 beats/min)
-like the SA node AP is due to currents
through the Ca 2+ - Na+ channels
- AP rises slowly & falls slowly
• In both SA & AV nodes the depolarising
phase of AP is carried almost entirely by Ca2+
• Na+ influx plays only a minor role
25
(2) Specialised high velocity
conducting tissue.
(a) bundle of His (b) the Purkinje
fibres
• AP is due to fast Na + currents upstroke of AP
• The slow Ca2+ - Na+ currents – Plateau
of AP
• K+ channels – repolarising phase
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(3) Atrial & Ventricular myocardium
• Fast sodium channels
• Ca 2+ - Na + channels
• K+ channels
• The fast sodium channels make conduction
velocity in atria & ventricles faster than that in
the AV node
• Allows electrical activation of the two to occur in
a short period of time
• Permits co-ordinated contraction
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CARDIAC DYSRHYTHMIAS
(ARRHYTHMIAS)
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Cardiac dysrhythmias (arrhythmias)
Disturbances of Cardiac Rhythm
•
•



Definition: Any disorder of cardiac rhythm is
termed an arrhythmia OR a dysrhythmia
Causes: These can result from:
Disorders of impulse generation
Disorders of impulse conduction
Disorders of a combination of both impulse
generation & conduction
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Factors predisposing to cardiac
dysrhythmias:
• are many include:
 Local ischaemia to the heart + myocardial
infarction (MI)
 Digitalis toxicity
 Catecholamines
 Local ionic changes ( Ca2+ and K+) (refer to
the ionic basis of a normal cardiac AP)
• These factors may increase pacemaker activity
in ectopic foci generating enhanced automaticity
and dysrhythmias
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• Clinically, dysrhythmias are classified
according to :
 the site of origin of the abnormalityatrial, junctional or ventricular
 whether the rate is:
- increased (tachycardia) or
- decreased (bradycardia)
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Types of Dysrhythmias
A) DISORDERS OF IMPULSE GENERATION:
• Supraventricular Dysrhythmias:
- Atrial Flutter
- Atrial fibrillation
- Supraventricular paroxysmal
tachycardia
• Ventricular Dysrhythmias:
- Ventricular fibrillation
- Ventricular paroxysmal tachycardia
32
Types of Dysrhythmias…
B) DISORDERS OF IMPULSE
CONDUCTION:
• Heart Block
• Re-entry dysrhythmias
33
A. Disorders of Impulse
Generation
•
The most common problem is the
development of an ectopic focus, a group of
cardiac cells that generate pacemaker
activity additional to the SA node.
Ectopic foci may be induced by:
(a) Mild damage to the cardiac muscle
(neighbouring myocardial infarction)
(b) Drugs e.g. general anaesthetics
(halogenated anaesthetics can sensitize the
myocardium to the actions of
catecholamines causing arrhythmias)
34
•
Ectopic foci may be induced by:…
c) Metabolic disturbances e.g. hyperthyroidism in
which there is increased sympathetic activity
& increased sensitivity to the actions of
catecholamines leading to arrhythmias
d) Emotion, excitement:
• release catecholamines
• Increase levels of cAMP which is
arrhythmogenic
35
• Arrhythmias due to disorders of impulse
generation can be classified into 2 groups
depending on the location of the ectopic focus:(A)Supraventricular arrhythmias
• Ectopic focus lies in the atria or AV node.
• Supraventricular arrhythmias drive the ventricles
at an increased rate which:
- reduce stroke volume – failure
- increase work load on the heart
36
Types of Supraventricular arrhythmias:
(1) Atrial flutter:
• Characterized by a regular and very fast atrial
rate (150 – 350/min)
• The ventricular rate becomes abnormally high
but regular
Cause of flutter
• A single ectopic focus in the atrial muscle
• ECG shows several P waves for each QRS
complex (in ratios of 2:1, 3:1, or 4:1)
• P waves are normal
37
(2) Atrial fibrillation:
• The atrial action potential rate is in the range of
200-600/min
• P waves are not normal
• The abnormality is due to the presence of
multiple ectopic foci in the atrial tissue
• Ventricular rate is higher and irregular, although
much lower than the atrial rate.
38
(3) Supraventricular paroxysmal tachycardia:
• Sporadic episodes of increased heart rate
• Caused by the appearance of an intermittent
ectopic focus in the atria
• Normal sinus rhythm can often be restored by
inducing acetylcholine release via reflex vagal
stimulation (pressure applied to the eyeballs or
to one of the carotid sinus)
39
(B) VENTRICULAR ARRYTHMIAS
• Occur when there is an ectopic focus in the
ventricles
Types:
(1) Ventricular fibrillation:
• rapid uncoordinated ventricular contractions
• severe reduction in cardiac output
NB:
-ventricular fibrillations are rapidly lethal
- pharmacological intervention has a limited role
-Patient should be given a DC electric shock to
cause reversion to normal rhythm
40
(2) Ventricular paroxysmal tachycardia
• caused by the intermittent appearance of an
ectopic focus in the ventricles
• characterized by:
(i) sporadic episodes of increased heart rate
• It is distinguished from the atrial kind by an
ECG record on which the QRS complexes
outnumber the P waves
41
B. Disorders of Impulse
Conduction
(1) Heart Block
• Common sites of heart block occur in the AV
node and the bundle of His
• There are different degrees of heart block
• a block may be caused by a localized damage
or depression of AV node or bundle of His
42
Causes:
1) ischaemia of AV node or nodal fibres
2) compression of AV node or bundle of His by
calcified heart tissue
3) inflammation of AV node or bundle of His
(different types of myocarditis e.g. diphtheria,
rheumatic fever)
4) extreme stimulation of the heart by the vagus
nerve (carotid sinus syndrome)
43
Degrees of heart block
1) 1st degree heart block: PR interval is
prolonged (longer than 0.2 S) but ECG
remains normal
2) 2nd degree block: Some P waves do not
initiate QRS complexes due to failure of AV
conduction BUT no additional beats arise
from the ventricular pacemaker activity
3) 3rd degree block: -AV conduction is blocked
- Ventricular contractions arise from the
ventricular pacemakers
44
Result:
• slower than normal ventricular rate
• no coordination between P waves and QRS
complexes
Treatment:
• Use of artificial pacemakers
• agonists at ß-adrenoceptors may be useful in
the short term but in general drug treatment is
of limited use for heart block
45
(2) Re-entry arrhythmias
• occur due to the presence in the cardiac muscle
of abnormal conduction pathways.
• The pathways may be the result of:
(a) damage to the heart muscle (myocardial
infarction caused by ischaemia)
(b) the effect of drugs e.g. ß-adrenoceptor
agonists, digoxin, quinidine which alter the
excitability of the heart muscle
46
Right bundle branch
left bundle branch
Normal heart (normal
conduction)
• wave of
depolarisation from
AV node enters both
L & R branches of
bundle of His
• waves of
depolarisation from
either side towards
the central portion of
ventricular muscle
cancel each other
47
• only waves
(B) LEFT BUNDLE
travelling upwards to
DAMAGED
L & R ventricular
muscle remain
• these diminish in
intensity and die off
as they come to the
base at the
connective tissue
between ventricles
& atria
48
• The right branch is damaged
by ischaemia
• anterograde but not
retrograde conduction is
blocked
• the wave of conduction from
the normal branch may enter
the damaged branch
retrogradely and reappear in
the normal branch
• this completes a re-entry
circuit
• Rare situation: the Wolff49
Parkinson-White syndrome
• Here an anatomically abnormal bundle of
cardiac muscle joins the atria to the ventricles,
bypassing the AV node.
• Thus the ventricles may be excited prematurely
via this short circuit in addition to the normal
pathway via the AV node to the bundle of His.
• Following excitation via the latter pathway, the
ventricular impulse may re-enter the atria
through the bypass to set up a circus of
excitation
50
To Continue……
• ………
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