1. CARDIAC ARRHYTHMIAS & ANTI-ARRHYTHMIC DRUGSOr
Cardiac Dysrhythmias
& Anti-dysrhythmic Drugs
16th Feb 2017

2. 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.

3. 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

4. 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-lipid-calcium deposits in the walls of arteries

5. Drugs Affecting the Heart: Introduction
This topic will consider effects of drugs on the heart under three main headings:
Rate and rhythm
Myocardial contraction
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.

6. 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)

7. 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

8. 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)

9. 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.

10. The Ionic Basis of Normal Cardiac Action Potential…
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

11. 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 L-type channel, which is also important in vascular smooth muscle; L-type channels are important in specialized conducting regions as well as in working myocardium.

12. The Ionic Basis of Normal Cardiac Action Potential…
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 types

13. Fig.1. Cardiac muscle cell AP

14. 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

15. 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

16. 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

17. 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.

18. 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.

19. 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

20. 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

21. (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

22. 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

23. 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

25. (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

26. (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

27. (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

28. CARDIAC DYSRHYTHMIAS (ARRHYTHMIAS)

29. 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

30. 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

31. Clinically, dysrhythmias are classified according to :
the site of origin of the abnormality-
atrial, junctional or ventricular
whether the rate is:
- increased (tachycardia) or
- decreased (bradycardia)

32. Types of Dysrhythmias DISORDERS OF IMPULSE GENERATION:
Supraventricular Dysrhythmias:
- Atrial Flutter
- Atrial fibrillation
- Supraventricular paroxysmal
tachycardia
Ventricular Dysrhythmias:
- Ventricular fibrillation
- Ventricular paroxysmal tachycardia

33. Types of Dysrhythmias…
B) DISORDERS OF IMPULSE CONDUCTION:
Heart Block
Re-entry dysrhythmias

34. 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:
Mild damage to the cardiac muscle (neighbouring myocardial infarction)
Drugs e.g. general anaesthetics (halogenated anaesthetics can sensitize the myocardium to the actions of catecholamines causing arrhythmias)

35. Ectopic foci may be induced by:…
Metabolic disturbances e.g. hyperthyroidism in which there is increased sympathetic activity & increased sensitivity to the actions of catecholamines leading to arrhythmias
Emotion, excitement:
release catecholamines
Increase levels of cAMP which is arrhythmogenic

36. 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

37. Types of Supraventricular arrhythmias:
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

38. (2) Atrial fibrillation:
The atrial action potential rate is in the range of /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.

39. (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)

40. (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

41. (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

42. 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

43. Causes:
ischaemia of AV node or nodal fibres
compression of AV node or bundle of His by calcified heart tissue
inflammation of AV node or bundle of His (different types of myocarditis e.g. diphtheria, rheumatic fever)
extreme stimulation of the heart by the vagus nerve (carotid sinus syndrome)

44. Degrees of heart block
1st degree heart block: PR interval is prolonged (longer than 0.2 S) but ECG remains normal
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
3rd degree block: -AV conduction is blocked
- Ventricular contractions arise from the ventricular pacemakers

45. 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

46. (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

47. 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

48. only waves travelling upwards to 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
(B) LEFT BUNDLE DAMAGED

49. 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 Wolff-Parkinson-White syndrome

50. 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

51. To Continue……
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