1. 1 CARDIAC ARRHYTHMIAS & ANTI-ARRHYTHMIC DRUGS Or Cardiac Dysrhythmias & Antidysrhythmic Drugs February, 2012

2. 2 Introduction: The Heart 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, and of autonomic control.  This provides a basis for understanding effects of drugs on the heart and their place in treating cardiac disease.  The main drugs considered are the antidysrhythmic drugs; drugs that increase the force of contraction of the heart (esp. digoxin), and anti- anginal drugs.

3. 3 Introduction:- The Heart… 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 Beta adrenoceptor antagonists

4. 4 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

5. 5 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)

6. 6 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 +, Ca 2+ 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.

7. 7 The ionic basis of normal cardiac action potential The cardiac action potential is conventionally divided for descriptive purposes into five phases. These broadly correlate with the opening and/or closing of different ion channel types

8. 8 Fig.1. Cardiac muscle cell AP Fig.1 O 1 2 o -90 3 4 MV (a) Cardiac muscle cell action potential

9. 9 Explanation Phase 0= rapid depolarization: The main upstroke of the cardiac action potential is primarily due to influx of Na+ through voltage sensitive Na+ channels

10. 10 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.

11. 11 Phase 2= the plateau is primarily due to Ca influx. The depolarization generated during phase 0 initiates the relatively slow action of L-type voltage-sensitive Ca channels. The influx of Ca 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.

12. 12 Phase 2= the plateau (continue) Entry of Ca 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.

13. 13 Phase 3= rapid repolarization due to K+ efflux. This phase terminates the AP Occurs as the Ca++ current inactivates and a delayed outwardly rectifying K+ current activates, causing outward K+ current.

14. 14 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 (inwards ??, outwards ??)

15. 15 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

16. 16 (2) Slow Ca 2+ - 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

17. 17 Cardiac muscle can be divided into 3 main types 1) Tissue with spontaneous pacemaker activity:- (a) SA node (b) The AV node (2) Specialised high velocity conducting tissue. (a) bundle of His (b) the Purkinje fibres (3) Atrial & Ventricular myocardium

18. 18 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

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20. 20 (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 Ca 2+ Na 2+ influx plays only a minor role

21. 21 (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 Ca 2+ - Na + currents – Plateau of AP K + channels – repolarising phase

22. 22 (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

23. 23 CARDIAC DYSRHYTHMIAS (ARRYTHMIAS)

24. 24 Cardiac dysrhythmias (arrythmias) 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

25. 25 Factors predisposing to cardiac dysrhythmias: are many include:  Local ischaemia to the heart + (MI)  Digitalis toxicity  Catecholamines  Local ionic changes ( Ca++ 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 dysrrhythmias

26. 26 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)

27. 27 Types of Dysrhythmias A)DISORDERS OF IMPULSE GENERATION: Supraventricular dysrhythmias: - Atrial Flutter - Atrial fibrillation - Supraventricular paroxysmal tachycardia Ventricular dysrhythmias: - Ventricullar fibrillation - Ventricular paroxysmal tachycardia

28. 28 Types of Dysrhythmias B) DISORDERS OF IMPULSE CONDUCTION: Heart Block Re-entry dysrhythmias

29. 29 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 arrythmias)

30. 30 (c) Metabolic disturbances e.g. hyperthyroidism in which there is increased sympathetic activity & increased sensitivity to the actions of catecholamines leading to arrythmias (d) Emotion, excitement: release catecholamines Increase levels of cAMP which is arrhythmogenic

31. 31 Arrythmias due to disorders of impulse generation can be classified into 2 groups depending on the location of the ectopic focus (A)Supraventricular arrythmias Ectopic focus lies in the atria or AV node. Supraventricular arrythmias drive the ventricles at an increased rate which: - reduce stroke volume – failure - increase work load on the heart

32. 32 Types of Supraventricular arrhymias: (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

33. 33 (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.

34. 34 (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)

35. 35 (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

36. 36 (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

37. 37 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

38. 38 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)

39. 39 Degrees of heart block (1) 1 st degree heart block: PR interval is prolonged (longer than 0.2 S) but ECG remains normal (2) 2 nd 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) 3 rd degree block: -AV conduction is blocked - Ventricular contractions arise from the ventricular pacemakers

40. 40 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

41. 41 (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

42. 42 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 V. muscle cancel each other

43. 43 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

44. 44 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

45. 45 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

46. 46 ANTIARRHYMIC or ANTIDYSRHYTHMIC DRUGS

47. 47 ANTIARRHYMIC DRUGS- Classification 4 classes: Class I: Inhibitors of Na + influx- subdivided into Ia, Ib and Ic Class II: ß-adrenoceptor antagonists Class III: Drugs that substantially prolong the cardiac action potential Class IV: Calcium antagonists

48. 48 Class I Drugs-Inhibitors of Na + Influx Inhibit the fast Na + channels also block the slow Ca 2+ - Na + channels reduce intracellular Ca 2+ leading to a -ve inotropic effect must be used with care where heart failure is suspected

49. 49 inhibition of Na + channels leads to either: - (a) slowing of conduction - (b) increase in refractory period Drugs under this class have local anaesthetic or membrane stabilizing effect Class I subgroups: Ia, Ib and Ic The reason for subdivision is that the earliest examples, quinidine and procainamide (Class Ia) have different effects from many of the more recently developed drugs, even though all share the same basic mechanism of action.

50. 50 Class Ia: suitable for ventricular & supraventricular arrythmias include:  quinidine  procainamide  Disopyramide  lorcainide

51. 51 Class Ia (continue) In the therapeutic concentrations they: raise the threshold for excitation (lengthen AP duration) cause minor slowing of intra-cardiac conduction widen the QRS complex they prolong the AP and lengthen the effective refractory period (probably results from K+ channel blockade) of atrial, ventricular & purkinje fibres

52. 52 Class Ia (continue): Quinidine, procainamide & disopyramide have a low therapeutic index their -ve inotropic effects extend to skeletal muscle (aggrevation of myasthenia gravis) and vascular smooth muscle (hypotension) -varying degree of atropine-like effect.

53. 53 Class Ib suitable for suppression of ventricular Arrhythmias after myocardial infaction include:  Lignocaine, Phenytoin, Mexiletene and tocainide Properties: -they shorten AP duration & effective refractory period - have no effect on intra-cardiac conduction or QRS complex

54. 54 Class Ib: Lignocaine/lidocaine Has a rapid onset of action and a short half- life (approx. 1h) given i/v as the 1st line drug in the treatment of ventricular arrhythmias after myocardial infarction and surgery inactive orally also an antagonist at muscarinic acetylcholine receptors and may evoke mild tachycardia by removing the effect of vagal tone on the SA node SE: confusion, fits, sweating and drowsiness

55. 55 Class Ib: Phenytoin used almost exclusively in digitalis- induced ventricular arrhythmias Its general anti arrhythmic effectiveness is less than that of lignocaine S.E: hypotension

56. 56 Class Ib: Tocainide: -analogue of lignocaine -active orally and i/v -has similar electrophysiological & haemodynamic properties to lignocaine. -longer acting Mexiletene: -similar electrophysiological properties to lignocaine - active orally and i/v

57. 57 Class Ic Drugs in this group have 2 effects: (a) slow intra-cardiac conduction (b) widen the QRS complex They do not so much affect the threshold of excitation Include: Flecainide, Encainide, and Propafenone

58. 58 Class Ic; Flecainide Slows conduction in atria, His-purkinje system, accessory pathways & ventricles in therapeutic concentrations it causes lengthening of the PR & QRS intervals it is a powerful broad spectrum antiarrhythmic effective vs atrial arrhythmias, tachycardia involving accessory pathways (Wolff-Parkinson- White syndrome) & ventricular arrhythmias

59. 59 Class Ic:Encainide: -similar antiarrhythmic spectrum to flecainide Class Ic: Propafenone: -has additional minor ß-blocking and calcium channel antagonist properties -effective against supraventricular and ventricular arrhythmias

60. 60 Class II: ß-adrenoceptor antagonists effective in arrhythmias associated with sympathetic overactivity or increased circulating catecholamines E.g. Myocardial infarction, emotion, exercise, anaesthesia they reduce automaticity (ectopic pacemaker)

61. 61 Class II: ß-adrenoceptor antagonists increase effective refractory period decrease conduction velocity Include:  Propronolol  Atenolol  Metoprolol  Acebutolol  timolol

62. 62 Class II Bretylium: has adrenergic neurone blocking activity suppresses release of NA It is both Class II & III

63. 63 Class III DRUGS THAT PROLONG BOTH THE ACTION POTENTIAL AND REFRACTORY PERIOD Also called slow repolarizers they block K + -channels prolong the duration of the plateau region of cardiac AP lengthen effective refractory period

64. 64 Drugs: Amiodarone, bretylium, sotalol Amiodarone: blocks K + & Na + - channels it is a non-competitive antagonist at alpha & ß-adrenoceptors (Class I and class II effects) effective against many arrhythmias including Wolff-Parkinson-White syndrome) due to side effects it is only used when other drugs can not be used

65. 65 It causes irreversible liver damage, thyroid disorders (its molecule contains iodine) it causes neuropathy & pulmonary alveolitis Sotalol: it is a non-selective beta-blocker also has class III activity prolongs atrial & ventricular action potential duration prolongs refractory period

66. 66 Class IV INHIBITORS OF CALCIUM INFLUX (Calcium antagonists) Inhibit the slow inward Ca2+ - current which result in: (1) slowed conduction (2) prolonged refractoriness in the AV node useful for supraventricular tachycardia involving the AV node. Blocks intranodal re-entry circuits

67. 67 effective in some types of re-entry tachycardia in which the AV node is involved Not effective in Wolff-Parkinson-White syndrome

68. 68 Class IV drug-Verapamil effective when the Ca 2+ channels are either activated or inactivated (occurs when frequency of AP is high) [use-dependent] It is the main drug Used to prevent recurrence of paroxysmal supraventricular tachycardia And to reduce the ventricular rate in patients with atrial fibrillation (especially if inadequately controlled with digoxin), provided they do not have Wolff-Parkinson-White or related disorder

69. 69 Class IV drug- Diltiazem: similar antiarrhythmic properties to verapamil

70. 70 Nifedipine: not anti-arrhythmic. It does not exhibit use-dependence it also blocks the slow Ca2+ channels but it is only effective when the channels are in the activated state

71. 71 NOT CLASSIFIED DIGOXIN: slows conduction and prolongs the refractory period in the AV node and bundle of His used in atrial fibrillation which it does not stop but it slows & strengthens the ventricular beat reduces the frequency at which impulses pass along the conducting tissue Principal indication: CHF associated with atrial fibrillation

72. 72 Adenine nucleotides Adenosine & ATP used as substitutes for verapamil in the treatment of supraventricular tachycardias (adenosine is safer than verapamil) they act via purinergic receptors situated in the SA & AV nodes stimulation of these receptors hyperpolarizes cells resulting in suppression of automaticity and conduction

73. 73 Interrupt re-entry circuits in AV nodal tachycardia, and AV tachycardia involving an accessory pathway (Wolff- parkinson-White syndrome). ALTERNATIVE TO DRUGS (1) use of pacemakers (2) DC shock - if atrial size is normal it causes reversion to normal rhythm in most patients with atrial fibrillation (relapse 60% within 1 yr)

74. 74 (3) surgical ablation of ectopic focus or bundle of His to control supraventricular arrhythmias - pacemaker

75. 75 References 1.Lecture notes on clinical pharmacology 4 th Ed. John L. Reid, Peter C. Rubin & Brian Whiting 2.Basic Pharmacology 4th Ed by R.W. Foster 3.Pharmacology 5 th ed by Rang & Dale et al 4.Medical Pharmacology at a glance by M.J. Neal 5.The Physiology of excitable cells 3 rd ed by David J. Aidley pg 313 6.Textbook of Medical physiology 7 th ed. By Arthur C. Guyton 7.Pharmacology by Rang & Dale, 7 th edition, chapter 18

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