Faculty of Pharmacy, Misr International University Outline I. Introduction (Pacemaker & myocardial Action Potentials, ECG) II. Definition and general classification of arrhythmia III. Abnormal impulse conduction (bradyarrhythmias) IV. Abnormal impulse generation (mechanism) V. Classification of antiarrhythmic drugs 5/16/2014 2 2 Pacemaker SA-node Primary pacemaker 105 impulse/min Sinus rhythm AV-node Secondary pacemaker 45-60 impulse/min Nodal rhythm Purkinje System Tertiary pacemaker 25-40 impulse/min Idioventricular rhythm Inhibitory vagal tone 5/16/2014 3 Pacemaker Potential 5/16/2014 4 3 Contractile myocardium action potential Phase 0: rapid depolarization due to rapid Na + influx Phase 1: early partial repolarization due to K + efflux Phase 2: plateau prolonged depolarization due to Ca 2+ influx through slow Ca channels (depolarizing Ca 2+ ) Phase 3: repolarization due to K + efflux without Ca 2+ influx Phase 4: complete repolarization by Na + /K + pump 5/16/2014 5 The absolute refractory period (ARP): The ventricles can not respond to any stimuli The relative refractory period (RRP): The ventricles can respond to strong stimuli Supernormal phase of excitability (SNP): The heart respond to weaker stimuli 5/16/2014 6 4 Electrocardiogram (ECG) 5/16/2014 7 II. What is Arrhythmia? Abnormal rate or rhythm of heart beats Abnormal Impulse Generation Abnormal Impulse Conduction Tachyarrhythmia Bradyarrhythmia Heart Block 5/16/2014 8 5 III. Abnormal Impulse Conduction Sinoatrial block (SA block) No P-wave Atrioventricular block (AV block) 1 st degree (prolonged AV conduction) so PR interval is long 2 nd degree (regular & irregular) 3 rd degree 5/16/2014 9 5/16/2014 10 6 IV. Abnormal Impulse Generation (Mechanism) Ectopic foci: It occurs when cells in the myocardium or conducting tissue develop a more rapid phase 4 depolarization than the SA node e.g. ischaemia Re-entry circus movement: It occurs when the impulse arrives at a part of the myocardium that is refractory to the stimulus because of abnormally slow repolarization 5/16/2014 11 5/16/2014 12 7 Normal and re-entrant electrical pathways: A. In normal impulse conduction, an impulse traveling down a pathway arrives at point a, where it is able to travel down two alternate pathways, 1 and 2. In the absence of re-entry, the impulses continue on and depolarize different areas of the ventricle. B. A re-entrant circuit can develop if one of the branch pathways is pathologically disrupted. When the impulse arrives at point a , it can travel only down pathway 1 because pathway 2 is blocked unidirectionally (i.e., the effective refractory period of the cells in pathway 2 is prolonged to such an extent that anterograde conduction is prohibited). The impulse conducts through pathway 1 and proceeds to point b . At this point, the cells in pathway 2 are no longer refractory, and the impulse conducts in a retrograde fashion up pathway 2 toward point a. When the retrograde impulse arrives at point a, it can initiate re-entry, resulting in a sustained pattern of rapid depolarizations that trigger tachyarrhythmias. This mechanism can occur over small or large regions of the heart 5/16/2014 13 V. Classification of Antiarrhythmic Drugs According to the effect on myocardial action potential (Vaughan Williams Classifications): Class-I: Sodium channel blockers Class-II: Beta-adrenoceptor blocker Class-II: Potassium channel blockers Class-IV: Calcium channel blockers Miscellaneous 5/16/2014 14 8 Class I: Sodium Channel Blockers Blocking of Na channel rate of depolarization during phase 0 The central concept in blocking Na channel is that of use- dependent channel block In general, the use-dependent characteristics enables class I to block the high frequency excitation of the myocardium without preventing the heart from beating at normal frequencies They have other function that have been proved by electrophysiological studies e.g. K+ channel blocking delay repolarization 5/16/2014 15 Class Examples Mechanism APD ARP AV Conduction Contractility Ia Quinidine Block Na + (moderate dissoc.) & K + channels
Procainamide Disopyramide Ib Lignocaine Mexiletine Block Na + channel (fast dissoc.) & opening K + channel - - Ic Flecainide Propafenone Block Na + channel (slow dissoc.) - - 5/16/2014 16 9 Sodium Channel Blockers (cont.) Pharmacological effects: Heart: direct myocardial depressant & atropine-like action Automaticity: of automatic cells especially ectopic foci > nodal cells by depressing the slope of phase 4 Rhythmicity (HR): Initial tachycardia due to atropine-like action then HR by direct suppression of SA node Excitability: They prolong the RP for all cardiac tissues (SA node, atria & ventricles) especially ectopic foci Conductivity: AV conduction at small dose (atropine-like action) then AV conduction by prolonging the RP Contractility: -ve inotroipc effect 5/16/2014 17 Sodium Channel Blockers (cont.) ECG: Prolongation of PR interval: AV conduction QRS Widening: duration of ventricular systole If >50% of the original value toxicity Prolongation of ST segment: Slow ventricular repolarization In case of toxicity Torsade de pointes arrythmia Abnormal T wave: inverted or depressed BP: Quinidine can depress vascular smooth muscle tone, in part by -receptor blockade PR and hypotension (at high dose) 5/16/2014 18 10 Sodium Channel Blockers (cont.) Therapeutic uses: Supraventricular arrhythmias: It is primarily used chronically and prophylactically to prevent recurrences of paroxysmal supraventricular tachycardia Atrial flutter and fibrillation: Quinidine should not be used without prior digitalization because its vagolytic action may increase the frequency of impulse transmission across the A-V node Ventricular arrhythmias 5/16/2014 19 Sodium Channel Blockers (cont.) Side effects and toxicity: GIT disturbance including nausea, vomiting and anorexia Quindinecan cause cinchonism Mild symptoms include tinnitus, haring loss, vomiting and diarrhea Severe symptoms include headache, diplopia, photophobia, altered perception of color, confusion and psychosis -ve inotropic producing hypotension particularly disopyramide Cardiotoxicity A-V block Torsade de pointes arrythmia CNS toxicity (drowsiness, tremor, confusion & convulsion) Antimuscarinic effects (urinary retention, dry mouth & blurred vision) Allergic reaction Contraindications: Heart block Digitalis-induced arrhythmia Idiosyncrasy hypersensitivity reaction 5/16/2014 20 11 Sodium Channel Blockers (cont.) Class Examples ECG Clinical Uses Side Effects Ia Quinidine PR prolongation QRS widening QT prolongation Supraventricular & ventricular arrhythmia (broad spectrum) GIT disturbance Cinchonism Atropine-like effects Hypotension Allergic reaction Cardiotoxicity Procainamide Disopyramide Ib Lignocaine No widening of QRS Small reduction of QT IV only for ventricular arrhythmia following MI GIT disturbance CNS toxicity Ic Flecainide Propafenone PR prolongation QRS widening Life threatening ventricular arrhythmia GIT disturbance Hypotension CNS toxicity 5/16/2014 21 Class II: - Blockers 5/16/2014 22 12 - Blockers Pharmacological effects: The mechanism in arrhythmias is primarily cardiac beta blockade and reduction of cAMP, which results in the reduction of Ca 2+ current and the suppression of abnormal pacemakers The A-V node is particularly sensitive to -blockers and PR interval is prolonged Certain -blockers block Na + channel (e.g. propranolol) 5/16/2014 23 - Blockers (cont.) Effects on the Heart 1. Decreases S-A node automaticity 2. Decreases A-V node conduction velocity 3. Decreases myocardial contractility Effects on ECG Prolong P-R interval (due to decreased AV node conduction to ventricle) Therapeutic Use Supraventricular tachycardia (above the AV node) 5/16/2014 24 13 - Blockers (cont.) Esmolol, a very short-acting -blocker for iv administration, is used almost exclusively in acute surgical arrhythmias Propranolol, metoprolol and timolol are commonly used as prophylactic drugs in patients who have had a myocardial infarction (these drugs provide a protective effect for two years or more after the infarct) 5/16/2014 25 Class III: Potassium channel blockers E.g. Amiodarone, Bretylium& Sotalol Effects on the Heart 1. Delays repolarization 2. Prolongs action potential duration 3. Prolongs ARP 4. Also they have -blocking activity Effects on ECG Prolongs QT interval Therapeutic Use Ventricular tachycardia and fibrillation 5/16/2014 26 14 Potassium channel blockers (cont.) Amiodarone may be considered the most efficacious antiarrhythmic drug It has a broad spectrum: it blocks sodium, calcium and potassiumchannels and beta adrenoceptors Because of its toxicity, amiodarone must be reserved for use in arrhythmias that are resistant to other drugs Amiodarone causes thyroid dysfunction, microcrystalline deposits in the cornea & skin, pulmonary fibrosis and hepatotoxicity Amiodarone rarely causes newarrhythmia 5/16/2014 27 Class IV: Calcium channel blockers Effects on the Heart 1. Reduction of S-A node automaticity 2. Reduction of A-V node conduction velocity 3. Reduction of myocardial contractility (less Ca) Effects on ECG Prolongs PR interval Therapeutic Use Supraventricular tachycardia 5/16/2014 28 15 Calcium channel blockers (cont.) e.g. Verapamil and Diltiazem Verapamil was the drug of choice in treating atrioventricular nodal reentry (also known as nodal tachycardia) until discovering adenosine Because of its effects on the A-V node, verapamil should not be used in patients with A-V nodal dysfunction Verapamil can depress myocardial contractility; therefore, it is contraindicated in patients with CHF 5/16/2014 29 Miscellaneous antiarrhythmic drugs Adenosine It is a normal component of the body, but when it is given in high doses as an IV bolus, the drug markedly slows conduction in the atrioventricular node, probably by reducing calcium current Adenosine is extremely effective in abolishing A-V nodal arrhythmia and, because of its very low toxicity, has become the drug of choice for this arrhythmia 5/16/2014 30 16 Miscellaneous antiarrhythmic drugs (cont.) Digitalis: In atrial flutter or fibrillation, digitalis slows A-V conduction sufficiently to protect the ventricles from excessive high rates The later applications of digitalis become less common since the development of calcium channel blockers and adenosine as antiarrhythmic drugs 5/16/2014 31 5/16/2014 32