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Antiarrhythmic Drugs Slide 2 Drug List Class 1 Sodium Channel Blockers Class 2 Beta-blockers Class 3 Potassium Channel blockers Class 4 Calcium Channel Blockers Others 1aProcainamide Quinidine Metoprolol Propranolol Amiodorone Ibutilide Dofetilide Sotalol Verapamil Diltiazem Adenosine Magnesium Digoxin 1bLidocaine Mexiletine Phenytoin 1cFlecainide More drugs have been mentioned in other slides Slide 3 Physiology Review To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchrony Relaxation must occur between contractions Coordination of heartbeat is a result of pacemaker activity of the SA node and transfer of impulses through AV node and the purkinje system Slide 4 Arrhythmia A condition where there is a disturbance in Pacemaker impulse formation Impulse conduction Combination of the two Results in change of heart rate or contraction of heart muscle in a way that is insufficient to maintain normal cardiac output To understand how antiarrhythmic drugs work, need to understand electrophysiology of normal contraction of heart Slide 5 Ventricular Arrhythmia Ventricular arrhythmias are common in most people and are usually not a problem but VA s are most common cause of sudden death Majority of sudden death occurs in people with neither a previously known heart disease nor history of VA s Medications which decrease incidence of VA s do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease! Slide 6 Electrophysiology - resting potential A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell Caused by unequal distribution of ions inside vs. outside cell Na + higher outside than inside cell Ca + much higher K + higher inside cell than outside Maintenance by ion selective channels, active pumps and exchangers Slide 7 ECG (EKG) showing wave segments Contraction of atria Contraction of ventricles Repolarization of ventricles Slide 8 Cardiac Action Potential Divided into five phases (0,1,2,3,4) Phase 4 - resting phase (resting membrane potential) Phase cardiac cells remain in until stimulated Associated with diastole portion of heart cycle Addition of current into cardiac muscle (stimulation) causes Phase 0 opening of fast Na channels and rapid depolarization Drives Na + into cell (inward current), changing membrane potential Transient outward current due to movement of Cl - and K + Phase 1 initial rapid repolarization Closure of the fast Na + channels Phase 0 and 1 together correspond to the R and S waves of the ECG Slide 9 Cardiac Action Potential Phase 2 - plateau phase sustained by the balance between the inward movement of Ca + and outward movement of K + Has a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect) Corresponds to ST segment of the ECG. Phase 3 repolarization K + channels remain open, Allows K + to build up outside the cell, causing the cell to repolarize K + channels finally close when membrane potential reaches certain level Corresponds to T wave on the ECG Slide 10 Differences between nonpacemaker and pacemaker cell action potentials Pacemaker Cells - Slow, continuous depolarization during rest Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization) Slide 11 Mechanisms of Cardiac Arrhythmias Result from disorders of impulse formation, conduction, or both Causes of arrhythmias Cardiac ischemia Excessive discharge or sensitivity to autonomic transmitters Exposure to toxic substances Unknown etiology Slide 12 Types of arrhythmias Tachyarrythmias Bradyarrhythmia Tachyarrythmias Atrial: A fibrillation, Aectopics, Atrial tachycardia Nodal: Supraventricular Tachycardia Sinus Tachycardia ventricular: Ventricular Tachycardia, ventricular ectopics,Ventricular fibrillation or flutter Slide 13 Brady arrhythmia: Heart rate is less than 60 except in ( athletes) 1.Heart block 2.Sinus brady -cardia Slide 14 Antiarrhythmic drugs Biggest problem antiarrhythmics can cause arrhythmia! Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmia Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing antiarrhythmics Slide 15 Classification of Antiarrhythmic Drugs Class I: Sodium channel blockers (membrane- stabilizing agents) 1 a: Block Na + channel and prolong action potential 1 b: Block Na + channel and shorten action potential 1 c: Block Na + channel with no effect on action potential Class II: - blockers Class III: Potassium channel blockers (main effect is to prolong the action potential) Class IV: Slow (L-type) calcium channel blockers Slide 16 Class 1a Drugs They are the oldest group of antiarrhythmic drugs and are still widely used. Procainamide Blocks sodium channels, slows the upstroke of the action potential, slows conduction, prolongs the QRS duration of the ECG. The drug also prolongs the action potential duration by nonspecific blockade of potassium channels. Procainamide has direct depressant actions on sinoatrial and atrioventricular nodes Slide 17 Procainamide Extracardiac Effects Procainamide has ganglion-blocking properties. This action reduces peripheral vascular resistance and can cause hypotension, particularly with intravenous use. Pharmacokinetics: Absorbed well orally. Metabolized in liver,portion of the drug can be acetylated to NAPA which has little class 3 activity it is excreted by kidney. Toxicity : QT interval prolongation, and induction of torsade de pointes arrhythmia and syncope. New arrhythmias can be precipitated. Lupus erythmatosus, Pleuritis, pericarditis, or parenchymal pulmonary disease. Nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (< 5%) Therapeutic Use : Therapeutic Use Atrial and ventricular arrhythmias Slide 18 Quinidine Similar to procainamide. Also blocks K+ channels. Adverse effects Anticholinergic (i.e. anti-muscarinic), blocks receptors. Diarrhea, nausea A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations. Excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. Not very commonly used these days and largely replaced by calcium antagonists in clinical practice Slide 19 Class 1b Drugs Lidocaine Block Na + channel and shorten action potential duration. Lidocaine has a low incidence of toxicity. A high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route. Cardiac Effects Lidocaine blocks activated and inactivated sodium channels with rapid kinetics it shorten the period of repolarization (phase 3) thereby the period of action potential,it has no effect in refractory period. Adverse effects: Lidocaine is one of the least cardiotoxic of the currently used sodium channel blockers.it shows little impaiment to left ventricular function and no negative iontropic effect,Paresthesias, nausea of central origin, lightheadedness, hearing disturbances. In preexisting heart failure, lidocaine may cause hypotension Slide 20 Class 1b Drugs Pharmacokinetics: Extensive first-pass hepatic metabolism Lidocaine must be given parenterally,Lidocaine has a half-life of 12 hours. Therapeutic Use: Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia (Myocardial infarction) Slide 21 Mexiletine (1b) Mexiletine is given orally. Its electrophysiologic and antiarrhythmic actions are similar to those of lidocaine. Therapeutic use: Treatment of ventricular arrhythmias associated with pervious MI. Pain due to diabetic neuropathy and nerve injury. Adverse effects: Tremor, blurred vision, and lethargy. Nausea Slide 22 Tocainde (1b) Similar to Mexilitine and Lidocaine It is used for treatment of ventricular tachy- arrhythmias Can lead to plumonary fibrosis Slide 23 Phenytoin (1b) It is an other agent in this category and is usually used to treat ventricular arrhythmias caused by cardiac glycosides Slide 24 Class 1c Drugs Flecainide Blocks Na + channel with no effect on action potential. Flecainide is a potent blocker of sodium and potassium channels. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval). It has no antimuscarinic effects, it prolong the effective refractory period. It suppress the upstroke of phase 0 in purkinji fibers and all myocardial tissues It shows depression of conduction in all cardiac cells Automaticity is reduced by an increase in threshold potential It has prominent effect even in normal heart Recent data have cast serious doubt about safety of this class Slide 25 Class 1c Drugs Pharmacokinetics: Flecainide is well absorbed and has a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney Therapeutic Uses: Premature ventricular contractions. Atrial fibrillation (AF), Wolf Parkinson White (WPW) syndrome Toxicity: Arrhythmia, can aggravate congestive heart failure because it has a negative ionotropic effect Slide 26 Class 1c Drugs Propafenone This drug is similar to Flecainide, slows conduction in all cardiac cells and is considered broad spectrum anti- arrhythmic agent. Slide 27 Class 2 Drugs. Beta Blockers PROPRANOLOL: Suppress adrenergically mediated ectopic activity. Drugs have antiarrhythmic properties by virtue of their -receptorblocking action and direct membrane effects Some of these drugs have selectivity for cardiac 1 receptors e.g. metopro

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