PM 719 Pharmacology II - Chapter 14 Antiarrhythmics PDF

PM 719 Pharmacology II Chapter 14 Antiarrhythmics RMRocco, PhD PM716 C4 Arrhythmias 1  Case Study 69 year old female, 1 month history palpitations, shortness of breath and fatigue. History of hypertension, ECG shows atrial fibrillation with ventricul...

PM 719 Pharmacology II Chapter 14 Antiarrhythmics RMRocco, PhD PM716 C4 Arrhythmias 1  Case Study 69 year old female, 1 month history palpitations, shortness of breath and fatigue. History of hypertension, ECG shows atrial fibrillation with ventricular response of 122 bpm. Echocardiogram shows left ventricular ejection fraction 38% Rhythm reverts to normal after 7 days of metoprolol, but she continues to show paroxysms of atrial fibrillation. What antiarrhythmic drug to maintain normal sinus rhythm? PM716 C4 Arrhythmias 2  Case Study A drug well tolerated in heart failure (reduced ejection volume) and which has ability to convert or prevent atrial fibrillation would be: amiodarone or dofetilide (doe FET il ide) PM716 C4 Arrhythmias 3  Normal Cardiac Rhythm (1) Sinoatrial (SA) node, electrical impulse 60-100 beats/min frequency. (2) Impulse spreads through atria and enters atrioventricular (AV) node. (3) Impulse propagates through His-Perkinje fibers into ventricles. (4) Ventricles contract. PM716 C4 Arrhythmias 4 Chapter 14 Agents Used in Cardiac Arrhythmias PM716 C4 Arrhythmias 5 © The McGraw-Hill Companies, Inc,  Cardiac Conduction System (Electrical System) SA Node in right atrium (“natural pacemaker”) starts the electrical impulse that leads to heart beat SA node produces 60-100 beats (electrical impulses) per min AV Node between atria and ventricles (upper and lower chambers) AV node is electrical bridge which passes currents through to ventricles. PM716 C4 Arrhythmias 6  Cardiac Conduction System His-Purkinje System located in ventricles signal passes through cells to contract ventricle His bundle (start of the system) Right bundle branch Left bundle branch Purkinje fibers (end of the system) PM716 C4 Arrhythmias 7  Conduction 1 2 0 3 4 Phase 0 Rapid depolarization Class I drugs Phase 1 Early-fast repolarization Class II Phase 2 Plateau Class IV Phase 3 Repolarization Class III Phase IV Resting potential Class II PM716 C4 Arrhythmias 8  Cardiac Cell Ion Intracellular Extracellular mM mM Na+ 5 150 K+ 115 5 Ca++ 0.007 7 Cl- low PM716 C4 Arrhythmias 110 9  Action Potential (AP) 0 mV cardiac cell AP depolarization - 85 mV OUT K+ Na+ Ca++ IN Na+ Ca++ K+ Na+ PM716 C4 Arrhythmias 10  His-Perkinje Fibers Jan Evangelista Purkinje (1787-1869) Born in Czech Republic 1839 discovers fibers that conduct pacemaker stimulus along inside walls of the ventricles. Invents the word plasma to describe cell free portion of the blood. 1823 discovered use of fingerprints First person to use a microtome for tissue sections. Wilhelm His Jr (1863-1934) Swiss cardiologist 1893 bundle of nerves discovered. Discovers that heartbeat has origin in the heart cells. PM716 C4 Arrhythmias 11  Major Mechanisms of Arrhythmias Abnormal automaticity or abnormal (reentrant) conduction. Examples of Arrhythmias atrial flutter atrial fibrillation atrioventricular nodal reentry premature ventricular beats (PVBs) ventricular tachycardia ventricular fibrillation PM716 C4 Arrhythmias 12  Arrhythmia Arrhythmia = cardiac depolarization that deviates from normal due to (a) Abnormal site of impulse origin (b) Change from normal in rate or regulatory control (c) Change in conduction velocity PM716 C4 Arrhythmias 13  Arrhythmia Electrical potential in cardiac cell controlled by ion flux in/out of the cell through pores or gates. Ions not directly soluble in the cell wall membrane. Each cardiac myocyte channel or gate is ion- specific. PM716 C4 Arrhythmias 14  Arrhythmia Cardiac action potential divided into phases which are determined by the ions that flow during that phase. PM716 C4 Arrhythmias 15  Arrhythmia Movement of ions controlled by Ohm’s Law Current = voltage (conductance) Mechanisms of arrhythmias in relation to ion conduction. (a) Disturbance in impulse formation (b) Disturbance in impulse conduction (c) Both of the above PM716 C4 Arrhythmias 16 Chapter 14 Agents Used in Cardiac Arrhythmias PM716 C4 Arrhythmias 17 © The McGraw-Hill Companies, Inc,  Terms torsade de pointes (twisting of the points, from ballet): polymorphic ventricular tachycardia increased QT interval Drug induced or genetic Reentry: cycling of electrical impulse through conductive tissue that has been recently stimulated. Tachycardia and arrhythmia (originating usually in AV node). PM716 C4 Arrhythmias 18 Torsade de pointes PM716 C4 Arrhythmias 19  Drugs Required The drugs required for this Chapter 14 are listed in BOLD on pg 2-5 in the Lecture Notes for Chapter 14 Cardiac Arrhythmias. PM716 C4 Arrhythmias 20  Table 1. Antiarrhythmic Drugs Drug Class Drugs Indications Class 1A quinidine AF, PVCs procainamide disopyramide Class 1B lidocaine PVCs mexiletin Class 1C flecainide severe vent arrhythmias Class 2 esmolol AF, atrial flutter, PVCs propranolol Class 3 amiodarone AF, severe vent sotalol arrhythmias Class 4 verapamil AF, atrial fibrillation diltiazem PM716 C4 Arrhythmias 21  Antiarrhythmic Drugs General Mechanisms of action: Block sodium channels Block sympathetic autonomic effects Prolongation of refractory period Block calcium channels PM716 C4 Arrhythmias 22  Classes of Drugs Used to Treat Arrhythmias Class I Sodium channel blockers Local anesthetics, differ in their binding affinity to sodium channels Ia Prolong action potential duration (APD), intermediate acting Ib Shorten effect on APD, bind rapidly Ic Minimal to no effect on APD, slow binding PM716 C4 Arrhythmias 23  Classes of Drugs Used to Treat Arrhythmias Class IIBeta Blockers reduce beta adrenergic activity in heart Class III Prolong APD Block potassium currents Class IV Block calcium currents PM716 C4 Arrhythmias 24  Antiarrhythmic Drugs Most drugs in the four classes have all four actions but each drug has a dominant action which is how it is put into a specific class (I - IV). PM716 C4 Arrhythmias 25  Antiarrhythmic Drugs Class Ia procainamide quinidine disopyramide Class Ib lidocaine mexiletine PM716 C4 Arrhythmias 26  Antiarrhythmic Drugs Class Ic flecainide Class IIBeta Blockers propranolol esmolol PM716 C4 Arrhythmias 27  Antiarrhythmic Drugs Class III Potassium channel blockers amiodarone dofetilide ibutilide sotalol PM716 C4 Arrhythmias 28  Antiarrthymic Drugs Class IV Calcium Channel Blockers diltiazem verapamil PM716 C4 Arrhythmias 29  Antiarrthymic Drugs Misc Additional Drugs that do not fall neatly into the I- IV classification adenosine magnesium PM716 C4 Arrhythmias 30  Mechanisms All Class I drugs slow or block conduction slow or abolish abnormal pacemakers if Na + channels involved block Na+ channels in abnormal tissues more effectively than in normal tissue PM716 C4 Arrhythmias 31  Mechanisms Class IA Drugs used for both atrial and ventricular arrhythmias drugs block Na+ flux and slow conduction Class IB Drugs act mostly on Purkinje and ventricular tissue reduce action potential (AP) duration little effect on EKG phenytoin used to reverse digixon induced arrhythmias. PM716 C4 Arrhythmias 32  Mechanisms Ic Drugs depress Na+ currents but no effect on ventricular AP duration or QT interval drugs cause increase in QRS duration on EKG PM716 C4 Arrhythmias 33  Class Ia Drugs Class Ia Drugs used for all types of arrhythmias Procainamide hypotension and lupus erythematous (L. wolf) joint inflammation, pain, fever, skin rash, pleurisy. Fast and slow acetylators (NAPA metabolite) 1/3 of all patients. Quinidine may cause cinchonism (headache, vertigo, tinnitus) Digoxin displaced from receptor by quinidine and Cp of digoxin rises to lethal levels (digoxin TI 1.2 - 2.0 ng/mL) All Class Ia drugs may cause arrhythmias. PM716 C4 Arrhythmias 34 Quinidine Quinidine Class Ia sodium channel blocker QRS duration in EKG is prolonged Major cardiac effects: QT interval prolongation, induction of Torsade de Pointes arrhythmia and syncope. PM716 C4 Arrhythmias 35 Quinidine Extraction of quinine from cinchona bark was costly and time consuming. Drug had a high price. In 1865 more easily extracted drugs from cinchona bark were tested for antimalarial effects: quinidine discovered. PM716 C4 Arrhythmias 36 Quinidine Ad 1961 PM716 C4 Arrhythmias 37  Class Ib Drugs Used in acute ventricular arrhythmias caused by ischemia following MI. (lidocaine iv only, high first pass effect, 95 % of po dose lost to first pass, acts exclusively at sodium channels) All Class Ib may cause arrhythmias PM716 C4 Arrhythmias 38  Class Ic Drugs Used for both atrial and ventricular arrhythmias All Class Ic cause greater mortality compared to placebo but used when all other antiarrhythmics fail. PM716 C4 Arrhythmias 39  Class II Drugs Beta blockers reduce sodium and calcium currents and suppress abnormal pacemakers Esmolol used iv only for acute arrhythmias Propranolol, metoprolol and timolol used as prophylactic drug treatment in patients following MI. PM716 C4 Arrhythmias 40  Class III Drugs Hallmark of this class is prolongation of the AP duration. Block of potassium channels = repolarization of the AP. On EKG the QT interval is increased. Clinical uses include post MI arrhythmias and recurrent ventricular fibrillation. Sotalol may precipitate torsade de pointes arrhythmia. PM716 C4 Arrhythmias 41  Amiodarone A special case used in most arrhythmias, broad spectrum drug blocks sodium, potassium and calcium channels drug blocks beta receptors High toxicity, used when all others fail deposits in cornea and skin causes thyroid dysfunction PM716 C4 Arrhythmias 42  Class IV Drugs Used for arrhythmias that traverse calcium dependent cardiac tissues (ex AV node) Used to convert AV nodal reentry (called nodal tachycardia) to normal sinus rhythm Most important toxicity (verapamil), constipation, nausea, flushing, dizziness. May cause heart failure. PM716 C4 Arrhythmias 43 Adenosine Adenosine (endogenous) but also used in high doses ( 6- 12 mg) iv with t1/2 of 15 seconds. Drug slows or blocks conduction in AV node and blocks AV nodal arrhythmias. Both potassium and calcium channels blocked. PM716 C4 Arrhythmias 44  Principles in the Clinical Use of Antiarrhythmic Agents Eliminate the cause: electrolyte disturbances, drugs etc Make a firm diagnosis: arrhythmia must be confirmed before the start of therapy Determine the baseline condition: few antiarrhythmic drugs are safe in patients with CHF and other underlining cardiac disease. Question the need for therapy: not all arrhythmia requires drug treatment. PM716 C4 Arrhythmias 45