Antiarrhythmic Agents

Learning Objectives Explain the mechanism of antiarrhythmic agents List classifications of antiarrhythmic agents Summarize the pharmacological effects, clinical applications and ADR of Quinidine, Lidocaine, Phenytoin, Propranolol , Amiodarone and Verapamil

arrhythmia Cardiac arrhythmia is a frequent problem in clinical practice. Disturbances of Impulse formation or conduction

Cardiac electrophysiology Inside cell: K+ ; Outside cell: Na+, Ca++ Ion channel status/ Transmembrane movement Membrane potential

Normal action potential in ventricular myocytes and Purkinje cells, Reproduced from Katzung & Trevor’s Pharmacology Examination & Board Review, 9th edition, McGraw-Hill, 2010.

Action potential (AP) and Phase 0-4 phase 0---reactivity---conduction--- Na + phase 1--------------------------------- K + phase 2, 3---afterdepolarization--- Ca ++ phase 4---automaticity--- Na + Action potential duration /Effective Refractory Period: membrane potential~-60 mV

Effects of Group I drugs on the action potential and ion currents in a typical ventricular cell or Purkinje cell. Reproduced from Katzung & Trevor’s Pharmacology Examination & Board Review, 9th edition, McGraw-Hill, 2010.

Mechanisms of arrhythmia 1. disturbances of impulse formation Automaticity Maximum Diastolic Potential , slope of phase 4 depolarization , threshold potential Afterdepolarization Early (P2,3: Ca inflow ) Delayed (P4:Ca Na inflow )

Mechanisms of arrhythmia 2. Abnormality of impulse conduction Reentry (circus movement)

cardiac conduction system

Normally, electrical excitation is transmitted around the circuit, and becomes extinguished at the other end of the circuit due to collision of impulses. Normal conduction

Forward impulse obstructed and extinguished Depressed region Unidirectional block

Retrograde impulse travels around the obstacle because the conduction time is longer than the refractory period Retrograde impulse

Retrograde impulse reexcites the tissue, and the reentry arrhythmia is extablished

For reentry to occur, three conditions must coexist There must be the presence of an anatomically or functionally defined circuit There must be unidirectional block at some point in the circuit; that is, conduction must die out in one direction but continue in the opposite direction Conduction time around the circuit must be long enough that the retrograde impulse does not enter refractory tissue as it travels around the obstacle; that is, the conduction time must exceed the effective refractory period.

16-word pithy formula – “CURE” 单向阻滞 有路可通 Circuit c Unidirectional block U 折返 16 字诀 超不应期 E R 逆向传导 Exceed ERP Retrograde conduction

Electrophysiologic effects of Antiarrhythmic drugs 1.To decrease Automaticity Increase MDP, Slow down slope of phase 4 , increase threshold potential (TP)

Electrophysiologic effects of Antiarrhythmic drugs 2.To reduce post depolarization and triggered activity antagonize cellular Ca to impaired EAD Inhibit Na influx to impaired LAD

Electrophysiologic effects of Antiarrhythmic drugs 3.To change membrane responsiveness, so to change the conduction, hence to terminate reentry To increase MR so suppress unidirectional block To decrease MR so change unidirectional block to bidirectional block

Electrophysiologic effects of Antiarrhythmic drugs 4.To change ERP and APD so terminate reentry Absolutely prolong ERP and APD Relatively prolong ERP(shorten APD) Symmetric ERP

20-word pithy formula – “AdCREA” 去后除极 降自律性 A Ad After- depolarization Automaticity Antiarrhythmia E C 减慢传导 延不应期 Conduction R ERP 消除折返 Reentry

Antiarrhythmic agents Ⅰ：sodium channel antagonists ⅠA ：block Na+ Channel ++, quinidine ⅠB ： + ，lidocaine ⅠC ： +++ ，flecainide Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics; drugs with class 1B action shorten the APD and dissociate from the channel with rapid kinetics; and drugs with class 1C action have minimal effects on the APD and dissociate from the channel with slow kinetics.

Antiarrhythmic agents Ⅱ： β -R blockers: propranolol Class 2 action is sympatholytic Drugs with this action reduce -adrenergic activity in the heart. Ⅲ： selective prolong APD: amiodarone Class 3 action manifests as prolongation of repolarization. Most drugs block the rapid component of the delayed rectifier potassium channel, IKr. Ⅳ： CCBs: verapamil

Antiarrhythmic agents-IA IA Quinidine Mechanism ( )Na---phase-0,4 Pharmacologic effects conduction automaticity(pukinje fiber ) ERP, APD Block alpha adrenoceptor so cause vasodilation Anti-M-cholinoceptor to increase heart rate

Antiarrhythmic agents-IA Clinical use (broad –spectrum ) Common in Atrial Fibrillation and flutter, occationally in ventricular tachycardia. ADR: 1. Cinchonism (headache, dizziness, tinnitus) 2. Gastrointestinal effects (diarrhea,nausea,vomiting) 3. allergic reaction(angioneurotic edema) 4. Quinidine syncope (excessive QT interval prolongation and torsade de pointes arrhythmia)

Antiarrhythmic agents-IA IA procainamide Mechanism : similar to quinidine Pharmacologic effects automaticity(pukinje fiber ) conduction ERP,APD Adverse reaction: cardiotoxic effects; Extracardiotoxicity: lupus-like syndrome

Drugs cause the lupus-like syndrome 笨扑一惊，狼来了！ 苯妥英钠 Phenytoin 普鲁卡因胺 Procainamide 异烟肼 Isoniazide 肼屈嗪 Hydralazine

Antiarrhythmic agents-Ib IB- lidocaine Mechanism: Na, + K Pharmacologic effects + K potential recover to the resting potential automaticity ( slow velocity of P-4 in PF ) terminate reentry

Clinic use : Adverse reaction : first choice for ventricular tachycardia and fibrillation after myocardial infarction Adverse reaction : Least cardiotoxic effects Neurologic: paresthesias,tremor, convulsions, slurred speech, hearing disturbances, lightheadedness

Antiarrhythmic agents-Ib IB-phenytoin sodium Mechanism similar to lidocaine Pharmacologic effects * decrease automaticity in PF * compete with cardiac glycoside for combination of Na-K-ATPase Clinic use: to treat digoxin-induced arrhythmias

Antiarrhythmic agents-Ic IC-Propafenone Mechanism Na, (0,4), β-R Pharmacologic effects automaticity conduction Clinic use: supraventricular arrhythmias ADR: QT ;metallic taste,constipation

Antiarrhythmic agents-II β-R antagonists: propranolol Mechanism β-R, Na, ERP Clinic use SVT, Af, hyperthyrosis ADR SB, AVB, HF, Hypotension, Asthma.

Antiarrhythmic agents-III Selectively prolong repolarization Mechanism (Amiodarone) : block K+ ,Na+, Ca++ Pharmacological actions • Reduce automaticity in sinoatrial node and PF • slow conduction in atrioventricular node and PF • prolong ERP in atria and PF

Antiarrhythmic agents-III Selectively prolong repolarization Clinic uses : • Supraventricular(atrial fibrillation), ventricular (tachycardia/fibrillation) tachyarrhythmias ADRs: photosensitive skin, thyroid abnormalities(hypo- and hyper-), pulmonary fibrosis, corneal microdeposits, neurological and gastrointestinal disturbances

Antiarrhythmic agents-IV CCB: verapamil Pharmacological actions • reduce automaticity in sinoatrial node and atrial-ventricular node by slowing P-4 velocity • slow conduction in atrioventricular node • prolong ERP Suppress afterdepolarization Clinic uses: • to prevent or terminate recurrence of paroxysmal SVT; • to reduce the ventricular rate in patients with atrial fibrillation

Antiarrhythmic agents Drugs to treate Bradycardia Atropine, Isoprenaline

Antiarrhythmic agents-ADR Common ADR of Antiarrhythmic agents is proarrhythmia.

Summary IA IB IC II III IV Agent Na - - K- Na- K+ Na- - - Na-K+ - β R Quni. Lido. Propa. Propra. Sotalol Ami. Ver. Ion Ch. Na - - K- Na- K+ Na- - - Na-K+ - β R Na-K-- Ca- Ca-- AP 0,4 0,2,4 0,1-3 0,2 ERP + - (r+) -(r+) ++ ClinicU AF, Af PVC,Vf PVC,VT SVT,pvc SVT,V SVT ADR Cinchoni -sm,gastrointestine QT+ CNS, - breath BC, asthma Ex.car organs constipation BC AVB Proarrhythmia, CO-

USMLE-STEP 1 A 57-year-old man is brought to the emergency room for a suspected myocardial infarction. An electrocardiogram indicates the appearance of a wide-complex ventricular tachycardia with a rate of 126 beats per minute. The physician prescribes a drug to decrease SA node automaticity, increase AV node refractoriness, and decrease AV node conduction velocity. Which of the following agents was most likely prescribed? A. Amiodarone B. Disopyramide C. Lidocaine D. Propranolol E. Verapamil