Drugs used in the treatment of arrhythmia I Dr. Asmaa Fady PhD., MSC., M.B, B.Ch اسم ورقم المقرر – Course Name and No. 8/2/2019

Learning Objectives: By the end of the lecture, the student should, understand the cardiac action potential and pathophysiology of arrhythmia. Recognize and categorize different antiarrhythmic drugs According to mechanism of action Describe the mechanism of action of antiarrhythmic drugs and their effects on action potential & ECG reading Identify the clinical uses of antiarrhythmic drugs Identify side effects & toxicity of antiarrhythmic drugs that limit their clinical usefulness اسم ورقم المقرر – Course Name and No. 8/2/2019

Cardiac conductive system AV bundle اسم ورقم المقرر – Course Name and No. 8/2/2019

Phases Of Cardiac Action Potential: Non- Pacemaker cells Phase 4 Pacemaker cells: SAN AVN Purkinji fibers 8/2/2019

Phases Of Cardiac Action Potential: Phase (0): (excitability& conductivity) Normal muscle fiber: influx of Na+ through activated Na Channels (Rapid Na+ Influx: Depolarization = Excitability & Conductivity ). SAN: Activation of Na & Ca + Channels (Rapid Ca+ Influx: Depolarization) Phase (1): Inactivation of Na+ channels. Start of K+ Efflux. Phase(2):Activation of Slow Ca + Channels( Slow Ca Influx: Plateau.) Phase (3): Inactivation of Ca2+ Channels. Full activation of K+ Channels : Rapid K+ Efflux : Rapid Repolarization. Phase (4): a- Normal Cardiac muscle fiber : Resting potential. (Inactivated ALL channels). Due to Activation of Na+ / K+ ATPase ( Na/K Pump) Restore electrolyte balance. b- Slope phase 4: (automaticity) S.A.N., Conductive tissue & Ectopic Focus (still Slow Na+ & Ca2+ Influx ) due to Opening of inactivated Na & Ca channels. Action Potential Duration (A.P.D) = Effective Refractory Period (E.R.P) 8/2/2019

Pathophysiology of Cardiac Dysrhythmia Dysrhythmia (Arrhythmia) means any abnormality in Rate, Regularity, Origin or Conduction of an Impulse. All arrhythmias result from: • Disturbances in impulse formation: Nodal abnormality (rate): SAN Ectopic Focus Formation: Any cell with Automaticity faster than S.AN. • Disturbances in impulse conduction (AVN- accessory pathways) • Disturbance in impulse formation and conduction اسم ورقم المقرر – Course Name and No. 8/2/2019

Antiarrhythmic Drugs Blocking ion Channels: 1- Block of Activated Na+ channels Slow Phase (0) Slow Excitability & Conductivity. 2- Block of Inactivated Na+ channels Slow Phase (4) Slow Automaticity. 3- Block of Slow Ca2+ Channel Short Phase (2) of cardiac muscle fiber. & Slow Automaticity (phase 0) of Ectopic focus. 4- Block of K+ channel Delay Repolarization Long Phase (3) Long A.P.D. & long E.R.P. اسم ورقم المقرر – Course Name and No. 8/2/2019

Goals of Antiarrhythmic Drugs • To maintain normal rhythm and conduction in the heart • Decrease conduction velocity • Increase the duration of the refractory period • Suppress abnormal automaticity اسم ورقم المقرر – Course Name and No. 8/2/2019

Vaughn William Classification Of Anti-arrythmic Drugs: Anti- arrhythmias Class I (Na channel blockers) A B C Class II (Beta blockers) Class III (K channel blockers) Class IV (Ca channel blockers) Others اسم ورقم المقرر – Course Name and No. 8/2/2019

8/2/2019 اسم ورقم المقرر – Course Name and No.

1)Class I (Na Channel blockers): (Membrane stabilizers) Mechanism: Block activated Na channels slow (phase 0): excitability & conductivity. Block inactivated Na channels Moderate Slow (phase 4): automaticity. Class I A : Action Potential Duration. (moderate channel blocker) Class I B: APD (weak channel blocker) Class I C: no effect on Action Potential Duration. (strong channel blocker) اسم ورقم المقرر – Course Name and No. 8/2/2019

Class I: Na+ Channel blockers = Membrane Stabilizers A) Group A: Block BOTH types of Na+ & K+ Channels: 034 1- Moderate block of Activated Na+ channel Moderate Slow of Phase(0) Moderate slow Excitability & Conductivity 2- Moderate Block Inactivated Na+ Channel Slow Phase (4) Slow Automaticity 3- Block K+ Channel Delay repolarization Long Phase (3) Long A.P.D., & E.R.P. Examples: Quinidine, Procainamide & Disopyramide. B) Group B: 4 1- Minimal Block of Activated Na+ channel Minimal effect on conductivity & Excitability 2- Block MAINLY Inactivated Na+ Channel Slow Phase (4) Slow Automaticity. 3- Activate K+ Channel Rapid repolarization Short Phase (3) Short APD & ERP Examples: Lidocaine & Mexiletine C) Group C: 0 1- Block MAINLY Activated Na+ Channels Marked Slow Phase (0) Marked Slow Excitability & Conductivity Examples: Flecainide, Encainide & Propafenone. اسم ورقم المقرر – Course Name and No. 8/2/2019

Cardiac effect of class I anti-arrthymic drugs Action potential duration APD no effect on APD 8/2/2019 اسم ورقم المقرر – Course Name and No.

Class I A Na channel blockers Quinidine, Disopyramide & procainamide. Mechanism Of Action: 0-3-4 1- all drugs in this class: a- Moderate block of Activated Na+ channel Moderate slow of phase (0) Moderate Slow of Excitability & Conductivity b- Block K+ channel Delay repolarization Long Phase (3) Long Action potential duration (APD) & Effective Refractory Period (ERP) c- moderate Block Inactivated Na+ channel Slow Phase (4) Slow Automaticity Stop Ectopic focus. 2- Quinidine blocks Vagal tone = Anti-Vagal = Vagolytic = Atropine-like effect. 3- procainamide is ganglion blocker. اسم ورقم المقرر – Course Name and No. 8/2/2019

Class I A Na channel blockers Quinidine, Disopyramide & procainamide Quinidine & Disopyramide are Rarely used Cardioversion or defibrillation and amiodarone have mostly replaced procainamide in clinical use. Therapeutic uses: Atrial fibrillation, flutter, supraventricular tachy-arrhythmias. Ventricular tachy-arrhythmias when other measure fail (last choice) اسم ورقم المقرر – Course Name and No. 8/2/2019

Class I A Na channel blockers Toxicity Quinidine Disopyramide Procainamide Non-Cardiac Toxicity GI (N, V, D) in 1/3 patients • Anticholinergic effect • Cinchonism •Profound anticholinergic effect • Negative inotropic • Drug-induced lupus syndrome • Hypotension (IV). *ganglion blocker Metabolism by liver acetylation. Into active (NAPA), excreted by kidneys Therapeutic Consideration • Quinidine induced Digoxin toxicity •Caution in LV systolic dysfunction patients •Lupus-like syndrome in slow acetylators - Baseline & periodic determination of (N-acetyl procainamide) Cardiac prolonge QT wave ⇒ torsades de pointes !!! Stop the drug immediately Cinchonism such as: blurred vision, tinnitus, headache, disorientation, and psychosis Anticholinergic effects such as: dry mouth, urinary retention, blurred vision, and constipation اسم ورقم المقرر – Course Name and No. 8/2/2019

Class IB Na channel blockers: Lidocaine (IV): oral form undergo extensive first pass hepatic effect Mechanism of action: 1)anti-arrythmic drug: 2- Block MAINLY Inactivated Na+ Channel Slow Phase (4) Slow Automaticity. 3- Opens K+ Channel Rapid repolarization Short Phase (3) Short APD & ERP 2) In Therapeutic Dose on Normal Heart: NO Atropine-like effect & NO Effect on S.A.N., A.V.N., Contractility or Blood pressure 3) Local Surface anesthetic. Therapeutic Uses: IV ( Emergency VF or pulseless VT if amiodarone is unavailable Toxicity: C.N.S. Stimulation & Allergy اسم ورقم المقرر – Course Name and No. 8/2/2019

Class IB Na+ channel blockers: Mexiletine: Orally active analog of lidocaine. Therapeutic Uses: in combination with other anti-arrhythmic such as amiodarone for chronic treatment of ventricular arrthymia. Observe: class I B has NO efficacy against atrial fibrillation, flutter; supraventricular tachy-arrhythmias اسم ورقم المقرر – Course Name and No. 8/2/2019

Class IC Na+ channel blockers: Flecainide & Propafenone. Mechanism of action: Potent Block Activated Na+ channel Slow Phase “0” Slow Excitability & Conductivity, Especially in Atria, Ventricles & Purkinje fibers. Propafenone has also B-Blocking effect Therpuetic uses: A. fibrillation, A. flutter, Paroxysmal Supra Ventricular Tachycardia, SVT in patients without structural heart diseases (left ventricular hypertrophy, heart failure, atherosclerotic heart disease). Ventricular tachycardia. Contraindicated in coronary artery disease or post-M. Infacrction Also used as “Pill-in-the-pocket” اسم ورقم المقرر – Course Name and No. 8/2/2019

Flecainide Propafenone Class IC Na+ channel blockers: Flecainide & Propafenone (adverse effects) Flecainide Propafenone Non-Cardiac Toxicity - Blurred vision (dose related) - CNS (dizziness, headache, tremor) - GI adverse effects - Bronchospasm (B blockade) Cardiac Toxicity • Significant negative inotropic (bring on new or worsen CHF) • Sinus bradycardia (B blockade) Therapeutic Consideration Avoid in patients with underlying heart abnormalities – CAD, ventricular dysfunction – can precipitates heart failure اسم ورقم المقرر – Course Name and No. 8/2/2019

2) Class II: B-Blockers Metoprolol, Propranolol & Esmolol antagonize sympathetic stimulation of β1- adrenergic receptors in SAN and AV node cells slow automaticity and slow rate (decrease all cardiac properties) 8/2/2019 اسم ورقم المقرر – Course Name and No.

Class II: B-Blockers Propranolol Mechanism of Action: a- Small Dose Blocks ONLY B-Adrenergic receptors b- Large Dose, It blocks also: Na+ channel = Class “I” Activity = Membrane stabilizer = Quinidine-like Slow Ca2+ channels = Class “IV” activity. Decrease K current: ⇒ increase refractory period of impulse ECG: PR prolongation BB: HR, conduction velocity, contractility SAN & AVN Phase 4 (AVN) prolongs phase 3 اسم ورقم المقرر – Course Name and No. 8/2/2019

Class II: B-Blockers Propranolol, Therapeutic uses: As Anti-Arrhythmic: a- Sympathetic-induced arrhythmia (Use Small Dose of Propranolol) b- Non-Sympathetic induced arrhythmia (Use Large Dose of Propranolol ) c- Particularly effective in Supra-ventricular arrhythmia Propranolol (decreases A-V conduction & Protects the ventricles) اسم ورقم المقرر – Course Name and No. 8/2/2019

Class II: B-Blockers Propranolol toxicity Non-cardiac toxicity: • Bronchospasm Cardiac toxicity: • Excessive negative inotropic effects, heart block • Hypotension •Sinus Tachycardia and/or hypertension upon sudden drug withdrawal Therapeutic considerations: • Taper drug withdrawal over 4-7 days اسم ورقم المقرر – Course Name and No. 8/2/2019

Beta blockers contraindications Beta blockers are contraindicated in cases of WPW syndrome. Because it slows the conduction via AV node and favors the accessory pathway conduction which my ppt. ventricular arrthymia and death اسم ورقم المقرر – Course Name and No. 8/2/2019

اسم ورقم المقرر – Course Name and No. 8/2/2019