MPP2 2025 L03 Arrhythmias and Antiarrhythmic Drugs PDF

Arrhythmias and Antiarrhythmic Drugs Lecture 03 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Describe the following arrhythmias and be able to recognize them from the ECG tracing a. Sinus bradycardi...

Arrhythmias and Antiarrhythmic Drugs Lecture 03 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Describe the following arrhythmias and be able to recognize them from the ECG tracing a. Sinus bradycardia b. Ventricular bradycardia c. Sinus tachycardia d. Atrial tachycardia and fibrillation e. Premature ventricular complex f. Ventricular tachycardia 2. Describe how abnormal automaticity and reentry can cause arrhythmias 3. List causes of abnormal conduction 4. Describe the utility and short-comings of the Vaughn-Williams classification scheme 5. Describe how specific Class I, III, and IV drugs affect ion channels and alter rate and conduction 6. Describe how the following drugs are used to treat arrhythmias: adenosine, atropine, and ivabradine 2 Learning resources Guided Learning: Pharmacologic Treatmentof Arrhythmias at cvpharmacology.com Links found on slides Klabunde, Cardiovascular Physiology Concepts, Wolters Kluwer: 3e, Ch 3: 47-50 3 Abnormal Rate: Bradycardia, Tachycardia, Fibrillation, Premature beats 4 Bradycardia (rate < 60 bpm) Atrial (sinus) bradycardia Physiological causes: Highly trained athletes can have a resting HR as low as 40 bpm https://www.shutterstock.com/search/sinus-bradycardia Pathological causes ○ Ischemia of the SAN ○ Excessive vagal tone ○ Electrolyte disorders ○ Drugs – e.g., beta-blockers, calcium-channel blockers Treatment ○ Remove the underlying cause if possible ○ Chronotropic drugs – e.g., atropine, beta-agonist ○ Pacemaker 5 Bradycardia (rate < 60 bpm; >5 large squares)) Ventricular bradycardia Pathological causes: ○ SA nodal failure unmasks slower, latent pacemakers within the AV node or ventricular conduction system 2° AV block ○ 2° AV block, which causes the ventricular rate to beat slower than the sinus rate because not all impulses travel through the AV node ○ 3° AV block, which leads to the expression of a pacemaker site within the ventricles that fires at a slow rate (30-40 3° AV block beats/min) ○ Damage or degeneration of bundle of His and bundle branches Treatment ○ Reverse AV block, if possible ○ Pacemaker 6 Tachycardia (rate > 100 bpm; < 3 large squares) Sinus tachycardia Physiological causes: ○ Exercise ○ Acute stress (sympathetic activation) Pathological causes: ○ Chronic stress ○ Hyperthyroidism ○ Fever and infection ○ Cardiac disease (structural, ischemic) ○ Anemia ○ Drugs & medications Treatment ○ Drugs that slow rate (e.g., beta-blockers, calcium-channel blockers) 7 Tachycardia (rate > 100 bpm) Atrial tachycardia Atrial flutter (250–350 bpm) ○ Causes Heart disease (structural, ischemic) Electrolyte disorders Thyroid disorders Medications, drugs & alcohol Genetic ○ Treatment Drugs Ablation 8 Tachycardia (rate > 100 bpm) Atrial tachycardia Atrial fibrillation ○ Rapid, random, spontaneous depolarizations within atria ○ Can lead to rapid ventricular rate ○ Causes Heart disease (structural, ischemic) Thyroid disease Excessive catecholamines Medications, drugs & alcohol Genetic ○ Treatment Drugs Ablation 9 Premature ventricular complex (PVC) Spontaneous firing of ventricular ectopic foci that is not triggered by normal conduction pathways Produces early, premature ventricular contraction Wide, atypical QRS 10 Tachycardia (rate > 100 bpm; < 3 large squares) Ventricular tachycardia Pathological causes: ○ Chronic stress ○ Hyperthyroidism ○ Fever and infection ○ Cardiac disease (structural, ischemic) https://www.healio.com/cardiology/learn-the-heart/ecg-review/ecg-archive/ventricular- ○ Anemia tachycardia-ecg-example-3 ○ Drugs & medications NOTE: Large variability in morphology Underlying electrophysiological mechanisms ○ Rapid spontaneous firing of ectopic ventricular site ○ Afterdepolarizations ○ Reentry (local and global) Treatment https://ecgwaves.com/topic/ventricular-tachycardia-vt-ecg-treatment-causes-management/ ○ Drugs that slow rate (e.g., beta-blockers, 11 calcium-channel blockers) Abnormal conduction (e.g., prolonged PR interval, QRS, QT interval) Functional abnormalities ○ Ischemic injury related to coronary artery disease depolarizes cells and inactivates fast Na+ channels (non-nodal tissue), which decreases the slope of phase 0 and decreases conduction velocity ○ Severe hyperkalemia (depolarizes cells) ○ Abnormal pacemaker sites (e.g., ectopic foci) ○ Excessive vagal activation of AV node Anatomic abnormalities ○ Congenital accessory pathways ○ Degenerative disease Chemical ○ β-adrenoceptor agonists or antagonists; muscarinic (M2) agonists/antagonists ○ Antiarrhythmic drugs (e.g., sodium channel blockers; calcium channel blockers) 12 Antiarrhythmic Drugs 13 Levels of learning 1. Vaughan-Williams classification of antiarrhythmic drugs 2. Basic mechanisms of each class 3. Prototypical drugs in each class 4. Class-related arrhythmia indications 5. Recognize names and classification of drugs listed in slides 6. Distinguishing pharmacokinetics, side effects, contraindications, drug interactions 14 Important issues concerning antiarrhythmic drugs Bradycardia is most commonly treated non-pharmacologically by implanting electrical pacemakers Tachycardia is commonly treated by drugs that suppress ○ Abnormal automaticity ○ Triggered activity (afterdepolarizations) ○ Reentry Some types of tachycardia are most effectively treated by tissue ablation Many antiarrhythmic drugs, particularly Class I and III drugs, have significant proarrhythmic activities 15 Classification of antiarrhythmic drugs Vaughan-Williams classification ○ Class I (IA, IB, IC, ID): Sodium-channel blockers ○ Class II: Beta-blockers ○ Class III: Potassium-channel blockers ○ Class IV: Calcium-channel blockers Drugs not fitting into Vaughan-Williams classification ○ Adenosine ○ Atropine ○ Digoxin ○ Magnesium ○ Ivabradine 16 Vaughan-Williams classification summary CLASS BASIC MECHANISM COMMENTS Class I sodium-channel blockade Reduce phase 0 slope and peak of action potential. IA - moderate Moderate reduction in phase 0 slope; increase APD; increase ERP. IB - weak Small reduction in phase 0 slope; reduce APD; decrease ERP. IC - strong Pronounced reduction in phase 0 slope; no effect on APD or ERP. ID - late current Increase APD and ERP. Class II beta-blockade Block sympathetic activity; reduce sinus rate and electrical conduction. Class III potassium-channel blocka Delay repolarization (phase 3) and thereby increase action potential de duration and effective refractory period. Class IV calcium-channel blockade Block L-type calcium-channels; most effective at SA and AV nodes; reduce sinus rate and electrical conduction. Abbreviations: APD, action potential duration; ERP, effective refractory period; SA, sinoatrial node; AV, atrioventricular node. 17 Class I Antiarrhythmic Drugs Sodium-channel blockers 18 Class I – sodium channel blockers Primarily inhibit fast sodium- channels found in non-nodal tissue SCBs Reduce slope of phase 0 Reduce conduction velocity in non-nodal tissue, which can suppress tachycardias caused by reentry circuits 19 Class I – Sodium channel blockers (IA, IB, and IC) Class IA: e.g., quinidine ○ Moderate fast Na+-channel blockade ○ ↑ ERP by ↓gK+ (Class III effect) Class IB: e.g., lidocaine ○ Weak fast Na+-channel blockade ○ ↓ ERP ○ Preferentially affects ischemic tissue Class IC: e.g., flecainide Na+ blockade: ○ Strong fast Na+-channel blockade IC > IA > IB Increasing ERP: ○ → ERP (Purkinje cells) IA > IC > IB (decreases) ○ ↑ ERP (nodal tissue; bypass tracts) 20 Class I drug list Class IA Class IC ○ quinidine* ○ flecainide* ○ procainamide ○ propafenone ○ disopyramide ○ moricizine Class IB Class ID ○ lidocaine* ○ ranolazine* ○ tocainide ○ mexiletine *prototype 21 Class I – additional mechanisms Suppressing abnormal pacemaker automaticity ○ ↓ phase 4 slope by unknown mechanism in His/Purkinje fibers and abnormal ectopic foci ○ ↑ threshold for triggering action potentials Anticholinergic properties ○ Class IA drugs (disopyramide>quinidine>procainamide) ○ Modifies actions on conduction and automaticity, particularly at sites with high vagal innervation (i.e., SAN & AVN) Blocking phase 2 late sodium currents (Class ID, ranolazine) 22 Class I – therapeutic indications Class IA ○ Atrial fibrillation & flutter ○ Ventricular tachyarrhythmias Class IB ○ Ventricular tachyarrhythmias (particularly those caused by ischemia) Class IC ○ Life-threatening supraventricular & ventricular tachyarrhythmias Class ID ○ Premature ventricular complexes NOTE: The use of Class IA and IC drugs is declining in favor of Class III drugs 23 Summary of Class I drugs Class IA: atrial fibrillation, flutter; supraventricular & ventricular tachyarrhythmias quinidine* anticholinergic (moderate) cinchonism (blurred vision, tinnitus, headache, psychosis); cramping and nausea; enhances digitalis toxicity procainamide anticholinergic (weak); lupus-like syndrome in 25-30% of patients relatively short half-life disopryamide anticholinergic (strong) negative inotropic effect Class IB: ventricular tachyarrhythmias (VT) lidocaine* IV only; VT and PVCs good efficacy in ischemic myocardium; binds primarily to inactivated Na +-channels in ischemic cells; therefore, little effect in normal cardiac cells tocainide orally active lidocaine analog can cause pulmonary fibrosis mexiletine orally active lidocaine analog good efficacy in ischemic myocardium Class IC: life-threatening supraventricular tachyarrhythmias (SVT) and ventricular tachyarrhythmias (VT) flecainide* SVT can induce life-threatening VT propafenone SVT & VT β-blocking and Ca++-channel blocking activity can worsen heart failure moricizine VT; IB activity Class ID: ventricular arrhythmias (premature ventricular complexes, PVC) ranolazine* PVC also classified and used as an antianginal 24 Class II Antiarrhythmic Drugs Beta-blockers 25 How do beta-blockers act as antiarrhythmics? Block the proarrhythmic effect of excessive sympathetic activation Decrease sinus rate Slow ventricular rate in atrial fibrillation and flutter by depressing AV nodal conduction Suppress abnormal automaticity (e.g., PVCs) Suppress reentry arrhythmias ○ ↑ ERP, especially at AV node ○ ↓ conduction velocity Suppress afterdepolarizations 26 Class II – Beta-blockers Propranolol is the prototypical beta-blocker ○ Non-selective for β1 and β2-adrenoceptors Newer beta-blockers (e.g., metoprolol, acebutolol, esmolol) differ in: ○ Selectivity for β1 and β2-adrenoceptors (e.g., metoprolol is ꞵ1-selective) ○ MSA (membrane stabilizing activity; related to sodium channel inhibition; e.g., metoprolol, propranolol) ○ ISA (intrinsic sympathomimetic activity (e.g., acebutolol) ○ Pharmacokinetics (e.g., esmolol has T½ = 9 min) Click here for comprehensive list of beta-blockers 27 Some contraindications of β-blockers Sinus bradycardia AV nodal block Heart failure (except for carvedilol and metoprolol) Asthma (particularly nonselective blockers) 28 Class III Antiarrhythmic Drugs Potassium-channel blockers 29 Class III – Delayed repolarization Structurally dissimilar drugs Mechanisms ○ Primary: K+- channel blockade, which delays repolarization (phase 3) and increases the ERP ○ Secondary: Other class (receptor & channel) effects Particularly effective in supraventricular and ventricular tachycardia caused by reentry Increased Q-T interval can lead to torsades de pointes (a form of ventricular tachycardia resulting from afterdepolarizations) http://lifeinthefastlane.com/ecg-library/tdp/ 30 Summary of Class III antiarrhythmics Drug Therapeutic Uses Comments amiodarone ventricular tachycardia, including very long half-life (25-60 days); Class I, II, III & IV actions and therefore decreases ventricular fibrillation; atrial fibrillation phase 4 slope and conduction velocity; side effects include (some serious): and flutter (off-label use) pulmonary fibrosis; hypothyroidism; hepatotoxicity; corneal micro-deposits, skin discoloration dronedarone atrial fibrillation (non-permanent) and structurally related (but non-iodinated) to amiodarone, but has a much smaller flutter volume of distribution and shorter elimination half-life (~24 hr); Class I, II, III & IV actions; contraindicated in severe or recently decompensated, symptomatic heart failure; although less toxic than amiodarone, it is less efficacious in atrial fibrillation bretylium life-threatening ventricular tachycardia IV only; initial sympathomimetic effect (norepinephrine release) followed by and fibrillation inhibition, which can lead to hypotension sotalol ventricular tachycardia; atrial flutter and inhibits opening of repolarizing K+ channels and increases ERP; also has Class II fibrillation (beta-blocker) activity and therefore slows sinus rate ibutilide atrial flutter and fibrillation (acute activates slow inward Na+ currents during early phase 3 and inhibits opening of termination) repolarizing K+ channels, which delays repolarization and increases ERP; IV only; can cause life-threatening ventricular arrhythmias; infrequent non-cardiac side effects dofetilide atrial flutter and fibrillation; paroxysmal approved for acute atrial flutter and fibrillation; very selective K+-channel blocker; supraventricular tachycardia (off-label) can cause life-threatening ventricular arrhythmias 31 Class IV Antiarrhythmic Drugs Calcium-channel blockers 32 Class IV – Calcium-channel blockers ERP Block L-type calcium channels, particularly in SA and AV nodes CCB ○ ↓ phase 0 slope of nodal action potentials ○ ↓ AV nodal conduction velocity ○ ↑ AV nodal ERP (prolongs repolarization) ○ Suppresses AVN reentry mechanisms Decrease automaticity ○ ↓ phase 4 slope ○ ↑ threshold 33 Class IV – Calcium channel blockers cont. Drugs (non-dihydropyridines) ○ Verapamil (highly cardioselective) ○ Diltiazem (moderately cardioselective) Indications ○ Supraventricular tachycardias involving AV nodal reentry ○ Slowing ventricular rate during atrial fibrillation/flutter by suppressing AV nodal conduction 34 Some contraindications of calcium-channel blockers Pre-existent bradycardia Conduction defects (especially WPW) Heart failure 35 DRUGS NOT FITTING INTO THE VAUGHAN-WILLIAMS CLASSIFICATION 36 Adenosine Rapidly suppresses supraventricular tachycardia caused by AV nodal reentry Fast acting, very short half-life (