Pharmacology of Antiarrhythmic Drugs Lecture PDF

Pharmacology of Antiarrhythmic Drugs Maria A. Pino, Ph.D Department of Clinical Specialties [email protected] Office of Academic Affairs  Session Objectives Recognize and categorize antiarrhythmic drugs Describe the electrophysiological mechanisms of the antiarrhythmic drug classes De...

Pharmacology of Antiarrhythmic Drugs Maria A. Pino, Ph.D Department of Clinical Specialties [email protected] Office of Academic Affairs  Session Objectives Recognize and categorize antiarrhythmic drugs Describe the electrophysiological mechanisms of the antiarrhythmic drug classes Describe the specific adverse effects associated with these drug classes Describe the uses of each group of antiarrhythmic. Include contraindications. Describe the miscellaneous drugs used to treat arrhythmias. Source: Course Syllabus Cardiac Action Potential Phase 0: Opening of sodium channels and entry of sodium into the cell via ion channels and down a concentration gradient. “upstroke” Phase 1: Sodium channels close. “initial repolarization”. Phase 2: Calcium channels open and allow calcium entry “plateau” Phase 3: Potassium channels open as calcium channels are closing “repolarization” Phase 4: Potassium remains the major conductive ion as the sodium-potassium pump resets the concentration gradient for each ion. Na+-Ca++ antiport re-establishes the appropriate K Ca+ concentrations. EKG P wave: atrial depolarization PR: AP thru atria and AV node QRS: ventricular depolarization T wave: ventricular repolarization (K+ levels) QT: duration of ventricular AP Mechanisms of Arrhythmias Kusumoto FM. Cardiovascular Disorders: Heart Disease. In: Hammer GD, McPhee SJ. eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, Seventh Edition New York, NY: McGraw-Hill; 2013. Classification of antiarrhythmic drugs (Vaughan-Williams) Class 1: Sodium channel blockade Class 2: Sympatholytic; β-adrenergic-blockade in the heart Class 3: Potassium channel blockade Class 4: Calcium channel blockade Class 5: Miscellaneous (digoxin, adenosine) http://tmedweb.tulane.edu/pharmwiki/doku.php/intro_to_antiarrhythmics  Class I: Use Dependent Drugs inhibit depolarization in tissues that are more frequently depolarizing. Increased sodium channel blockade at fast rates. Class Ia Drugs : The Queen, Prefers, Discos Slow the rate of rise of phase 0 and prolongs the ERP of the ventricle. Works on open channel Some K+ channel blockade Treats atrial and ventricular arrhythmias Prolongs QT and QRS Quinidine, Procainamide, Disopyramide Quinidine QT-interval prolongation; torsades de pointes M2 blockade Cinchonism: headache, dizziness, and tinnitus. Like quinine (treats P. falciparum) Immunologic reactions: thrombocytopenia, hepatitis. Procainamide QT-interval prolongation; torsades de pointes M2 and alpha blockade Acetylation (N- acetylprocainamide, NAPA)  Disopyramide Most “atropine- like” activity” Adverse effects?? Administer with an AV node suppressant Class Ib Drugs: Lidocaine, Mexiletine Minimal effect on phase 0, shorten the AP and ERP Works on activated and inactivated channels Rapid dissociation from channel Prevents ventricular arrhythmias post MI Decreased QT interval  Lidocaine, Mexiletine Lidocaine (IV) Inactivation in depolarized cells reduces conduction. Local anesthetic; produces neurological adverse effects. Substrate for CYP450. Mexiletine (po) and phenytoin; Similar MOA Mexiletine: GI adverse effects Phenytoin: hirsuitism, gingival hyperplasia, nystagmus Class Ic Drugs: Flecainide, Propafenone Minimal effects on the APD Dissociate from the channel slowly Works on open channel Treats refractory ventricular arrhythmias in patients without structural damage. Also, for atrial fibrillation Increase QRS. Can increase ventricular Prolong depolarization rate. Negative inotropic effects (worsens CHF) Flecainide: blocks ryanodine receptor Class II: Beta-receptor antagonists Decreased slope of Phase IV Beta-receptor antagonists  Beta-receptor antagonists Beta 1: decrease HR, CO, and renin from JXA. Suppress AV and SA nodes. Increase refractory period and AP duration Use: hypertension, MI, CHF, arrhythmia, thyrotoxicosis Beta 1: (atenolol, metoprolol) Beta 1, 2: (nadolol, sotalol, propranolol, timolol). Bronchoconstriction, hypoglycemia, PVD (Beta 2 block) Pindolol, acebutolol (ISA). Worsens condition Esmolol (ultra-short acting) Class III: Potassium Channel Blockers Delay repolarization Prolong AP and ERP without altering phase 0 depolarization or the RMP. Treats: A.fib, atrial flutter, ventricular tachycardia Prolongs QT (torsades) “Reverse-use dependence” Amiodarone, ibutilide, dofetilide, sotalol  Amiodarone Broad-spectrum; blocks potassium, calcium, and sodium channels. Some beta and alpha-adrenergic blockade. Lower incidence of increased QT vs Class Ia drugs Substrate of CYP3A4 (drug interactions) Also inhibits P450 enzymes (digoxin, warfarin, statins) Long half life (~60 days) Desethylamiodarone (hepatotoxic)  Amiodarone Stops conversion of T4 to T3 (hypothyroidism) Iodinated (hyperthyroidism) “Smurf-skin” Corneal deposits Amiodarone Baseline and yearly chest X-rays are recommended for patients starting amiodarone, and in some cases, pulmonary function tests Management: D/C drug; Administer glucocorticoids Review: Other drugs that cause pulmonary fibrosis Bleomycin Busulfan Methotrexate Nitrofurantoin  Amiodarone and Lung Tissue Interstitial inflammation Hyperplasia of Type II pneumocytes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687560/  Class III Drugs Dronedarone: (like amiodarone, with no I-) Sotalol: non-selective β-adrenergic receptor- blocker (II) and increases AP (III). Also, for atrial fibrillation treatment Dofetilide, ibutilide: slow cardiac repolarization. Used for management of atrial fibrillation and flutter. Class IV: Calcium Channel Blockers Increase ERP, especially in AV node Slow inward calcium current between phase 0 and 2 Decrease phase IV in SA, AV node (like Beta blockers) Prevent SVT, atrial fibrillation Verapamil and Diltiazem. NOT -dipines Calcium Channel Blockers  Calcium Channel Blockers Arteriole and Heart; Verapamil > Diltiazem Resist the SANS reflex, can be used in place of beta blockers Use: Hypertension, angina, arrhythmias (SVT, Phase IV) Adverse effects: Dizziness, headache, edema, tachycardia (dihydropyridines). Bradycardia, constipation (most with verapamil), gingival overgrowth, grapefruit drug interaction.  Digoxin http://www.cvpharmacology.com/cardiostimulatory/digitalis  Digoxin (Digitalis) Long t1/2 Negative chronotropic: increases parasympathetic tone (vagal) Positive inotropic: increases contractility Increased afterdepolarizations (monitor patient for low potassium) Inhibition of (Na+/K+ ATPase)  Digoxin N/V/D, anorexia Ventricular arrhythmias: High Ca, low K, Mg (monitor diuretic use) Yellow vision (halos)--Xanthopsia Gynecomastia (estrogenic) DI: antacids, cholestyramine (absorption) amiodarone (CYP inhibition), verapamil and quinidine (elimination) Renal impairment (reduced digoxin elimination) Antidote: DigFab, manage electrolytes. Give magnesium (torsades)  Digoxin Increases PR interval (reduced AV node) ST depression (hockey stick configuration)  Adenosine Short half life (~5 sec) PSVT treatment Gi (A1 receptor), decreased SA and AV node action Gs (A2 receptor), vasodilation Gq (A2B receptor), bronchoconstriction  Adenosine Hypotension Bronchoconstriction “Opposite” to theophylline in mechanism (Methylxanthine)  AV nodal suppressants Calcium channel blockers (Class IV). Verapamil and Diltiazem Adenosine (Gi mechanism, for PSVT) Digoxin (vagal, parasympathetic) Beta-adrenergic receptor antagonists (Class II) Magnesium For digitalis-induced arrhythmias and torsades. Inhibits calcium flux into cytosol.  Potassium Hypokalemia: Slowed repolarization. Early and late after- Hyperkalemia: Depressed pacemaker and depolarizations. slowed conduction. Decreased AP duration. ---hyperkalemia digoxin Digoxin  Ivabradine Selective If inhibitor (“funny channel” blocker) Inhibits action in the SA node without affecting the duration of the action potential Use: CHF and stable angina, especially those who can’t tolerate or be managed with beta antagonist Adverse effects: bradycardia, vision changes, not in pregnancy. Caution with CYP 3A4 inhibitors  Ranolazine Use: Chronic angina, CHF? Arrhythmia? Adverse effects: bradycardia, constipation. Metabolized by CYP 3A4 Blocks K+ channel (increased QT) Wolff-Parkinson-White AV node suppressant not used for WPW in patients with atrial fibrillation or antidromic AV reentry tachycardia Use Procainamide (inhibits initiation) or Amiodarone (increases refractoriness) Delta wave  Drug Indications Sinus tachycardia: Class II, IV Atrial flutter: Class Ia, Ic, II, III, IV, or digoxin PSVT: adenosine AV block: atropine (M2 blockade) Ventricular tachycardia: Class I, III, use Ib if ischemia Ventricular fibrillation: Class Ia, Ib, III Torsades: Magnesium, Class II, IV. Tricyclic-antidepressant overdose: Sodium bicarbonate  Summary Slide Correlate the electrophysiology of the cardiac action potential with antiarrhythmic drug mechanisms Describe the MOA and adverse effects of these drugs. Core References: Katzung & Trevor Basic and Clinical Pharmacology, 16e, 2024; Chapter 14, Agents Used in Cardiac Arrhythmias Pharmacology of Antiarrhythmic Drugs Summary (Maria A. Pino, Ph.D) Scholar Bricks: https://exchange.scholarrx.com/brick/antiarrhythmic-drugs-classes-i-and-iii https://exchange.scholarrx.com/brick/antiarrhythmic-drugs-classes-ii-iv-and-v  Review Question A 65-year-old female presented to the clinic with chest pain on exertion. She has a history of type II diabetes and smokes two packs of cigarettes daily. Her pulse is 74/min and blood pressure is 155/105 mm Hg. Serum studies reveal an LDL cholesterol level of 180 mg/dL. She was prescribed a medication that inhibits the hepatic production of circulating molecules implicated in the pathogenesis of coronary artery disease. The concomitant use of gemfibrozil with this medication would increase the incidence of: A. Bradycardia B. GI bleed C. Hyperkalemia D. Metabolic alkalosis E. Myoglobinuria F. Pancreatitis  Lecture Feedback Form: https://comresearchdata.nyit.edu/redcap/surveys/?s=HRCY448FWYXREL4R