42-Antiarrhythmic Drugs PDF

42-Antiarrhythmic Drugs Pharmacology 2 (1601314) January 15 First Semester 2024-2025 Asst. Prof. Dr. Najlaa Saadi Fourteenth week: Wednesday PhD Clinical Pharmacology Normal Electrical Cardiac Function (Normal Sinus Rhythm)  The heart's rhythm relies on the impulse from...

42-Antiarrhythmic Drugs Pharmacology 2 (1601314) January 15 First Semester 2024-2025 Asst. Prof. Dr. Najlaa Saadi Fourteenth week: Wednesday PhD Clinical Pharmacology Normal Electrical Cardiac Function (Normal Sinus Rhythm)  The heart's rhythm relies on the impulse from the sinoatrial (SA) node, traveling through the atrial muscle, AV node, Purkinje fibers, and ventricular muscle.  Proper action potentials, dependent on sodium, calcium, and potassium channels, under autonomic control, are essential for normal peacemaking and conduction.  Phases 0-3 of the action potential (AP) are generated by various ionic currents.  The sodium pump and sodium-calcium exchanger maintain ionic steady state during repetitive activity.  In most of the heart, the sodium channel (INa) dominates phase 0 of the AP and determines its conduction velocity.  After brief activation, the sodium current enters a prolonged inactivation.  In the calcium-dependent AV node, the calcium current (ICa) dominates the upstroke and AP conduction velocity.  The plateau of the AP (phase 2) is dominated by calcium current (ICa) and one or more potassium IK- repolarizing currents.  At the end of the plateau, IK causes rapid repolarization (phase 3).  Significant currents occur during diastole (phase 4) in addition to the pump and exchanger activity.  In non-pacemaker cells, the outward potassium current during phase 4 is sufficient to maintain a stable negative resting potential.  In pacemaker cells, the potassium current is smaller, and the depolarizing currents (sodium, calcium, or both) during phase 4 are large enough to gradually depolarize the cell during diastole. Action potential (AP) Components in Purkinje/Ventricular Cells Mechanisms of Arrhythmias:  Abnormal automaticity: Pacemaker activity that originates outside the sinoatrial (SA) node.  Abnormal conduction: Impulse conduction that doesn't follow the normal path or reenters previously excited tissue. Classes of Antiarrhythmic Drugs:  Class I: Sodium channel blocking agents Quinidine, procainamide, Lidocaine, and Flecainide  Class II: Beta - blocking drugs  Class III: Drugs that prolong effective refractory period by prolonging action potential Amiodarone, Sotalol.  Class IV: Calcium channel blocking drugs Other Antiarrhythmic Drugs: Cardiac glycosides, Adenosine Class I (Sodium channel blockade):  Restrict Na inflow during phase 0  Slow depolarization rate (membrane stabilizing)  Class IA: Lengthen action potential (AP) duration (Quinidine, Procainamide)  Class IB: Shorten AP duration (Lignocaine, Mexiletine, Tocainide, Phenytoin)  Class IC: Negligible effect on AP duration (Flecainide, Propafenone) Class IA Procainamide  INa blockade (primary)  IK blockade (secondary)  Slows conduction velocity and pacemaker rate  Prolongs action potential duration  Direct depressant effects on sinoatrial (SA) and atrioventricular (AV) node Class IA Pharmacokinetics of Procainamide  Oral, IV, IM  Eliminated by hepatic metabolism and renal elimination Class IA Side Effects of Procainamide  Cardiotoxic effects: Excessive AP prolongation, QT- interval prolongation, torsades de pointes, syncope.  Hypotension: with rapid procainamide infusion.  Lupus-like syndrome: Arthritis, pleuritis, pericarditis, pulmonary disease.  Other effects: Nausea, diarrhea, rash, fever, hepatitis. Class IB Lidocaine Mechanism of Action:  Sodium channel (INa) blockade  Blocks activated and inactivated channels with fast kinetics  Does not prolong and may shorten action potential Administration:  IV  First-pass hepatic metabolism  Reduce dose in patients with heart failure or liver disease Side Effects:  Neurologic symptoms  Hypotension Class IC Flecainide  Oral  Hepatic and kidney eliminatioin  Half life ∼ 20 h  Do not use in ischemic conditions (post-myocardial infarction Side Effects of Flecainide  Cardiac failure  Ventricular arrhythmias  Blurred vision  Paraesthesia  Metalic taste The Effects of Class I Agents.  All group 1 drugs reduce phase 0 and phase 4 sodium currents in susceptible cells.  Group 1A: Reduce phase 3 potassium current (IK) and prolong AP duration, significantly prolonging ERP.  Group 1B and 1C: Have different or no effects on potassium current, thus shortening or having no effect on AP duration.  All group 1 drugs prolong ERP by slowing recovery of sodium channels from inactivation. The Effects of Class I Agents Class II:β-Adrenoceptor Blockade(Propranolol, Esmolol) Propranolol  Direct membrane effects (sodium channel block)  Prolongation of action potential duration  Slows SA node automaticity and AV nodal conduction velocity Class III Amiodarone  Blocks IK, INa, ICa -L channels, β adrenoceptors  Prolongs action potential duration and QT interval, slows heart rate and AV node conduction, low incidence of torsades de pointes Class III Amiodarone  Oral, IV, large Vd  Hepatic metabolism Side Effects:  Bradycardia and heart block  Photosensitive rashes  Gery/blue discoloration of skin  Pulmonary fibrosis  Hyper- or hypothyroidism  CNS and GIT side effect The Effects of Class III Agents  Prolong AP duration by reducing phase 3 potassium current (IK).  Prolong effective refractory period.  Phase 4 potassium current is not affected.. Class IV Drugs (Ca+2 Channel Blockers) Verapamil and Diltiazem.  Verapamil blocks L-type calcium channels.  Prolongs AV nodal conduction time and effective refractory period.  Slows SA node, may cause a small reflex increase in SA rate due to hypotension.  Can induce AV block in large doses or in patients with AV nodal disease. Group IV Drugs in Calcium-Dependent AV Node Cells Miscellaneous Drugs Digoxin  Shortens the refractory period in atrial and ventricular myocardial cells  Prolonging the refractory period and diminishing conduction velocity in the AV node. Magnesium  Indicated in Digitalis-induced arrhythmias with hypomagnesemia, torsades de pointes (even with normal serum magnesium).  Magnesium infusion has antiarrhythmic effects even with normal serum magnesium levels.  Influences Na+/K+-ATPase, sodium channels, certain potassium channels, and calcium channels. Potassium  Potassium therapy appears to be indicated in patients with digitalis-induced arrhythmias with hypokalemia