Antiarrhythmic Agents PDF Lecture Notes 2025

PHARMACOLOGY II LECTURE TITLE: Antiarrhythmic Agents LECTURER: Amy M. Franks, PharmD SUGGESTED REVIEW: Cardiac Electrophysiology & Arrhythmia Generation Supplemental Handout / Review of Co...

PHARMACOLOGY II LECTURE TITLE: Antiarrhythmic Agents LECTURER: Amy M. Franks, PharmD SUGGESTED REVIEW: Cardiac Electrophysiology & Arrhythmia Generation Supplemental Handout / Review of Concepts SUGGESTED READING: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 14th ed, Chapter 34: Antiarrhythmic Drugs LEARNING OBJECTIVES: After completing this 3-hour lecture, the student will be able to: 1. Compare and contrast action potentials of the SA/AV nodal cells and non-nodal myocytes according to phase and major ion current(s). 2. Identify the pathway for normal impulse propagation through the heart and how it relates to the waveforms on the electrocardiogram during normal sinus rhythm. 3. Identify antiarrhythmic drugs according to Vaughan Williams classification. 4. Describe the mechanism of action and effect on the cardiac action potential for individual antiarrhythmic drugs. 5. Describe how an antiarrhythmic drug’s specific drug properties and patient care considerations may impact its use in a selected patient population. 6. Explain adverse effects and contraindications to therapy for individual antiarrhythmic drugs. 7. Recommend necessary monitoring parameters for antiarrhythmic drugs. Franks – Antiarrhythmic Agents 1 DEFINITIONS AND TERMINOLOGY Arrhythmia: any disturbance in the ___________, ___________, site of origin, or ___________ of the cardiac electrical impulse. Transmembrane/membrane potential: electrical charge across the plasma membrane of cardiac cell; difference in electrical potential between interior and exterior of the cell. Action potential: change in electrical potential associated with the propagation of an impulse along the membrane of a cell. Refractory period: period of time in which a cell is incapable of _______________________ to prevent overlapping impulses. Occurs from the time of depolarization to about halfway through the repolarization phase. Electrocardiogram (ECG, aka EKG): measures the overall electrical activity of the heart. Torsades de pointes (TDP): polymorphic ventricular tachycardia with a ____________________ CARDIAC ACTION POTENTIALS SA/AV nodal pacemaker cells Atrial and ventricular (non-nodal) cells Draw a typical AP Ion responsible for phase 0 upstroke in AP? I. Sinus (sinoatrial, SA) and atrioventricular (AV) nodal APs: Depolarization of the SA and AV nodes is Ca++ dependent. These cells have no real resting potential, instead exhibiting spontaneous firing (pacemaker cells). Franks – Antiarrhythmic Agents 2  A. At end of repolarization, the hyperpolarized negative membrane potential triggers the slow inward (depolarizing) Na+ channels to open (funny channels, If). Opening of If causes spontaneous depolarization (phase 4). B. As membrane potential becomes more positive, the transient T-type Ca++ channel opens and Ca++ enters the cell. This further depolarization opens the long-lasting L- type Ca++ channels, and influx of Ca++ causes the threshold potential to be reached and depolarization (phase 0) occurs. 1. Ca++ channels open more slowly than fast Na+ channels, so the upstroke of the SA/AV nodal APs is slower than in non-nodal cells. C. Repolarization (phase 3) occurs as the L-type Ca++ channels close, decreasing the inward Ca++ current and the delayed rectifier K+ channels open and increase outward flow of K+. II. Non-Nodal Cell APs: In non-nodal cells in the conducting system, this depolarization is a Na+ dependent process: A. Myocytes become depolarized above threshold potential, usually via __________________ by a neighboring myocyte. B. Fast Na+ channels open, intracellular Na+ increases, causing rapid depolarization (phase 0) https://ep-easy.com/concept-of-source-load/ C. Rapid depolarization overshoots the electrical potential, leading to brief rapid repolarization (phase 1) as Na+ channels convert to inactive, nonconducting state. Franks – Antiarrhythmic Agents 3  D. When cell is depolarized by Na+ current, the transient outward K+ channels open, resulting in outward (repolarizing) K+ current and forms the “notch” (early repolarization phase) in the AP. These channels inactivate rapidly. E. During phase 2 (plateau), the L-type Ca++ channels open, causing an inward depolarizing Ca++ current. These channels eventually inactivate and K+ efflux begins. F. Repolarization (phase 3) occurs through ______efflux and rapidly activating (IKr) and slowly activating (IKs) delayed rectifier potassium currents. K+ currents increase over time and Ca++ currents inactivate over time, producing a net result of repolarization of cardiac cells and a return to resting potential (phase 4). NORMAL IMPULSE PROPAGATION I. Pacemaker cells can spontaneously initiate APs (automaticity) A. Sinoatrial (SA) node B. Atrioventricular (AV) node C. Ventricular conducting system A _________________ Cardiac Conduction Pathway Figure E11-9 (Dipiro) B _________________ Answer Bank: Aorta C _________________ Aortic valve Atrioventricular node Bundle of His His-Purkinje conduction system Left atrial appendage D _________________ Mitral valve Sinoatrial node Intrinsic rate of spontaneous depolarization (in order from fastest to slowest rate): ______________ > _______________ > ________________ Franks – Antiarrhythmic Agents 4 Normal impulse propagation and alignment of APs to corresponding ECG Figure 30-4 (G&G) P wave: atrial depolarization QRS complex: ventricular muscle depolarization T wave: ventricular repolarization Electrocardiographic waveforms I. Normal sinus rhythm (NSR) is the regular rhythm of __________ bpm that originates with depolarization of the ___________ node. MECHANISMS OF ARRHYTHMIAS I. Arrhythmias range from incidental asymptomatic clinical findings to life-threatening abnormalities. Can be a single beat or sustained rhythm. Many factors precipitate or Franks – Antiarrhythmic Agents 5  exacerbate arrhythmias, including ischemia, electrolyte abnormalities, scar tissue, drug toxicity, etc. A. All arrhythmias result from one of two basic mechanisms: 1. Disturbances in impulse __________________ a. Altered automaticity b. Triggered activity 2. Disturbances in impulse __________________ a. Heart block b. Reentry II. Example arrhythmias Figure 14-8 (Katzung). ECG from patient with torsades de pointes. NSB=single normal sinus beat Figure 30-9 (G&G). Normal and abnormal cardiac rhythms. Franks – Antiarrhythmic Agents 6 ANTIARRHYTHMIC DRUG THERAPY I. 2 goals of antiarrhythmic therapy may apply: A. Terminate ongoing arrhythmia B. Prevent future/recurrent arrhythmia II. Antiarrhythmics suppress arrhythmias by: A. Blocking flow through specific ion channels B. Altering autonomic nervous system function III. Antiarrhythmics generally work by altering one or more of the following: A. Automaticity: slope of phase 4 depolarization B. Threshold potential (increase/decrease) C. Maximum diastolic potential in pacemaker cells (how negative the membrane potential gets at the end of phase 3) D. AP duration IV. All antiarrhythmics are proarrhythmic. A. Prolonging the AP and the QT interval, especially when the heart rate is slow, can cause TDP. 1. Consider risk for TDP based on baseline QT interval and the use of other drugs that may increase the QT interval. B. Drug-induced ventricular arrhythmias can occur because of slowed conduction velocity 1. Ex: atrial flutter with rate of 300/min and 2:1 or 4:1 atrial:ventricular conduction (heart rate of 150 or 75 bpm) can be slowed to rate of 220/min but with 1:1 conduction (heart rate of 220 bpm). C. Bradycardia and/or heart block can result from decreased conduction velocity, especially together with increased AV nodal refractoriness (i.e., Ca++ block). V. Vaughan Williams classification – according to common electrophysiological properties A. Introduced by Miles Vaughan Williams in 1970 B. Antiarrhythmic agents usually exert multiple actions; may involve multiple classes. Usually classified according to dominate action. Prolong AP Conduction Class Major Action Drug(s) (Refractory Automaticity velocity Period) quinidine, Na+ channel block Ia procainamide,    (intermediate) disopyramide Na+ channel block Ib lidocaine, mexiletine -/ -/  (fast on-off) Franks – Antiarrhythmic Agents 7  Prolong AP Conduction Class Major Action Drug(s) (Refractory Automaticity velocity Period) Na+ channel block flecainide, Ic  -  (slow on-off) propafenone Beta blockade Various: metoprolol, II    (indirect Ca++ block) labetalol, etc. Amiodarone, dofetilide, sotalol, III K+ channel block -  - dronedarone, ibutilide IV Ca++ channel block Diltiazem, verapamil    Adapted from Table 39-1 (Dipiro). CLASS I ANTIARRHYTHMICS: SODIUM CHANNEL BLOCKERS I. MOA: Block __________ or ___________ Na+ channels. Thus during each AP, drugs bind to and block Na+ channels, then dissociate and release block during diastolic interval (phase 4). A. Exhibit use-dependent block (aka state-dependent): Bind readily to activated (phase 0) or inactivated (phase 2) channels, but do not bind to closed/at rest channels. Therefore, these drugs block electrical activity when there are many channel activations and inactivations per unit of time (________ heart rates). B. Subclassified according to rate of recovery from drug-induced block and effect on AP duration; characteristic ECG changes, adverse effects, and clinical efficacy according to subclass. 1. Class Ia: ____________ dissociation rate of recovery 1-10 sec, prolong AP duration. a. Examples: quinidine, procainamide, disopyramide. 2. Class Ib: ____________ dissociation kinetics with rate of recovery _____ hours because of accumulation due to competition between parent drug and metabolites. a. Therapeutic range 1.5-5 mcg/mL Franks – Antiarrhythmic Agents 9  3. Adverse effects a. Dose/accumulation-related neurologic effects: tremor, confusion, altered consciousness. Nystagmus is early sign of toxicity. b. Seizures can occur with rapid administration of large IV doses. C. Flecainide (Ic) 1. Used for supraventricular arrhythmias in patients with structurally _________ hearts 2. Blocks Na+ and K+ channels a. Only weak QT prolongation (primarily prolongs the QRS complex); TDP is rare 3. Adverse effects: very well tolerated a. Dose-related blurred vision b. Arrhythmias c. Exacerbates heart failure 4. Patient care considerations a. Increased mortality in patients with structural heart disease (MI), presumably from proarrhythmic properties CLASS II ANTIARRHYTHMICS: BETA-ADRENERGIC BLOCKERS I. Sympathetic (SNS) stimulation leads to a positive chronotropic effect via norepinephrine (NE). When NE stimulates beta-1 adrenergic receptors, it causes the opening of L-type Ca++ channels and causes: A. Increased automaticity (phase 4 slope) → increased sinus rate B. Faster conduction by increasing magnitude of Ca++ current and slowing its inactivation C. Increased magnitude of repolarizing K+ current (decreases refractory period) II. Beta blocker MOA: Block the positive chronotropic action of norepinephrine (NE). The electrophysiologic actions of beta blockers are to: A. Decrease SA node automaticity → reduce heart rate B. Slow AV nodal conduction → increase PR interval C. Prolong AV nodal refractoriness D. Decrease intracellular Ca++ overload (calcium-triggered calcium release from SR) E. Increase energy required to cause fibrillation → protective in myocardial infarction/ischemic tissue Franks – Antiarrhythmic Agents 10 III. Specific drug properties A. Lots of agents available. Any can be used except for those with intrinsic sympathomimetic activity (ISA; acebutolol, pindolol). Consider patient specifics and comorbidities when choosing agent. B. Sotalol is NOT considered a beta-blocker (see class III). C. Selected agents and properties:  Drug Other effects Selectivity Metoprolol Yes IV and PO Esmolol Yes Short-acting (t½ ~ 9 min); IV only Propranolol No IV and PO Carvedilol No Blocks alpha-1 receptors Nebivolol Yes Stimulates NO release and vasodilation D. Additional drug properties of specific agents will be discussed in later lectures. IV. Adverse effects are caused by 3 main mechanisms A. Exaggeration of therapeutic effects: bradycardia, heart block B. Smooth muscle spasm: bronchospasm, cold extremities, impotence C. CNS penetration: insomnia, fatigue, depression D. Additional adverse effects will be discussed in later lectures. V. Patient care considerations (use, special populations, concerns, etc.) A. Rebound arrhythmias can occur with abrupt discontinuation of chronic therapy. Taper over __________ before discontinuing. B. Strong evidence of protective effect on mortality in patients with myocardial infarction and heart failure. CLASS III ANTIARRHYTHMICS: K+ CHANNEL BLOCKERS I. MOA: Block delayed rectifier K+ channels (IKr) and prolong the refractory period. II. Specific drug properties A. Amiodarone is a commonly used antiarrhythmic. It has many advantages despite its long list of adverse effects. It is important to recognize adverse effects associated with amiodarone. B. Use the diagrams below to indicate common and/or serious adverse effects associated with amiodarone and dronedarone. Franks – Antiarrhythmic Agents 11  Introducing…Aimee O. Darone! And Little Bro: Dro Ned Darone Franks – Antiarrhythmic Agents 12  Drug MOA Drug properties Adverse Effects Patient Considerations IV and PO use IV admin assoc. w/ Very commonly Amiodarone blocks K+, Na+, hypotension (vasodilation), used Ca++ channels; Structural analog of solvent also contributes to nonselective thyroid hormone; 37% Used in SV/V reduced BP beta blocker, iodine arrhythmias See above diagram for alpha blocker Highly lipophilic / Avoid in advanced specific ADRs. Most are water insoluble (IV related to tissue lung disease solvent required) accumulation. Monitor pulmonary Highly concentrated function tests in many tissues and/or chest X-ray Loading doses take Monitor LFTs, several weeks thyroid function Eliminated very slowly Do not monitor (t½ = weeks to plasma months) → ADR concentrations resolve slowly Safe in heart failure Many drug intx: inhibits CYP 3A4, CYP 2C9, P-gp Dronedarone blocks K+, Na+, PO only Not as many ADRs as Used in AF, AFl Ca++ channels; Derivative of amiodarone but associated Less effective than nonselective amiodarone, no with worsened amiodarone beta blockade, iodine moiety cardiovascular outcomes Monitor LFTs first 6 alpha blockade (CV death, HF) Many drug intx: months o metabolized by Avoid if high risk for CYP3A4 vascular events, o inhibits 3A4, 2D6, P- including HF gp (mortality risk) Sotalol K+ channel IV or PO Prolongs QT; Used in SV/V blocker, Eliminated renally concentration-dependent arrhythmias nonselective risk for TDP Avoid in HF Few drug interactions beta blocker Bradycardia, other ADR Dose-adjust with associated with beta CrCL