Antiarrhythmic Pharmacology Lecture Slides PDF

Learning objectives 1 be able to draw a diagram explaining the 3 main cellular mechanisms of arrhythmias: triggered activity, re-entry, and enhanced automaticity. 2 When given a specific phase (0 thru 4) of either a nodal or myocyte action potential, be able to identify the key ion chan...

Learning objectives 1 be able to draw a diagram explaining the 3 main cellular mechanisms of arrhythmias: triggered activity, re-entry, and enhanced automaticity. 2 When given a specific phase (0 thru 4) of either a nodal or myocyte action potential, be able to identify the key ion channel(s) that account for the major current flow during that phase. 3 After being told how an action potential is modulated either by an arrhythmia or a drug, predict whether the change in the action potential will be proarrhythmic or antiarrhythmic and be able to explain why. 4 When given a description of a change in a cardiac action potential, predict the effect (if any) on the ECG. 5 When given the name of a specific antiarrhythmic agent or its structure, be able to explain whether/how it exhibits selectivity for atrial or ventricular tissues. If applicable, also explain why it has a greater effect in arrhythmogenic cells. 6 When given the name of a specific antiarrhythmic agent or its structure, recall and explain the drug’s mechanism of action at the molecular/cellular/whole-heart level. 7 When given a clinical description of someone being treated with an antiarrhythmic drug and experiencing toxic side effects from the drug, predict what drug or drug class they are taking.  Antiarrhythmic Drug Pharmacology Module #1: Ion Channels & Cardiac Action Potentials Module #2: The Electrocardiogram Module #3: Common Arrhythmias Module #4: Antiarrhythmic Drugs Module #5: Ms. Southern case study Electrical Conduction in the Heart  Antiarrhythmic Drug Pharmacology Pacemaker cells have automaticity. But input from the sympathetic and parasympathetic nervous systems can influence nodal firing. Cardiac Conduction System 5 http://www.medimmersion.com/visitorTopic/page/ECG%20Image  Antiarrhythmic Drug Pharmacology Module #1: Ion Channels & Cardiac Action Potentials Module #2: The Electrocardiogram Module #3: Common Arrhythmias Module #4: Antiarrhythmic Drugs Module #5: Ms. Southern Case study Important Ion Channels in the heart Ion Channels in the Heart Daniel C. Bartos,* Eleonora Grandi,* and Crystal M. Ripplinger  Important Ion Channels in the heart Sodium channels (voltage-gated, Nav1.5) Calcium channels (N-type Cav2.2, T-type Cav3.x) Potassium channels (Kir, Kv) HCN channel (HCN1, HCN4) hERG (KCNH2, KV11.1, an important channel to avoid being targeted when developing new drugs). Many good drug leads were abandoned early during the development because of their interaction with hERG channels  In vitro Proarrhythmia assay WASHINGTON, D.C., Dec. 23, 2022 -- The U.S. House gave final approval Human Induced Pluripotent Stem Cells today to the FDA Modernization Act (iPSCs)-derived cardiomyocytes 2.0, revamping the drug approval process and promising a dramatic reduction in the use of animals in laboratory tests. In vitro Proarrhythmia assay K+ Na+ Action potential in the myocytes Ion Channels Mediating Cardiac Action Potentials +50 Pacemaker Cell Ventricular Myocyte (SA & AV Node) 0 mV -50 -100 Pacemaker Cells: Ventricular Myocytes: Specialized, non-contractile cells contractile cells physiologically depolarized hyperpolarized high automaticity low automaticity Ca2+- dependent spikes Na+- dependent spikes 14  Pacemaker Action Potentials Currents important for pacemaker cell +30 Action Potentials iK iCa – carries AP upstroke (phase 0) iK – repolarizing K+ current (phase 3) if – diastolic pacemaker current (phase 4) 0 iK(ACh) – K+ current activated by vagus (phase 4) mV 0 3 -30 threshold 4 4 -60 iCa(L) if if iK(ACh) 15  Ion Channel Signaling in Pacemaker Cells Norepinephrine (NE) Na+ Ca2+ HCN channel L-type Ca2+ AR AC + Channel cAMP cAMP + cAMP PKA PKA NE highest during the fight-or-flight response 16  Acetylcholine (ACh) ACh Na+ Ca2+ HCN channel L-type Ca2+ M1R + Channel AC cAMP Gi cAMP + cAMP PKA PKA ACh Acetylcholine M1R + Decreased HCN and Ca2+ current Hyperpolarization (GIRK) Atrium and SA/AV nodes GIRK channel K+ 17  Myocyte Action Potentials Currents important for Myocyte Action Potentials iNa – carries AP upstroke (phase 0) iKto iKto – “transient outward” repolarizing K+ +50 current (phase 1) 1 iK iCa(L) – plateau Ca2+ current critical for 2 muscle contraction (phase 2) 0 iK – repolarizing K+ current (phase 3) if – pacemaker current (phase 4; very iCa(L) mV minimal) 0 3 -50 4 4 -100 iNa Neuronal action potential (no calcium channel involved) 18  Phase 0: Voltage-Gated Na+ Channels Rest Open Inactivated 19 Na+ Channel Inactivation & the Refractory Period Voltage-Gated Na+ Channels Rest Open Inactivated Vm = -80mV Vm = -20mV Vm = -20mV 1 to 3 msec mm m m m m h h h Recovery from Inactivation 20 msec to > 10 sec 20  The Refractory Period Result of a 2nd stimulus on ability to elicit an AP is greater as you progress through the RRP (relative refractory period) 21  Phase 2: Voltage-Gated Ca2+ Channels Rest Open Inactivated Voltage- Gated Na+ depolarization Channels Phase 2 Ca2+ L-type Ca2+ + Channel + VG K+ Channel K+  Phase 3: Voltage-Gated K+ Channels Rest Open Inactivated Voltage- Gated Na+ depolarization Channels Phase 3 Ca2+ L-type Ca2+ + Channel + VG K+ Channel K+  Antiarrhythmic Drug Pharmacology Module #1: Ion Channels & Cardiac Action Potentials Module #2: The Electrocardiogram Module #3: Common Arrhythmias Module #4: Antiarrhythmic Drugs Module #5: Ms. Southern Case Study G&G: Effects of Antiarrhythmic Drugs on the Electrocardiogram Action potential vs ECG 26  Antiarrhythmic Drug Pharmacology Module #1: Ion Channels & Cardiac Action Potentials Module #2: The Electrocardiogram Module #3: Common Arrhythmias Module #4: Antiarrhythmic Drugs Module #5: Ms. Southern Case Study 5 min break  Common Arrhythmias 1. Atrial sinus arrhythmia 2. Re-entry arrhythmias 3. Atrial fibrillation 4. Wolf-Parkinson White 5. Monomorphic ventricular tachycardia 6. AV nodal re-entrant tachycardia 7. Premature ventricular complexes  Re-Entry Arrhythmia http://tmedweb.tulane.edu/pharmwiki 30  Re-Entry Arrhythmia ischemic damage http://tmedweb.tulane.edu/pharmwiki 31  Re-Entry Arrhythmia next sinus beat Re-Entry Requirements: 1. Multiple parallel pathways re-entrant circuit 2. Unidirectional block 3. Conduction time greater than ERP (effective refractory period) http://tmedweb.tulane.edu/pharmwiki 32  Antiarrhythmic Drug Pharmacology Module #1: Ion Channels & Cardiac Action Potentials Module #2: The Electrocardiogram Module #3: Common Arrhythmias Module #4: Antiarrhythmic Drugs Module #5: Ms. Southern Case study  Antiarrhythmic Drugs Vaughan-Williams-Singh Scale Class 1- Na+ channel blockers Class 2- Beta adrenergic antagonists Class 3- Agents that prolong refractory period (K+ channel blockers) Class 4- Ca2+ channel blockers (miscellaneous antiarrhythmic agents) 34  Class 2 & 4 Antiarrhythmics NE Na+ Ca2+ HCN channel L-type Ca2+ AR AC + Channel cAMP cAMP + cAMP PKA PKA AR blockade Ca2+ channel blockade +30 +30 Class 2 Class 4 0 0 mV mV -30 -30 -60 -60 35 Summary and Review: Class 2 and 4 Antiarrhythmics Class 2: AR blockers Slow pacemaker and Ca2+ currents in SA, AV node Increase refractoriness of SA, AV node Increase P-R interval Arrhythmias involving catecholamines (epinephrine, norepinephrine, etc…) Class 4: Ca2+ channel blockers Frequency-dependent block Increase refractoriness of AV node and P-R interval Protect ventricular rate from atrial tachycardia 36  AR Blockers used as Antiarrhythmics 1. Esmolol cardioselective (1 AR) very short half-life (~9 min) due to plasma esterase hydrolysis given IV 2. Acebutolol cardioselective weak partial agonist at 1AR (sympathomimetic) weak Na+ channel blockade 3. Propanolol non-selective weak Na+ channel blockade Clinical Uses: arrhythmias involving catecholamines atrial arrhythmias (protect ventricular rate) Post-MI prevention of ventricular arrhythmias Prophylaxis in Long QT syndrome (catechol.-sens) 37 Ca2+ Channel Blockers used as Antiarrhythmics Verapamil Mechanism of Action: Frequency-dependent block of Cav1.2 channels Selective block for channels opening more frequently Accumulation of blockade in rapidly depolarizing tissue (i.e. tachycardia) Diltiazem Clinical Uses: Block re-entrant arrhythmias involving AV node Protect ventricular rate in atrial flutter and atrial fibrillation 38  Antiarrhythmic Drugs Vaughan-Williams-Singh Scale Class 1- Na+ channel blockers Class 2- Beta adrenergic antagonists Class 3- Agents that prolong refractory period (K+ channel blockers) Class 4- Ca2+ channel blockers (miscellaneous antiarrhythmic agents) 39  Class 1 Antiarrhythmics: Effect on Action Potential Class 1A Class 1B Class 1C Mixed block: Na+ and Na+ channel block Strong Na+ channel K+ channels Blocks open & block Blocks open state inactivated state Blocks open state Moderate, incomplete Rapid, complete Very slow, incomplete dissociation dissociation dissociation Widen QRS Slight narrowing of Widen QRS Prolonged QT action potential No clinically significant effect on ECG no drug drug 40  Class 1 Antiarrhythmics: Drugs Class 1A Class 1B Class 1C Quinidine Lidocaine Propafenone Procainamide Tocainide Flecainide Disopyramide Mexiletine Moricizine Phenytoin no drug drug 41  no drug Class 1 Antiarrhythmics: Drugs drug Class 1A Class 1B Class 1C Quinidine Flecainide 2-8% risk of Ventricular and Torsades de Pointes supraventricular Anti-muscarinic Orally available activity Lidocaine IV only; not effective orally Among top choices for rapid Procainamide control of ventricular Propafenone Lupus-like arrhythmias Ventricular and syndrome only ventricular, not atrial supraventricular Ganglionic AR blocking blocker activity Orally available Disopyramide Anti-muscarinic Mexiletine activity Orally available, similar to lidocaine in efficacy 42  Class 3 Antiarrhythmics: Mechanism of Action no drug Class 3 Antiarrhythmics: Class 3 Block IKr, prolong action potential duration and Q-T interval drug Increases effective refractory period (ERP) In re-entrant circuit, increased ERP above conduction time R around circuit will terminate re-entry P T Q S inexcitable http://tmedweb.tulane.edu/pharmwiki 43 Class 3 Antiarrhythmics: Torsade de Pointes (TdP) Torsade de Pointes: “twisting of the points” IKr block induces early afterdepolarization (EADs) and triggered upstrokes Multifocal/polymorphic ventricular tachycardia Can degenerate into ventricular fibrillation Ikr hERG channel! http://tmedweb.tulane.edu/pharmwiki 44 Class 3 Antiarrhythmics: Drugs Amiodarone Activity like all 4 antiarrhythmic drug classes, but IKr block most important Commonly used to suppress emergency ventricular and atrial arrhythmias Prevention of atrial fibrillation Very long half life (weeks) Adverse: hypothyroidism, pulmonary fibrosis, photosensitization Dronedarone Amiodarone analog used for atrial fibrillation prevention Reduced toxicity compared to amiodarone (iodine atoms removed) Ibutilide 2% incidence of TdP Rapid conversion of atrial fibrillation/flutter to normal rhthym Sotalol 2% incidence of TdP One isomer has AR blocking activity Life-threatening ventricular arrhythmias or maintenance of normal sinus rhythm after atrial fibrillation/flutter Dofetilide High (10%) risk of TdP, drug very restricted, used infrequently Atrial arrhythmias 45  Class 3 Antiarrhythmics: Clinical Use Amiodarone – top choice for rate control in A-fib, suppression of post-MI Ventricular Arrhythmias Dronedarone – A-fib Sotalol – prevent A-fib re-occurrence Ibutilide – convert A-fib to sinus rhythm 46  Acquired Long QT Syndrome Acquired LQTS Drugs belonging to the following classes have Drug-induced been shown to have risk for TdP: Electrolyte imbalances Antiarrhythmics Block of HERG channel (IKr potassium Antibiotics current) Antiemetics Antineoplastics Ca2+ channel blockers Gastric pro-motility Opiates Antihistamines Antipsychotics Antidepressants Diuretics Drug Interaction with Congenital LQTS Most drugs known to precipitate TdP should be avoided in patients with diagnosed congenital LQTS Genetic mutations (KCNQ1, KCNH2, SCN5A) cause LQTS Misc. (Class V) Antiarrhythmic Drugs/Agents Digoxin Inhibition of AV node Also increase intropy, used for CHF. Magnesium chloride treat hypomagnesemia convert TdP prevent MI and digoxin associated arrhythmias Potassium Chloride hypokalemia reduces Ikr current, which can prolong action potentials and be pro-arrhythmic Adenosine similar to M2 muscarinic activation: depresses pacemaker cells suppress atrial tachycardia short half-life, given IV 49  Adenosine Adenosine has multiple effects on different cells in the heart. Its half-life in the blood is very short. Leads a brief but potent slowing of the heart. What drugs/conditions can cause the following changes? A, widen QRS B, increase PR C, Lengthen QT D, no change  Antiarrhythmic Drug Pharmacology Module #1: Ion Channels & Cardiac Action Potentials Module #2: The Electrocardiogram Module #3: Common Arrhythmias Module #4: Antiarrhythmic Drugs Module #5: Ms. Southern Case study