University:
West Coast University
Course:
PHAR 740 | IPC Cardiopulmonary and Renal III
Academic year:

2024
Views:

396

Pages:

67
Author:

Asal A.

Antiarrhythmic Drugs Adam Kassan, PhD Associate Professor, Pharmaceutical Sciences West Coast University, School of Pharmacy Spring 2023 Antiarrhythmic Drugs Classification • Traditionally organized into four classes  known as the Vaughan-Williams classification  based on their mechanism of action • Limitation of Vaughan-Williams classification  does not allow the classification of other drugs o digoxin or adenosine  not entirely selective o many can block more than one channel type Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class I: Na+ Channel Blockers • By blocking Na+ channels  threshold for excitability is decreased o ↓upstroke velocity of phase 0 o ↓conduc on velocity through cardiac ssue o therefore, stop re-entrant pathway Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class Ia: Na+ Channel Blockers: Mechanism of Action • Intermediate dissociation • Moderate block on Na+ channels  ↓phase 0 upstroke velocity  ↓conduc on velocity • Block of K+ channels  ↓outward IK responsible for repolarization  ↑repolariza on (APD)  ↑eﬀec ve refractory period Class Ia: Na+ Channel Blockers: Mechanism of Action • Class Ia drugs have anticholinergic (vagolytic) actions to varying degrees possibly by  inhibiting Ach-mediated activation of K+ channels  or inhibition of Ach release • By inhibiting cholinergic activity  they can improve AV nodal conduction  however, because they also directly depress AV nodal conduction, there is a variable effect on AV nodal conduction Class Ia: Na+ Channel Blockers: Indications • Broad-spectrum AADs  indicated for both supraventricular and ventricular arrhythmias • In reentrant tachycardias, they depress conduction and prolong refractoriness  transforming the area of unidirectional block into a bidirectional block Class Ia: Na+ Channel Blockers: Clinical Considerations • Should not be used alone in atrial flutter or fibrillation • Ventricular rate may dramatically increase through a combination of:  the anticholinergic effect on AV node  increased impulses passing through the AV node • Contraindicated in heart failure • Infrequent use in clinical practice  limited efficacy and significant toxicities Class Ia: Na+ Channel Blockers Quinidine • Less frequently used due to its adverse effects • QT prolongation  leading to torsades de pointes (1-8%) • Ventricular tachycardia  anticholinergic (vagolytic) effect in the AV node  add β-antagonist or verapamil Class Ia: Na+ Channel Blockers Quinidine Contraindication • History of torsades de pointes or prolonged QT interval • Concurrent use of drugs that prolong QT interval • Conduction defects • Quinidine-induced digoxin toxicity • Cinchonism  quinidine is the d-isomer of quinine Class Ia: Na+ Channel Blockers Procainamide • Only available IV in the US • t1/2 ~3h • Acetylated in liver to N-acetyl-procainamide (NAPA)  active metabolite producing class III effects • Acetylation is genetically determined  depend on rapid or slow acetylation phenotypes • In slow acetylation: accumulation of unacetylated procainamide can lead to lupus-like syndromes • 50% of intact procainamide and majority of its metabolites are eliminated renally  dose adjustment renal failure Class Ia: Na+ Channel Blockers Procainamide Therapeutic considerations • 2nd or 3rd choice (after lidocaine or amiodarone) for treatment of ventricular arrhythmias associated with acute MI • Has the least amount of vagolytic activity • Contraindicated with drugs that prolong QT interval • Does not alter plasma levels of digoxin Class Ia: Na+ Channel Blockers Disopyramide • Only available for oral use in the USA  treatment of ventricular arrhythmias • Profound anticholinergic effects  producing adverse effects as urinary retention, dry mouth, constipation  however, less toxic than quinidine • Depresses cardiac contractility  contraindicated in patients with heart failure Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class Ib: Na+ Channel Blockers • Fast dissociation • Mild block on Na+ channels  ↓phase 0 upstroke velocity  ↓conduc on velocity • Enhance K+ outflow  ↑outward IK responsible for repolarization  ↓repolariza on (APD)  ↓eﬀec ve refractory period Class Ib: Na+ Channel Blockers • Most effective in ischemic heart  more Na+ channels in the inactivated state • Ib binds more to inactivated state  Ia and Ic bind to both activated and inactivated • Considerably more effective in ventricular arrhythmias than supraventricular arrhythmias  less incidence of atrial ischemia Class Ib: Na+ Channel Blockers Lidocaine • Prototypical class Ib agent • Significant 1st pass metabolism if administered orally  only 3% appears in the plasma  administered IV • Metabolized in the liver by CYP450 enzymes (CYP1A2, CYP3A4)  adjusted with P450 inhibitors and inducers Class Ib: Na+ Channel Blockers Lidocaine Adverse effects  CNS: dizziness, seizures  CVS: hypotension, arrhythmias • Shortens repolarization  doesn’t increase QT interval  safe for use in patients with long QT syndrome Class Ib: Na+ Channel Blockers Mexiletine Analogue of lidocaine Available in oral formulation Does not prolong QT and lacks vagolytic effects Indicated for ventricular arrhythmia  also used as adjunct to other antiarrhythmic agents • Major adverse effects include dose-related nausea and tremor  ameliorated when taken with food • Undergoes hepatic metabolism • • • • Class Ib: Na+ Channel Blockers Phenytoin • Limited use  ventricular tachycardia of young children o congenital prolonged QT syndrome • Inducer of P450 3A4  affects plasma levels of other antiarrhythmic agents o mexiletine, lidocaine, and quinidine Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class Ic: Na+ Channel Blockers • Slow dissociation • Marked block of Na+ channels  ↓phase 0 upstroke velocity  ↓conduc on velocity • No effect on K channels  no effect on repolarization (APD) • Pro-arrhythmic effects Class Ic: Na+ Channel Blockers Flecainide • Prototypical class Ic drug • Prevention of atrial arrhythmias (e.g., atrial fibrillation)  in patients with structurally normal hearts  can cause arrhythmia in patients with a history of MI Class Ic: Na+ Channel Blockers Flecainide • Eliminated slowly from the body  t1/2 ~ 20h • Metabolized by the liver and eliminated renally • Associated with  sinus-node dysfunction  marked decrease in conduction velocity  conduction block  cardiac arrest Class Ic: Na+ Channel Blockers • Although effective for both ventricular and supraventricular arrhythmias  their use for ventricular arrhythmias has been limited by the risk of pro-arrhythmia Class I: Na+ Channel Blockers Summary • Class Ia  intermediate on-off • Class Ib  fast on-off • Class Ic  slow on-off • Decrease re-entry, and thereby prevent arrhythmia by  ↓ conduc on velocity  ↑refractory period o Ia Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class II: β-blockers Block sympathetic stimulation of β1-adrenergic receptors in: • SA node  ↓slope of phase 4 depolarization o ↓automa city • AV nodes  prolong repolarization o ↑eﬀec ve refractory period o ↓re-entry • Cardiomyocytes  prolong repolarization Class II: β-blockers • The most useful antiarrhythmic agents currently available  wide spectrum of clinical application o treatment of supraventricular and ventricular arrhythmias o most useful in tachycardias affecting AV node  established safety record o reduce mortality after MI Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class III: K+ channel Blockers • AKA inhibitors of repolarization • Block K+ channels  beneficial o prolonged repolarization o ↑eﬀec ve refractory period o ↓re-entry  toxic o ↑EAD and torsade de pointes • No effects on Na+ channels Class III: K+ channel Blockers With the exception of amiodarone, K+ channel blockers also exhibit “reverse use-dependence” • The effect on APD relies heavily on HR  less effective when HR increases  more effective when HR decreases ADP: Action Potential Duration Class III: K+ channel Blockers Ibutilide • Also enhances a slow inward Na+ current  further prolongs repolarization • Extensive 1st pass metabolism  administered IV • Major adverse effect  prolongation of the QT interval o 2% develop torsades de pointes  not administered to patients with long QT • Clinical application  atrial fibrillation or atrial flutter Class III: K+ channel Blockers Dofetilide • Has no effect on the inward Na+ current • Clinical application  atrial fibrillation or atrial flutter • Major adverse effect  prolongation of the QT interval o 1-3% develop torsades de pointes  not administered to patients with long QT • 80% excreted by the kidneys  dose adjustment in renal dysfunction Class III: K+ channel Blockers Sotalol • Mixed class II and class III antiarrhythmic agent  nonselective β-blocker o class II action  ↑ APD by blocking K+ channels o class III action • Clinical application  atrial fibrillation or flutter  life-threatening ventricular arrhythmias • Major adverse effect  like other β-antagonists: fatigue and bradycardia  like other class III AADs: torsades de pointes • 80-90% unchanged in urine  dose adjustment in renal impairment Class III: K+ channel Blockers Amiodarone • Mainly class III  also acts as a class I, class II, and class IV antiarrhythmic  alteration of the lipid membrane in which ion channels and receptors are located • Frequently used to treat life-threatening arrhythmias  including ventricular and supraventricular Class III: K+ channel Blockers Amiodarone Pharmacokinetics • Insoluble in water  necessitating the use of solvents such as dimethyl sulfoxide (DMSO) o can have electrophysiological effects on its own • Variably absorbed with a bioavailability of 22-86% • Undergoes hepatic metabolism (CYP3A4)  major metabolite, desethylamiodarone, is bioactive with similar t1/2 • Dose adjustment is not required Class III: K+ channel Blockers Amiodarone Pharmacokinetics • Lipophilic, concentrated in many tissues, and eliminated extremely slowly • The elimination t1/2 is complex  rapid component of 3–10 days (50% of the drug)  slower component of several weeks  after discontinuation, ~ for 1–3 months • Measurable tissue levels may be observed up to 1 year after discontinuation Class III: K+ channel Blockers Amiodarone Adverse effects • In the heart  ↓AV or SA node func on by blocking Ca2+ channels  ↓ contrac lity by inhibi ng β-adrenergic receptors • Can cause hypotension as an α-adrenergic antagonist • Contraindicated in  2nd or 3rd degree heart block  severe SA node dysfunction with marked sinus bradycardia or syncope Class III: K+ channel Blockers Amiodarone Adverse effects • In the lungs  severe pulmonary complications o pneumonitis leading to pulmonary fibrosis (5%10% of patients) • Structural similarity to thyroxine  affects thyroid hormone metabolism o by inhibiting peripheral conversion of thyroxine (T4) to triiodothyronine (T3)  either hyperthyroidism or hypothyroidism can occur Class III: K+ channel Blockers Amiodarone Adverse effects • 10–20% abnormal increase in liver enzymes  reversible when the dose of the drug is reduced • Neurological symptoms  peripheral neuropathy, headache, ataxia, and tremors • Photosensitivity, and blue-gray skin pigmentation on exposed areas are common • Patients taking amiodarone should be monitored for abnormal pulmonary, thyroid, and liver function Class III: K+ channel Blockers Amiodarone Drug Interactions • Inhibitor of  many CYP isoenzymes (CYP2C9, CYP2D6, CYP3A4) o can increase [warfarin] and INR - warfarin dose should be reduced by ~30% • P-glycoprotein  can increase [digoxin] by ~ 2-fold o digoxin should be empirically reduced by 50%  can increase [dabigatran], especially with severe renal impairment o avoid dabigatran in these patients Class III: K+ channel Blockers Amiodarone Drug Interactions • Co-administration of β-blockers or CCBs  may increase risk of sinus bradycardia, sinus arrest, and AV block • Co-administration of cholestyramine  increases amiodarone elimination • Co-administration of drugs that prolong QT interval (quinidine, tricyclic antidepressants)  may lead to torsades de pointes Class III: K+ channel Blockers Dronedarone • Structural analog of amiodarone designed to eliminate side effects  however, significantly less effective in maintaining sinus rhythm • Less lipophilic  resulting in a shorter t1/2 ~24h • lacks iodine moieties  reducing the incidence of thyroid toxicity Naccarelli et al. Clinical Medicine Insights: Cardiology 2011:5 103–119 Class III: K+ channel Blockers Dronedarone • Absorption increases 2 to 3-fold with food • Elimination is primarily non-renal • Rare but severe hepatotoxicity  liver function should be monitored periodically • Substrate of CYP3A4 and moderate inhibitor of the CYP2D6 and CYP3A4  potent CYP3A4 inhibitors or inducers should be avoided • Clinical application  atrial fibrillation Class III: K+ channel Blockers • Amiodarone and sotalol  effective in most supraventricular and ventricular arrhythmias • Dronedarone, ibutilide, and dofetilide  only approved for the treatment of supraventricular arrhythmias Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class IV: Ca2+ channel Blockers • Act preferentially on SA and AV nodes  depend on Ca2+ for the depolarization phase • Major therapeutic action  ↓ ac on poten al upstroke in AV node o ↓conduc on velocity through AV node o blocks re-entrant paroxysmal supraventricular tachycardias Class IV: Ca2+ channel Blockers • Can cause AV nodal block  by ↓ the conduc on velocity excessively • Co-administration is contraindicated with β-blockers  can lead to severe heart failure and irreversible electromechanical dissociation • Verapamil and dil azem ↑plasma digoxin levels  by competing with digoxin for renal excretion Vaughan Williams classification Antiarrhythmic Drugs Class I Na+ channel blockers Ia • • • Quinidine Procainamide Disopyramide Class II β-Blockers • • Propranolol Esmolol Ib • • • Lidocaine Mexiletine Phenytoin Class III K+ channel blockers • • • • • Ic • • Flecainide Propafenone Amiodarone Dofetilide Dronedarone Sotalol Ibutilide Class IV Ca2+ channel blockers • • Verapamil Diltiazem Class V Miscellaneous • • Adenosine Digoxin Class V Adenosine • A nucleoside that occurs naturally throughout the body • Administered as a rapid IV bolus  slow administration results in elimination of the drug prior to its arrival at the heart  t1/2 < 10 sec Class V Adenosine • Not considered a classical antiarrhythmic agent  has important effects on cardiac electrophysiology • Affect mainly AV node  by ↓inward Ca2+ current o termination of reentrant supraventricular arrhythmias o slow conduction through the AV node o inhibition of DADs elicited by sympathetic stimulation  often used as 1st line agent for paroxysmal supraventricular tachycardia Class V Adenosine • Activates inward rectifier K+ channels  hyperpolarization during diastole o ↓ automa city • Inhibits adenylate cyclase  ↓If  ↓inward Ca2+ current o slow conduction through the AV node Class V Adenosine • Most adverse effects are transient  headache, flushing, chest pain, and excessive AV or SA nodal inhibition • Can cause bronchoconstriction lasting for up to 30 minutes in patients with asthma • Transient asystole is common at the onset of administration  usually lasts < 5 sec Class V Digoxin: Mechanism of Action • Selectively binds to and inhibits Na+/K+-ATPase  ↓ Na+ extrusion and ↑cytosolic [Na+]  ↓ driving force of Na+/Ca2+ exchanger o leading to ↑ cytosolic and SR [Ca2+] • More Ca2+ released from SR during contraction  ↑ contrac on Class V Digoxin: Mechanism of Action • Inhibition of sympathetic nervous outflow, baroreceptors, and ↑ parasympathe c tone • Alters the electrophysiological properties of the heart  ↓ AV node automa city  ↑ERP of AV node o ↓ conduc on velocity through the node • Clinical application  atrial fibrillation and heart failure Class V Digoxin: Pharmacokinetics • Administered orally or IV • Oral bioavailability ~ 75% • A minority of patients harbor gut flora (Eggerthella lenta) that metabolize digoxin to inactive metabolite  co-administer antibiotics • ~ 80% excreted unchanged in urine (dose adjustment)  rest is excreted in gut or via hepatic metabolism • t1/2 ~ 36-40 h Class V Digoxin: Toxicity • SR is overloaded with Ca2+ in diastole • Leakiness of internal Ca2+ store • Stimulates 3Na+/1Ca2+ exchanger  a net inflow of positive charge (Na+)  a depolarization after the action potential • If depolarization reaches a threshold, a premature action potential follows and may trigger:  DAD (most common) o if DAD reaches a threshold, it triggers a premature action potential  EAD Class V Digoxin: Toxicity • The most common is hypokalemia  increases myocardial localization of digoxin o increasing plasma [K+] can help to relieve symptoms of digoxin toxicity • Hypomagnesemia and hypercalcemia • Contraindicated with amiodarone  may raise serum [digoxin] by altering its clearance or volume of distribution Class V Digoxin: Toxicity Treatment • Treatment of digoxin toxicity relies on  normalizing plasma [K+] in case of hypokalemia o administration of K+  minimizing the potential for arrhythmias o atropine for bradyarrhythmias, or lidocaine for ectopy • Life-threatening digoxin toxicity can be treated with administration of digoxin-specific antibodies Class V Digoxin: Drug-Drug Interactions • β-blockers ↓ AV conduc on  co-administra on with digoxin can ↑ the risk of high-grade AV block • Both β-blockers and CCBs can ↓ cardiac contrac lity  potentially attenuate the inotropic effects of digoxin • K+-was ng diure cs (e.g., furosemide) can ↓ [K+]  ↑ aﬃnity of digoxin for the Na+/K+-ATPase and thereby predispose to digoxin toxicity Class V Digoxin: Drug-Drug Interactions • Antibiotics (e.g. erythromycin), can ↑digoxin absorp on  by killing enteric bacteria that metabolize digoxin before its absorption • Co-administration with verapamil (CCB), quinidine (class IA), or amiodarone (class III) can ↑digoxin levels  impact of these drugs on the volume of distribution and/or renal clearance of digoxin Nonpharmacological treatments • The use of antiarrhythmic drugs in the USA has declined • Most patients cannot tolerate long-term therapy and will have to discontinue therapy because of  adverse drug reactions  development of life-threatening arrhythmias  increased mortality  complex pharmacokinetic characteristics Nonpharmacological treatments • Advancing technology of nonpharmacologic therapies  catheter ablation  implantable cardioverter-defibrillator (ICD) • Gene therapy References • • • • • • • • • • • • Levick’s Introduction to Cardiovascular Physiology, 6th edition, CRC Press Pathophysiology of Heart Disease, 7th edition, Wolters Kluwer Cardiovascular Physiology, 9th edition, McGraw Hill Human Physiology, 15th edition, Oxford The pharmacological Basis of Therapeutics, 14th edition, McGraw Hill Principles of Pharmacology, 4th edition, Wolters Kluwer Hurt’s the Heart, 14th edition, McGraw Hill Basic and Clinical Pharmacology, 15th edition, McGraw Hill Ganong's Review of Medical Physiology, 26th edition, McGraw Hill An Introduction to Medicinal Chemistry, 6th edition, Oxford Foye’s Principals of Medicinal Chemistry, 8th edition, Wolters Kluwer Medicinal Chemistry, 1st edition, CRC Press

Antiarrhythmic Drugs

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