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• Arrhythmia


  1. Irregular heartbeat

  2. Too fast (tachycardia)

  3. Too slow (bradycardia)

  4. Electrical conduction system in the heart is out of rhythm or out of sync
• Normal Sinus Rhythm (NSR)


  Normal electrical cardiac function where the heart follows a specific rhythm or pattern
• Normal electrical cardiac function

  SA node -> AV node -> Purkinje conduction system -> Ventricles
• Normal action potential


  • Dependent on Na, K, and Ca channel activity under appropriate autonomic control

  
• Phases of action potential

  1. Phase 0 (Upstroke - Depolarization, Na influx)

  2. Phase 1 (Early fast depolarization - Initial repolarization, K efflux)

  3. Phase 2 (Plateau - Ca influx, K efflux)

  4. Phase 3 (Late repolarization - K efflux predominates)

  5. Phase 4 (Resting membrane potential - Coincides with diastole)

  
• Two major mechanisms for arrhythmia

  • Abnormal automaticity (Pacemaking imbalance, Afterdepolarizations)
  • Abnormal conduction (Heart block, Reentry)

  
• Wolff-Parkinson White Syndrome (WPW)

  Accessory pathway (Bundle of Kent) that connects the SA node directly to the ventricles, causing reentry circuit and tachycardia

  
• Torsade de Pointes


  Polymorphic ventricular tachycardia, 150-250 bpm, can lead to sudden cardiac death
• Classes of antiarrhythmic drugs

  • Class I (Na+ channel blockers)
  • Class II (β-blockers)
  • Class III (K+ channel blockers)
  • Class IV (Ca2+ channel blockers)
  • Miscellaneous agents
• Class I antiarrhythmic drugs

  • Slow conduction in ischemic and depolarized cells, slow down or abolish abnormal pacemakers
  • Class IB are most selective, Class IA and IC are less selective
• Use-dependent or state-dependent action

  Effectiveness of the drug is greater for faster heart rate or more active cells
• Class I-A antiarrhythmic drugs

  • Slow the upstroke of action potential and conduction, prolong action potential duration by non-specific K-channel blockade, have direct depressant action on SA and AV nodes
• Procainamide (Class IA prototype) has ganglion-blocking properties which reduces peripheral vascular resistance and may cause hypotension
• Excessive prolongation of action potential and QT interval by Class IA drugs can induce torsades de pointes and other arrhythmias
• Na-channel blocker


  Binds to the receptor rapidly when the channel is open or inactivated and less readily when resting or fully repolarized
• State-dependent action


  The effectiveness of the drug is greater for faster heart rate or more active cells (directly proportional)
• Class I-A antiarrhythmic drugs


  • Procainamide (class IA prototype)
• Quinidine (class IA)


  • Slows the upstroke of AP and conduction; prolongs QRS duration of the ECG
  • Prolongs APD (Class III activity) by blockade of several K-channels including ITO
• Disopyramide (class IA)


  • Slows the upstroke of AP and conduction; prolongs QRS duration of the ECG
  • Prolongs APD (Class III activity) by blockade of several K-channels including ITO
• Mexiletine (class IB)


  • Orally active congener of lidocaine (same structure, different functional group) with very similar electrophysiologic and anti-arrhythmic actions
  • Primarily used for ventricular arrhythmias
  • T1/2 is 8-20 hours and will require 2-3 dosing per day
  • Dose-related ADRs (mostly neurologic) seen even at therapeutic dosage: tremors, blurred vision, nausea, lethargy
  • It has beneficial effects in relieving chronic pain due to diabetic neuropathy or nerve injury (off-label use at 450-750 mg/d)
• Flecainide (class IC)


  • It is a potent Na+ and K+ channel blocker (but without prolongation of AP or QT interval) with slow unblocking kinetics
  • Currently used for normal heart patients with supraventricular arrhythmia and is very effective in suppressing premature ventricular contractions
  • Proarrhythmic effects — severe exacerbation of arrhythmia among patients with pre-existing ventricular tachyarrhythmia, myocardial infarction, ventricular ectopy (impulse is originating somewhere else or outside the normal flow of NSR)
  • T1/2 is ~20 hours (100-200 mg/d) and is eliminated by the liver and kidney

  
• Propafenone (class IC)


  • It is structurally similar to propranolol thus the weak β-blocking action
  • Primarily used for supraventricular arrhythmias
  • Its spectrum of action is very similar to Quinidine (IA) but does not prolong action potential. Its Na+-channel blocking kinetics is similar to Flecainide (IC)
  • Most common ADRs: metallic taste, constipation, exacerbate arrhythmia
  • T1/2 is 5-7 hours (450-900 mg/d in 3 divided doses) and is metabolized in the liver
• Class II antiarrhythmic drugs (β-blockers)

  • Propranolol, esmolol, sotalol, and other agents
  • Used for long term/preventive management, especially in the cases of patients with pre-existing cardiovascular disease
  • MOA: Blocks β-adrenoreceptor and reduction of cAMP leading to reduction of Na+ and Ca+2 currents and suppression of abnormal pacemakers
  • The use of Class II drugs reduces progression of chronic heart failure and incidence of potentially fatal arrhythmia
  • Sotalol is generally a Class III but has Class II action as well
  • Esmolol is exclusively used for acute arrhythmias and cannot be used for chronic manifestations
  • Propanolol, nadolol, metoprolol, timolol are used chronically to prevent arrhythmias in patients with a history of myocardial infarction (propranolol and nadolol are more effective)
  • ADRs: bronchospasms (can be fatal), heart failure, CNS sedation, lethargy, sleep disturbances
• Class III antiarrhythmic drugs

  • Is a good drug for arrhythmia but is also a drug of concern due to its proarrhythmic effect which can lead to Torsades De Pointes
  • Requires strict monitoring
  • The hallmark is APD (action potential duration) prolongation caused mainly by the blockade of IKR (rapid delay potassium rectifier) channel which is responsible for AP repolarization
  • This increases ERP (effective refractory period) and reduces the ability of the heart to respond to rapid tachycardias or fibrillation
  • The action is observed in the ECG as an increase in QT interval
  • Is reverse use dependent: effect is less during fast HR and more during slow HR

  
• Amiodarone (class III prototype)


  • Can accumulate in heart, liver, and skin with great concentration in tears
  • Also has Class IA activity despite being predominantly Class III. It has the greatest action potential prolonging effect because of the additional Class III activity which is K blocking
• Dronedarone


  • It is a structural analog to amiodarone where the iodine atoms are removed — no thyroid dysfunction or pulmonary toxicity
  • It has multi-channel (IKR, IKS, ICA, INA) and β-adrenergic blocking action
• IV loading


  Useful to get pharmacologic results
• IV loading dose


  • PREVENTS QT prolongation but has BRADYCARDIC and AV BLOCKING effect
• AV blocking

  The impulse is stuck at the AV node
• AMIODARONE METABOLISM


  Affected by enzyme inducers/inhibitors. It may inhibit CYP450 for other drugs
• AMIODARONE


  Has an active metabolite - DESETHYLAMIODARONE. T1/2 is complex with rapid and slow components
• Active metabolite


  Prolongs the drug's activity
• RAPID COMPONENT


  3 to 10 days, consumes 50% of the drug
• DRONEDARONE


  Structural analog to amiodarone where the iodine atoms are removed - NO THYROID DYSFUNCTION OR PULMONARY TOXICITY
• DRONEDARONE


  • Multi-channel (IKR, IKS, ICA, INA) and β-ADRENERGIC BLOCKING action
• DRONEDARONE T1/2


  24 HRS (400mg/d, 2x). Best absorbed with food and eliminated primarily through the feces (non-renal)
• DRONEDARONE


  Can inhibit tubular secretion of creatine (increase levels). Affected by coadministration of CYP3A4 inhibitors (inhibits drug metabolism)
• SOTALOL


  Non-selective β-blocker (Class II) with AP prolonging (Class III) action
• SOTALOL T1/2


  ~12 HRS. It is well absorbed and excreted unchanged by the kidneys
• SOTALOL


  • Most important ADR — dose-related incidence TORSADE DE POINTES. Patients with heart failure — further depression of LEFT VENTRICULAR FUNCTION