Pharmacy Quiz: Anti-Arrhythmic Drugs

Normal Cardiac Function

• Normal sinus rhythm (NSR) depends on:
  • Generation of an impulse in the sinoatrial (SA) node pacemaker
  • Conduction of impulse through:
    • Atrial muscle
    • Atrioventricular (AV) node
    • Purkinje conduction system
    • Ventricular muscle
• Normal pacemaking and conduction require normal action potentials, dependent on sodium, calcium, and potassium channel activity, under appropriate autonomic control

Cardiac Action Potential

• Describes electrical activity of an individual cardiac cell
• The electrical impulse of the heart is the summation of thousands of tiny electrical currents generated by thousands of individual cardiac cells
• Divided into five phases: 0-4

Depolarization (Phase 0)

• Occurs when rapid sodium channels in the cell membrane are stimulated to open
• Allows positively charged sodium ions to rush into the cell, causing a voltage spike

Repolarization (Phases 1-3)

• Process of getting ions back to where they started
• Corresponds to phases 1-3
• Accounts for almost the entire duration of the action potential
• The cell is refractory to depolarization until after it is repolarized

Resting Phase (Phase 4)

• Period of time between two action potentials
• Quiescent: no net movement of ions across the cell membrane

Abnormal Conduction

• Mechanisms of tachyarrhythmias divided into two categories:
  • Abnormality in impulse generation (automatic tachyarrhythmia)
  • Abnormality in impulse conduction (reentrant tachyarrhythmia)

Disorders of Impulse Formation

• Abnormal automaticity can occur in:
  • Atria: automatic atrial tachycardia
  • AV junction: automatic junctional tachycardia
  • Ventricles: ventricular tachycardia

Reentry

• Mechanism of abnormal impulse conduction
• Requires:
  1. Two roughly parallel conducting pathways connected proximally and distally by conducting tissue
  2. One pathway has a longer refractory period than the other
  3. The pathway with the shorter refractory period conducts electrical impulses more slowly than the opposite pathway

Antiarrhythmic Drugs

• Classified into four main categories:
  1. Sodium channel blockade (Class I)
  2. Beta-adrenergic receptor blockade (Class II)
  3. Prolongation of the action potential duration (Class III)
  4. Calcium channel blockade (Class IV)

Sodium Channel Blockers (Class I)

• Slow the upstroke of sodium-dependent action potentials and prolong QRS duration

• Subclasses:

  • Class Ia: procainamide, disopyramide, and quinidine
  • Class Ib: lidocaine and Mexiletine
  • Class Ic: propafenone and flecainide### Antiarrhythmic Agents

• Idiosyncratic or immunologic reactions, including thrombocytopenia, hepatitis, and fever, are observed rarely.

Disopyramide

• Effects are similar to procainamide and quinidine.
• Cardiac antimuscarinic effects are more pronounced than quinidine, which may precipitate heart failure.
• Should be administered with a drug that slows AV conduction when treating atrial flutter or fibrillation.

Disopyramide Side Effects

• Toxic concentrations can precipitate electrophysiologic disturbances.
• Negative inotropic effect may precipitate heart failure.
• Atropine-like activity causes urinary retention, dry mouth, blurred vision, constipation, and worsening of glaucoma.

Lidocaine

• Low incidence of toxicity and high degree of effectiveness in arrhythmias associated with acute myocardial infarction.
• Class IB agents rapidly associate and dissociate from sodium channels.
• Actions are manifested when the cardiac cell is depolarized or firing rapidly.
• Blocks activated and inactivated sodium channels with rapid kinetics.
• Shortens phase 3 repolarization and decreases the duration of the action potential.

Lidocaine Side Effects

• Proarrhythmic effects, including SA node arrest, worsening of impaired conduction, and ventricular arrhythmias.
• No negative inotropic effect.
• Large doses, especially in patients with preexisting heart failure, may cause hypotension.
• Paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions.

Mexiletine

• Congener of lidocaine, orally active.
• Electrophysiologic and antiarrhythmic actions are similar to those of lidocaine.
• Side effects include tremor, blurred vision, and lethargy, as well as nausea.

Flecainide

• Potent blocker of sodium and potassium channels with slow unblocking kinetics.
• Slowly dissociates from resting sodium channels and shows prominent effects even at normal heart rates.
• Very effective in suppressing premature ventricular contractions.
• May cause severe exacerbation of arrhythmia even when normal doses are administered.
• Side effects include blurred vision, dizziness, and nausea.

Propafenone

• Has some structural similarities to propranolol and possesses weak β-blocking activity.
• Sodium channel-blocking kinetics are similar to those of flecainide.
• Similar side effect profile to flecainide.
• May cause bronchospasm due to β-blocking effects.

β-Adrenergic Blockers (Class II)

• Diminish phase 4 depolarization, depressing automaticity.
• Prolong AV conduction.
• Decrease heart rate and contractility.
• Useful in treating tachyarrhythmias caused by increased sympathetic activity.

Class II β-Adrenergic Blockers

• Based on two major actions:
  • Blockade of myocardial β-adrenergic receptors.
  • Direct membrane-stabilizing effects related to Na+ channel blockade.
• The AV node is more sensitive than the SA node to the effects of β1-antagonists.

K+ Channel Blockers (Class III)

• Class III agents block potassium channels, diminishing the outward potassium current during repolarization of cardiac cells.
• Prolong the duration of the action potential without altering phase 0 of depolarization or the resting membrane potential.
• Prolong the effective refractory period, increasing refractoriness.
• All class III drugs have the potential to induce arrhythmias.

Amiodarone

• Contains iodine and is related structurally to thyroxine.
• Blocks sodium, calcium, and potassium channels and β adrenoceptors.
• Has a broad spectrum of actions, which may account for its relatively high efficacy and low incidence of torsade’s de pointes.
• Has a prolonged half-life of several weeks and is extensively distributed in adipose tissue.
• May cause peripheral vasodilation.
• Side effects include pulmonary fibrosis, neuropathy, and hepatotoxicity, as well as microcrystalline deposits in the cornea and skin.

Dronedarone

• Benzofuran amiodarone derivative, which is less lipophilic and has lower tissue accumulation and a shorter serum half-life.
• Does not have the iodine moieties responsible for thyroid dysfunction associated with amiodarone.
• Like amiodarone, it has class I, II, III, and IV actions.
• Liver toxicity has been reported.
• A substrate and inhibitor of CYP3A4 and should not be co-administered with potent inhibitors of this enzyme.

Sotalol

• Has both β-adrenergic receptor-blocking (class 2) and action potential-prolonging (class 3) actions.
• Formulated as a racemic mixture of D- and L-sotalol.
• All β-adrenergic-blocking activity resides in the L-isomer; the D- and L-isomers share action potential-prolonging effects.

Dofetilide

• Pure potassium channel blocker.
• Can be used as a first-line antiarrhythmic agent in patients with persistent atrial fibrillation and heart failure or in those with coronary artery disease.
• Can cause torsades de pointes.

Ibutilide

• Potassium channel blocker that also activates the inward sodium current (mixed class III and IA action).
• Undergoes extensive first-pass metabolism and is not used orally.
• Most important adverse effect is excessive QT-interval prolongation and torsade’s de pointes.

Calcium Channel Blockers (Class IV)

• Class IV drugs are the nondihydropyridine calcium channel blockers verapamil and diltiazem.

Verapamil

• Blocks both activated and inactivated L-type calcium channels.
• Its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current.
• AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic concentrations.

Digoxin and Other Antiarrhythmic Drugs

• Digoxin.
• Adenosine.
• Ivabradine.
• Ranolazine.
• Magnesium.
• Potassium.

Adenosine

• Naturally occurring nucleoside: a normal component of the body.
• At high doses, decreases conduction velocity, prolongs the refractory period, and decreases automaticity in the AV node.
• Cardiac mechanism of action involves activation of an inward rectifier K+ current and inhibition of calcium current.

Ivabradine

• Selective blocker of If (funny channel: pacemaker current).
• Ivabradine slows pacemaker activity by decreasing diastolic depolarization of sinus node cells.
• It is an open channel blocker that shows use-dependent block.

Ranolazine

• Was originally developed as an antianginal agent.
• Has antiarrhythmic properties that are dependent on the blockade of multiple ion channels.
• Blocks the inward sodium current in the heart.
• Also blocks the rapid component of the delayed rectifier K+ current IKr.

Magnesium

• Originally used for patients with digitalis-induced arrhythmias who were hypomagnesemic.
• Magnesium infusion has been found to have antiarrhythmic effects in some patients with normal serum magnesium levels.
• The mechanisms of these effects are not known, but magnesium is recognized to influence Na+/K+-ATPase, sodium channels, certain potassium channels, and calcium channels.

Potassium

• Hypokalemia results in an increased risk of early and delayed afterdepolarizations, and ectopic pacemaker activity, especially in the presence of digitalis.
• Hyperkalemia depresses ectopic pacemakers (severe hyperkalemia is required to suppress the SA node) and slows conduction.