When a normal action potential triggers extra abnormal depolarizations / oscillations -\> arrhythmias Early afterdepolarizations Delayed afterdepolarizations

Fast channel blockers (Na+) Decreased Na+ entry slows rate of rise of Phase 0 depolarization Use / state-dependent (IA) Quinidine, procainamide, disopyramide (IB) Lidocaine, mexiletine (IC) Flecainide, propafenone

beta-blockers (Ca2+) Propranolol, metoprolol, esmolol

inhibitors of repolarization (K+) Amiodarone, sotalol, dofetilide

calcium channel blockers (Ca2+) Verapamil, diltiazem

Concomitant Class III activity (block K+ channels) Can precipitate arrhythmias Due to toxicity is being replaced by Ca2+ antagonists Clinical Applications Conversion and prevention of relapse into atrial fibrillation +/or flutter Suppression of supraventricular and ventricular arrhythmias Replaced by more effective/safer antiarrhythmic agents PK Quinidine sulfate = rapid oral absorption Forms active metabolites (CYP 3A4) Inhibits CYP 2D6, 3A4 & P-glycoprotein Adverse Arrhythmias (torsades de pointes) SA & AV block or asystole Nausea, vomiting & diarrhea (30-50%) Thrombocytopenic purpura Toxic doses – ventricular tachycardia (exacerbated by hyperkalemia) Cinchonism (blurred vision, tinnitus, headache, psychosis) Mixed alpha-adrenergic block & antimuscarinic properties Can increase [digoxin] by decreasing renal clearance Contraindications Do not use in patients with: Complete heart block Use with extreme caution in patients with: Prolonged QT interval History of Torsades de Pointes Incomplete heart block Uncompensated heart failure Myocarditis Severe myocardial damage Drug interaction: don't take quinidine w antacids (will incr absorption and toxicitiy)

Derivative of local anesthetic procaine Similar actions to quinidine Blockade of Na+ channels in activated state Blockade of K+ channels Antimuscarinic properties Clinical Applications Ventricular arrhythmias Due to proarrhythmic effects use should be reserved for life-threatening arrhythmias PK IV Metabolized by CYP 2D6 Partly acetylated to N-acetylprocainamide (NAPA) which prolongs duration of action potential (class III) Adverse Chronic use = high incidence of AE Reversible lupus-like syndrome (25-30%) Toxic doses: asystole, induction of ventricular arrhythmias CNS effects (depression, hallucination, psychosis) Weak anticholingeric effects Hypotension Contraindications Hypersensitivity Complete heart block 2nd degree AV block SLE in slow acetylators Torsades de Pointes Heart failure & hypertension (use with caution)

MOA Strong negative inotropic effect (\> quinidine & procainamide) Strong antimuscarinic properties Causes peripheral vasoconstriction Blocks K+ channels Clinical: Supraventricular and ventricular arrhythmias Adverse Pronounced negative inotropic effects Severe antimuscarinic effects (dry-mouth, urinary retention, blurred vision, constipation) May induce hypotension & cardiac failure without pre- existing myocardial dysfunction

MOA Local anesthetic More effect on ischemic or diseased tissue Particularly useful in treating ventricular arrhythmias LITTLE EFFECT on K+ channels PK: IV only (extensive first-pass metabolism) Uses Acute treatment of ventricular arrhythmias from myocardial infarction or cardiac manipulation (eg, cardiac surgery) Lidocaine’s use for VT has declined as a consequence of trials showing IV amiodarone to be superior Little effect on atrial or AV junction arrhythmias Adverse Wide toxic-therapeutic ratio CNS effects (drowsiness, slurred speech, agitation etc.) Little impairment of left ventricular function NO negative inotropic effect Cardiac arrhythmias (\<10%) Toxic doses: convulsions, coma

Orally active derivative of lidocaine Can be used both orally and IV Uses: Management of severe ventricular arrhythmias Adverse Effects: Mainly CNS & GI

Lecture 19: Antiarrhythmic Flashcards by Minh Lam

Afterdepol

When a normal action potential triggers extra abnormal depolarizations / oscillations -> arrhythmias

Early afterdepolarizations
Delayed afterdepolarizations

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Early Afterdepol

Early-afterdepolarizations occur during inciting action potential (phase 2 or 3)
Triggered by conditions that prolong action potential (eg, drugs that prolong QT interval)

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Delayed Afterdepol

Delayed-afterdepolarizations occur shortly after the completion of repolarization
Mechanism not well understood

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Anti-arrhythmic drugs

Class I (Na+ channel blockers)
Class II (Beta-blockers)
Class III (K+ channel blockers)
Class IV (Ca2+ channel blockers)

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Class I

Fast channel blockers (Na+)
Decreased Na+ entry slows rate of rise of Phase 0 depolarization
Use / state-dependent
(IA) Quinidine, procainamide, disopyramide
(IB) Lidocaine, mexiletine
(IC) Flecainide, propafenone

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Class II

beta-blockers (Ca2+)
Propranolol, metoprolol, esmolol

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Class III

inhibitors of repolarization (K+)
Amiodarone, sotalol, dofetilide

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Class IV

calcium channel blockers (Ca2+)
Verapamil, diltiazem

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Class IA

Quinidine, Procainamide, Disopyramide
Slow rate of change of phase 0
- Slowing conduction, prolonging action potential & increasing ventricular effective refractory period
Intermediate speed of association with activated / inactivated Na+ channels & intermediate rate of dissociation

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Quinidine

Concomitant Class III activity (block K+ channels)
Can precipitate arrhythmias
Due to toxicity is being replaced by Ca2+ antagonists

Clinical Applications

Conversion and prevention of relapse into atrial fibrillation +/or flutter
Suppression of supraventricular and ventricular arrhythmias
Replaced by more effective/safer antiarrhythmic agents

Quinidine sulfate = rapid oral absorption
Forms active metabolites (CYP 3A4)
Inhibits CYP 2D6, 3A4 & P-glycoprotein

Adverse

Arrhythmias (torsades de pointes)
SA & AV block or asystole
Nausea, vomiting & diarrhea (30-50%)
Thrombocytopenic purpura
Toxic doses – ventricular tachycardia (exacerbated by hyperkalemia)
Cinchonism (blurred vision, tinnitus, headache, psychosis)
Mixed alpha-adrenergic block & antimuscarinic properties
Can increase [digoxin] by decreasing renal clearance

Contraindications

Do not use in patients with: Complete heart block
Use with extreme caution in patients with:
- Prolonged QT interval
- History of Torsades de Pointes
- Incomplete heart block
- Uncompensated heart failure
- Myocarditis
- Severe myocardial damage
Drug interaction: don’t take quinidine w antacids (will incr absorption and toxicitiy)

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Procainamide

Derivative of local anesthetic procaine
Similar actions to quinidine
Blockade of Na+ channels in activated state
Blockade of K+ channels
Antimuscarinic properties

Clinical Applications

Ventricular arrhythmias
Due to proarrhythmic effects use should be reserved for life-threatening arrhythmias

IV
Metabolized by CYP 2D6
Partly acetylated to N-acetylprocainamide (NAPA) which prolongs duration of action potential (class III)

Adverse

Chronic use = high incidence of AE
Reversible lupus-like syndrome (25-30%)
Toxic doses: asystole, induction of ventricular arrhythmias
CNS effects (depression, hallucination, psychosis)
Weak anticholingeric effects
Hypotension

Contraindications

Hypersensitivity
Complete heart block
2nd degree AV block
SLE in slow acetylators
Torsades de Pointes
Heart failure & hypertension (use with caution)

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Disopyramide

MOA

Strong negative inotropic effect (> quinidine & procainamide)
Strong antimuscarinic properties
Causes peripheral vasoconstriction
Blocks K+ channels

Clinical: Supraventricular and ventricular arrhythmias

Adverse

Pronounced negative inotropic effects
Severe antimuscarinic effects (dry-mouth, urinary retention, blurred vision, constipation)
May induce hypotension & cardiac failure without pre- existing myocardial dysfunction

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Class IB:antiarrhythmics

Lidocaine, Mexiletine
Slow Phase 0 & decreases slope of Phase 4
Shorten Phase 3 repolarization; QT interval: shortened
Little effect on depolarization phase of action potential in normal cells; QRS: no change
Rapidly associate and dissociate with Na+ channels
IB drug are used in settings of:
- Post-MI
- Digoxin toxicity

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Lidocaine

MOA

Local anesthetic
More effect on ischemic or diseased tissue
Particularly useful in treating ventricular arrhythmias
LITTLE EFFECT on K+ channels

PK: IV only (extensive first-pass metabolism)

Uses

Acute treatment of ventricular arrhythmias from myocardial infarction or cardiac manipulation (eg, cardiac surgery)
Lidocaine’s use for VT has declined as a consequence of trials showing IV amiodarone to be superior
Little effect on atrial or AV junction arrhythmias

Adverse

Wide toxic-therapeutic ratio
CNS effects (drowsiness, slurred speech, agitation etc.)
Little impairment of left ventricular function
NO negative inotropic effect
Cardiac arrhythmias (<10%)
Toxic doses: convulsions, coma

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Mexiletine

Orally active derivative of lidocaine
Can be used both orally and IV

Uses: Management of severe ventricular arrhythmias

Adverse Effects: Mainly CNS & GI

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Class IC antiarrhythmics

Flecainide, Propafenone
Markedly depress Phase 0 of action potential -> marked slowing of conduction of action potential but, little effect on duration or ventricular effective refractory period
Associate and re-associate slowly with Na+ channels
Show prominent effects even at normal heart rates

Flecainide

Severe symptomatic ventricular arrhythmias (life- threatening only), premature ventricular contraction or ventricular tachycardia resistant to other therapy
Severe symptomatic supraventricular arrhythmias & prevention of paroxysmal atrial fibrillation
Flecainide and propafenone are associated with the potential for fatal ventricular arrhythmias in persons with structural heart disease.

Adverse

Aggravates CHF (negative inotropic effect)
CNS effects: dizziness, blurred vision, headache
GI effects: nausea, vomiting, diarrhea
Life-threatening arrhythmias & ventricular tachycardia

Propafenone

Used for treatment of life-threatening ventricular arrhythmias and the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation

Adverse

Similar to flecainide
Also has Beta-blocking activity therefore bronchospasm, aggravation of underlying heart failure etc.

Class II antiarrhythmics

Reduce both heart rate & myocardial contractility (Beta1) by decr SA firing and AV conducting by decr phase 4 of AP
Slow conduction of impulses through myocardial conducting system
Reduce rate of spontaneous depolarization in cells with pacemaker activity (block of adrenergic release)
Little effect on action potential in most myocardial cells

Adverse

Bradycardia, hypotension, CNS effects etc.
Contraindicated in acute CHF, severe bradycardia or heart block and severe hyperactive airway disease

Propanolol, Metoprolol: Uses

Reduce incidence of sudden arrhythmic death after MI
Control of supraventricular tachycardias (atrial fibrillation & flutter, AV nodal re-entrant tachycardias)
Ventricular tachycardias (catecholamine-induced arrhythmias, digoxin toxicity)

Esmolol: Uses

Short-acting 1-selective antagonist
t1/2 =~9min
Used IV for treatment of acute arrhythmias occurring during surgery or in emergency situations

Class III antiarrhythmics

Block repolarizing K+ channels
Prolong action potential (and QT interval) without altering Phase 0 or resting membrane potential
Prolong ERP and APD
All have potential to induce arrhythmias

Amiodarone

Related structurally to thyroxine (contains iodine)
Complex MOA showing Class I, II and III (& some IV) effects
Dominant effect = K+ channel blockade.
Decreases AV conduction & sinus node function.
Blocks mostly inactivated Na+ channels
Weak Ca2+ channel blocker
Inhibits adrenergic stimulation (alpha & beta-blocking properties)
Antianginal & antiarrhythmic activity

Uses

Used in the management of ventricular & supraventricular arrhythmias
Amiodarone is the drug of choice for acute VT refractory to cardioversion shock.
Low doses for maintaining normal sinus rhythm in patients with atrial fibrillation

Oral (very well absorbed)
t1/2 = several weeks (extensively distributed in adipose tissue), loading dose required
Full clinical effects (& adverse effects) may take 6 weeks to achieve

Adverse

IPF, liver toxicity, GI intolerance, tremor, ataxia, dizziness, hyper- or hypothyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, hypotension, bradycardia, AV block, arrhythmias
blue skin discoloration (iodine accumulation)
despite prolonging the QT interval, has low incidence of Torsades de Pointes.

Contraindications

Patients taking: Digoxin, theophylline, warfarin, quinidine
Patients with:
- Bradycardia
- SA or AV block
- Severe hypotension
- Severe respiratory failure

Sotalol

MOA

Potent non-selective Beta-blocker
Inhibits rapid outward K+ current
decr SA and AV nodal conduction
Prolongs repolarization & duration of action potential
Lengthens refractory period

Uses

Treatment of life-threatening ventricular arrhythmias
Maintenance of sinus rhythm in patients with atrial fibrillation & flutter who are currently in sinus rhythm
Due to pro-arrhythmic effects – do not use for asymptomatic arrhythmias

Adverse

As for beta-blockers
Lowest rate (of antiarrhythmics) of acute or long-term adverse effects
Torsades de pointes (prolongs QT interval)
Use with caution in patients with renal impairment

Dofetilide

* Potent and pure K+ channel blocker Clinical Applications * Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation / flutter of longer than one week duration who have been converted to normal sinus rhythm * Conversion of atrial fibrillation / flutter to normal sinus rhythm PK: Excreted in urine (~80 % unchanged) Adverse * Headache, chest pain, dizziness, ventricular tachycardia * Torsade de Pointes (prolongs QT interval)

Class IV antiarrhythmics

* Block Ca2+ channels * Decrease inward Ca2+ current leads to decreased rate of Phase 0 spontaneous depolarization * Slow conduction in tissues dependent on Ca2+ current (SA & AV nodes) * Major effects on both vascular & cardiac smooth muscle

Verapamil, Diltiazem

Verapamil = relatively selective for the myocardium and is less effective as a systemic vasodilator drug Diltiazem = intermediate selectivity for the myocardium between verapamil and the dihydropyridines Major Effects: * Decrease contractility (negative inotropy) * Decrease heart rate (negative chronotropy) * Decrease conduction velocity (negative dromotropy) MOA * Inhibit voltage-sensitive Ca2+ channels  decrease in slow inward current that triggers cardiac contraction * Bind only to open, depolarized channels, preventing repolarization before drug dissociates * Use/state-dependent * Slow conduction & prolong effective refractory period Uses * More effective against atrial than ventricular arrhythmias * Supraventricular tachycardia is major arrhythmia indication * Reduction of ventricular rate in atrial fibrillation & flutter * Hypertension, angina Adverse * Negative inotropes * Transient decrease in BP * CNS effects (headache, fatigue, dizziness) * GI effects (constipation, nausea) Contraindications * Verapamil can increase the concentrations of other cardiovascular drugs such as digoxin, dofetilide, simvastatin, & lovastatin

Digoxin

* Shortens refractory period in atrial & ventricular myocardial cells * Prolongs effective refractory period & diminishes conduction velocity in AV node * Uses: Control of ventricular response rate in atrial fibrillation & flutter with impaired left ventricular function or heart failure MOA Heart Failure: Positive inotrope (increases intracellular [Ca2+]i) Arrhythmias * Direct AV node blocking effects & vagomimetic properties: * Inhibition of Ca2+ currents in AV node * Activation of Ach-mediated K+ currents in atrium Major indirect actions * Hyperpolarization * Shortening of atrial action potentials * Increases in AV nodal refractoriness Antiarrhythmic actions * (1) Slows AV conduction, and * (2) Prolongs effective refractory period of the AV node * thereby decreasing the fraction of atrial impulses that are conducted through the node -\> useful in treating atrial flutter / fibrillation (by controlling ventricular rate) Adverse Toxic doses: Ectopic ventricular beats -\> ventricular tachycardia & fibrillation

Adenosine

* Naturally occurring nucleoside (P1 receptor agonist) * High doses = decreases conduction velocity & prolongs refractory period as well as decreasing automaticity in AV node * Very short t1/2 (15 s) MOA * Enhances K+ conductance * Inhibits cAMP-mediated Ca2+ influx * Leads to hyperpolarization esp. in AV node * drug of choice for paroxysmal SVT Uses: IV adenosine = drug of choice for abolishing acute supraventricular tachycardia Adverse * SOB Low toxicity * Flushing * Burning * Chest pain * Hypotension * Bronchoconstriction in asthmatics (may persist up to 30 min)

Magnesium

* Functional Ca2+ antagonist Used for treatment of: * Torsades de pointes (prolonged QT interval) * Digitalis-induced arrhythmia * Prophylaxis of arrhythmia in acute MI *

Atropine

Used in bradyarrhythmias to decrease vagal tone

Rate control

* negative dromotropic agents * Ca2+ channel blockers * Beta-blockers * **Digoxin is DOC in rate control in patients with reduced EF or CHF w A-fib** * Amiodarone (when other agents can’t be used)

Rhythm control

* Class IC antiarrhythmics, (flecainide, propafenone) * Class III antiarrhythmics, (amiodarone, dofetilide) Warnings: Pt can revert back to A-fib

Prevention of thromboembolic events

* Heparin (IV) * Unstable patients who require immediate cardioversion * Warfarin (oral): In stable patients cardioversion should be delayed for 3- 4 weeks until adequate anticoagulation has been achieved * Control of ventricular rate should be undertaken whilst patient is waiting for cardioversion * Oral anticoagulants usually continued for at least 4 weeks after procedure