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Pharm S2015 > Lecture 19: Antiarrhythmic > Flashcards

Lecture 19: Antiarrhythmic Flashcards

1
Q

Afterdepol

A

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

  • Early afterdepolarizations
  • Delayed afterdepolarizations
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2
Q

Early Afterdepol

A
  • 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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3
Q

Delayed Afterdepol

A
  • Delayed-afterdepolarizations occur shortly after the completion of repolarization
  • Mechanism not well understood
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4
Q

Anti-arrhythmic drugs

A
  • Class I (Na+ channel blockers)
  • Class II (Beta-blockers)
  • Class III (K+ channel blockers)
  • Class IV (Ca2+ channel blockers)
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5
Q

Class I

A
  • 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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6
Q

Class II

A
  • beta-blockers (Ca2+)
  • Propranolol, metoprolol, esmolol
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7
Q

Class III

A
  • inhibitors of repolarization (K+)
  • Amiodarone, sotalol, dofetilide
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8
Q

Class IV

A
  • calcium channel blockers (Ca2+)
  • Verapamil, diltiazem
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9
Q

Class IA

A
  • 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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10
Q

Quinidine

A
  • 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)
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11
Q

Procainamide

A
  • 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)
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12
Q

Disopyramide

A

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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13
Q

Class IB:antiarrhythmics

A
  • 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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14
Q

Lidocaine

A

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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15
Q

Mexiletine

A
  • 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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16
Q

Class IC antiarrhythmics

A
  • 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
17
Q

Flecainide

A
  • 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
18
Q

Propafenone

A

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.
19
Q

Class II antiarrhythmics

A
  • 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
20
Q

Propanolol, Metoprolol: Uses

A
  • 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)
21
Q

Esmolol: Uses

A
  • Short-acting 1-selective antagonist
  • t1/2 =~9min
  • Used IV for treatment of acute arrhythmias occurring during surgery or in emergency situations
22
Q

Class III antiarrhythmics

A
  • 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
23
Q

Amiodarone

A
  • 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

PK

  • 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
24
Q

Sotalol

A

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
25
Q

Dofetilide

A
  • 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)
26
Q

Class IV antiarrhythmics

A
  • 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
27
Q

Verapamil, Diltiazem

A

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
28
Q

Digoxin

A
  • 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

29
Q

Adenosine

A
  • 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)
30
Q

Magnesium

A
  • Functional Ca2+ antagonist

Used for treatment of:

  • Torsades de pointes (prolonged QT interval)
  • Digitalis-induced arrhythmia
  • Prophylaxis of arrhythmia in acute MI
    *
31
Q

Atropine

A

Used in bradyarrhythmias to decrease vagal tone

32
Q

Rate control

A
  • 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)
33
Q

Rhythm control

A
  • Class IC antiarrhythmics, (flecainide, propafenone)
  • Class III antiarrhythmics, (amiodarone, dofetilide)

Warnings: Pt can revert back to A-fib

34
Q

Prevention of thromboembolic events

A
  • 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

Pharm S2015 (47 decks)

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