Antiarrhythmics

Vaughan-williams

Class I

• All reduce the slope of Phase 0
• Class Ia – Prolonged action potential duration
• Class Ib – Decreased action potential duration
• Class Ic – No change in action potential duration

Class IA – Intermediate Na channel block

• Block open sodium channels and have slow dissociation causing increased refractory period
• Quinidine and disopyramide are rarely used
• Procainamide

Class IA – Procainamide

• Pharmacodynamics
  • Increases refractory period, decreases automaticity and conduction, prolongs cardiac action potentials
• Pharmacokinetics
  • NAPA (active metabolite) blocks potassium channels leading to QT prolongation
  • Hepatic metabolite then renally excreted
  • 2.5-4.7hr half-life; NAPA 6-8hrs half-life
  • Onset 5-10 min and duration 1-2 hours
• Dosing
  • 20-50mg/min IV until arrhythmia suppressed, hypotension or QRS >50% longer than original followed by 1-4mg/min
    • OR
  • 100mg IV every 5 min until above

Class Ib (fast – weak blockade)

• High affinity for open and inactive sodium channels with very rapid dissociation
• Increases threshold for excitability to reduce automaticity
• Rapid dissociation means they are less effective for myocardial tissues with rapid conduction e.g. atrial tissue
• Ratio of effective refractory period to action potential is increased
• Good efficacy in ischaemic myocardium

Class IB – Lignocaine

• Pharmacodynamics
  • Preferentially acts on ischaemic tissues to decrease conduction
  • Negligable effect on cardiac action potential
  • Minimal effect on QT or refractory period either
• Pharmacokinetics
  • Hepatically metabolised and renally excreted
  • 7-30min half-life (initial) and terminal half-life 1.5-2 hours
  • Onset 45-90s and duration 10-20 min

Class IB – lignocaine

• Dosing in ventricular arrhythmia
  • Loading dose 1mg/kg IV over 2 minutes
  • Maintenance 4mg/min for 1 hour; 2mg/min for 1 hour then 1mg/min for 22 hours
• Dosing in VF
  • 1-1.5mg/kg IV loading then 0.5-0.75mg/kg every 5-10min
• Indications
  • Second-line to amiodarone in ventricular arrhythmias
• Adverse effects
  • CNS numbness speech impairment, somnolence, dizziness and seizures

Class Ic – strong slow dissociation

• Generally indicated for SVT
• Marked prolongation of QRS without QT prolongation
• Only act on open sodium channels
• High proarrhythmic potential that is amplified by myocardial tissue disease, increased sympathetic tone and higher heart rates
• Associated with increased mortality when used in cardiovascular disease or MI

Propafenone

• Also beta-blocker
• Selective for rapid conducting tissues e.g. atrial tissue
• Indicated for recent-onset AF (<7 days)
• Single oral dose 450mg (<70kg) or 600mg (>70kg)
• Adverse effects
  • Hypotension, bradycardia, bronchospasm, Aflutter with 1:1 conduction and ventricular proarrhythmia
  • Avoid in CAD or structural heart disease, asthma, hepatic dysfunction or CCF

flecainide

• Reduces excitability primarily in His-Purkinje and ventricular myocardium
• Indicated for conversion of new-onset AF (<7 days)
• One-time oral dose of 200mg (<70kg) or 300mg (>70kg)
• Adverse effects
  • Hypotension, Aflut with 1:1 and ventricular proarrhythmia
  • Avoid in CCF, CAD, structural heart disease or hypokalaemia

Class II: Beta-blockers

• Indications: HTN, SVT, ventricular arrhythmias, recurrent AF (rate control) and thyrotoxicosis
• Non-cardioselective (beta-1 and 2): Propranolol
• Cardioselective (beta-1): Esmolol, metoprolol
  • Better for those with asthma, COAD, IDDM
  • Dose-dependent cardioselective means lost at high doses
• Vasodilatory, non-selective: Labetalol

Propranolol

• Non-selective beta-1 and beta-2 antagonist
• Pharmacokinetics
  • Onset oral 1-2 hours; IV <1 min
  • Hepatically metabolised
  • 3-6 hour half-life
  • Dosing
    • Tachyarrhythmia: 1-3mg slow IV push, repeated very 2-5 min up to 5mg total
• Adverse effects include bradycardia, heart block, hypotension, acute heart failure and bronchospasm

Esmolol

• Short-acting, selective beta-1 antagonist which prevents excessive adrenergic stimulation of the myocardium, causing increased sinus cycle length, prolongation of sinoatrial recovery time and decreased AV nodal conduction
• Onset 2-10min
• Duration of action 10-30 min
• Metabolised in blood by RBC esterases
• Half-life 9 min
• Dosing
  • SVT – 500mcg/kg bolus over 1 min then infusion 50mcg/kg/min titrated to therapeutic effect in 50mcg/kg/min increments every 4 minutes
• Adverse effects
  • Hypotension (most common), bradycardia, heart block
  • Nausea, bronchospasm, pulmonary oedema

Metoprolol

• Selective beta-1 antagonist
• Decreases CO, reduced sympathetic outflow and suppresses renin activity to treat hypertension
• Onset of action 1-2 hrs PO and 20 min IV
• Hepatically metabolised
• Half-life 3-4 hours
• Dosing
  • 1.25-5mg IV every 5 minutes up to total 15mg
• Adverse effects
  • Bradycardia, heart block, hypotension and bronchospasm

Labetalol

• Combined selective alpha-1 and non-selective beta blocker
• Beta-blocker: Alpha-block 3:1 in oral and 7:1 in parenteral formulation
• Used primarily for antihypertensive effect
• Onset 20min – 2hr orally or 2-5min IV
• Duration 8-12hr oral or 2-18 hr IV
• Hepatically metabolised
• Half-life 6-8 hr oral and 5.5hr IV
• Dosing
  • 20mg IV push over 2 min; then 40-80mg at 10 min intervals up to 300mg
  • 2mg/min infusion titrated to response (total 300mg cumulative dose)
• Adverse effects
  • Orthostatic hypotension, nausea, dizziness, fatigue, heart failure, hyperkalaemia, hepatotoxicity and bronchospasm

Class III – Potassium-channel blockers

• Inhibit inward potassium currents leading to significantly lengthened refractory period
• Myocardial tissue in a refractory state is less prone to reentrant tachycardia
• Prolong the QT and carry risk of Torsades

Amiodarone

• Used in acute management and chronic suppression of SVT and ventricular arrhythmias
• MOA:
  • Alpha, beta, calcium channel, potassium channel blockade
  • Blocks inactivated sodium channels to prolong the refractory period which in turn decreases the HR and may cause sinus bradycardia
  • Non-competitive alpha and beta-blockade decreases sinoatrial node function leading to reduced heart rate, prolonged PR interval
  • Blocks inward K+ channel rectifier to slow AV nodal conduction and prolong the PR interval
  • Blocks myocardial calcium channels to modify automaticity of Purkinje fibres
• Effects on ECG
  • Slowed heart rate and possibly sinus bradycardia
  • Prolonged PR, QRS and QT intervals

amiodarone

• Highly lipophilic and extensively distributed into tissues
• Large oral or IV loading doses are required to fill this tissue reservoir or serum levels drop precipitously
• Terminal-phase elimination dominates after tissue stores become saturated leading to half-life of <55 days and duration of action of 50 days
• Hepatically metabolised and biliary excretion

amiodarone

• Indications
  • Acute rate control or cardioversion and maintenance of sinus rhythm
  • Acute management and chronic suppression of ventricular arrhythmias
• Dosing
  • Pulseless VT/VF: 300mg IV rapid bolus with single repeat 150mg if required
  • Stable VT or polymorphic VT with normal QT OR Cardioversion of AF or rate control in pre-excitation tachycarrhythmias
    • 150mg IV in 100mL 5% dextrose over 10 min, followed by 1mg/min for 6 hours, then 0.5mg/min for next 18 hours
    • Alternatively LITFL states
      • 5mg/kg bolus in 250mL 5% dextrose over 60 min then 15mg/kg/day infusion

amiodarone

• Adverse reactions to IV dosing
  • Bradycardia, hypotension and phlebitis
  • Infusion rates should not exceed 30mg/min and total daily doses not exceed 2.2g
  • Amiodarone precipitates in saline
  • Dose adjustments only required for severe hepatic dysfunction
• Adverse reactions
  • Cardiovascular – Sinus bradycardia (5% with oral), Torsades (<1%), thrombophlebitis, AV nodal block, hypotension (16% with IV) [may be due to infusion rate or IV solution emulsifier polysorbate 80]
  • CNS – Gait and movement disorders, paraesthesias, peripheral neuropathy or dizziness
  • GI – Nausea, vomiting, anorexia, constipation (10-33%)
  • Hepatic – Raised LFT (in 15-50%), monitor at baseline and 6 monthly
  • Pulmonary – 2-7% incidence. Often reversible pulmonary fibrosis, eosinophilia, interstitial pneumonia, allergic alveolitis. Monitor baseline PFT’s and repeat CXR annually
  • Thyroid – Hypothyroidism (4-22%), hyperthyroidism (3-10%) monitor 3-6 monthly
  • Ocular corneal deposits

amiodarone

• Interactions
  • Need dose reductions for digoxin, warfarin, procainamide, quinidine, simvastatin, lovastatin

dronedarone

• Non-iodinated, less lipophilic derivative of amiodarone
• Primarily Class III but has all four mechanisms like amiodarone
• Lower rates of pulmonary and thyroid toxicity

sotalol

• Unique non-selective beta-blocker with electrophysiological characteristics of Class III agents
• Prolongs repolarisation and refractoriness without affecting conduction
• Onset of action 1-2 hours for oral and 5-10 hrs after IV
• Duration of action 8-16 hours
• Half-life 12 hours and increases in renal impairment
• No metabolites and is excreted unchanged in urine
• Effective agent for supression of unstable ventricular arrhythmias refractory to other agents

sotalol

• Can suppress SVT and AF but not indicated for cardioversion of AF
• Normal PO dose is 80mg BD
• In monomorphic VT can give 1.5mg/kg IV over 5 min
• Contraindicated if QTc >450ms and infusion ceased if QTc lengthens to >500ms (must be calculated q2-4hrly)
• Adverse effects include bradycardia, hypotension
• 4.3% rate of new or worsened arrhythmia and 2.4% rate of Torsades

Ibutilide

• Prolongs refractory period in atrial and ventricular tissues
• Inhibits slow inward funny sodium current (rather than outward potassium currents)
• Blockade of delayed rectifier potassium current may also contribute
• Onset of action 90 min
• Metabolised in liver with 2-12 hour half-life
• Indicated for rapid cardioversion of AF or flutter 
• Can be used in AF with accessory pathway
• Loading dose 1mg IV or 0.01mg/kg over 10 minutes and repeated every 10 mnutes
• Adverse effects include hypotension, hypertension, bradycardia, sinus arrest, syncope, QTc prolongation, congestive heart failure and torsades

Vernakalant

• Inhibits sodium and potassium channels
• Atria more susceptible to refractory period prolongation
• Used for rapid cardioversion of AF

Class IV: Calcium-channel blockers

Inihibit L-type calcium cahnnels, resulting in slowed AV nodal conduction and increased refractory period of nodal tissue

In myocardium effects the action potential plateau and modulate strength of muscle contraction

Non-dihydropyridine CCB’s have more cardioselectivity and are generally used for SVT and rate control in AF

Diltiazem

• Slows AV nodal conduction, increases AV nodal refractory period, decreases automaticity and prolongs the PR interval
• Oral onset 15-60min
• Duration 1-3 hours
• More commonly used for rate control vs. cardioversion for rapid AF
• CI: Wide-complex tachyarrhythmia as may be due to WPW with aberrancy, sick sinus, 2^nd/3^rd degree block, severe hypotension, cardiogenic shock, use with IV beta-blockers and ventricular tachycardia
• IV bolus 0.25mg/kg over 2 min and infusion 5-15mg/hr then transition to oral therapy
• Adverse: Bradyarrhythmia, asystole, fatigue, headache, hypotension, AV block, peripheral oedema, syncope and dizziness

verapamil

• Non-dihydropyridine
• More frequently used for SVT management than diltiazem as more potent AV blockade
• Longer half-life and duration of action than diltiazem
• Hepatically metabolised with active metabolites
• 70% renally excreted
• 3-7hr half-life

verapamil

• Onset 1-5min after IV and 10-20min duration
• SVT conversion rate to sinus of around 90% (similar to adenosine)
• Same CI as diltiazem
• 2.5-5mg IV over 2 minutes
• Similar adverse effect profile

digoxin

• Cardiac glycoside with positive inotropic, negative chronotropic and negative dromotropic effects due to inhibition of Na-K ATPase and direct vagal effect
• Narrow therapeutic index (0.5-2ng/mL)
• Numerous drug interactions
• Indications
  • Rate control in AF (specifically in those with CCF)
  • Symptom reduction in CCF unrelieved by diuretics and ACEi
  • Contraindicated in ventricular arrhyhthmias but should also be avoided WPW due to risk of VF, acute MI, beri-beri, electrolyte imbalances, sinus node disease, AV block and renal impairment
  • Conflicing results on mortality

digoxin

• For AF 250mcg IV loading every 2 hours up to 1.5mg total with reduced dosing in elderly or renal impairment
• Adverse effects
  • GI, gynaecomastia, skin rash, eosinophilia, thrombocytopaenia
  • Can cause sinus bradycardia, AV and sinoatrial block and ventricular arrhythmias
• Symptoms of toxicity
  • Mental status changes, visual disturbance, delirium and seizures
  • Typically PAT with block but can cause any arrhythmia except for fast AF
• Hepatic metabolism with 50-70% renal excretion mostly as unchanged drug
• 38 hour half-life
• Onset 5-60min, peak 1-6 hours and duration 3-4 days

Atropine

• Rapid onset of action, 2-3 hour half-life
• Hepatically metabolised
• Dose 600mcg IV every 3-5 minutes (max 3mg)
• No longer indicated for asystole or PEA
• Use with caution in coronary heart disease, acute MI, CCF, tachycardia and hypertension as may worsen clinical state through initiating tachyarrhythmia
• Doses <0.5mg and slow injection have been associated with paradoxical bradycardia
• Adverse effects include tachyarrhythmia, constipation, blurred vision and photophobia

adenosine

• Endogenous nucleoside that binds adenosine receptors and inhibits adenylate cyclase, resulting in decreased flow of calcium ions into the AV node
• Decreases sinoatrial node depolarisation by activation of acetylcholine-sensitive potassium currents
• Results in hyperpolarisation and automaticity in cardiac nodal tissue
• Used for treatment of SVT with or without reentry pathways
• Ineffective for AF, flutter or ventricular tachycardias but can be diagnostic in this setting
• Half-life <10s

adenosine

• Dosing schedule
  • 6/12/12 mg
• Reduce initial dose to 3mg if on dipyramidole or carbamazepine due to upregulation of adenosine receptors, heart transplant patients or central line administration
• Effects antagonised by caffeine, theophylline and may require higher doses
• Adverse effects
  • Transient asystole (<5s), chest pressure, headache, flushing, nausea
  • Bronchospasm and AF can occur but incidence is rare

Magnesium sulphate

• Inhibits calcium currents that cause pathologic early after-depolarisations and cardiac dyssynchrony
• Slows sinoatrial node activity, prolongs myocardial conduction time, stabilises excitable membranes and is a cofactor in ion movement
• Rapid onset of action and indicated in Torsades, polymorphic VT associated with prolonged QT and cardiac arrest where VF or pulseless VT is associated with Torsades
• If have pulse, 1-2g (5-10mmol) IV diluted and administered as rapid bolus
• Rapid IV administration leads to vasodilation, flushing and hypotension

Isoprenaline/isoproterenol

• Beta-1 and beta-2 agonist
• Increased chronotropic and inotropic activities
• Vasodilatory
• Immediate onset, half-life 2.5-5min and duration 10-15min
• Indications: Refractory bradyarrhythmias, AV nodal block and refractory torsades (overdrive pacing)
• Contraindicated in angina, pre-existing ventricular arrhythmias, tachyarrhythmias or digoxin toxicity
• Initiate with bolus 20mcg then infusion at 2mcg/min and titrate every 5-10min up to 10mcg/min
• Adverse effects – Hypotension, premature ventricular beats, tachyarrhythmias, ventricular arrhythmia, dyspnoea and pulmonary oedema

Last Updated on October 28, 2020 by Andrew Crofton