Pharmacology of Antiarrhythmic Agents

Heart, Lung, and Kidney

Uzoma Ikonne PhD
IkonneUS@evms.edu
757-446-7448
Learning Points
1. Brief Overview of Antiarrhythmic Drugs
2. Describe the mechanism of action, therapeutic use, pharmacokinetics, and adverse effects and contraindications of the Class 1
Antiarrhythmic Drug:
• Class IA -- Procainamide, Quinidine, Disopyramide
• Class IB – Lidocaine, Mexiletine
• Class IC -- Flecainide
3. Describe the mechanism of action, therapeutic use, pharmacokinetics, and adverse effects and contraindications of the Class 2
Antiarrhythmic Drug:
• Beta-Adrenergic Antagonists – Propranolol and Metoprolol
4. Describe the mechanism of action, therapeutic use, pharmacokinetics, and adverse effects and contraindications of the Class 3
Antiarrhythmic Drug: Amiodarone, Sotalol, Dofetilide and Ibutilide
5. Describe the mechanism of action, therapeutic use, pharmacokinetics, and adverse effects and contraindications of the Class 4
Antiarrhythmic Drug:
• Calcium Channel Blockers – Verapamil and Diltiazem
6. Describe the mechanism of action, therapeutic use, pharmacokinetics, and adverse effects and contraindications of the Other
Modulators of Cardiac Rhythm and Ion Channels: Adenosine, Magnesium and Ivabradine
7. Principles for Clinical Use of Arrhythmic Agents
Cardiac Arrhythmias

Arrhythmia:

Dysfunction in electrical
component of the heart

• Abnormal impulse generation

and or/propagation

Drugs target Proarrhythmic

regions of heart

Macle, L., & Nattel, S. (2016). Advances in drug, ablation, and device therapy for cardiac arrhythmias. Nature Reviews
Cardiology, 13(2), 67-68.
 Antiarrhythmic Drugs

Please Note: Drugs can

demonstrate properties of
multiple classes of drugs are
classified by their prominent
mechanism of action

Barton, A. K., McGowan, M., Smyth, A., Wright, G. A., & Gardner, R. S. (2020). Classification and choice of antiarrhythmic
therapies. Prescriber, 31(3), 11-17.
Antiarrhythmic Agents: State-dependent ion
channel block

State-dependent Ion Channel Block:

• Drug bind to channels with differing

affinities of ion channel state

• i.e. Na+ blockers prefer

open/inactivated states
Class I Antiarrhythmic Agents: Fast Na+
Channel Blockers
General Mechanism of Action:

Reduction in automaticity of SA Node

• fewer NA channels available to respond

to membrane depolarization

Decrease re-entry, prevent arrhythmia

• Decrease conduction velocity

• Increase refractory period of

ventricular myocytes
Conduction Abnormality: Re-entry

Defect in conduction that leads to

continuous wave of excitation
(circus movement)
Class IA-C Effects: Ventricular Action Potential
Class IA: Moderate Na+ Blockers
Agents:

Procainamide
Quinidine (prototype)
Disopyramide

Mechanism of Action:

• Slow conduction velocity (block Na+

channels)
• prolong repolarization (blockade of K+
channels)

Prolong Action Potential Duration

effective refractory period (ERP)

Please Note: not used frequently due to

adverse effects
 Class IA: Procainamide
• Therapeutic Use
• Atrial and ventricular arrhythmias
• Avoid long-term use

• Pharmacokinetics
• Route of Admin: oral, IV and IM
• Reduced dosage renal failure
• Metabolite N-acetylprocainamide (NAPA)
• Class III Antiarrhythmic activity

• Adverse effects
• GI effects
• Hypotension (IV)
• Excessive action potential prolongation
• QT-interval prolongation
• Induction of torsades de pointes arrhythmias – linked to NAPA
• Syndrome similar Lupus erythematosus

• Precautions & Contraindications

• Renal Failure – torsades de pointes
Class IA: Quinidine
• Therapeutic Use
• Rarely used for arrhythmias
• Brugada syndrome
• Malaria

• Pharmacokinetics
• Route of Admin: oral and parenteral

• Adverse effects
• Cinchonism
• Headache, tinnitus, and dizziness
• QT-interval prolongation
• Induction of torsades de pointes
• Antimuscarinic effects in heart
• Administer w/drug that slows AV conduction

• Contraindications
• Patients w/ prolonged QT-interval
• Or medication that predisposes them
Class IA: Disopyramide
• Therapeutic Use
• Ventricular arrhythmias
• Supraventricular arrhythmias
• Not FDA approved

• Pharmacokinetics
• Route of Admin: oral
• Reduce renal impairment

• Adverse effects
• Similar to Quinidine electrophysiological disturbances
• Antimuscarinic (more than quinidine)
• i.e. sedation and dry mouth
• Administer w/drug that slows AV conduction
• Atrial flutter or atrial fibrillation
• Precipitate heart failure

• Contraindications
• Patients w/glaucoma
• Heart Failure
Class IB: Weak Na+ Blockers Agents:

Lidocaine
Mexiletine
Phenytoin (antiepileptic)

Mechanism of Action:

• Slow conduction velocity (block Na+

channels)

• Shorten repolarization sometimes

No change/decrease action potential

Prefer ischemic tissue or Purkinje and

ventricular cells due to increased action
potentials
Class IB: Lidocaine
• Therapeutic Use
• Local Anesthetic
• Ventricular tachycardia (agent of choice)

• Pharmacokinetics
• Route of admin: parenteral

• Adverse effects
• Neurologic
• dizziness, tremor, hallucination, convulsions
• Hypotension (patients with heart failure)
Class IB: Mexiletine
• Therapeutic Use
• Ventricular arrhythmias
• Chronic Pain (diabetic neuropathy)

• Pharmacokinetics
• Route of admin: oral

• Adverse effects
• Nausea
• Neurological [similar to lidocaine]
Class IC: Strong Na+ Blockers
Agents:

Flecainide
Propafenone

Mechanism of Action:

• Slow conduction velocity (block Na+

channels)

• Prolong ERP (AV Node)

Minimal effect on action potential duration

Class IC Antiarrhythmics: Flecainide
• Therapeutic Use
• Supraventricular arrhythmias
• Structurally normal hearts

• Pharmacokinetics
• Route of Admin: Oral

• Adverse effects
• Proarrhythmic
• Pre-existing ventricular arrhythmia and MI
• Suppress Cardiac Function
• Decrease conduction velocity
Class IC Antiarrhythmics: Propafenone
• Therapeutic Use
• Supraventricular arrhythmias

• Pharmacokinetics
• Route of Admin: oral

• Adverse Effects
• GI
• Arrhythmia exacerbation
Class II Antiarrhythmic Agents: β-adrenergic
Antagonist Agents:

Propranolol
Esmolol

Mechanism of Action:

reduce sympathetic stimulation SA and AV

nodes of heart
• suppress Ca2+ and K+ current

• Decrease SA/AV node activity

• AV node more sensitive

• Prolong repolarization, increase ERP (AV

Node)
Class II: Beta-Adrenergic Antagonist
• Therapeutic Use
• Supraventricular /ventricular arrhythmia
• Reduce mortality after MI
• intraoperative arrhythmia (Esmolol)

• Pharmacokinetics
• Route of Admin: Oral and IV
• Esmolol short-acting

• Adverse effects
• Smooth muscle spasm
• Bradycardia, reduced contractility
• Insomnia and depression (CNS)

• Contraindications
• Insulin-dependent diabetics
Class III Antiarrhythmics Agents: Inhibitors of
Repolarization Agents:

Amiodarone (Class I-IV effects)

Sotalol (β-Adrenergic Antagonist)
Dofetilide
Ibutilide

Mechanism of Action:

Block K+ channels, prolong repolarization

• Prolong action potential

• Reverse use dependency (exception
amiodarone)
• Less effective at fast rates
• Most effective at slow rates
(torsades de pointes)
• ERP
Amiodarone
• Therapeutic Use
• Maintaining sinus rhythm
• Patients with Atrial Fibrillation
• Ventricular tachycardia

• Pharmacokinetics
• Route of Admin: Oral and IV
• Highly lipophilic – alters lipid membranes

• Adverse effects
• Cardiovascular: bradycardia, hypotension
• Skin: discoloration, gray-blue (sun exposure)
• Pulmonary: pulmonary fibrosis
• Thyroid dysfunction (more in HRH)
• Neurological: Peripheral Neuropathy, headache

• Precautions
• Check thyroid function before/during treatment
SOTALOL
• Therapeutic Use
• Life-threatening ventricular arrhythmias
• Maintenance of sinus rhythm w/AF
• Supraventricular/ventricular arrhythmia
• Pediatric age group

• Pharmacokinetics
• Route of Admin: Oral

• Adverse effects
• Torsades de pointes
• Beta-adrenergic antagonism

• Precaution
• Left Ventricle depression in Heart Failure
DOFETILIDE
• Therapeutic Use
• Maintenance/restoring of normal sinus rhythm (AF)

• Pharmacokinetics
• Route of Admin: oral
• Dosage based on creatinine clearance
• Minimum 3 days in hospital

• Adverse effects
• Dose-related
• QT prolongation
• Ventricular Proarrhythmic

• Drug Interactions
• Increase half-life
• Inhibitors of renal cation secretion (cimetidine)

• Contraindications
• Severe renal impairment
IBUTILIDE
• Therapeutic Use
• Acute conversion of AF and atrial flutter

• Pharmacokinetics
• Route of Admin: IV

• Adverse effects
• QT prolongation
• Torsades de Pointes
Class IV Antiarrhythmic Agents: Ca2+ Channel
Blockers
Agents:

Verapamil
Diltiazem

Mechanism of Action:

Inhibit calcium channel current

• reduce upstroke and conduction in AV

node

Therapeutic Use
Supraventricular tachycardia
Rate control in AF and atrial flutter

Route of Admin: Oral and IV

Other Modulators of Cardiac Rhythm and Ion
Channels
Agents:

Adenosine
Magnesium
Ivabradine
Ranolazine*

*Mechanism Covered in Other Presentations

Macle, L., & Nattel, S. (2016). Advances in drug, ablation, and device therapy for cardiac arrhythmias. Nature Reviews
Cardiology, 13(2), 67-68.
 Adenosine Agents:
Adenosine

Mechanism of Action:
Activation of inward rectifying K+ current
and inhibition of Ca2+ current

• Inhibits AV nodal conduction, lesser SA

• Increases AV nodal refractory period

Therapeutic Use
Conversion of paroxysmal supraventricular
tachycardia to sinus rhythm (drug of choice)

Route of Admin: Oral and IV

Affects blunted by adenosine receptor
antagonist

Adverse Effects: Flushing, shortness of

Layland, J., Carrick, D., Lee, M., Oldroyd, K., & Berry, C. (2014). Adenosine: physiology, pharmacology, and clinical
breath or AF
applications. JACC: Cardiovascular Interventions, 7(6), 581-591.
 Magnesium
Agents:

Magnesium

Mechanism of Action:

Not fully Elucidated

Therapeutic Use
Digitalis induced arrhythmia
(hypomagnesium)

Torsades de pointes

Route of Admin: IV

Geiger, H., & Wanner, C. (2012). Magnesium in disease. Clinical kidney journal, 5(Suppl_1), i25-i38.
Ivabradine
Agent

Ivabradine

Mechanism of Action:

Inhibit funny current (If), slows depolarization

SA Node

• Decrease Heart Rate not contractility

Therapeutic Use
Heart Failure
Chronic Angina
Sinus Tachycardia

Pharmacokinetics
Route of Admin: Oral
Psotka, M. A., & Teerlink, J. R. (2016). Ivabradine: role in the chronic heart failure armamentarium. Circulation, 133(21), 2066-
2075.
Adverse Effects: Visual Disturbances
 Atropine for Bradyarrhythymia

Wess, J., Eglen, R. M., & Gautam, D. (2007). Muscarinic acetylcholine receptors: mutant mice provide new insights for drug
development. Nature reviews Drug discovery, 6(9), 721-733.
Principles for Clinical Use of Antiarrhythmic
Agents

Margin between efficacy and toxicity is small

Pretreatment Evaluation:

• Eliminate the Cause

• Make a firm diagnosis

• Determine the Baseline Condition

• Question the need for therapy

Macle, L., & Nattel, S. (2016). Advances in drug, ablation, and device therapy for cardiac arrhythmias. Nature Reviews
Cardiology, 13(2), 67-68.
References