Antiarrhythmic drugs are classified according to their mechanism of action and effects on cardiac electrophysiology. Class I drugs block sodium channels, while Class II are beta blockers, Class III block potassium channels, and Class IV block calcium channels. The main classes used are Class Ia (quinidine, procainamide), Class Ic (flecainide, propafenone), Class III (amiodarone, sotalol), and calcium channel blockers (verapamil, diltiazem). Each drug has therapeutic uses for specific arrhythmias as well as adverse effects that must be considered.

1. Antiarrhythmics
Dr. M. Ahsan, MBBS, MD

2. Learning Outcomes….
• Describe the cardiac electrophysiology
• Describe the causes of arrhythmia
• Classify antiarrhythmics
• Describe the mechanism of action, therapeutic uses,
pharmacokinetics and adverse effects of each class of antiarrhythmic
drugs

3. Antiarrhythmics
• These are drugs used to prevent or treat irregularities of cardiac
rhythm.
• Arrhythmias are the most important cause of sudden cardiac death
Ischaemia, electrolyte and pH imbalance, mechanical injury, stretching
(due to heart failure), neurogenic and drug influences, including
antiarrhythmic drugs themselves, can cause arrhythmias by altering
electrophysiological properties of cardiac fibres.

5. Cardiac
electrophysiology
 Heart contains specialized
cells that exhibit
automaticity
 Pacemaker cells differ from
other myocardial cells –
spontaneous
depolarization during
diastole (phase 4) by
inward positive Na current
 Spontaneous
depolarization is fastest in
SA node

6. Arrhythmias
• Arrhythmias are caused by abnormalities in:
• Impulse formation
• Conduction in the myocardium
• Arrhythmias are classified according to the anatomic site of the
abnormality…….atria, AV node or ventricles
Common arrhythmias requiring drug therapy:
Atrial arrhythmias – atrial flutter, atrial fibrillation
Supraventricular tachycardias – AV nodal re-entry, Acute supraventricular tachycardia
Ventricular tachycardias – Acute ventricular tachycardia, ventricular fibrillation

7. Abnormal automaticity
• Normally, SA node sets the pace of contraction of myocardium
• If cardiac sites other than SA node show enhanced automaticity,
arrhythmias arise
Most antiarrhythmic drugs suppress automaticity by blocking either Na or Ca channels
This decreases the slope of phase 4 depolarization
Raises the threshold of discharge to a less negative voltage
Leading to overall decrease in frequency of discharge
This effect is more pronounced in ectopic pacemaker activity than in normal cells

8. Abnormalities in
impulse conduction
A phenomenon called re-entry can occur if a
unidirectional block caused by myocardial injury or a
prolonged refractory period results in abnormal
conduction pathway
Antiarrhythmic agents prevent re-entry by slowing
conduction and/or increasing the refractory period –
thus creating a unidirectional block into a bidirectional
block

9. Antiarrhythmic drugs
Antiarrhythmic drugs are used to:
Decrease or increase conduction velocity
Alter the excitability of cardiac cells by changing the duration of the
effective refractory period
Suppress abnormal automaticity
• They are classified according to the Vaughan-Williams Classification
according to their predominant effects on the action potential
Antiarrhythmics have
narrow therapeutic
window – have
dangerous
proarrhythmic actions
Limitations of Vaughan-Williams Classification:
Antiarrhythmic drugs have multiple electrophysiological and pharmacological effects
Action depends on route of administration, plasma levels and active metabolites (metabolites may have a different action)

10. Antiarrhythmic drugs
• Class I (Na channel blockers)
IA: Quinidine, Procainamide, Disopyramide
IB: Lidocaine, Mexiletine
IC: Flecainide, Propafenone
• Class II (β blockers)
Atenolol
Metoprolol
Esmolol
• Class III (K channel blockers)
Sotalol Dofetilide
Amiodarone Ibutilide
• Class IV (Ca channel blockers)
Diltiazem
Verapamil
• Other antiarrhythmics
Adenosine
Digoxin
Magnesium sulphate
Ranolazine

11. Class I Antiarrhythmic drugs
• Block voltage-sensitive Na channels
• Subdivided into three groups according to the effect on the duration
of the cardiac action potential:
• IA – intermediate blockers of Na channels
• IB – fast blockers of Na channels
• IC – slow blockers of Na channels
The use of Na channels has declined due to their pro-arrhythmic effects, particularly in
patients with reduced left ventricular function and atherosclerotic heart disease

12. Class IA antiarrhythmic drugs
Mechanism of action:
• Bind to open and inactivated Na channels and prevent Na influx
Slows the rapid upstroke during phase 0
• Decrease the slope of
phase 4 spontaneous depolarization
• Inhibit K channels
• Block Ca channels
Quinidine (prototype)
Procainamide
Disopyramide
Slows conduction
velocity and increases
refractoriness

13. Class IA antiarrhythmic drugs

14. Class IA antiarrhythmic drugs
Additional properties:
• Quinidine also has mild :
α-adrenergic blocking property (not seen in procainamide and
disopyramide)
Anticholinergic property (procainamide has less anticholinergic
activity while disopyramide has more anticholinergic activity)
• Disopyramide has greater negative inotropic effect and causes
peripheral vasoconstriction
Quinidine (prototype)
Procainamide
Disopyramide

15. Class IA antiarrhythmic drugs
Quinidine:
Atrial, AV junctional and
ventricular tachyarrythmias
Rarely used due to its adverse
effects
Procainamide:
Used as intravenous formulation
to treat acute atrial and
ventricular arrhythmias
Mostly replaced by electrical
cardioversion and amiodarone
Quinidine (prototype)
Procainamide
Disopyramide
Therapeutic Uses:
Disopyramide:
Vagally mediated atrial fibrillation, Hypertrophic obstructive cardiomyopathy
and as an alternative therapy in ventricular arrhythmias

16. Class IA antiarrhythmic drugs
Pharmacokinetics:
Quinidine (prototype)
Procainamide
Disopyramide
Quinidine
• Gluconate or sulfate
salt is well absorbed
orally
• Undergoes hepatic
metabolism by
CYP3A4 forming
active metabolites
Procainamide
• Given iv
• Acetylated in the liver to
N-acetylpocainamide
(NAPA)….NAPA has
properties and adverse
effects of class III drug
• Dose needs to be reduced
in renal
dysfunction…(NAPA is
excreted through kidneys)
Disopyramide
• Well absorbed after
oral administration
• Metabolized by
CYP3A4 to inactive
metabolites
• Half of drug is
excreted unchanged
by kidneys

17. Class IA antiarrhythmic drugs
Adverse effects:
• Should not be used in patients of atherosclerotic heart disease or systolic
heart failure (due to enhanced pro-arrhythmic properties and ability to
worsen heart failure)
• Cinchonism – Quinidine
(blurred vision, tinnitus, headache, disorientation and psychosis)
• Hypotension and DLE - Procainamide
• Anticholinergic side effects – Disopyramide
(dry mouth, urinary retention, blurred vision and constipation)
• Drug interactions are common (quinidine inhibits CYP2D6 and P-gp;
Disopyramide and quinidine should be used cautiously with CYP3A4
inhibitors)
Quinidine (prototype)
Procainamide
Disopyramide

18. Class IB antiarrhythmic drugs
• Class IB agents rapidly associate and dissociate with Na channels
Mechanism of action:
• Block Na channel
• Shorten phase 3 repolarization
• Decrease the duration of action potential
Uses:
• Intravenous lidocaine is used as an alternative (to amiodarone) in treating
ventricular arrhythmias (VT and VF)
• Iv lidocaine is combined with amiodarone for VT storm
• Oral mexiletine is used for chronic treatment of ventricular arrhythmias
(with amiodarone)
Lidocaine
Mexiletine
No negative inotropic effect

19. Class IB antiarrhythmic drugs

20. Class IB antiarrhythmic drugs
Pharmacokinetics:
• Lidocaine:
Given iv because of extensive
first pass metabolism
Metabolized to active
metabolites by CYP1A2 and
CYP3A4
• Mexiletine :
Well absorbed orally
Metabolized in the liver by
CYP2D6 to inactive metabolites
and excreted via biliary route
Lidocaine
Mexiletine
Adverse effects:
Lidocaine: (wide therapeutic index) - Nystagmus (early indicator of toxicity), drowsiness, slurred
speech, paresthesia, agitation, confusion, convulsions
……..limits the duration of continuous infusion
Mexiletine: (narrow therapeutic index) - Nausea, vomiting, dyspepsia

21. Class IC antiarrhythmic drugs
• Slowly dissociate from resting Na channels and show prominent
effects even at normal heart rates.
• Avoided in structural heart disease such as left ventricular
hypertrophy, heart failure and atherosclerotic heart disease because
of negative inotropic effects and pro-arrhythmic effects
Flecainide
Propafenone

22. Class IC antiarrhythmic drugs
Mechanism of action:
Suppress phase 0 upstroke in Purkinje and myocardial fibres
Leads to marked slowing of conduction in all cardiac tissues
• Minor effect on duration of AP and refractoriness
• Increase in threshold potential reduces automaticity
Flecainide also blocks K channels (leads to increased duration of AP)
Propafenone has weak β- blocking property (no effect on K channels)
Flecainide
Propafenone

23. Class IC antiarrhythmic drugs

24. Class IC antiarrhythmic drugs
Therapeutic uses:
• Used to maintain sinus rhythm in AF (in patients without structural
heart disease)
• Used in combination with an AV blocking agent to prevent conduction
through AV node in cases of atrial flutter/fibrillation
(class IC agents increase AV nodal conduction)
• Treatment of refractory ventricular arrhythmias
Flecainide
Propafenone

25. Class IC antiarrhythmic drugs
Adverse effects:
Blurred vision, dizziness, nausea
Propafenone can also cause bronchospasm (avoided in asthmatics)
Propafenone is an inhibitor of P-gp
Both drugs should be used cautiously with potent inhibitors of CYP2D6
Flecainide
Propafenone
Both drugs are metabolized by CYP2D6
Propafenone is also metabolized by CYP1A2 and CYP3A4
Metabolites are excreted in urine and faeces

26. Class II antiarrhythmic agents
• Class II agents are β-blockers
• They diminish phase 4 depolarization
• Depress automaticity, prolong AV conduction, and decrease heart rate
and contractility
Uses:
Used in treating arrythmias caused by increased sympathetic activity
Atrial flutter
Atrial fibrillation
AV nodal re-entrant tachycardia
β-blockers prevent life-threatening ventricular arrythmias following
myocardial infarction
Propranolol
Atenolol
Metoprolol
Esmolol

27. Class II antiarrhythmic agents
Propranolol:
• Useful in treating inappropriate
sinus tachycardia.
• Atrial and nodal ESs, especially
those provoked by emotion or
exercise
• Highly effective in sympathetically
mediated arrhythmias seen in
pheochromocytoma and during
anesthesia
Metoprolol:
Compared to nonselective beta
blocker, it reduces the risk of
bronchospasm
Esmolol:
Very short and fast acting beta
blocker
Used iv to control arrythmias
during surgery
Metabolized by esterases in
RBCs….no pharmacokinetic drug
interactions
Common adverse effects:
bradycardia,
hypotension, and fatigue

28. Class III antiarrhythmic drugs
Block K channels
Diminish the outward K current during repolarization
Prolong the duration of action potential, thus prolong the effective
refractory period
(without altering phase 0 of depolarization or the resting membrane
potential)
Amiodarone
Dronedarone
Sotalol
Dofetilide
Ibutilide
All Phase III drugs have the potential to induce arrhythmias

29. Class III antiarrhythmic drugs

30. Class III antiarrhythmic drugs
Amiodarone:
• Contains iodine (structurally related to thyroxine)
• Shows Class I, II, III and IV actions in addition to α blocking activity
• Prolongs the action potential duration and the refractory period by
blocking K channels
Uses:
• Atrial fibrillation/flutter
• Severe supraventricular tachyarrhythmia
• Ventricular tachyarrhythmias
Least pro-arrhythmic
agent among class I and
III drugs

31. Class III antiarrhythmic drugs
Amiodarone:
• Incompletely absorbed after oral administration
• Long t ½ of several weeks
• Distributes extensively in tissues
• Loading doses are needed to achieve full clinical effects
• Numerous drug interactions (it is metabolized by CYP3A4; inhibitor of P-gp,
CYP1A2, CYP2C9, CYP2D6
Adverse
Effects
Pulmonary
fibrosis
Neuropathy Hepatotoxicity Corneal deposits
Blue-gray discolouration of skin Hypo/hyper-
thyroidism
Optic neuritis

32. Class III antiarrhythmic drugs
Dronedarone:
• Less lipophilic and has shorter t ½
• No iodine component and no thyroid
dysfunction
• Has class I, II, III and IV actions
• Can cause liver failure
• Contraindicated in heart failure and
permanent AF
• Used to maintain sinus rhythm in
atrial fibrillation/flutter
Sotalol:
• Class III antiarrhythmic agent with
non-selective β blocking activity
• Blocks rapid outward K current
(delayed rectifier current)
• Prolongs both repolarization and
duration of action potential, thus
lengthening the refractory period
• Used to maintain sinus rhythm in
AF/flutter or refractory PSVT

33. Class III antiarrhythmic drugs
Dofetilide:
• Pure K channel blocker
• First line anti-arrhythmic drug in
persistent Atrial fibrillation (in HF or
CAD)
• Excreted through kidneys: so drugs
that inhibit active tubular secretion
are contraindicated with dofetilide
Ibutilide:
• K channel blocker that also activates
inward Na current (class III and IA
action)
• Drug of choice for chemical
conversion of atrial flutter (electric
cardioversion is preferred)

34. Class IV antiarrhythmic drugs
• Non-dihydropyridne Ca channel blockers (verapamil and diltiazem) are
used
Bind to open depolarized voltage-sensitive Ca channels
Decrease the inward Ca current
• These drugs are use-dependent: prevent repolarization until the drug
dissociates from the channel
• Decrease rate of phase 4 spontaneous depolarization
• Slow conduction in tissues that are dependent on Ca currents (AV node, SA
node)

35. Class IV antiarrhythmic drugs
Uses:
• More effective in atrial tachyarrhythmias than ventricular tachycardia
• Useful in treating re-entrant supraventricular tachycardia
• Reduce the ventricular rate in atrial flutter/fibrillation
Adverse effects:
• Bradycardia, hypotension, peripheral edema

36. Digoxin
• Inhibits Na-K-ATPase
• Shortens the refractory period in atrial and ventricular cells
• Prolongs the effective refractory period and diminishes the
conduction velocity in AV node
• Used to control ventricular response rate in atrial fibrillation and
flutter
• At toxic doses it can cause ectopic ventricular betas that may result in
VT and fibrillation

37. Adenosine
• Adenosine:
Decreases the conduction velocity
Prolongs the refractory period
Decreases automaticity in the AV node
• It has extremely short duration of action (10-15 seconds) due to uptake
by erythrocytes and endothelial cells
Adenosine (iv) is used for converting acute supraventricular tachycardias
Can cause flushing, chest pain and hypotension

38. Magnesium sulphate
• Magnesium is necessary for transport of Na, Ca, and K across cell
membranes
• It slows the rate of SA node firing and prolongs conduction time
Magnesium sulphate (iv) is used for:
Torsades de pointes
Digoxin-induced arrhythmia

39. Ranolazine
• Antianginal drug with antiarrhythmic properties (similar to
amiodarone)
• Shortens repolarization and action potential duration ( similar to
mexiletine)
• Used to treat refractory atrial and ventricular arrhythmias
• Dizziness and constipation are common adverse effects

40. Antiarrhythmic drugs used to treat different
arrythmias
CONDITION DRUG CLASS DRUG OF CHOICE COMMENTS
Sinus tachycardia Class II, IV Propranolol Other underlying causes
may need treatment
Atrial fibrillation/flutter Classes IA, IC, II, III, IV
Digitalis, adenosine
Esmolol, verapamil,
digoxin
Ventricular rate control is
important;
anticoagulation needed
Paroxysmal
supraventricular
tachycardia
Classes IA, IC, II, III, IV,
adenosine
Adenosine, esmolol -
AV block Atropine Atropine Acute reversal
Ventricular tachycardia Classes I,II,III Lidocaine, procainamide,
amiodarone
-
Ventricular fibrillation Classes II, IV, Mg salts Lidocaine, amiodarone -
Digitalis toxicity Class IB, Mg salts; KCl - -

41. Thankyou

42. References
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.
• Clinical Medicine: A Textbook for Medical Students & Kumar PJ
and Clark ML (8th ed.); Elsevier Saunders