This presentation was use as an aid for lecture class. Students are requested to refer to book for further learning.

1. Anti-arrhythmic Drugs
Dr. Pravin Prasad
MBBS, MD Clinical Pharmacology
Assistant Professor, Department of Clinical Pharmacology
Maharajgunj Medical Campus, Kathmandu
10 June 2020 (28 Jestha 2077), Wednesday

2. By the end of this discussion, BNS 1st year
students will be able to:
Review the ionic basis of action potential in cardiac tissues
Classify drugs used as anti-arrhythmic agents
Explain the pharmacology of different anti-arrhythmic agents in
terms of:
Mechanism of action
Important pharmacokinetic properties
Uses
Side effects/ interactions
List the drugs used in PSVT and AV block
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3. Reviewing Cardiac Action Potential
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4. Pacemaker Potentials
4
INa+
ICa++
ICa++
OK+

5. Classification
Vaughan Williams Classification of anti-dysrhythmic drugs
Class Actions Drugs
I Membrane Stabilizing Agents
A. Moderately decrease dv/dt of phase 0 Quinidine, Procainamide,
Disopyramide
B. Little decrease in dv/dt of phase 0 Lidocaine, Mexiletine
C. Marked decrease in dv/dt of phase 0 Propafenone, Flecainide
II Antiadrenergic agents (β blockers) Propanolol, Esmolol, Sotalol (also
class III)
III Agents widening Action Potential (prolong
repolarization and Effective refractory period)
Amiodarone, Dronedarone,
Dofetilide, Ibutilide
IV Calcium channel blockers Verapamil, Diltiazem
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6. Other Anti-dysrhythmic drugs
Drugs not classified by Williams
Drugs Use
Atropine Sinus bradycardia
Adrenaline Cardiac Arrest
Isoprenaline Heart block
Digoxin Rapid atrial fibrillation
Adenosine Supraventricular tachycardia
Calcium chloride Ventricular tachycardia due to
hyperkalemia
Magnesium chloride Ventricular fibrillation, digoxin toxicity
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7. Clinical Classification: Anti-dysrhythmic drugs
Supraventricular
arrhythmias only
Supraventricular and ventricular
arrhythmias
Ventricular
arrhythmias only
• Adenosine
• Verapamil,
Diltiazem
• Dronedarone
• Digoxin
• Amiodarone
• β – blockers
• Sotalol
• Propranolol
• Esmolol
• Procainamide
• Disopyramide
• Quinidine
• Flecainide
• Propafenone
• Lidocaine
• Mexiletine
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8. Mechanism of Action: Class I
Blocks Na+ channels
Open and inactivated channels blocked
 Blocks only high frequency excitation of myocardial cells
Decrease the slope of phase 0
 Reduces maximum rate of depolarization
Additional action on conducting tissues:
Reduce rate of phase 4 depolarization  reduced automaticity
Further divided into Ia, Ib, Ic
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9. Subclass Ia: Quinidine
d-isomer of quinine
Mechanism of action:
Blocks Na+ channels in open state
Additional anti-vagal action  prolongation of atrial ERP
A-V node:
 Inconsistent effect
May precipitate failure in damaged heart: depresses myocardial contractility
ECG: broad QRS, increased PR, QT intervals, T wave changes
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10. Subclass Ia: Quinidine
Use:
To maintain sinus rhythm after termination of Atrial Fibrillation (AF) or Atrial
Flutter (AFl)
Atrial and ventricular arrhythmia
Side Effects:
Arrhythmias: Torsades de pointes (TdP), Ventricular Fibrillation (VF), Sudden
cardiac arrest
Neurological effects: ringing in ears, vertigo, visual disturbances, mental
changes: cinchonism
Idiosyncratic angioedema
Vascular collapse
Thrombocytopenia
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11. Subclass Ia: Procainamide
Orally active amide derivative of procaine
Action similar to quinidine
Difference form quinidine:
Less effective in suppressing ectopic automaticity
Less marked depression of contractility and A-V conduction
No anti-vagal action
Less fall in BP (no α blockade; ganglion blockade at high doses)
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12. Subclass Ia: Procainamide
Use:
Occasionally used i.v. to terminate
monomorphic VT and SVTs
WPW reciprocal VTs
Prevent recurrences of VF
Adverse Effects
Cardiac toxicity: potential to cause
TdP
Hypersensitivity reaction: rashes,
fever, angioedema, agranulocytosis
and anaemia (rare)
Long term high dose: SLE in slow
acetylators
GI intolerance: nausea/vomiting
CNS: weakness, mental confusion,
hallucination (higher doses)
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13. Subclass Ia: Disopyramide
Prominent cardiac depressant and anticholinergic activity; no α blocking
property
Inconsistent effect on sinus rate
Effect on PR interval and QRS broadening: less marked
Use:
Second line drug for prevention of recurrences of VT
Maintenance therapy after cardioversion of AF or AFl
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14. Subclass Ia: Disopyramide
Adverse Effects:
Arrhythmia: TdP
Depression of cardiac contractility: precipitation of heart failure,
hypotension
Less GI effects
Anticholinergics side effects
Contra-indications:
Sick sinus, cardiac failure
Prostate hypertrophy
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15. Subclass Ib: Lidocaine
Acts by:
Blocks inactivated Na+ channels
Supresses automaticity in ectopic foci (phase 4)
 Automaticity/After depolarization of Purkinje Fibres (PF) antagonised
Acts on channels found predominantly in ventricles
Suppresses re-entrant ventricular arrhythmia:
One way block converted to two way block
No anti-arrhythmic potential, least cardiotoxic
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16. Subclass Ib: Lidocaine
Administered intravenously
Effect lasts only for 10-20 mins
Metabolised in liver, excreted in urine
Initial t1/2 8 mins, later 2 hrs
Prolonged in CHF: Reduce dose
Use: (slow i.v. injection)
Supress VT, prevent VF
Supress VT due to digitalis toxicity
Adverse Effects:
Drowsiness, paresthesia, nausea,
blurred vision, disorientation,
nystagmus, twitching and fits
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17. Subclass Ic
Most potent Na+ channel blockers
Acts on open state, has longest recovery time:
Delays conduction, prolongs PR interval, broadens QRS complex,
Variable effect on APD
Have high pro-arrhythmic potential
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18. Subclass Ic: Propafenone
Na+ channel blockers:
Depresses impulse transmission through normal as well as aberrant
pathways
Pharmacokinetics:
Variable bioavailability, first pass metabolism, t1/2
Side effects:
Nausea/vomiting, bitter taste, constipation, blurred vision
Can worsen CHF, precipitate asthma, increase risk of sudden death
Use:
Prophylaxis and treatment of ventricular arrhythmia, re-entrant tachycardias
Maintain sinus rhythm in AF
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19. Class II: Propanolol
Non-selective beta blocker
Most commonly used beta blocker as anti-arrhythmic
Acts by:
Blocking cardiac adrenergic stimulation
 Decreased automaticity in SA node, PF and other ectopic foci
Prolong ERP of A-V node:
 No paradoxical tachycardia when rate reduced in AF or AFl
Membrane stabilizing property at high doses
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20. Class II: Propanolol
Use:
Inappropriate sinus tachycardia
Control ventricular rate in AF or AFl
Non-sustained VT, prevent recurrence of VT
Prophylactic treatment in post-MI patients
Terminate torsades de pointes
Re-entrant arrhythmias:
 PSVT, WPW syndrome
Arrhythmias due to pheochromocytoma, during anaesthesia with halothane
Digitalis induced tachyarrhythmia
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21. Class II: Esmolol
Quick and short acting β1 blocker
Used i.v. for emergency control of ventricular rate in AF/AFl
Can terminate SVT when associated with anaesthesia
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22. Class II: Sotalol
Non-selective β blocker
Delays A-V conduction prolongs ERP
Additional prominent class III action
Prolongs repolarization by blocking cardiac inward rectifier K+ channels
Use:
Polymorphic VT
WPW arrhythmias
Maintain sinus rhythm in AF/AFl
Side effects:
Dose dependent torsades de pointes
 CONTRAINDICATED in pts with long QT interval
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23. Class III: Amiodarone
Acts by:
Blocks myocardial rectifier K+ channels (Class III)
 Prolongs APD and QT interval
 Uniformity of refractoriness among different fibres achieved
Blocks inactivated Na+ channels (Class I)
 Partially depolarized tissues gets depressed
 Have longer APD
Inhibits Ca2+ partially (Class IV)
β blocker property (Class II)
Results in slowed conduction, depression of ectopic automaticity
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24. Class III: Amiodarone
Incompletely & slowly absorbed orally
Action develops over several days or weeks
Rapid action on i.v. injection
Affects cardiac contractility as well as BP
Large Volume of Distribution
Accumulates in fat and muscle
Metabolised in liver (CYP3A4)
Duration of action: 3-8 weeks
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25. Class III: Amiodarone
Use:
VTs and SVTs
 Resistant VT, recurrent VF
! Rapid termination of VT/VF
 PSVT, Nodal tachycardia, VT, AF, AFl
 Maintain sinus rhythm in AF
 WPW tachyarrhythmias
Chronic prophylactic therapy:
 Reduce sudden cardiac death
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26. Class III: Amiodarone
Side Effects
Related to dose and duration
 Hypotension, bradycardia, myocardial depression
! Seen with intravenous administration
! Long duration of therapy
 Oral (loading phase): nausea, g.i. upset
 Pulmonary alveolitis, fibrosis
 Photosensitization, sun burn
 Corneal microdeposits: headlight dazzle – reversible
 Peripheral neuropathy: shoulder/pelvic muscles weakness
 Chronic use: Goiter, hypo/hyperthyroidism
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27. Class IV: Verapamil
Blocks the Ca++ mediated slow inward current (pre-potential current) and
depolarization
Suppressed impulse generation (automaticity)
 Bradycardia
Dampened delayed after depolarization in PFs
Prolonged A-V nodal ERP
 Suppress re-entry arrhythmias
Negative inotropic action
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28. Class IV: Verapamil
Uses and precaution:
Control ventricular rate in AF or AFl: first line of drug
PSVT-to terminate attacks, prevent recurrences
 Rule out: hypotension, Heart failure
Contraindicated in:
Ventricular Tachycardia/ Ventricular Fibrillation
Broad QRS complex WPW syndrome
Digitalis toxicity
Partial Heart block and sick sinus
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29. Class IV: Diltiazem (Benzothiazepine)
Similar to verapamil
Less marked bradycardia and depression of cardiac contractility
Use:
Alternate drug for termination as well as prophylaxis of PSVT
Control of ventricular rate in AF or AFl: preferred over verapamil
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30. Drugs For PSVT: Adenosine
Rapidly acting; terminates PSVT attack within 30s in 90% cases involving AV
node
Acts by binding to A1 receptors  activates ATP sensitive K+ channels 
membrane hyperpolarization
SA node: pacemaker depression  bradycardia
AV node: prolongation of ERP  slowing of conduction
Atrium: reduced excitability, decreased AP
Additional reduction of Ca2+ current reduction in AV node
Depression of re-entrant current through AV node  termination of PSVT
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31. Drugs for AV block
Atropine:
Anti-vagal effects
Abbreviates A-V node ERP and
increases conduction velocity in
bundle of His
Sympathomimetics (Adr,
Isoprenaline):
Acts by facilitating AV conduction
and shortening of ERP of
conducting tissues
To maintain idioventricular rate in
complete heart block till external
pacemaker can be implanted
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32. Conclusion
Depolarization in cardiac muscle is dependent on Na+, and in
conducting tissues in dependent on Ca++
Phase 4 of pacemaker cells is not flat and is known as
prepotential
Anti-arrhythmic agents are classified into four groups
Activity of anti-arrhythmic agents on different tissues of heart
varies
Adenosine is a very short acting drug used in PSVT
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33. Questions??
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