Anti arrhythmic drugs

1. ANTI-ARRHYTHMIC DRUGS

2. • Cardiac cells undergo depolarization and repolarization to
form cardiac action potentials.
• The shape and duration of each action potential are
determined by the activity of ion channel protein
complexes in the membranes of individual cells.
• Arrhythmias can range from incidental, asymptomatic
clinical findings to life threatening abnormalities.

3. • Anti-arrhythmic drug therapy can have two goals-
– Termination of an ongoing arrhythmia.
– Prevention of an arrhythmia.
• On long term therapy, anti-arrhythmic drugs not only
help to control arrhythmias but also can cause them.

4. Physiology of cardiac function
• Normally, the chambers of the heart contract in a
coordinated manner which is achieved by specialized
conducting system.
• Sinus rhythm is characterized by:
– Impulses arising in the SA node.
– Conduction through atria, AV node, bundle of His,
Purkinje fibers and ventricles.

6. • Cardiac cells owe electrical excitability to voltage
sensitive plasma membrane channels selective for Na+,
K+, and Ca2+ ions.
• Electrophysiological features of cardiac muscle:
– Pacemaker activity
– Absence of fast Na+ current in SA and AV nodes where
slow inward Ca2+ current iniates action potential
– Long action potential (plateau) and refractory period.
– Influx of Ca2+ during the plateau.

7. • Cardiac rate and rhythm is controlled by-
– Intracellular Ca2+ channels
–Ryanodine receptors
–Inositol triphosphate activated calcium channels.
– Voltage dependent calcium channels in the plasma
membrane.
• Main type of voltage dependent calcium channel is
the L-type channel.

8. Phases of cardiac action potential
Phase 0 Rapid depolarization
Phase 1 Partial reploarisation
Phase 2 Plateau
Phase 3 Repolarisation
Phase 4 Pacemaker potential

10. Phase 0- Rapid Depolarization
• Occurs when membrane potential reaches a critical firing
threshold of about -60mV causing an increase in Na+
influx resulting in depolarization.
• Na+ channel proteins change from closed(resting) state to
the open(conducting) allowing upto 107 ions/sec to enter
each cell.

11. • This surge lasts only about a millisecond after which
the Na+ channel protein rapidly moves to an
inactivated non conducting state.
• Once inactivated, cannot reopen until they reassume
the closed conformation.

13. Phase 1- Partial Repolarisation
• Occurs as the Na+ current is inactivated.
• Opening of transient outward channel causing K+
efflux.
• Inactivated rapidly.

14. Phase 2- Plateau
• Results from an inward Ca2+ current.
• These channels show a pattern of voltage sensitive
activation and inactivation similar to sodium channels
but in a slower time.
• Assisted by a special property of cardiac muscle
membrane- ‘Inward going rectification’ meaning K+
conductance falls to a low level when membrane is
depolarized.

15. • Hence there is little tendency for outward K+ current
to restore the RMP during the plateau.
• So a small inward calcium current is sufficient to
maintain the plateau.

16. Phase 3- Repolarisation
• Inactivation of Ca2+ current and activation of a delayed
outwardly rectifying K+ current outward K+ current.
• Augmented by-
– Another K+ activated by high intracellular Ca2+
– Through channels activated by ACh and arachidonic acid.

17. Phase 4- Pacemaker Potential
• Gradual depolarization during diastole.
• Caused by a combination of increasing inward currents
and declining outward currents during diastole.
• Normally found only in the nodal and conducting tissue.
• Usually most rapid in the cells of the SA node, therefore
SA node acts as a pacemaker of the whole heart.

18. • Cells in the SA node have greater background
conductance to Na+ than do atrial and ventricular
myocytes leading to greater inward current.
• Inactivation of voltage dependent calcium channels
wears off during diastole increased Ca2+ current during
late diastole.
• Activation of T-type Ca2+ channels during late diastole
contribute to pacemaker activity in the SA node.

20. Impulse propagation and ECG
• Normal cardiac impulse originates in the sinus node.
• Propagates through atria atrial systole and P wave of
surface ECG.
• At AV node, inward current is slow compared to that in
atria, ventricles, subendocardial conducting system
propagation slows.
• Delay atrial contraction propulsion of blood into the
ventricle cardiac output optimised.

21. • Once impulses exit AV node, they enter the conducting
system spreads throughout the ventricles ventricular
contraction
• Manifests as QRS complex on ECG.
• T wave on ECG ventricular repolarisation

22. • ECG used to guide properties of cardiac tissues-
– Heart rate SA node automaticity
– PR interval duration AV nodal conduction time
– QRS duration conduction time in the ventricle
– QT interval measure of ventricular APD

23. Mechanism of Cardiac Arrhythmias
• Arrhythmia Disturbance in the normal sequence of
impulse initiation and propagation.
• Classified according to:
– Site of origin of abnormality- atrial/junctional/ventricular
– Heart rate- increased or decreased.
• Diagnosis mainly depends on surface ECG.

24. • Three major mechanisms:
–Enhanced automaticity
–Triggered automaticity
–Reentry

25. Enhanced Automaticity
• Occurs in the cells that display diastolic depolarization.
• Increase in the phase 4 slope and pacemaker rate caused
by:
– β- adrenergic stimulation
– Hypokalemia
– Mechanical stretch of cardiac muscle cell
• Reduced by acetylcholine.

26. • Automatic behavior also occurs in sites lacking
spontaneous pacemaker activity ‘Abnormal
automaticity’.
• Impulse propagate from region of enhanced normal
/abnormal automaticity induction of functional
reentry complex arrhythmias.

27. Triggered Automaticity &
Afterdepolarisations
• Pathophysiological condition Normal cardiac action
potential Interrupted/ followed by abnormal
depolarization Abnormal rhythms (Triggered rhythms)
• In the first form, there is intracellular/sarcoplasmic
reticulum Ca2+ overload.
• A normal action potential is followed by a Delayed
afterdepolarisation.
• Also responsible for exercise induced ventricular
tachycardia.

28. • In the second type marked prolongation of action
potential interruption in Phase 3 repolarisation by an
early afterdepolarisation.
• More readily induced in Purkinje cells.
• Activity is more when heart rate is slow and extracellular
K+ is low.
• Prolonged cardiac repolarisation polymorphic
ventricular tachycardia with long QT interval (torsades de
pointes syndrome)

29. Re-entry
• Occurs when a cardiac impulse travels in a path such as
to return to its original site and self perpetuate rapid
activation independent of normal sinus conduction.
• Requires anisotropic conduction slowing due to either
an anatomic/functional barrier.

30. • Anatomically defined reentry:
– Occurs when impulses propagate by more than one
pathway between 2 points in the heart.
– Commonly occurs in the AV node(AV nodal reentrant
tachycardia) and atria (atrial flutter)

31. • Functionally defined reentry:
– May occur in the absence of an anatomically defined
pathway.
– Eg: Atrial/ ventricular fibrillation
– Cells are re-excited as soon as they are repolarised
sufficiently to allow enough Na+ channels to recover
from inactivation.

32. Types of Cardiac Arrhythmias
• Extrasystoles(ES):
– Premature beats due to abnormal automaticity or after
depolarisation arising from an ectopic focus in the atrium,
AV node or ventricle.
• Paroxysmal Supraventricular Tachycardia(PSVT):
– Sudden onset episodes of atrial tachycardia(150-200/min)
• Atrial Flutter:
– Atria beat at a rate of 200-350/min
– A physiological 2:1 to 4:1 or higher AV block

33. • Atrial Fibrillation:
– Atrial fibres are activated asynchronously at a rate of
350-550/min associated with irregular and fast
ventricular response (100-160/min)
• Torsades de pointes:
– A life threatening form of polymorphic ventricular
tachycardia
– Associated with long Q-T interval

35. Antiarrhythmic Drugs

36. Class 1- Sodium Channel Blockers
• Action is sodium channel blockade.
• Subclasses Effects on action potential duration (APD)
and kinetics of sodium channel blockade.
• Class 1A Prolong APD; Dissociates from channel with
intermediate kinetics
• Class 1B Shortens APD; Dissociates with rapid kinetics
• Class 1C Minimal effects on APD; Dissociates with slow
kinetics.

37. Drugs of Class 1A
PROCAINAMIDE:
• Analog of procaine.
• Acts by blocking sodium as well as potassium channels
slows upstroke of action potential; prolongs QRS of ECG.
• Pharmacokinetics:
– Well absorbed orally, IM/IV safely administered
– Hepatic metabolism; N-acetyl procainamide (NAPA)
– Renal excretion; t1/2: 2-4 hrs

38. • Use- Drug of 2nd or 3rd choice against most
atrial/ventricular arrhythmias.
• Dose:
– Loading dose: Upto 12mg/kg at a rate of 0.3mg/kg/min
– Maintainance dose: 2-5mg/min
• ADR Hypotension, Lupus erythematosus, arthralgia,
arthritis, pleuritis, pericarditis or parenchymal
pulmonary disease.

39. QUINIDINE:
• A diastereomer of antimalarial quinine extracted from
the bark of cinchona plant.
• Actions same as that of procainamide.
• Used to maintain sinus rhythm in patients with atrial
flutter/fibrillation.
• To prevent recurrence of ventricular tachycardia/VF

40. • ADR-
– Immunologic reactions- Thrombocytopenia
– ‘Cinchonism’:
• Related to elevated plasma quinidine
concentration
• Includes headache, dizziness and tinnitus
• Managed by dose reduction.

41. Drugs of Class 1B
LIDOCAINE
• A local anaesthetic; agent of choice for termination of
ventricular tachycardia and prevention of ventricular
fibrillation.
• Blocks both open and inactivated sodium channels with
rapid kinetics.
• Has greater effects on cells with long action potential
(Purkinje cells & ventricular cells)
• No significant effect on PR or QRS duration.

42. • ADR-
– Nystagmus is the early sign of lignocaine toxicity.
– Neurlogic effects like paresthesias, tremor, nausea,
lightheadedness, hearing disturbances, slurred speech,
convulsions.
– May cause hypotension in patient with preexisting
heart failure.

43. • Pharmacokinetics:
– Undergoes extensive first pass metabolism; 3% of
the oral drug appears in the plasma.
– T1/2- 1-2hrs
• Dose-
– Loading dose- 150-200mg for 15 minutes
– Maintainance dose- 2-4mg/min

44. Drugs of Class 1C
FLECAINIDE
• A potent blocker of sodium and potassium channels with
slow unblocking kinetics.
• Effective in suppressing premature ventricular contractions.
• Normal dose may cause exacerbation of arrhythmia when
administered in patients with preexisting ventricular
tachyarrhytmia- demonstrated in Cardiac Arrhythmia
Suppression Trial (CAST)

45. • Well absorbed; t1/2- 20 hrs
• Elimination by hepatic metabolism and by the
kidney.
• Dose- 100-200mg BD

46. Class 2: β Adrenergic Blockers
• Actions:
– Reduce the heart rate.
– Decrease intracellular Ca2+ overload
– Inhibit afterdepolarisation mediated automaticity.
– Increase AV nodal conduction time and prolong AV nodal
refractoriness.
• Adverse effects:
– Fatigue, bronchospasm, hypotension, impotence,
depression, worsening of symptoms.

47. ESMOLOL:
• A β1 selective agent, metabolised by erythrocyte
esterases.
• Very short elimination, t1/2- 9min
• IV esmolol is useful in situations in which immediate β
adrenergic blockade is desired.
– Eg: for rate control of rapidly conducted atrial fibrillation.

48. SOTALOL
• Non selective β adrenergic receptor antagonist.
• Prolongs QT interval, decreases automaticity, slows AV
nodal conduction, prolongs AV refractoriness by
blocking both K+ channels and β adrenergic receptors.
• Causes EADs and triggered activity in vitro and can cause
torsade de pointes

49. Class 3- Potassium Channel Blockers
• Prolong action potential by blocking potassium channels
in cardiac muscles.
• Action potential prolongation “Reverse use
dependence” action potential prolongation is least
marked at fast rates and most marked at slow rates risk
of torsade de pointes.
• Also evokes QT prolongation.

50. AMIODARONE
• A structural analog of thyroid hormone.
• Highly lipophilic; concentrated in the tissues; eliminated
extremely slowly.
• Prolongs action potential and QT intervals.
• Also has weak adrenergic and calcium channel blocking
actions Slowing of heart rate and AV node conduction.
• Oral amiodarone is effective in maintaining sinus rhythm in
patients with atrial fibrillation.

51. • ADR-
– Symptomatic bradycardia and heart block in patients
with sinus or AV node disease.
– Dose related pulmonary toxicity fatal pulmonary
fibrosis even on low dose of 200mg/d
– Abnormal liver function tests & hypersensitivity
hepatitis.

52. – Photodermatitis; Gray-blue skin discolorations in sun
exposed areas.
– May result in hypothyroidism or hyperthyroidism.
• Pharmacokinetics:
– Bioavailability: 35-65%
– Undergoes hepatic metabolism; Desethylamiodarone

53. • Dose:
– Loading dose: 10g achieved with 0.8-1.2g daily
– Maintainence dose: 200-400mg daily.
• Uses:
– Low doses (100-200mg/d)- maintains normal sinus
rhythm in patients with atrial fibrillation
– Effective in prevention of recurrence of ventricular
tachycardia.
• Dronedarone- a derivative of amiodarone is approved for
the treatment of atrial fibrillation and atrial flutter.

54. DOFETILIDE
• Prolongs action potential by dose dependent blockade of
the rapid component of the delayed rectifier potassium
current.
• Bioavailability- 100%
• 80% of oral dose is excreted unchanged; remaining
eliminated in the urine as inactive metabolites.
• QT prolonging effect and ventricular proarrhythmia,
directly related to plasma concentration.

55. • Contraindications for treatment with Dofetilide:
– Baseline QTc more than 450ms
– Bradycardia, <50bpm
– Hypokalemia
• Used for maintaining normal sinus rhythm in patients
with atrial fibrillation.

56. Class 4- Calcium Channel Blockers
VERAPAMIL
• Blocks both activated and inactivated L-type calcium
channels.
• Effect is more marked in SA and AV node.
• Can suppress both early and delayed afterdepolarizations.
• ADR-
• induces AV block when used in large doses or in patients
with AV nodal disease.
• Constipation, nervousness, peripheral edema

57. • Pharmacokinetics:
– Half life is 7 hrs.
– Bioavailability is 20% after oral absorption
– Extensively metabolised by the liver.
• Dose:
– Initial bolus of 5mg for 2-5min followed by second
5mg bolus if needed.
– Thereafter, 5-10mg can be administered every 4-6hrs
or a constant infusion of 0.4mcg/kg/min.

58. • Uses:
– Supraventricular tachycardia
– To reduce ventricular rate in atrial fibrillation or atrial
flutter.
• Diltiazem:
– Similar to verapamil in the management of
supraventricular arrhythmias, including rate control in
atrial fibrillation.

59. Miscellaneous Agents
ADENOSINE
• Natural nucleoside; drug of choice for conversion of PSVT
to sinus rhythm.
• Short duration of action; t1/2<10s
• Dose- 6mg bolus followed by 12mg
• ADR-
– Flushing(20%), shortness of breath, chest burning(10%).
– Less common- headache, hypotension, nausea,
paraesthesias.

60. • Mechanism of action:
• When given as bolus dose, directly inhibits AV nodal
conduction and increases AV nodal refractory period.
Activation of inward K+
current
Inhibition of calcium
current
Hyperpolarisation
Suppression of calcium
dependent action potentials

61. MAGNESIUM
• Known to influence Na+, K+ ATPase, Na+ channels, certain
K+ and Ca2+ channels.
• Indications:
– Digitalis induced arrhythmia if hypomagnesaemia is
present
– Torsade de pointes
• Dose- 1g IV over 20 min. Repeated if necessary.

62. POTASSIUM
• Hypokalaemia increased risk of EAD & DAD.
• Hyperkalaemia suppresses SA node and slows
conduction.
• Both insufficient and excess potassium is arrhythmogenic.
• Hence potassium therapy is directed toward normalising
potassium gradients in the body.

63. Principles in the Clinical Use of
Antiarrhythmic Agents
• Pre-treatment evaluation:
– Eliminate the cause
– Make a firm diagnosis
– Determine the baseline condition
– Question the need for therapy
• Benefits:
– Reduction of arrhythmia-related symptoms (palpitations,
syncope, cardiac arrest)
– Reduction in long term mortality in asymptomatic patients.

64. • Risks:
– Related to high dose/plasma concentration
– Combination of drug therapy
– Underlying heart disease
– Drugs like Quinidine, Dofetilide slow repolarisation &
prolong action potential QT prolongation & Torsades
de pointes.
• Rx- recognition, withdrawal of offending agent,
correction of hypokalaemia, treatment with manoeuvres
to increase heart rate.

65. • Conduct of Antiarrhythmic Therapy:
– Urgency of clinical situation determines the route and
rate of drug initiation.
– For immediate drug action IV route
– Therapeutic drug levels multiple slow IV bolus
– Drug therapy effective target arrhythmia
suppressed and toxicities are absent.
– Managing plasma drug concentrations

66. References
• Goodman and Gilman’s Pharmacological Basis of
Therapeutics
• Rang and Dales pharmacology.
• Basic and clinical pharmacology – Katzung.
• KD Tripathi

67. THANK YOU