Antiarrhythmic drugs for medical students

Antiarrhythmic drugs for medical students

1. Antiarrhythmic drugs
Arrhythmia: Abnormality in rate or rhythm
due to abnormal impulse initiation or
conduction.
Interference with ion channel function lead to
arrhythmias.
Antiarrhythmic drugs suppress arrhythmias
by blocking flow through specific ion
channels or by altering autonomic function.

2. Arrhythmias classified depending on:
•the site of origin of the abnormality- atrial,
junctional or ventricular
•whether the rate is increased (tachycardia)
or decreased (bradycardia)
Symptoms:
•Palpitations, breathlessness
•Symptoms from cerebral hypoperfusion
( unconsciousness)
Diagnosis depends on the ECG

3. Principles of treatment of
arrhythmia
1.Identify & remove the precipitating
cause- hypoxia, electrolyte imbalance,
drugs, myocardial ischamia
2.Establish the goals of treatment:
termination of an ongoing arrhythmia,
prevention of an arrhythmia
3.Minimize risks- monitoring for AE &
plasma conc.

4. PHYSIOLOGY OF CARDIAC
FUNCTION
•Electrical excitability of cardiac cells :
voltage-sensitive Na+, K+ and
Ca2+channels
•Ions move across cell membranes in
response to electrical and concentration
gradients through specific ion channels
•Cardiac cell at rest - transmembrane
potential 80 to 90 mV negative to the
exterior

5. Unique electrophysiological
features of cardiac muscle

•pacemaker activity
•absence of fast Na+ current in SA and AV
nodes, where slow inward Ca2+ current
initiates action potentials
•long action potential ('plateau') and
refractory period
•influx of Ca2+ during the plateau.

6. Cardiac action potential

7. Five phases:
Phase 0, rapid depolarisation: Opening
of Na
+
channels, occurs when the
membrane potential reaches a critical
firing threshold (about -60 mV)
Phase 1, partial repolarisation: Na+
current is inactivated. Opening transient
outward K
+
channels.

8. •Phase 2, the plateau: results from an
inward Ca2+ current and outward K
+
current
•Phase 3, repolarisation: Ca2+ current
inactivates and a delayed outwardly
rectifying K+ current activates, causing
outward K+ current, assisted by Ca2+
activated, acetylcholine activated,
arachidonic acid activated K
+
channels

9. •Phase 4, the pacemaker potential:
Found in nodal & conducting tissues, is a
gradual depolarisation during diastole-
Caused by a combination of increasing
inward currents and declining outward
currents during diastole.
Most rapid in cells of the SA node-
pacemaker.
Activation of T-type calcium channels during
late diastole contributes to pacemaker
activity in the SA node.

10. Cardiac action potential

11. Differing Action Potential
Behaviors among Cardiac Cells:
•Atrium: Short AP (larger I
TO
& activation
additional repolarizing current by Ach)
•His Purkinje system & ventricles: Long
AP
•SA node, AV node: Lack Na
+
current
Spontaneous phase 4 depolarization-
highest in SA node (pacemaker)

13. Maintenance of Intracellular
Homeostasis
•Na
+
K
+
ATPase pump
•Action potential Increases intracellular Ca
+


Removal of intracellular Ca
+
by:
- ATP dependent pump
- Na
+
- Ca
+
exchange pump

14. Impulse Propagation & ECG
•SA node to Atria- Atrial systole: P wave
•Slow propagation in AV node (allows
atrial contraction to propel blood to
ventricles): PR interval
•Conducting system in ventricles (larger
Na
+
current)- faster propagation: QRS
complex
•Ventricular repolarization: T wave
•Ventricular AP duration: QT interval

15. Refractoriness
•Fast response tissue- depends on
recovery of Na
+
channels- voltage
dependent
•Slow response tissue- depends on
recovery of Ca
+
channels- time dependent

16. MECHANISMS OF CARDIAC
ARRHYTHMIAS
Abnormal impulse initiation:
•Increased automaticity: Normal (sinus
arrhythmias)/ ectopic pacemaker activity
•Triggered activity: Early & delayed after
depolarizations
Abnormal impulse conduction:
•Conduction blocks
•Re-entry

17. Increased automaticity
•Enhanced normal automaticity: Increased
phase 4 depolarization slope-
hypokalemia, beta receptor stimulation,
positive chronotropic drugs, acidosis
•Abnormal automaticity (Ectopic
pacemaker activity): Occurs when
ventricular cells are depolarised (eg:
ischaemia).

18. After depolarizations
•Normal cardiac AP interrupted or followed
by abnormal depolarization
•Abnormal depolarization reaches
threshold giving second upstroke
•Triggered by initial normal AP- triggered
rhythms
•Two forms: EAD & DAD

19. After depolarizations

20. Delayed after-depolarisation
•Interrupt Phase 4
•Due to abnormally raised Ca2+, which
triggers inward current and hence a
train of abnormal action potentials
•Exacerbated by fast heart rates
•Arrhythmias due to digitalis intoxication,
catecholamines, myocardial ischaemia

21. Early after depolarization
•Arise from plateau
•Interrupt phase 3
•Inward Ca
+
& Na
+
current.
•Due to prolonged APD
•Exacerbated at slow heart rate
•Involved in long QT related arrhythmias

22. Re-entry (Circus movement)
•Occurs when impulse propagate by more
than one pathway between two points in
the heart
•Pathways should have heterogenous
electrophysiological properties- slow
conduction in one pathway
•Impulse re-excites regions of the
myocardium after the refractory period has
subsided, causing continuous circulation
of action potentials.

23. Result from anatomical anomalies/
myocardial damage.
•Anatomically Defined Re-entry (WPW
syndrome)
•Functionally Defined Re-entry
Re-entry is facilitated when parts of the
myocardium are depolarised as a result of
disease

24. •Normally, an impulse branches around the circuit,
propagate in both directions and die out when the
two impulses meet
•Damaged area causes either a transient block or
unidirectional block
•Anterograde impulse blocked, but the retrograde
impulse transmitted
•Impulse will re-excite the tissue it had already
passed through

26. Anatomical re-entry

27. Three conditions required for
reentry to occur:
•Anatomical or physiological obstruction to
homogenous conduction, establishing a
circuit
•Unidirectional block
•Conduction time around the circuit should
exceed the refractory period of tissue it
reenters

28. Conduction blocks
•Heart block results from fibrosis of, or
ischaemic damage to the conducting system
(often in the AV node).
•In complete heart block, the atria and
ventricles beat independently of one another
•(Stokes-Adams attacks): Complete failure of
AV conduction- sudden periods of
unconsciousness, treated by implanting an
artificial pacemaker.

29. MECHANISMS OF ANTIARRHYTHMIC
ACTION
Slowing automaticity by:
•Increasing maximum diastolic potential:
Adenosine and acetylcholine
•Decreasing phase 4 slope
Beta blockers
•Alter threshold potential:
Na+ or Ca2+ channels blockers
•Increasing action potential duration:
K+ channels blockers.

31. Blocking arrhythmias owing to DADs or
EADs by:
•DADs- Interference with the inward current
( Na+ or Ca2+ channels), which is
responsible for the upstroke.
verapamil, quinidine
• EADs- inhibited by shortening action
potential duration:
Isoproterenol infusion, by pacing, Mg2

32. Reentry arrhythmias blocked by:
•Further slowing depressed conduction and
thus causing bidirectional block: Na
+
&Ca+
channel blockers
•Accelerating conduction
•Increasing refractory period in tissues near
the site of block

33. Prolongation of refractory period by
•In AV node (slow response tissue):
CCB, beta blockers, digitalis glycosides
•In fast-response tissues: delaying the
recovery of Na+ channels from inactivation.
Na+ channel blockers
•By increasing APD without direct action on
Na+ channels.
K+ channel blockers.
•Interfering with cell-cell coupling
Amiodarone

34. State dependent ion channel
blockade
3 states of channel: Closed (resting), activated
(conducting), inactivated (nonconducting)
•Drugs bind to specific site on open &/or
inactivated channel, dissociate during diastole
•Use-dependent channel block - bind to channels
most strongly when they are in either the open
or the refractory state
When heart rate increases blockade increases
•Ischaemia- cells are depolarised- increased
blockade

35. Classification based on Vaughan
Williams system
Class I: Sodium channels blockers.
Subdivided depending on the effect on APD & kinetics
of Na
+
channel blockade :
IA. Prolong APD & Intermediate dissociation from
channel.
Quinidine, procainamide, disopyramide
IB. No effects on APD & Fast dissociation.
Lidocaine, phenytoin, mexiletine
IC. Minimal effects on APD & slow dissociation.
Propafenone, flecainide, encainide

36. Class II: β-blockers.
Propranolol, esmolol
Class III: Agents widening AP (K
+
channel blockers).
Amiodarone, sotalol, ibutilide, dofetilide
Class IV: Calcium antagonists.
Verapamil, diltiazem

37. Antiarrhythmic drugs unclassified in
the Vaughan Williams system
•Atropine: Sinus bradycardia
•Adrenaline: Cardiac arrest
•Isoprenaline: Heart block
•Digoxin: Rapid atrial fibrillation
•Adenosine: Supraventricular tachycardia
•Calcium chloride: Ventricular tachycardia due
to hyperkalaemia
•Magnesium chloride: Ventricular fibrillation,
digoxin toxicity

38. Na
+
channel blockers
•Increases threshold for excitability
•Decreases conduction in fast response tissue &
increases QRS duration
•APD- increased/ unaffected
•Inhibits EAD &DAD
•Decreases phase 4 slope- decreases
automaticity
•Increases refractoriness
•Slows conduction in anatomically defined reentry

39. Class Ib drugs
•Associate & dissociate rapidly
•Binds to open channels during phase 0
•Affects rate of rise very little, but leaving
many of the channels blocked by the time
the action potential reaches its peak
•Premature beat aborted
•Bind selectively to refractory channels and
thus block preferentially when the cells are
depolarised (Eg: ischaemia).

40. Class Ic drugs
•Associate and dissociate much more slowly
•Marginal preference for refractory channels, so
are not specific for damaged myocardium.
•General reduction in excitability and do not
discriminate occasional premature beats
•Suppress re-entrant rhythms
•Inhibit conduction through the His-Purkinje
system

41. Class Ia drugs
•Quinidine, procainamide, disopyramide
•Lies midway in its properties between Ib
and Ic
•Also prolongs repolarisation, less
markedly than class III drugs

42. Quinidine (IA)
•Dextroisomer of quinine
•Blocks K
+
channel also- prolongs APD
•Vagolytic action
•Alfa blocking action
•Inhibits CYP2D6
•Inhibits clearance of digoxin
•A/E: Diarrhoea, cinchonism, lupus
syndrome, hepatitis, bone marrow
suppression, torsade de pointes

43. Procainamide (IA)
•Amide derivative of procaine
•Active metabolite: N-acetyl procainamide
•Blocks K
+
channel also, prolongs APD
•Less vagolytic action
•No alfa blocking action
A/E: Hypotension, torsades de pintes,
agranulocytosis, aplastic anaemia, lupus
erythematous
Uses: VT, recurrent VF

44. Disopyramide
•Anticholinergic action
•No alfa blocking action
•Use: Prevention of VT & VF, maintain
sinus rhythm in atrial flutter & fibrillation

45. Lidocaine (IB)
•Local anaesthetic
•Recovery from block is rapid- exert more
effect on depolarized tissues (eg:
ishaemic)
•Greater effect on cells with long AP
(ventricle).
•Not effective in atrial arrhythmias ( atrial
AP is very short)

46. High 1
st
pass metabolism (oral BA-3%),
Given IV only
VD & clearance decreased in heart failure.
Acute MI – decreased free drug
Adverse effects:
Cardiac: proarrhythmic effects
Extracardiac: neurologial- tremors,
parasthesia, dizziness, slurred speech,
convulsions
Use: Agent of choice to terminate VT &
prevent VF after cardioversion.

47. Mexilitine (IB)
•Congener of lidocaine,
•Resistant to 1
st
pass metabolism, effective
orally
•Actions similar to lidocaine
Use: Ventricular arrhythmias
Chronic pain of diabetic neuropathy,
nerve injury (unlabelled)

48. Flecainide (IC)
•Blocks Na
+
& delayed rectifier K
+

channels
•Delayed recovery from block
•A/E: Blurred vision, ppt of CCF,
arrhythmias
•Use: Supraventricular arrhythmias

49. Propafenone (IC)
•Structural similarity to propranolol
•Weak beta blocking activity
•Blocks K
+
channel also
•A/E: Metallic taste, constipation,
arrhythmia exacerbation
•Use: Supraventricular arrhythmias

50. Moricizine (IC)
•Phenothiazine derivative
•Used for ventricular arrhythmias

51. Uses of class I agents
•Class Ia
–ventricular arrhythmias
–prevention of recurrent paroxysmal atrial fibrillation
•Class Ib
–treatment and prevention of ventricular tachycardia
and fibrillation during and immediately after
myocardial infarction.
•Class Ic
–to prevent paroxysmal atrial fibrillation
–recurrent tachyarrhythmias associated with abnormal
conducting pathways

52. Class II agents
Beta receptor stimulation causes:
•Increased Ca
+
current
•Increased repolarizing K
+
& Cl
-
current
•Increased pacemaker current
•Increased sinus rate
•Increased DAD & EAD mediated arrhythmias
AV conduction depends critically on sympathetic
activity

53. Beta blockers:
•Increase AV nodal conduction time &
prolong AV nodal refractoriness
•Block arrhythmias triggered by physical
or emotional stress
•Useful in arrhythmia caused by Na
+

channel blockers- by decreasing heart
rate
Propranolol- also blocks Na
+
channel
Sotalol- also blocks K
+
channel

54. Uses of class II agents
•To reduce mortality following myocardial
infarction.
•To prevent recurrence of tachyarrhythmias
(e.g. paroxysmal atrial fibrillation)
provoked by increased sympathetic
activity
•Esmolol: used for intra-operative & other
acute arrhythmias

55. Class III agents
•Substantially prolong the cardiac action potential
(detected clinically as QT prolongation).
•Blocks potassium channels
•Increases refractory period
•Decreases automaticity
•Interrupts re-entrant tachycardia and suppress
ectopic activity.
•Proarrhythmic effects, notably a polymorphic
form of ventricular tachycardia called (torsades
de pointes)

56. Amiodarone
•Structural analog of thyroid hormones
•Highly lipophilic, eliminated slowly
•Increases refractory period by blocking
inactivated Na
+
,Ca
+
& K
+
channels &
inhibition of cell-cell coupling
•Also has noncompetitive adrenergic
blocking effect.
•Used for recurrent VT, VF & AF
•Half- life: 3-8weeks, high tissue binding

57. Adverse effects
•Hypotension
•Pulmonary fibrosis
•Corneal microdeposits
•Hepatic dysfunction
•Hypo/hyperthyroidism
•Photosensitization
•Neuromusular symptoms-peripheral
neuropathy, proximal muscle weakness

58. Dofetilide
•Potent & pure blocker of delayed rectifier
K
+
channels
•Effective in maintaining sinus rhythm in
atrial fibrillation
•A/E: Torsades de pointes

59. Uses of class III agents
Amiodarone: tachycardia associated with
the Wolff-Parkinson-White syndrome.
•Other supraventricular and ventricular
tachyarrhythmias
Sotalol: Paroxysmal supraventricular
dysrhythmias
•Suppresses ventricular ectopic beats and
short runs of ventricular tachycardia.

60. Class IV agents
•Blocks voltage-sensitive calcium channels.
( L-type)
•Slow conduction in the SA and AV nodes
( Ca2+ dependent AP)
•Shorten the plateau of the action potential
and reduce the force of contraction.
•Reduced Ca2+ entry reduces after-
depolarisation and thus suppresses
premature ectopic beats.
•Decreased AV conduction velocity &
increased PR interval

61. Uses of class IV agents
Verapamil:
–to prevent recurrence of paroxysmal
supraventricular tachycardia (SVT)
–to reduce the ventricular rate in patients with
atrial fibrillation
Contraindicated in Wolff-Parkinson-White or
a related disorder.

62. Adenosine
•Nucleoside
•IV bolus admn.- to terminate PSVT
•Binds to adenosine receptor(A1)- activate
Ach sensitive K
+
channel in atrium, SA &
AV nodes
•Shorten APD, hyperpolarization,
decreased automaticity
•Slows SA& AV nodal conduction,
increases AV nodal refractoriness

63. •Taken up by specific nucleoside transporter
by red blood cells
•Metabolised by enzymes on the luminal
surface of vascular endothelium.
•Effects of a bolus dose of last only 20-30
seconds.
Adverse effects: Chest pain, shortness of
breath, dizziness and nausea.

64. Drug interactions
•Theophylline and other xanthine alkaloids
block adenosine receptors and inhibits its
actions
•Dipyridamole : blocks the nucleoside
uptake , potentiates action and prolongs
adverse effects.