Antiarrhythmic Drugs

1. ANTIARRHYTHMIC DRUGS
Dr. Sayeedur Rahman Khan Rumi
Dr.rumibd@gmail.com
MD Final Part Student
NHFH&RI

2. Mechanism of arrhythmias
• Three major mechanisms contribute to
development of cardiac arrhythmias:
– Automaticity
– Reentry and
– Triggered activity.

3. Classification of Antiarrhythmic Drugs
• There are four established classes of
antiarrhythmic action.
• The original Vaughan Williams classification
with four classes now incorporates ionic
mechanisms and receptors as the basis of
the more complex Sicilian Gambit system
for antiarrhythmic drug classification.

5. Classification of Antiarrhythmic Drugs
• Class I agents decrease phase zero of the rapid
depolarization of the action potential (rapid sodium
channel).
• Class II agents, b-blocking drugs, have complex actions
including inhibition of spontaneous depolarization (phase
4) and indirect closure of calcium channels.
• Class III agents block the outward potassium channels to
prolong the action potential duration and hence
refractoriness.
• Class IV agents, verapamil and diltiazem, and the
indirect calcium antagonist, adenosine, all inhibit the
inward calcium channel, which is most prominent in
nodal tissue, particularly the atrioventricular node.

7. Mechanism of AADs in various phase of action
potential

8. Class IA: Quinidine and
Similar Compounds

9. • Historically, quinidine was the first
antiarrhythmic drug used.
• can cause proarrhythmic complications by
prolonging the QT interval in certain
genetically predisposed individuals or by
depressing conduction and promoting
reentry.

10. Class IB

11. Lidocaine
• Class IB agents act selectively on diseased or ischemic
tissue, where they are thought to promote conduction
block, thereby interrupting reentry circuits.
• Lidocaine acts preferentially on the ischemic
myocardium and is more effective in the presence of a
high external potassium concentration.
• Therefore hypokalemia must be corrected for maximum
efficacy.
• This intravenous drug has no role in the control of
chronic recurrent ventricular arrhythmias.
• No value in treating supraventricular tachyarrhythmias.

12. • Dose:
– IV 75-200 mg; then 2-4 mg/min for 24-30 h.
(No oral use)
– Reduce dose by half if liver blood flow low
(shock, b-blockade, cirrhosis, cimetidine,
severe heart failure).
• Pharmacokinetics and Metabolism:
– Effect of single bolus lasts only few min,
– T ½ approximately 2 h.
– Rapid hepatic metabolism.
– Level 1.4-5 mcg/mL; toxic >9 mcg/mL.

13. • Side Effects:
– Generally free of hemodynamic side effects, even in
patients with congestive heart failure (CHF), and it
seldom impairs nodal function or conduction
– High-dose CNS effects - drowsiness, numbness,
speech disturbances, and dizziness, especially in
patients older than 60 years of age.
• Drug Interactions
– b-blockers decrease hepatic blood flow and increase
blood levels.
– Cimetidine (decreased hepatic metabolism of
lidocaine).

14. Class IC

15. • Class IC agents have acquired a particularly bad
reputation as a result of the proarrhythmic
effects seen in the Cardiac Arrhythmia
Suppression Trial (CAST) (flecainide) and the
Cardiac Arrest Study Hamburg (CASH) study
(propafenone).
• These drugs must be avoided in patients with
structural heart disease.

16. Flecainide
• Dose:
– Oral 100-400 mg 2 times daily.
• Pharmacokinetics and Metabolism:
T ½ 13-19 h.
Hepatic 2⁄3; 1⁄3 renal excretion uncharged
• Indications:
– Paroxysmal supraventricular tachycardia (AF, Atrial
flutter, WPW)
– Life-threatening sustained VT
– Catecholaminergic polymorphic VT
– For maintenance of sinus rhythm after cardioversion
of AF

17. • Contraindications:
– Patients with structural heart disease
– Patients with right bundle branch block and left
anterior hemiblock
– In the sick sinus syndrome, when the left ventricle is
depressed, and in the postinfarct state
• Side effects:
– QRS prolongation.
– Proarrhythmia.

18. Propafenone
• Dose:
– Oral 150-300 mg 3 times daily.
• Pharmacokinetics and Metabolism:
– T ½ variable 2-10 h, up to 32 h in nonmetabolizers.
– Level 0.2-3 mcg/mL.
• Indications:
– Life-threatening ventricular arrhythmias
– Suppression of supraventricular arrhythmias, including those of
WPW syndrome and recurrent atrial flutter or fibrillation.

19. • Contraindications:
– preexisting sinus, AV or bundle branch abnormalities
– depressed left ventricular (LV) function.
– Patients with asthma and bronchospastic disease including
chronic bronchitis
• Side effects:
– QRS prolongation.
– Modest negative inotropic effect.
– GI side effects.
– Proarrhythmia.

20. Class II Agents:
b-Adrenoceptor
Antagonists

21. • At present, b-blockers are the closest to
an ideal class of antiarrhythmic agents for
general use because of their broad
spectrum of activity and established safety
record.
• Furthermore, the use of b-blockers in
combination with other antiarrhythmic
agents may have a synergistic role and
can reduce the proarrhythmic effects

23. Mixed Class III
Agents: Amiodarone
and Sotalol

24. Amiodarone
• Lengthens the effective refractory period by prolonging
the APD in all cardiac tissues, including bypass tracts
• Amiodarone makes the action potential pattern more
uniform throughout the myocardium, thereby opposing
EP heterogeneity that underlies some serious ventricular
arrhythmias.
• The incidence of torsades with amiodarone is much
lower than expected from its class III effects.
• The weak calcium antagonist (class IV) effect might
explain bradycardia and AV nodal inhibition and the
relatively low incidence of torsades de pointes.

25. Dose
• Oral loading dose 1200-1600 mg daily; maintenance
200-400 mg daily
• IV 150 mg over 10 min, then 360 mg over 6 h, then 540
mg over remaining 24 h, then 0.5 mg/min.
• For AF in AMI or after cardiac surgery, 5 mg/kg over 20
minutes, 500 to 1000 mg over 24 hours, then orally, and
then 0.5 mg/minute
• Caution: Be aware of the risk of hypotension with
intravenous amiodarone.
• Generally, intravenous amiodarone is used for 48 to 96
hours while oral amiodarone is instituted.

26. Pharmacokinetics
• T ½ 25-110 days (up to 6 months)
• The therapeutic range 1-2.5 mcg/mL.
• Hepatic metabolism.
• Lipid soluble with extensive distribution in body.
Because of this, amiodarone must fill an
enormous peripheral-tissue depot to achieve
adequate blood and cardiac concentrations.
• Excretion by skin, biliary tract, lachrymal glands.

27. Indications
• VT
• VF
• AF, Atrial flutter: Amiodarone is probably the
most effective of the available drugs to prevent
recurrences of paroxysmal AF or flutter and
reasonable choice for patients with structural
cardiac disease or CHF
• AF in WPW syndrome
• Other SVTs

28. Benefits of Amiodarone
in AF may be explained
at least in part by
prolongation of the
refractory periods of
both the left and right
superior pulmonary
veins, and inhibition of
the AV node

29. Contraindications
• Severe sinus node dysfunction with
marked sinus bradycardia or syncope
• Second- or third-degree heart block
• Known hypersensitivity
• Cardiogenic shock
• Severe chronic lung disease.

30. Side effects
• Sinus bradycardia (in older adults)
• QT prolongation
• Hypothyroidism
• Hyperthyroidism
• Pulmonary toxicity (very rarely occurs
with the low doses of about 200 mg
daily)
• Hepatotoxicity (elevated enzyme levels,
epatitis and cirrhosis)
• Optic neuropathy/neuritis
• Blue-gray skin discoloration
• Photosensitivity
• Peripheral neuropathy
• Testicular dysfunction

31. Recommended preventative
actions
• baseline and 6-monthly thyroid function
tests and liver enzymes
• baseline and yearly ECG and chest
radiography
• physical examination of skin, eyes, and
peripheral nerves if symptoms develop

32. Drugs interactions
• A serious and common interaction is with warfarin.
Amiodarone prolongs the prothrombin time and may cause
bleeding in patients on warfarin
• Amiodarone increases the plasma digoxin concentration,
predisposing to digitalis toxic effects (not arrhythmias because
amiodarone protects)
• an additive proarrhythmic effect with other drugs prolonging
the QT interval, such as class IA antiarrhythmic agents,
phenothiazines, tricyclic antidepressants, thiazide diuretics,
and sotalol.

33. Sotalol
• Dose:
– 160-640 mg daily, occasionally higher in two divided doses.
• Pharmacokinetics:
– T ½ 12 h
– Not metabolized
– Hydrophilic
– Renal loss
• Side effects:
– Myocardial depression
– Sinus bradycardia
– AV block
– Torsades if hypokalemic

34. • Indications:
– severe ventricular arrhythmias
– AF for maintenance of sinus rhythm in patients with recurrent
symptomatic AF or atrial flutter.
– can be given to patients with structural heart disease
• Contraindications:
– Asthma
– reduced creatinine clearance, below 40 mL/minute

35. Dronedarone
• Should only be prescribed for maintaining
sinus rhythm in patients with paroxysmal
AF or persistent AF after successful
cardioversion.
• Without a history of heart failure and with
good ventricular function

36. Class IV and Class IV-
Like Agents

37. Verapamil and diltiazem
• They slow the ventricular response rate in atrial
arrhythmias, particularly AF.
• They can also terminate or prevent reentrant
arrhythmias in which the circuit involves the AV
node.
• For the termination of AV nodal dependent
supraventricular tachycardias, verapamil and
diltiazem are alternatives to adenosine.

38. Adenosine
• It is a first-line agent for terminating narrow complex
PSVTs
• Dose:
– For paroxysmal SVT, initial dose 6 mg by rapid IV. If the dose is
ineffective within 1 to 2 minutes, 12 mg may be given and if
necessary, 12 mg after a further 1 to 2 minutes.
– The initial dose needs to be reduced to 3 mg or less in patients
taking verapamil, diltiazem, or b-blockers or dipyridamole or in
older adults at risk of sick sinus syndrome
• T ½: 10-30 seconds.

40. • Indications:
– Paroxysmal narrow complex SVT (usually AV nodal
reentry or AV reentry such as in the WPW syndrome
or in patients with a concealed accessory pathway).
– In wide-complex tachycardia of uncertain origin,
adenosine can help the management by
differentiating between VT or SVT (with aberrant
conduction)
• Contraindication
– In asthmatic,
– Second- or third-degree AV block,
– Sick sinus syndrome.

41. • Side effects: Usually transient and include
– nausea
– light-headedness
– headache
– flushing
– bronchospasm
– provocation of chest pain
– sinus or AV nodal inhibition
– bradycardia
– and with large dose infusion rare side effects
hypotension, tachycardia

42. Antiarrhythmic drugs In pregnancy
and Lactation
• In pregnancy, only
Sotalol is category
B.
• It is not teratogenic,
but does cross the
placenta and may
depress fetal vital
functions.
• Sotalol is also
excreted in mother’s
milk.

43. Newer Antiarrhythmic
Agents

44. Vernakalant
 Vernakalant is the first in the new generation of AADs
that demonstrate electrophysiological effects
preferentially in the atrium and not in the ventricle.
 Atrial-selective agents are currently being developed to
restore and maintain sinus rhythm in AF while avoiding
adverse ventricular events, such as QTc prolongation
and torsades de pointes.
• The recommended dose is a single intravenous infusion
of 3 mg/kg administered over 10 minutes.
• No dose adjustment is necessarily based on patient
characteristics and concomitant drugs.

45. • The ACT I(Atrial Arrhythmia Conversion) and ACT III
trials investigated vernakalant in the treatment of
patients with sustained AF
 No episodes of drug-induced torsades de pointes were
reported in the ACT trials.
 The AVRO trial demonstrated that vernakalant achieved
a superior conversion rate (51.7% of patients to sinus
rhythm at 90 minutes) compared to amiodarone (5.2%).

46. Tedisamil
• Tedisamil blocks multiple potassium
channels.
• These ion channels effect prolong atrial
and ventricular action potential duration
and refractoriness.

47. Ivabradine
 High resting sinus heart rates have been independently
associated with mortality and major adverse
cardiovascular outcomes.
 Ivabradine is a selective If current blocker in the sinus
node, resulting in sinus slowing, independent of
autonomic tone.
 Ivabradine, in combination with a b-blocker, can be
effective to prevent angina.
 Usual dose for ivabradine is 5–7.5 mg twice a day.

48. • Systolic Heart Failure Treatment with If Inhibitor
Ivabradine Trial (SHIFT)159 of patients with congestive
heart failure (LV EF ≤35% and HR ≥70 despite standard
medical therapy) indicated that ivabradine can
consistently lower the heart rate over long-term when
compared to matching placebo and can significantly
improve the primary endpoint of cardiovascular death or
hospitalization for worsening heart failure.
• Ivabradine has emerged as a promising treatment for
inappropriate sinus tachycardia (IST), which, at times,
can be debilitating and refractory to medical therapy.

49. Ranolazine
 Ranolazine is an antianginal drug approved for the
treatment of chronic angina in patients who have not
responded to standard antianginal medications.
• The antianginal mechanism of ranolazine was believed
to result from the drug’s ability to block the late sodium
current, thereby, suppressing calcium and sodium
overload in response to ischemia.
 Selective affinity for the late sodium current has resulted
in ranolazine being investigated as a novel AAD.

50.  (MERLIN-TIMI 36) trial, ranolazine significantly lowered
nonsustained VT and supraventricular tachyarrhythmias
in patients with non-ST elevation myocardial infarction
when compared to placebo.
 Early clinical studies have shown that a single dose of 2
g of ranolazine was highly effective as a “pill-in-
thepocket” approach to AF, converting 77% of patients,
without any significant side effects.
• These included patients with structural heart disease, a
contraindication for current class IC agents, and could
potentially expand the use of ranolazine.

51. On the horizon
• Cellular Calcium Handling
• Gene therapies—potential (“near practical”) applications:
There are a variety of exciting possibilities with regard to
the use of gene therapies as antiarrhythmic therapy.
Consideration has been given to use gene therapy
 to enhance automaticity in patients with bradycardia (a biological
pacemaker)
 gene therapy to affect AV conduction and slow conduction in AF
 to affect the presence of VT by affecting repolarization and
accelerating conduction.

52. Outpatient Vs. In-hospital Initiation for
antiarrhythmic drug therapy
• The severity of the arrhythmia and the proarrhythmic risk of the AAD
determine whether the drug should be initiated in the hospital.
• All class IA AADs should be started in the hospital given the
potential risk of idiosyncratic, non dose dependent torsades de
pointes.
• Mexiletine, the only orally available class IB AAD, can be started
and titrated as an outpatient treatment, as the risk of proarrhythmia
is low.
• Class IC AADs have a very low risk of proarrhythmia and can be
started as an outpatient treatment, provided structural heart disease
and severe left ventricular hypertrophy are ruled out.
• If initiated for AF, it is recommended to add an AV blocking drug
along with the class IC agent to reduce the risk of atrial flutter with
rapid ventricular rates.

53. • Sotalol and dofetilide should be initiated in the hospital
due to the risk of developing dose-dependent QT
prolongation and torsades de pointes. Dofetilide must be
started in the hospital and strict regulations govern its
initiation and titration.
• Amiodarone can be started as an outpatient for patients
who have AF and atrial flutter, as the proarrhythmic risk
is low.
• On the other hand, if used for secondary prevention of
VT, it is preferable to initiate amiodarone in the hospital.
• Although amiodarone prolongs QT interval, incidence of
torsades de pointes with amiodarone is extremely low.
• Dronedarone is generally not proarrhythmic and can be
started outside the hospital.

54. Pill-in-the-pocket
• Intermittent oral administration of single doses of flecainide
(200 to 300 mg) or propafenone (450 to 600 mg) when an
episode begins—may be effective in selected patients with
AF and no structural heart disease.
• The major potential complication of this approach is the
possibility for organization and slowing of the arrhythmia to
atrial flutter, which may then conduct with a 1:1 AV ratio at a
very high ventricular rate.
• Intermittent drug self-administration should be used
cautiously and only in patients likely to tolerate this potential
proarrhythmic effect.
• The efficacy of this approach is often tested in a monitored
setting before being used on an outpatient basis.

55. Thank you