1. ANTI-ARRHYTHMIC DRUGS
DR BUSARI. A.A
(MB.BS, M.Sc., MMCP, FWACP)
Consultant Nephrologist & Lecturer
Dept. Of Pharmacology, Therapeutics and Toxicology

2. Outline Definition Principles of cardiac electrophysiology
Causes of arrhythmias
Antiarrhymic drugs classification
Pharmacology of antiarrhymic drugs

3. Cardiac arrhythmias
Also known as cardiac dysrhythmia or irregular heartbeat, is a group of conditions in which the heartbeat is irregular, too fast, or too slow.
An abnormality in terms of site of origin, rate or conduction of impulses.
Usually asymptomatic.
When symptoms are present, these may include palpitations miss heartbeats, lightheadedness, syncope, shortness of breath, or chest pain.

4. Cardiac arrhythmias
While most arrhythmias are not serious some predispose a person to complications such as stroke or heart failure. Others may result in cardiac arrest and death.
There are four main types of arrhythmias: extra beats, supraventricular tachycardias, ventricular arrhythmias, and bradyarrhythmias.

5. Causes of Arrhythmiaia
Arrhythmia /dysrhythmia: abnormality in the site of origin of impulse, rate, or conduction
Causes of arrhythmia
arteriosclerosis
Coronary artery spasm
Heart block
Myocardial ischemia
If the arrhythmia arises from atria, SA node, or AV node it is called supraventricular arrhythmia
If the arrhythmia arises from the ventricles it is called ventricular arrhythmia

9. Principles of cardiac electrophysiology
Cardiac cell undergo depolarization and repolarisation to form cardiac action potential about 6 times per minute.
The flow of ions across cell membrane generate the current that that makes of Cardiac action potential (AP)

10. In the SA node and AV node, AP curve consists of 3 phases
Action potential of the heart:
In the atria, purkinje, and ventricles the AP curve consists of 5 phases
In the SA node and AV node, AP curve consists of 3 phases

11. Non-pacemaker action potential
Phase 1: partial repolarization
Due to rapid efflux of K+
Phase 2: plateu
Due to Ca++ influx
Phase 0: fast upstroke
Due to Na+ influx
Phase 3: repolarization
Due to K+ efflux
Phase 4: resting membrane potential
N.B. The slope of phase 0 = conduction velocity
Also the peak of phase 0 = Vmax

12. Pacemaker AP
Phase 0: upstroke:
Due to Ca++ influx
Phase 3: repolarization:
Due to K+ efflux
Phase 4: pacemaker potential
Na influx and K efflux and Ca influx until the cell reaches threshold and then turns into phase 0
Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously

13. Cardiac action potential (AP)
0 – Depolarisation due to opening of Na+ channels.
1 – Repolarisation due to inactivation of Na+ channels (fast Na+ channels, activation of K+ channels that let K+ out of the cell.
2 – Plateau phase. Due to slow inward current caused by Ca2+ channels (L-type Ca2+ channels) opening. This Ca2+ influx also leads to cardiac muscle contraction.

14. Cardiac action potential (AP)
3 – Repolarisation due to K+ leaving cells.
4 – Spontaneous depolarisation to threshold where critical voltage activates Na+ channels. If this phase is steeper, then heart rate increases. Involves the spontaneous action of various channel types.

15. Mechnisms of Arrhythmogenesis
1- Abnormal impulse generation a) Automatic rhythms Ectopic focus automaticity Enhanced normal b) Triggered rhythms Delayed afterdepolarization Early afterdepolarization

16. Mechnisms of Arrhythmogenesis
2-Abnormal impulse conduction
Conduction block
1st degree
2nd degree
3rd degree
Reentry
Circus movement
Reflection

17. Mechnisms of Arrhythmogenesis
1- Abnormal impulse generation
Automatic rhythms
Ectopic focus
Enhanced normal automaticity
Triggered rhythms
Delayed afterdepolarization
Early afterdepolarization
AP arises from sites other than SA node
↑AP from SA node

18. 1-This pathway is blocked
2-Abnormal conduction
Conduction block
1st degree
2nd degree
3rd degree
Reentry
Circus movement
Reflection
1-This pathway is blocked
This is when the impulse is not conducted from the atria to the ventricles
3-So the cells here will be reexcited (first by the original pathway and the other from the retrograde)
2-The impulse from this pathway travels in a retrograde fashion (backward)

20. Types of Arrhythmias
Supraventricular Arrhythmias
Sinus Tachycardia: high sinus rate of beats/min, occurs during exercise or other conditions that lead to increased SA nodal firing rate
Atrial Tachycardia: a series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min

21. Types of Arrhythmias
Paroxysmal Atrial Tachycardia (PAT): tachycardia which begins and ends in acute manner
Atrial Flutter: sinus rate of beats/min.
Atrial Fibrillation: uncoordinated atrial depolarizations.
AV blocks
A conduction block within the AV node , occasionally in the bundle of His, that impairs impulse conduction from the atria to the ventricles.

22. Ventricular Arrhythmias
Ventricular Premature Beats (VPBs): caused by ectopic ventricular foci; characterized by widened QRS.
Ventricular Tachycardia (VT): high ventricular rate caused by abnormal ventricular automaticity or by intraventricular reentry; can be sustained or non-sustained (paroxysmal); characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening.

23. Ventricular Arrhythmias
Ventricular Flutter - ventricular depolarizations >200/min.
Ventricular Fibrillation - uncoordinated ventricular depolarizations

24. Factors precipitate arrhythmias
May includes :
Ischemia,
hypoxia,
electrolytes disturbance,
excessive catecholamines exposure ,
drug toxicity.

25. ANTI-ARRHYTHMIC DRUGS

26. Pharmacologic Rationale & Goals
The ultimate goal of antiarrhythmic drug therapy:
Restore normal sinus rhythm and conduction
Prevent more serious and possibly lethal arrhythmias from occurring.
Antiarrhythmic drugs are used to:
decrease conduction velocity
change the duration of the effective refractory period (ERP)
suppress abnormal automaticity

27. Classification
The Singh Vaughan Williams classification was introduced in 1970.
As a doctoral candidate at Oxford University working in the lab of Vaughan Williams, Dr. Bramah Singh determined that amiodarone and sotalol had antiarrhythmic properties and belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents).

28. Classification
With regards to management of atrial fibrillation, Class I and III are used in rhythm control as medical cardioversion agents while Class II and IV are used as rate control agents.
There are five main classes in the Singh Vaughan Williams classification of antiarrhythmic agents:

29. Classification Class I agents interfere with the sodium (Na+) channel.
Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers.
Class III agents affect potassium (K+) efflux.
Class IV agents affect calcium channels and the AV node.
Class V agents work by other or unknown mechanisms.

30. Anti-arrhythmic drug Class I - Fast Channel Blockers
Ia - Quinidine, Disopyramide, Procainamide
Ib - Lidocaine, Phenytoin, Mexilitine, Tocaininde
Ic - Ecainide, Flecainide, Propafenone, Indecainide, Moricizine

31. Anti-arrhythmic drug Class II - Beta Blockers
Propanolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Labetalol, Metoprolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol

32. Anti-arrhythmic drug Class III Bretylium, Amiodarone, Sotalol
Class IV - Calcium Channel Blockers
Verapamil, Diltiazem
Unclassified - Digoxin, Adenosine, Mg

33. Clinical uses in cardiology
Class
Known as
Examples
Mechanism
Clinical uses in cardiology Ia
fast-channel blockers-affect QRS complex
Quinidine
Procainamide
Disopyramide
(Na+) channel block (intermediate association/
dissociation)
Ventricular arrhythmias
prevention of paroxysmal recurrent atrial fibrillation (triggered by vagaloveractivity)
procainamide in Wolff-Parkinson-White syndrome
Increases QT interval Ib
Can prolong QRS in overdose
Lidocaine
Phenytoin
Mexiletine
Tocainide
(Na+) channel block (fast association/
treatment and prevention during and immediately after myocardial infarction, though this practice is now discouraged given the increased risk of asystole
ventricular tachycardia Ic
Encainide
Flecainide
Propafenone
Moricizine
(Na+) channel block (slow association/
prevents paroxysmal atrial fibrillation
treats recurrent tachyarrhythmias of abnormal conduction system.
contraindicated immediately post-myocardial infarction.

34. Clinical uses in cardiology
Class
Known as
Examples
Mechanism
Clinical uses in cardiology II
Beta-blockers
carvedilol
Propranolol
Esmolol
Timolol
Metoprolol
Atenolol
Bisoprolol
beta blocking Propranolol also shows some class I action
decrease myocardial infarction mortality
prevent recurrence of tachyarrhythmias
Propranolol has sodium channel blocking effects
III
Amiodarone
Sotalol
Ibutilide
Dofetilide
Dronedarone
E-4031
K+ channel blocker Sotalol is also a beta blocker Amiodarone has Class I, II, III & IV activity
In Wolff-Parkinson-White syndrome
(sotalol:) ventricular tachycardias and atrial fibrillation
(Ibutilide:) atrial flutter and atrial fibrillation

35. Clinical uses in cardiology
Class
Known as
Examples
Mechanism
Clinical uses in cardiology IV
slow-channel blockers
Verapamil
Diltiazem
Ca2+ channel blocker
prevent recurrence of paroxysmal supraventricular tachycardia
reduce ventricular rate in patients with atrial fibrillation V
Adenosine
Digoxin
Magnesium Sulfate
Work by other or unknown mechanisms (Direct nodal inhibition).
Used in supraventricular arrhythmias, especially in Heart Failure with Atrial Fibrillation, contraindicated in ventricular arrhythmias. Or in the case of Magnesium Sulfate, used in Torsades de Pointes.

38. Anti arrhythmic mech of action
Class 1 : Na+ channel blockers
Local anaesthetic effect
-ve inotropic action
Class 1( A ): prolongs duration of action potential & refractory period.
Have K+ channel blocking effect
Antimuscarinic & hypotensive effects.

39. Anti arrhythmic mech of action
Class I(B):Shorten the duration of action potential & refractory period
Class1(C) : No effect on the duration of action or refractory period.
Class II : β-adrenoceptor blockers.
Class III: K+ channel blockers,
Prolong duration of action potential and refractory period.
Class1V : Ca++ channel blockers.
Miscellaneous drugs.

40. Class 1(A) Quinidine: Cinchona plant
Block open & inactivated sodium channel
Block potassium channel
-ve inotropic effect
Antimuscarinic effect
duration of action potential & refractory periods of atrium & ventricles.
Hypotensive
ECG changes
Prolong Q-T interval
Widening QRS complex

42. Pharmacokinetics/Clinical uses
Well absorbed orally
Highly bound to plasma proteins
Metabolized in liver ( active metabolite)
20% excreted unchanged in urine
Usually given as slow release formulation
I.M. painful, I.V(marked hypotension)
Clinical uses
Atrial flutter & fibrillation it returns the rhythm back to normal sinus rhythm.
Used in treatment of ventricular arrhythmia.

43. Adverse effects 1- Cardiac effects
A) Due to antimuscarinic effect ,in A.F.or A.F. may precipitate ventricular tachycardia
B) Syncope
C)Torsade de pointes
D) Cardiac stand still (asystole) in patients with sick sinus syndrome .

44. Torsade de pointes

45. Extracardiac adverse effects
Hypotension
Cinchonism (headache, dizziness,tinnitus,deafness )
Hypersensitivity reactions (hepatitis,thrombocytopenia)
GIT, diarrhea,nausea,vomiting

46. Drug interactions Quinidine increases the plasma level of digoxin by :
a) displacement from tissue binding sites
b) decreasing digoxin renal clearance

47. Procainamide - Actions
Suppresses automaticity
decreasing the rate and amplitude of phase 4 diastolic depolarization
prolongs action potential duration
reduces the speed of impulse conduction
suppresses fibrillatory activity in the atria and ventricles
Dose dependant anticholinergic activity

48. Procainamide - Actions
Negative Inotrope
more pronounced in ischemic myocardium
Hypotension in high doses
vasodilatation of peripheral vasculature

49. Procainamide- Pharmacokinetics
Onset
minutes IV
minutes IM
Half Life
2.5 to 4.7 hrs in normal renal function
increased in CHF, Renal Failure
Metabolized to N-acetyl Procainamide
NAPA

50. Procainamide - Indications
Ventricular arrhythmias
Stable Ventricular Tachycardia
Premature Ventricular Contractions
Ventricular Fibrillation / Pulseless VT
Supraventricular tachyarrhythmias
PSVT, PAT, paroxysmal AV junctional
Atrial flutter and fibrillation

51. Procainamide- Contraindications
AV block
Second or third degree
Long QT interval
Torsade de pointes
Caution
SLE, CHF, hepatic or renal disease

52. Procainamide - Administration
Continuous infusion safer than bolus
Infusion of mg/min until
control of arrhythmia
hypotension
QRS widens by > 50%
QT interval prolongation
Total of 17 mg/kg has been administered

53. Procainamide - Adverse Effects
Myocardial Depression
prolonged QRS, QT, AV conduction, VF and Torsade de pointes
Hypotension
High doses or rapidly administered
Hypersensitivity
angioedema, bronchoconstriction, vascular collapse, febrile episodes, respiratory arrest

54. Lidocaine - Actions Shorten the duration of A.P.& R.P.
Class IB antiarrhythmic
blocks fast sodium channels
decreases slope of phase 4
decreased automaticity in the His-purkinje system
action potential duration and effective refractory period of His-purkinje increased
Acts preferentially on ischemic tissue
Shorten the duration of A.P.& R.P.
Effective in ventricular arrhythmias.

56. Lidocaine Causes little or no effect on AV conduction
Elevates v-fib threshold
Supresses ventricular ectopy
negligible effect
autonomic nervous system
myocardial contractility
peripheral vascular tone

57. Pharmacokinetics
Well absorbed after oral administration . Only 3% reach general circulation.
Given only by I.V. route
Excreted via kidney .
Half-life 2hrs.
Therapeutic Levels
1.5 to 6 ug/ml
>5 ug/ml may cause CNS toxicity

58. Therapeutic uses
First drug of choice in treatment of ventricular arrhythmias due to
Acute myocardial infarction
Digitalis toxicity
Anaesthesia
Open heart surgery

59. Lidocaine - Administration
Initial Dose IV
Ventricular Ectopy
1 mg/kg bolus
additional doses of 0.5 mg/kg q 5-10 min
Ventricular Fibrillation
1.5 mg/kg
Total Dose IV
3 mg/kg

60. Adverse effects Neurological effects :
(contraindicated in epileptic patients ).
Arrhythmias uncommon
Hypotension

61. Mexiletine Effective orally Half-life (8-20hrs ).
Used in chronic treatment of ventricular arrhythmias.
Effective in relieving chronic pain due to diabetic neuropathy& nerve injury.
Adverse effects -Neurologic side effects

62. Class1(c)- Flecainide No effect on the duration of A.P.& R.P.
Proarrhythmic
Approved for refractory ventricular arrhythmias.

64. Class1(c) -Propafenone
Has a weak β-blocking effect.
Used to maintain sinus rhythm in patients with supraventricular arrhythmias including AF.
Adverse effects :
Metallic taste, constipation .

66. ANTI – ARRHYTHMIC DRUGS: CLASS II

67. Beta Blockers - Actions
Block effects of catacholamines on Beta receptors
Selective Beta blockers
metoprolol
acebutolol
atenolol
esmolol

68. Class II - beta blockers
Beta-Adrenoceptor-Blocking Drugs.
Effective in atrial & ventricular arrhythmias that associated with
Increase in sympathetic activity .
Reduce the incidence of sudden arrhythmic death after myocardial infarction.
Propranolol
Metoprolol ( β1 selective)
Esmolol - Very short acting used for intraoperative & acute arrhythmias

69. Class II - beta blockers
Negative
Chronotropic
slows sinus rate
depresses AV conduction
Decreases cardiac output
Inotropic
Vasodilatation

70. Beta Blockers- Pharmacokinetics
Onset
rapid - within 1 minute IV
Half Life
1 to 26 hours
Excretion is renal and GI
Dose adjustment necessary for renal failure for some beta blockers

71. Beta Blockers - Administration
Metoprolol
5 mg IV push
selective B1
Half life of 3-7 hrs
Esmolol
ultra-short half life of 9 minutes
25-50 ug/kg/min
load of 500 ug/kg not necessary

72. Beta Blockers - Adverse Effects
Similar for most Beta blockers
nausea, vomiting, light headedness, mental depression, bradycardia, hypotension, bronchospasm
Contraindicated
> first degree heart block
CHF or cardiogenic shock
Caution with calcium channel blockers

73. Class III Potassium channel blockers
( Drugs that Prolong duration of action potential & refractory period ).

74. Class III - Amiodarone A) cardiac effects Sodium channel blocking
Potassium channel blocking
Calcium channel blocking
β- adrenoceptor blocking
B) Extracardiac effect
Peripheral vasodilation

75. Pharmacokinetics Given orally Slow onset of action
Long half-life( hrs ).
Cumulative drug
Is highly lipophilic , is concentrated in many tissues.
Eliminated by liver mostly as active metabolites.

76. Clinical uses
Recurrent & refractory ventricular & supraventricular arrhythmias .
Arrhythmias associated with Wolff Parkinson syndrome.
In maintaining sinus rhythm in patients with AF.

77. Adverse effects Gray- blue skin discoloration & photodermatitis .
Corneal microdeposits corneal opacity ,optic neuritis, blindness
pulmonary fibrosis
hypo or hyperthyroidism
Nausea & constipation
Hepatic impairment
neurological effects
A-V block & bradycardia
Hypotension

78. Drug interactions Oral anticoagulant bleeding
Digoxindigoxin toxicity
β- blockers additive effect

79. Bretylium - Actions Class III Biphasic Effects Norepinephrine release
effects last 20 minutes
Blocks release of norepinephrine
45 to 60 minutes after administration
Affects phase 3 (repolarization) prolongs refractoriness - antifibrillatory

80. Bretylium - Actions Class III Biphasic Effects Norepinephrine release
effects last 20 minutes
Blocks release of norepinephrine
45 to 60 minutes after administration
Affects phase 3 (repolarization) prolongs refractoriness - antifibrillatory

81. Sotalol Nonselective β- adrenergic receptor antagonist .
Is used for the treatment of :
Life- threatening ventricular arrhythmias.
To maintain sinus rhythm in patients with atrial fibrillation.
For treatment of supra & ventricular arrhythmias in pediatric age group.

82. Ibutilide Given by a rapid I.V. infusion
excreted mainly as metabolites by kidney.
Used for the acute conversion of atrial flutter or atrial fibrillation to normal sinus rhythm.
Q-T interval prolongation , so it precipitates torsade de pointes.

83. ANTI –ARRHYTHMIC DRUG - Class IV

84. Class IV Calcium channel blockers e.g. Verapamil, Diltiazem
Their main site of action is A.V.N & S.A.N.
Effective only in atrial arrhythmias
Second drugs of choice for the treatment of paroxysmal supraventricular tachycardia
Not effective in Wolff Parkinson White syndrome
Adverse effect
-Ve inotropic effect causes H.F., A-V block
Constipation , headache , peripheral edema

86. Miscellaneous drugs

87. Adenosine - Actions Endogenous Nucleoside
produced by dephosphorylation of ATP
Negative Chronotropic effects on SA and AV node
blockade of the AV node
potent vasodilator - no effects due to metabolism
Adenosine - Binds to specific G protein - coupled adenosine receptors (A1&A2)  opening K+ channel  hyperpolarization.
 influx of calcium

88. Adenosine - Pharmacokinetics
Very rapid onset of action .
Short half- life (seconds)
Given as a rapid I.V. bolus injection
For the acute termination of re-entrant supraventricular tachycardia ( paroxysmal attack) First choice.

89. Adverse effects Bronchospasm Chest pain Shortness of breath Flushing
A-V block
Hypotension

90. Contraindications/Interaction
Bronchial asthma
A-V block
Drug Interactions
Less effective with adenosine receptor blockers ( Caffeine or theophylline
More effective with uptake inhibitors as dipyridamole

91. Magnesium
Used in: Digitalis induced arrhythmias, Torsade de pointes, Sinus tachycardia
Directly
Na, K+, ATPase pump
Indirectly
calcium channel blocking activity
Effects
Increases membrane potential
prolongs AV conduction
Corrects hypomagnesemia/hypokalemia

92. Vasoactive Medications
Epinephrine
Dopamine
Norepinephrine
Atropine
Nitroglycerin

93. THANKS