new guidelines of Antiarrhythmic drugs

1. ANTIARRHYTHMIC
DRUGS
Edit By
Ahmed Majid Alkufy
Under Supervision Of
Prof.Dr.Najah Almosawi

2. Objectives Of Seminar
• Physiology of heart electricity (exitibility
and conductivity) and normal action
potential and its phases and describe the
refractory period
• Know what is arrhythmia,causes,types,and
complication
• Guidelines treatment of dysrrythmia

3. Electrophysiology Of Cardiac
Tissue
• Impulse Generation And
Transmission
• Myocardial Action Potential
• Depolarization And Repolarization
Waves As Seen In ECG

4. Types Of Cardiac Tissue
(On The Basis Of Impulse
Generation)
Automatic/ Pacemaker/ Conducting Fibers
(Ca++ Driven Tissues)
• Includes SA Node, AV Node, Bundle Of His,
• Purkinje Fibres
• Capable Of Generating Their Own Impulse
• Normally SA Node Acts As Pacemaker Of Heart
 Non-automatic Myocardial Contractile
Fibers
(Na+ Driven Tissues)
• Cannot Generate Own Impulse

5. Impulse Generation And
Transmission

6. Cardiac Action Potential
When THE STIMULUS REACH THE CARDIAC CELL,
SPECIFIC Ions Moves Into And Out Of The Eliciting
The Action Potential Cell. Such MOVEMENT OF
IONS IS Divided Into Following Or Phases:

7. Phases Of Cardiac Action
Potential
• Phase 0: Rapid Depolarization Of Cell Membrane
During Which Theirs Is Fast Entry Of Na Ions Into
The Cells Through Na Channels, This Is Followed
By Repolarization.
• Phase 1: Is Short Initial Rapid Repolarization Due
To Ka Efflux
• Phase 2:prolonged Plateue Phase Due To Slow Ca
Influx
• Phases 3: Rapid Repolarization With Ka Efflux
• Phase 4: Resting Phase During Which Ka Ions
Return Into The Cell While Na And Ka Move Out
Of It And Resting Membrane Potential Is Stored

9. Common Terms
• Automaticity
– Capacity Of A Cell To Undergo Spontaneous
Diastolic Depolarization
• Excitability
– Ability Of A Cell To Respond To External
Stimulus By
Depolariztion
• Threshold Potential
– Level Of Intracellular Negativity At Which Abrupt
And Complete Depolarization Occurs

10. Refractory Period

11. ECG Is Used As A Rough Guide To
Some
Cellular Properties Of Cardiac Tissue
• P Wave: Atrial Depolarization
• PR-interval Reflects AV Nodal
Conduction Time
• QRS DURATION Reflects Conduction
Time In Ventricles
• T-wave: Ventricular Repolarization
• QT Interval Is A Measure Of
Ventricular APD

13. A-RHYTHM –IA
• Defn- Arrhythmia Is Deviation Of
Heart From Normal RHYTHM.
• Rhythm
1) Hr- 60-100
2) Should Origin From SAN
3) Cardiac Impulse Should Propagate
Through Normal Conduction Pathway
With Normal Velocity

14. ARRHYTHMIAS MY BE :
Sinus
arrythmia
Atrial
arrythmia
Nodal
arrhythmia
(junctional)
SVT
Ventricular
Arrhythmia

15. Mechanisms Of Cardiac
Arrythmia
• Abnormal Impulse Generation:
• Depressed Automaticity
• Enhanced Automaticity
• Triggered Activity (After Depolarization):
• Delayed After Depolarization
• Early After Depolarization
• Abnormal Impulse Conduction:
• Conduction Block
• Re-entry Phenomenon
• Accessory Tract Pathways

16. Main Symptoms Of Arrhythmia

17. Complications Of Arrythmia
• Hypertension
• Heart Failure
• IHD
• Pulmonary Embolism
• DVT
• Valvular Heart Disease
FINALLY IF NOT TREATED WILL LEAD TO
DEATH

18. Antiarrhythmic Drugs
 The Ultimate Goal Of Antiarrhythmic Drug Therapy:
O Restore Normal Sinus Rhythm And Conduction
O Prevent More Serious And Possibly Lethal Arrhythmias
From Occurring.
 Antiarrhythmic Drugs Are Used To:
O Decrease Conduction Velocity
O Change The Duration Of The Effective Refractory Period
(ERP)
O Suppress Abnormal Automaticity

19. Modrenized Vaughan-williams
Classification
Class 0: HCN channel–mediated pacemaker current (If) block
Ivabradine
Class I: Block Na+ Channels
Ia (Quinidine, Procainamide, Ajmaline, Disopyramide)
Ib (Lignocaine)
Ic (Flecainide)
ld (Ranolazine)
Class II:Autonomic inhibitors and activators
lla (ß-adrenoceptor Antagonists selective and non-selective)
(Atenolol, Sotalol,esmolol,propranolol,nadolol,celiprolol etc…)
llb (Nonselective β-adrenergic receptor activators)
(Isoproterenol)

20. Modrenized Vaughan-williams
Classification
llc (Muscarinic M2 receptor inhibitors)
(Atropine,anisodamine,hyoscine,scopolamine)
lld (Muscarinic M2 receptor activators)
(Carbachol,pilocarpine,methacholine,digoxin)
Ile (Adenosine A1 receptor activators)
(Adenosine)
Class III: Block K-Channels (Prolong Action Potential And Prolong Refractory
Period) and K-Channels Openners
llla (Amiodarone, Dofetilide, Sotalol,Ambasilide,dronedarone,ibutilide)
lllb (Nicorandil,pinacidil)
Class IV: Ca2+ Channel Antagonists
(Verapamil, Diltiazem)

21. Modrenized Vaughan-williams
Classification
Class VI: Upstream Target Modulators
These Include The Following:
(Angiotensin Converting Enzyme Inhibitors,
Angiotensin
Receptor Blockers, Omega-3 Fatty Acids, Statins)
All These Groups Have The Same Action On
Arrhythmia By Reduction Of Structural And
Electrophysiological Remodeling Changes That
Compromise AP Conduction And Increase
Reentrant Tendency

22. What Is HCN Channels??
Hyperpolarization-activated Cyclic Nucleotide–gated
(HCN) Channels Are Intermembrane Proteins That Serve
As Nonselective Voltage-gated Cation Channels In The
Plasma Membranes Of Heart And Brain Cells.[1] HCN
Channels Are Sometimes Referred To As Pacemaker
Channels Because They Help To Generate Rhythmic
Activity Within Groups Of Heart And Brain Cells. HCN
Channels Are Encoded By Four Genes (HCN1, 2, 3, 4)
And Are Widely Expressed Throughout The Heart And
The Central Nervous System.The Current Through HCN
Channels, Designated If Or Ih, Plays A Key Role In The
Control Of Cardiac And Neuronal Rhythmicity And Is
Called The Pacemaker Current Or "Funny" Current.

23. Class 0 HCN Channel Blockers
Ivabradine
Mech.of action:HCN channel–mediated pacemaker current
(If) block
Pharmacological activity:Reduction in SAN automaticity
Uses:Stable angina and chronic heart failure with heart
rate ≥70 bpm,Potential new applications for
tachyarrhythmias
CI:Ivabradine is contraindicated in sick sinus syndrome. It
should also not be used concomitantly with potent
inhibitors of CYP3A4, including azole antifungals (such as
ketoconazole), macrolide antibiotics, nefazodone and the
antiretroviral drugs nelfinavir and ritonavir.Use of

24. Ivabradine
AE:overall, 14.5% Of Patients Taking Ivabradine Experience
Luminous Phenomena (By Patients Described As
Sensations Of Enhanced Brightness In A Fully Maintained
Visual Field). This Is Probably Due To Blockage Of Ih Ion
Channels In The Retina, Which Are Very Similar To Cardiac
If. These Symptoms Are Mild, Transient, And Fully
Reversible.

25. Na+ Channel Blocker
• Bind To And Block Na+ Channels (And K+
Also)
• Act On Initial Rapid Depolarisation (Slowing
Effect)
• Local Anaesthetic (Higher Concentration):
Block Nerve Conduction
• Do Not Alter Resting Membrane Potential
(Membrane Stabilisers)
• At Times, Post Repolarization Refractoriness.
• Bind Preferentially To The Open Channel State

26. Class IA

27. Quinidine
• Historically First Antiarrhythmic Drug Used.
• In 18th Century, The Bark Of The Cinchona Plant
Was Used To Treat "Rebellious Palpitations“
Pharmacological Effects
Threshold For Excitability
Automaticity
Prolongs AP

28. Clinical Pharmacokinetics
• Well Absorbed
• 80% Bound To Plasma Proteins (Albumin)
• Extensive Hepatic Oxidative Metabolism
• 3-hydroxyquinidine,
• Is Nearly As Potent As Quinidine In
Blocking
Cardiac Na+ Channels And Prolonging
Cardiac
Action Potentials.

29. Uses
• To Maintain Sinus Rhythm In Patients
With
Atrial Flutter Or Atrial Fibrillation
• To Prevent Recurrence Of Ventricular
Tachycardia Or VF

30. Adverse Effects
Non Cardiac
• Diarrhea, Thrombocytopenia,
• Cinchonism & Skin Rashes.
Cardiac
Marked Qt-interval Prolongation &Torsades
De Pointes (2-8% )
Hypotension
Tachycardia

31. Drug Interactions
• Metabolized By CYP450
• Increases Digoxin Levels
• Cardiac Depression With Beta
Blockers
• Inhibits CYP2D6

32. Disopyramide
• Exerts Electrophysiologic Effects Very Similar To Those Of
Quinidine.
• Better Tolerated Than Quinidine
• Exert Prominent Anticholinergic Actions
• Negative Ionotropic Action.
• A/E
• Precipitation Of Glaucoma,
• Constipation, Dry Mouth,
• Urinary Retention

33. Procainamide
• Lesser Vagolytic Action , Depression Of
Contractility & Fall In BP
• Metabolized By Acetylation To N-acetyl
Procainamide Which Can Block K+
Channels
• Doesn’t Alter Plasma Digoxin Levels
• Cardiac Adverse Effects Like Quinidine
• Can Cause SLE Not Recommended > 6
Months
• Use: Monomorphic VT, WPW Syndrome

34. Class IB Drugs
Lignocaine, Phenytoin,
Mexiletine
Block Sodium Channels
Also Shorten
Repolarization

35. Lignocaine
• Blocks Inactivated Sodium Channels More
Than
Open State
• Relatively Selective For Partially
Depolarized
Cells
• Selectively Acts On Diseased Myocardium
• Rapid Onset & Shorter Duration Of Action
• Useful Only In Ventricular Arrhythmias ,
Digitalis Induced Ventricular Arrhythmias

36. Lignocaine
• Lidocaine Is Not Useful In Atrial
Arrhythmias??
• Atrial Action Potentials Are So Short That
The Na+ Channel Is In The Inactivated State
Only Briefly Compared With Diastolic
(Recovery) Times, Which Are Relatively Long

37. Pharmacokinetics
• High First Pass Metabolism
• Metabolism Dependent On Hepatic Blood
Flow
• T ½ = 8 Min – Distributive, 2 Hrs –
Elimination
• Propranolol Decreases Half Life Of
Lignocaine
• Dose= 50-100 Mg Bolus Followed By 20-
40 Mg

38. Adverse Effects
• Relatively Safe In Recommended
Doses
• Drowsiness, Disorientation, Muscle
Twitchings
• Rarely Convulsions, Blurred
Vision,Nystagmus
• Least Cardiotoxic Antiarrhythmic

39. • Local Anaesthetic
• Inactive Orally
• Given IV For Antiarrhythmic Action
• Na+ Channel Blockade Which Occurs
• Only In Inactive State Of Na+ Channels
• CNS Side Effects In High Doses
• Action Lasts Only For 15 Min
• Inhibits Purkinje Fibers And Ventricles But
• No Action On AVN And SAN So
• Effective In Ventricular Arrhythmias Only

40. Mexiletine
• Oral Analogue Of Lignocaine
• No First Pass Metabolism In Liver
• Use:
– Chronic Treatment Of Ventricular Arrhythmias
Associated With Previous MI
– Unlabelled Use In Diabetic Neuropathy
• Tremor Is Early Sign Of Mexiletine
Toxicity
• Hypotension, Bradycardia, Widened QRS ,
Dizziness, Nystagmus May Occur

41. Tocainide
• Structurally Similar To Lignocaine
But Can Be
Administered Orally
• Serious Non Cardiac Side Effects
Like
Pulmonary Fibrosis, Agranulocytosis,
Thrombocytopenia Limit Its Use

42. Class I C DRUGS
Encainide, Flecainide,
Propafenone
Have Minimal Effect On
Repolarization
Are Most Potent Sodium
Channel Blockers
• Risk Of Cardiac Arrest ,
Sudden Death So Not Used
Commonly
• May Be Used In Severe
Ventricular Arrhythmias

43. Propafenone
• Structural Similarity With Propranolol & Has
B-blocking Action
• Undergoes Variable First Pass Metabolism
• Reserve Drug For Ventricular Arrhythmias,
Reentrant
Tachycardia Involving Accesory Pathway
• Adverse Effects: Metallic Taste, Constipation
And Is Proarrhythmic

44. Flecainde
• Potent Blocker Of Na & K Channels With Slow
Unblocking Kinetics
• Blocks K Channels But Does Not Prolong APD & QT
Interval
• Maintain Sinus Rhythm In Supraventricular
Arrhythmias

45. Cardiac Arrhythmia Suppression Test
(CAST Trial):
When Flecainide & Other Class Ic Given
Prophylactically To Patients Convalescing From
Myocardial Infarction It Increased Mortality By 2½
Fold. Therefore The Trial Had To Be Prematurely
Terminated

46. ld (Ranolazine)
It Decrease In AP Recovery Time And
Can Use In Treatment Of Stable
Angina, Ventricular
Tachycardia.Consider As A Potential
New Class Of Drugs For The
Management Of Tachyarrhythmias

47. Class II:Autonomic inhibitors and
activators
Class lla: Beta Blockers
•B-receptor Stimulation lead to:
• ↑ Automaticity,
• ↑ AV Conduction Velocity,
• ↓ Refractory Period
• B-adrenergic Blockers Competitively Block
Catecholamine Induced Stimulation Of Cardiac
B-receptors

48. Beta Blockers
• Depress Phase 4 Depolarization Of Pacemaker
Cells,
• Slow Sinus As Well As AV Nodal Conduction :
– ↓ HR, ↑ PR
• ↑ ERP, Prolong AP Duration By ↓ AV
Conduction
• Reduce Myocardial Oxygen Demand
• Well Tolerated, Safer

49. Use In Arrhythmia
• Control Supraventricular Arrhythmias
• Atrial Flutter, Fibrillation, PSVT
• Treat Tachyarrhythmias Caused By
Adrenergic Activation
•
Hyperthyroidism,pheochromocytoma,durin
g Anaesthesia With Halothane
• Digitalis Induced Tachyarrythmias
• Prophylactic In Post-mi
• Ventricular Arrhythmias In Prolonged QT

50. Esmolol
• Β1 Selective Agent
• Very Short Elimination T1/2 9 Mins
• Metabolized By RBC Esterases
• Rate Control Of Rapidly Conducted AF
• Use:
• Arrythmia Associated With Anaesthesia
• Supraventricular Tachycardia

51. Ilb:nonselective Β-adrenergic
Receptor Activators
Isoproterenol
Accelerating Rates Of Ventricular
Escape Rhythm In Cases Of Complete
Atrioventricular Block Before
Definitive Pacemaker Implantation.

52. Ilc: Muscarinic M2
Receptor Inhibitors
Atropine,anisodamine,hyoscine,scopolami
ne
Used in Mild or moderate
symptomatic sinus bradycardia
Supra-His, AVN, conduction block,
eg, in vagal syncope or acute inferior
myocardial infarction By Increase in
SAN Automaticity Increase in AVN
conduction.

53. Ild Muscarinic M2 Receptor
Activators
CARBACHOL,PILOCARPINE,METHACHOLINE,DIGO
XIN
Used in Sinus Tachycardia Or Supraventricular
Tachyarrhythmias Reduction In SAN Automaticity
Reduced SAN Reentry by Reduction In AVN
Conduction and terminating Reentry.
Ile: Adenosine A1receptor
activetors
Adenosine:Will Be Discuss Later

54. Class III Drugs
llla: ↑APD & ↑RP By Blocking The K+ Channels

55. Amiodarone
• Iodine Containing Long Acting Drug
• Mechanism Of Action: (Multiple Actions)
– Prolongs APD By Blocking K+ Channels
– Blocks Inactivated Sodium Channels
– Β Blocking Action , Blocks Ca2+ Channels
– ↓ Conduction, ↓Ectopic Automaticity

56. Amiodarone
• Pharmacokinetics:
–Variable Absorption 35-65%
– Slow Onset 2days To Several Weeks
– Duration Of Action : Weeks To Months
• Dose
– Loading Dose: 150 Mg Over 10min
– Then 1 Mg/Min For 6 Hrs
– Then Maintenance Infusion Of 0.5 Mg/Min
For 24 Hr

57. Amiodarone
• Uses:
– Can Be Used For Both Supraventricular And Ventricular Tachycardia
• Adverse Effects:
– Cardiac: Heart Block , QT Prolongation, Bradycardia, Cardiac Failure,
Hypotension
– Pulmonary: Pneumonitis Leading To Pulmonary Fibrosis
– Bluish Discoloration Of Skin, Corneal Microdeposits
– GIT Disturbances, Hepatotoxicity
– Blocks Peripheral Conversion Of T4to T3 Can Cause Hypothyroidism
Or Hyperthyroidism

58. • Antiarrhythmic
• Multiple Actions
• Iodine Containing
• Orally Used Mainly
• Duration Of Action Is Very Long (T ½ = 3-8 Weeks)
• APD & ERP Increases
• Resistant AF, V Tach, Recurrent VF Are
Indications
• On Prolonged Use- Pulmonary Fibrosis
• Neuropathy May Occur
• Eye : Corneal Microdeposits May Occur

59. • Bretylium:
– Adrenergic Neuron Blocker Used In
Resistant Ventricular Arrhythmias
• Sotalol:
– Beta Blocker
• Dofetilide, Ibutilide :
– Selective K+ Channel Blocker, Less Adverse
Events
– Use In AF To Convert Or Maintain Sinus
Rhythm
– May Cause QT Prolongation

60. Newer Class III Drugs
• Dronedarone
• Vernakalant
• Azimilide
• Tedisamil

61. lllb (Nicorandil,pinacidil)
K-Channel Openners
Nicorandil: Treatment Of Stable
Angina (Second Line).
Pinacidil: Investigationaldrug For
The Treatment Of Hypertension.
And Both Can Be Used In
Treatment Of Arrhythmia By
Potential Decrease In AP Recovery

62. Calcium Channel Blockers (Class
IV)
• Inhibit The Inward
Movement Of Calcium
↓ Contractility,
Automaticity , And AV
Conduction.
• Verapamil & Diltiazem

63. Verapamil
• Uses:
– Terminate PSVT
– Control Ventricular Rate In Atrial Flutter Or
Fibrillation
• Drug Interactions:
– Displaces Digoxin From Binding Sites
– ↓ Renal Clearance Of Digoxin

64. Other Antiarrhythmics
• Adenosine :
– Purine Nucleoside Having Short And Rapid Action
– IV Suppresses Automaticity, AV Conduction And
Dilates Coronaries
– Drug Of Choice For PSVT
– Adverse Events:
• Nausea, Dyspnoea, Flushing, Headache

65. Mechanism Of Action Adenosine
• Acts On Specific G Protein-coupled Adenosine Receptors
• Activates A1-R Sensitive K+ Channels In SA Node, AV Node & Atrium
• Shortens APD, Hyperpolarization & ↓ Automaticity
• Inhibits Effects Of ↑ Camp With Sympathetic Stimulation
• ↓ Ca Currents
• ↑AV Nodal Refractoriness

66. Other Antiarrhythmics
• Atropine: Used In Sinus
Bradycardia
• Digitalis: Atrial Fibrillation And
Atrial Flutter
• Magnesium SO4: Digitalis Induced
Arrhythmias

67. Magnesium
• Its Mechanism Of Action Is Unknown But May
Influence Na+/K+atpase, Na+ Channels,Certain K+
Channels & Ca2+ Channels
• Use: Digitalis Induced Arrhythmias If
Hypomagnesemia Present, Refractory Ventricular
Tachyarrythmias, Torsade De Pointes Even If Serum
Mg2+ Is Normal
• Given 1g Over 20mins

68. Refrences
Katzung & Trevors
Pharmacology
Pubmed (circulation journal)
Slideshare

69. Thank You