Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV Guide to treat some types of arrhythmia

1. Presented by
S.Lakshmi Sravanthi
11AB1R0051
Vignan pharmacy college
(Approved by AICTE , PCI & Affiliated to JNTU kakinada)
Vadlamudi , Guntur (Dt)-522213

2. Electrophysiology of the heart
Arrhythmia: definition, mechanisms,
types
Drugs :class I, II, III, IV
Guide to treat some types of arrhythmia

3. CARDIAC
ARRYTHMIAS
Definition
 Cardiac arrythmias results from alterations in the orderly
sequence of depolarisation followed by repolarization in the heart.
 Cardiac arrythmias may result in alterations in heart rate or rhythm
and arise from alterations in simple generation or conduction.

4. ELECTROPHYSIOLOGY – CARDIAC RHYTHM

5. IMPULSE GENERATION AND CONDUCTION
 Conducting tissue
• SA node,AV node,bundle of his & purkije fibers.
Contractile tissue
• Atria and ventricles.

6. CARDIAC ACTION
POTENTIAL
 Divided into five phases (0,1,2,3,4)
• Phase 0 – rapid depolarization
• Phase 1 – early repolarization
• Phase 2 – plateau phase
• Phase 3 – rapid repolarization
• Phase 4 – resting phase, diastolic depolarization

7. Action Potential
Phase 0
Phase 3
Phase 4
Phase 1
Phase 2
30 mV
0 mV
- 90 mV
Non nodal tissues

8. 0 1 2 3 4
• Effective refractory period
• Absolute refractory period
• Relative refractory period
1
0
2
3
4
ARP RRP

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

10. Contraction
of atria
Contraction of
ventricles
Repolarization
of ventricles

11. Abnormal impulse
generation
Triggered activity
Abnormal impulse
conduction

12. Abnormal impulse
generation
 Depressed automaticity of SA node
 Enhanced automaticity of SA node
 Impulse from ectopic loci
 Ischemia, digitalis, catecholamine's, acidosis, hypokalaemia
 Less (-) resting membrane potential
 More (-) TP

13. Triggered Activity
 Extra abnormal depolarisation
- Due to abnormal intracellular Ca2+ regulation
- During or immediately after phase 3
- After depolarisation may be categorized in to
- Early after depolarisation
- Delay after depolarisation

14. After depolarizations
EADs  prolonged APD
Clinical arrhythmia:
e.g., torsades de pointes
due to: long QT syndrome
genetic defects
DADs  HR or [Ca2+]i
Clinical arrhythmia:
e.g., Ca2+ overload
due to: digoxin or
PDE inhibitor toxicity

15. Conduction
block
Reentry
phenomenon
Accessory
tract pathway
Abnormal impulse
conduction

16. Conduction Block
 Due to depression of impulse conduction at AV node & bundle of
His, due to vagal influence or ischemia.
 Types :
 1st degree heart block – slowed conduction
 2nd degree block – some supraventricular complex not conducted
 3rd degree block – no supraventricular complex are conducted

17. Re-entry phenomenon
 Due to abnormality of conduction , an impulse may recirculate
in the heart and causes repetitive activation without the need
for any new impulse to be generated. These are called
reentrant arrythmias.
Circus movement type:
 A premature impulse temporarily blocked in one direction by
refractory tissue, makes a one-way transit around an obstacle
finds the original spot in an advanced state of recovery and
rexicites it, setting up recurrent activation of adjacent myocardium.

19. ACCESSORY TRACT
PATHWAY
Accessory
pathway in the
heart called
Bundle of Kent

20. IMPORTANT CARDIAC
ARRHYTHMIAS
– premature beats
 Due to abnormal automaticity or impulse arising from
ectopic focus.
– Sudden onset of AT 150-200/min
 Due to circus movement type of Re-entry or accessory
pathway
– 200-300 / min
 Due to re entry circuit in right atrium

21. ATRIAL FIBRILLATION
o 350-550/min
o Due to electrophysiological inhomogenesity
of atrial fibers.

22. – 4 or more consecutive ventricular extrasystoles
 Due to either discharge from ectopic focus or reentry
circuits
 Polymorphic VT with rapid asynchronous complex, twisting
along the baseline on ECG with long QT interval
 Grossly irregular, rapid & fractionated action of ventrcles –
resulting in incoordinated contraction of ventricles with loss of
pumping function.

23. POSSIBLE MECHANISMS OF ANTIARRHYTHMIC DRUGS
1. Suppressing the Automaticity
 ↓ Rate of phase 0
 ↓ Slope of phase 0
 Duration ERP ↑
 TP less negative
 Resting membrane potential more negative
2. Abolishing reentry
 Slow conduction
 ↑ ERP

24. Pharmacological
goals
 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

25. VAUGHAN-WILLIAMS CLASSIFICATION
CLASS MECHANISM
I Na+ channel blocker
II β blocker
III K+ channel blocker
IV Ca++ channel blocker

26. Anti arrythmic drugs
class mechanism action notes
I Na+ channel blocker
Change the slope of
phase 0
Can abolish
tachyarrhythmia
caused by reentry
circuit
II β blocker
↓heart rate and
conduction velocity
Can indirectly alter
K and Ca
conductance
III K+ channel blocker
1. ↑action potential
duration (APD) or
effective refractory
period (ERP).
2. Delay
repolarization.
Inhibit reentry
tachycardia
IV Ca++ channel blocker
Slowing the rate of rise
in phase 4 of SA node.
↓conduction velocity
in SA and AV node

27. Class I
IA IB IC
They ↓ automaticity in non-nodal
tissues (atria, ventricles, and purkinje
fibers)
They act on open Na+
channels or
inactivated only
Use dependence
Have moderate K+ channel
blockade

28. IA
Quinidine Procainamide Disopyramide Moricizine
 Slowing the rate of rise in phase 0
 They prolong action potential & ERP
 ↓ the slope of Phase 4 spontaneous depolarization
 ↑ QRS & QT interval

29. QUINIDINE
 Antimalarial, antipyretic, skeletal muscle relaxant and atropine like
action.
Mechanism of action
• Quinidine binds to open and inactivated sodium channels
and prevents sodium influx, slowing the rapid upstroke during
phase o.
• It also decreases the slope of phase 4 spontaneous
depolarization and inhibits potassium channels.

30.  Diarrhoea
 “Cinchonism” – tinnitus, vertigo,
headache, nausea & blurred vision.
200-400 mg orally tds
C/I
AV block
QT prolongation
- Torsades de pointes
Digoxin, enzyme
inducer
Myasthenia gravis
A/E

31. Uses
• Ventricular tachyarrythmias
• Used in the termination of ventricular tachycardia
Drug interactions
• Quinidine can interact the plasma concentration of digoxin,
which may in turn lead to signs and symptoms of digitalis
toxicity.
• Cimitidine increases hepatic metabolism of quinidine

32. PROCAINAMIDE
 Procaine derivative, quinidine like action
Mechanism of action
 Procainamide binds to open and inactivated Na+ channels and
prevents sodium influx, slowing the rapid upstroke during
phase 0
 Hypotension
 Hypersensitivity reaction
A/E

33.  Premature atrial contractions
 Paroxysmal atrial tachycardia
Dose:1-1.5g rate of 20-50mg/min
• Procainamide
hypersensitivity
• Bronchial asthma
• Cimitidine inhibits the
metabolism of procainamide
Uses
C/I Drug Interactions

34. DISOPYRAMIDE
Mechanism of
action
 Disopyramide produces a negative ionotropic effects
that is greater than weak effect exerted by quinidine and
procainamide, and unlike the latter drugs, disopyramide
causes peripheral vasoconstriction.
• Myocardial depression
• Urinary retention
• Constipation
A/E

35. • ventricular tachycardia
• AF & AFI
- CHF
Disopyramide
Uses
C/I
Drug Interactions
 In the presence of phenytoin, the metabolism of disopyramide
is increased and the accumulation of its metabolite is also
increased, there by increasing the probability of
anticholinergic properties.

36. A/E
 Nausea
 Dizziness
 A-V block
Uses
 Ventricular
tachycardia
C/I
 A-V block
 Drug
hypersensitivity
MORICIZINE
Drug
interactions
No significant
interactions
Mechanism of action
Moricizine reduces the maximal
upstroke of phase 0 and shortens
the cardiac transmembrane action
potential.
The phenomenon may explain
the efficacy of moricizine in
suppressing rapid ecotopic
activity.

37.  They shorten Phase 3 repolarization
 ↓ the duration of the cardiac action potential
 Prolong phase 4
IB
Lidocaine Mexiletine Phenytoin

38. LIDOCAINE
the duration of action potential decreases
 It shorten phase 3 repolarization and decreases the
duration of action potential
• Drowsiness
• Slurred speech
• Confusion and convulsions
• VA
• Digitalis toxicity
A/E
Uses
Mechanism of action

39. C/I
 Lidocaine is contraindicated
in the presence of second and
third degree heart block, since it
may increase the degree of block
and can abolish the
idioventricular Pacemaker
responsible for maintaining the
cardiac rhythm.
Drug interactions
• Proponolol increases its
toxicity.
• The myocardial depressant
effect of lidocaine is enhanced
by phenytoin administration.

40. PHENYTOIN
 Phenytoin was originally introduced for the control of
convulsive disorders but now also been shown to be
effective in the treatment of cardiac arrythmias.
Uses
 Anaesthesia
 Open heart surgery
 Digitalized induced and ventricular arrythmia in children

41. A/E C/I
 Respiratory arrest Severe bradycardia
 Hypotension Severe heart failure
AF & AFI
Drug Interactions
 Plasma phenytoin concentrations are increased in
the presence of chloramphenicol, disulfiram, and
isoniazid, since the later drugs inhibit the hepatic
metabolism of phenytoin

42. MEXELETINE
Mechanism of action
 It is a local anaesthatic and an active antiarrythmic by the
oral route; chemically and pharmacologically similar to lidocaine.
 It reduces automaticity in PF, both by decreasing phase 4 slow
and by increasing threshold voltage.
 By reducing the rate of 0 phase depolarization in ischemic
PF it may convert one-way block to two-way block.

43. A/E C/I
 Tremor
 Hypotension
 Bradycardia
• Cardiogenic shock
• Second or third-degree
heart block
Uses Drug Interactions
• VA
• Congenital long
QT syndrome
• When mexiletine is administered with phenytoin
or rifampin, since these drugs stimulate the hepatic
metabolism of mexiletine, reducing its plasma
concentration.

44. IC
flecainide Encainide Propafenone moricizine
 markedly slow Phase 0 depolarization
 slow conduction in the myocardial tissue
 minor effects on the duration of action potential
and ERP
 reduce automaticity by increasing threshold potential
rather than decreasing slope of Phase 4 depolarization.

45. FLECAINIDE &
ENCAINIDE
Mechanism of action
 Flecainide suppresses phase 0 upstroke in purkinje
and myocardial fibers.
 This causes marked slowing of conduction in all cardiac
tissues, with a minor effect on the duration of the action
potential and refractoriness.
 Automaticity is reduced by an increase in the threshold
potential rather than a decrease in the slope of phase
4 depolarization

46.  Proarrhythmogenic efffect on
patients with coronary artery
disease
 Use- ventricular arrhythmia
 A/E – torsades de point, visual
disturbances & headache
 Digoxin toxicity
 C/I- cardiogenic shock

47. PROPAFENONE
 Structural similarities with
propranolol
 C/I – Heart failure
 A/E – proarrhythmogenic effect,
metallic taste & constipation
 150-200mg at 8 hourly
 Uses – VT & supra ventricular
arrhythmias.

48. MORICIZINE
 Has all three subclass properties
 Less proarrhythmogenic effect
 Used in ventricular arrhythmias
 200-400mg orally at 8hourly

49. CLASS II DRUGS – PROPRANOLOL,
METOPROLOL, ESMOLOL, ACEBUTOLOL
Depress phase 4 depolarization
depress automaticity
prolong AV conduction
↑ ERP
Prolong PR interval
 HR
 contractility

50. Hypoglycemia
(infants)
Asthma
Branchospasm
C/I
Asthma
Bradycardia
Severe CHF
PROPANOLOL
Mechanism of action
 Propanolol decreases the slope of
phase 4 depolarization and
other ectopic foci.
Prolong the ERP of A-V node.
Uses
 AF
Digitalis-induced arrythmias
A/E

51.  Acebutolol is a cardioselective
β1-adrenoreceptor blocking agent
that also has some minor membrane
stabilizing effect on the action
potential.
Mechanism of action
 Acebutolol reduces blood pressure in
patients with essential hypotension
primarily through its negative
ionotropic and chronotropic effects.
Acebutolol
A/E
Bradycardia
GI upset
Uses
• VA
• Angina pectoris
C/I
Cardiogenic shock
Severe bradycardia
ACEBUTOLOL

52. ESOMOLOL
 Esomolol is a short-acting i.v administered β1-selective
adrenoreceptor blocking agent.
 It doesn’t posses membrane-stabilizing activity.
A/E
 Hypotension
 Nausea
 Headache
 Dyspnea
Uses
 Supraventricular
tachyarrythmias
C/I
 Asthma
 Sinus bradycardia
 A-V block
 Severe CHF

53. USES
Sympathetically mediated
arrhythmia Sinus tachycardia
Supraventricular arrhythmia –
AF / PSVT
Ventricular arrhythmia – QT

54. • K+ channel blockers
• AP / ERP without affecting
phase 0 / 4
• Prolong QT & PR
Class III
Amiodarone Bretylium Sotalol

55. Amiodarone
Iodine –
containing
Block K+ Na+ ,
Ca++ & β
HR & AV
nodal
conduction
 Arrhythmic
death in post MI
Uses =VF, VT
& AF
QT prolongation
LD-150mg slow
IV
MD-1mg/min
for 6hrs
A/E – heart block,
pulmonary,
hepatitis, dermatitis,
corneal deposits &
thyroidism
Interaction –
digoxin,
diltiazem &
quinidine

56. Bretylium
Antihypertensive
Uses-VF & VT
C/I – digitalis
induced, shock
A/E – postural
hypotension

57. Sotalol Like – Amiodarone
 Non cardioselective blocker
 Has both class II & class III
actions
 Oral dose 80mg twice daily
 Proarrhythmic effect
 C/I - hypokalaemia
 Arrhythmic
death in post MI
Uses =VF, VT &
AF
A/E= fatigue,
Headache, chest
pain
Drug interactions
Drug with inherent
QT-Interval prolonging activity may
enhance the class 3 effects of sotalol.

58. NEWER CLASS III
Dronedarone
Vernakalant
Azimilide
Tedisamil
Without iodine, short t1/2, AF
Oral 400mg twice daily
Na+ & K+, atrial ERP, AF
Block both rapid & slow k+ channel

59. Verapamil Diltiazem
Mechanism
Class IV
• Block L-type calcium channels.
•  Rate of phase 4 in SA / AV node
• Slow conduction – prolong ERP
• Phase 0 upstroke 

61. Verapamil
 Stronger action on heart than smooth muscle
 Used in supraventricular arrhythmia
 80-120mg three times a day
 A/E – ankle oedema, constipation
 C/I – AV block, LVF, hypotention & WPW
 It  digoxin toxicity
Diltiazem
 Mixed action
 Oral dose 30-90mg 6hourly

62. WHICH OTHER DRUGS……
Adenosine
Naturally occurring nucleoside
Adenosine receptors – open GP-K+ & inhibits nodal conduction
Used in Reentry circuit, PSVTs & SVT
Ultra short t1/2 (10-20 sec)
A/E – facial flushing, short breath, bronchospasm, metallic taste
Dipyridamole  it’s action
3mg IV bolus

63. Magnesium
Na+/K+ATPase, Na+, K+ & Ca++
VT, digitalis-induced & torsades de point
Potassium
Normal –  conduction,  ERP &  automaticity
Hypokalaemia – EAD & DAD

64. ARRHYTHMIAS ACUTE THERAPY CHRONIC THERAPY
FIRST CHOICE ALTERNATIVES FIRST CHOICE ALTERNATIVES
1 AF/AFL ESMOLOL VERAPAMILE DIGOXIN
PROPRANOLOL
2 PSVT ADENOSINE ESMOLOL
DILTIZEM
VERAPAMIL
DIGOXIN
VERAPAMILE
PROPRANOLOL
PROPAFENONE
3 VT LIDOCAINE
CARDIOVERSION
PROCAINAMIDE
MEXILETINE
AMIODARONE
AMIODARONE
DOFETILIDE
MEXILETINE
PROPRANOLOL
PROPAFENONE
4 TORSADES DE
POINT
PACING ISOPRENALINE
MAGNESIUM
PROPRANOLOL PACING
5 VF ELECTRICAL
DEFIBRILLATION
LIDOCAINE
AMIODARONE
AMIODARONE PROCAINAMIDE
DOFETILIDE
6 WPW CARDIOVERSION AMIODARONE
PROPAFENONE
PROCAINAMIDE
AMIODARONE
PROPRANOLOL
QUINIDINE
PROPAFENONE

65. Drugs that prolong QT interval
Antiarrhythimcs Quinidine
Procainamide
Disopyramide
Propafenone
Amiodarone
Antimicrobials Quinine
Mefloquine
Artemisinin
Sparfloxacin &
gatifloxacin
Antihistaminics Terfenadine
Astemizole
Ebastine
Antidepressants Amitryptylline
Antipsychotics Thioridazine
Risperidone
Prokinetics Cisapride

66. REFERENCES
o Lippincotts,Pharmacology-IV Edition,Pg.no:196-207
o P.N.Bennet,M.J.Brown,Clinical Pharmacology-IX Edition,Pg no:497-519
o K .D. Tripathi,Essentials Of Medical Pharmacology, Pg.no:508-520
oRang/ dale,Pharmacology, V Edition , Pg no:277-280
o Charles R.Ciaig,Robert E. Stitzel,Modern Pharmacology With Clinical
Applications

67. ACKNOWLEDGEMENT
 I thank principal sir Dr. P. Srinivasa Babu for giving me this
opportunity.
 I Also thankful to my guide Mrs.B.DEEPTI M.Pharm(Ph.D)
for her constant guidance.