FOR medical student to understand how important drugs acting in arrhythmia.

1. PHARMACOTHERAPY
OF ARRHYTHMIA
PRESENTER – DR. RAHUL VAISH
JNMC BELGAUM

2. Introduction
▪ Arrhythmia is by definition a perturbation of the normal sequence of
impulse initiation and propagation.
• Irregularity in Cardiac Rhythm
• Bradyarrhythmia: Failure of impulse generation resulting in slow
heart rates.
• Tachyarrhythmias: Abnormally rapid heart rhythms
• Heart Block: Results from failure of impulse to propagate normally
from atrium to ventricle – usually defect in AV node or His-Purkinje
system 2

3. Impulse generation and transmission
3

4. Action potential in Nonautomatic
Fibres & Automatic fibers
4

5. 5

6. Mechanism of Arrhythmia
▪ Normal heart rate – 60 -100 bpm
▪ Causes-
▪ 1. Defect in impulse generation (SA node is defective- sick
sinus syndrome) Doc – Atropine
▪ 2. Defect in impulse propagation of conduction ( AV node
block , bundle branch block ) - Atropine
<60/min
Bradyarrhyth
mia
>100/min
Tachyarrhyth
mia
6

7. Mechanism of Arrhythmia
▪ >100/min
▪ Tachyarrhythmia
7

8. Mechanisms of cardiac Arrhythmias
▪ Enhanced/ectopic pacemaker activity –
• Enhanced automaticity may occur in cells that normally
display spontaneous diastolic depolarization in sinus and
AV nodes and His Purkinje system.
• β Adrenergic stimulation, hypokalemia, and mechanical
stretch of cardiac muscle cells increase phase 4 slope and
accelerate pacemaker rate.
• acetylcholine reduces pacemaker rate both by decreasing
phase 4 slope and by hyperpolarization.
8

9. Triggered Activity
• A normal AP interrupted/followed by a abnormal depolarization (a triggering rhythm)
• Delayed After Depolarization: Caused by Digoxin toxicity, Myocardial
Ischaemia or Adrenergic stress or Heart failure – due to Ca++ overload
• Early After Depolarization: Due to interruption in phase 3 repolarization
result from depression of delayed rectifier K+ current.
• Causes: Slow heart rate, Hypokalaemia and drugs prolonging QT interval
– quinidine, sotalol, procainamide etc. (block IK channel)
• Torsades de pointes: due to marked prolongation of APD – polymorphic
ventricular tachycardia – long QT interval and frequent changing of QRS
9

10. 10

11. Drugs that prolong Q-T interval (have potential
to precipitate Torsades de pointes)
11

12. Re-entry
 Reentry occurs when a cardiac impulse travels in a path
such as to return to its original site and reactivate the
original site, thus perpetuating rapid reactivation
independent of normal sinus node function.
 Anatomically Defined Re-entry
 Example of reentry is the WPW syndrome in which
patients have an accessory connection between the atrium
and ventricle .
 With each sinus node depolarization, impulses can excite
the ventricle via the normal structures (AV node) or the
accessory pathway, and this often results in an unusual and
characteristic QRS complex in normal sinus rhythm.
12

13. Functionally Defined Re-entry
▪ In this type of reentry there is no fixed ‘obstacle' or
'pathway’.
▪ A functional obstacle (core of the circuit) and
unidirectional conduction pathway is created by a
premature impulse which travels through ectro-
physiologically in homogeneous myocardium.
▪ Functional re-entry may be responsible for ventricular
extrasystoles, polymorphic ventricular tachycardia.
atrial/ventricular fibrillation.
13

14. TYPES OF ARRHYTHMIAS
• Extrasystole: premature beats due to abnormal automaticity/after
depolarization – AES, VES or AV nodal ES
• Paroxysmal Supraventricular Tachycardia (PSVT): Sudden onset
of atrial tachycardia 150-200/minute (1:1), re-entry phenomenon (AV node)
• Atrial Flutter: 200-350/minute (2:1 to 4:1 AV block), re-entrant circuit in right
atrium.
• Atrial Fibrillation: Asynchronous activation of atrial fibres 350 -550/min with
irregular 100 to 160 ventricular beats – due to electrophysiological in homogeneity of
atrial muscles influence or ischaemia .
14

15. • Ventricular tachycardia: 4 or more consecutive extrasystole of
ventricles – monomorphic or polymorphic
• Ventricular Fibrillation: rapid irregular contractions – fatal (MI)
• Torsades de pointes: polymorphic ventricular tachycardia, rapid
asynchronous complexes, rise and fall in baseline of ECG
• Atrio-ventricular Block (A-V Block): is due to depression of impulse
conduction through the A-V node and bundle of His, mostly due to vagal
influence or ischemia.
15

16. Vaughan Williams and Singh CLASSIFICATION
16

17. CLASS I
▪ The primary action of drugs in this class is to limit the conductance of Na+ (and K+) across
cell membrane. They mainly affect phase 0.
▪ They also reduce rate of phase-4 depolarization in automatic cells.
▪ Class I antiarrhythmics: are further classified to
▪ Ia, Ib and Ic – based on repolarization and potency of Na+ blockade – state dependent
manner
▪ Na+ blockade:Ic>1a>1b
▪ ERP:1a>1c>1b
17

18. CLASS I
18
Ia Ib Ic
1 – 10 SEC <1 sec >10 sec
Intermediate acting Rapid acting Slowest acting
It blocks open state Na channel It blocks inactive state Na
channel but do not delay
channel recovery
It blocks both
It also block K+ channel They open K+ channel Negligible effect
ERP AND APD No prolongation ERP AND
APD
Variable effect on APD except
propafenone
PROLONG QT interval on Ecg
Prolong PR, QRS,
No prolongation Qt interval markedly prolong PR and QRS
complex

19. Ia Ib Ic
Useful in conditions
where Na+ channel
open frequently
–ectopic beats
–atrial tachycardia
atrial fibrillation
Ventricular
arrhythmia
Used in Treatment and
prevention of Ventricular
tachycardia and fibrillation
after Myocardial Infarction
– lignocaine IV
Used in life threatening
ventricular fibrillation
since they have highest
affinity to Na+ channels
involving AV node - WPW
syndrome and Paroxysmal
atrial fibrillation
Lengthen action potential,
slow rate of rise of phase 0
• Shorten action
potential, Limited effect
on rate of rise of phase
0.
No effect on length of
action potential,
Markedly
reduces rate of rise of
phase 0 and-marked
delay in AV conduction.19

20. Quinidine
▪ 1st Antiarrhythmic drug
▪ Dextro-isomer of Quinine: Na+ channel blocking and anti vagal action.
• Inhibition of Na+ channel – slanted 0 phase and Decreases phase 4
• Prolongation of APD – due to K+ channel block
• Increase in ERP – due to delay in Na+ and K+ channel recovery
• Net result is delay in conductivity and increase in refractoriness
• Fall in BP – direct cardiac depression
• Other actions include – alpha blockade, decreased skeletal muscle contractility, uterine
contraction .
 Adverse effects: Not used now for adverse effects like Proarrhythmic (torsades de pointes),
sudden cardiac arrest or VF, cinchonism, angioedema, vascular collapse etc. 20

21. Lidocaine (Lignocaine)
▪ It is a popular antiarrhythmic in intensive care units.
▪ Enhanced phase-4 depolarization in partially depolarized or stretched PFs, and
after-depolarizations are antagonized, but SA node automaticity is not depressed.
– Practically no effect on APD and ERP of Atrial fibers
– Rate of 0 phase in AVN and ventricles – not affected
– Reduction in APD in PF and ventricular myocardium
– Suppression of automaticity in ectopic foci (reentry) – one way or two way
block
– Little effects on cardiac contractility and arterial BP 21

22. ▪ Pharmacokinetics
▪ Inactive orally due to high first pass metabolism in liver.
▪ Metabolism of lidocaine is hepatic blood flow dependent.
▪ Its t½ is prolonged in CHF, because of decrease in volume of distribution and hepatic
blood flow.
• Adverse effects: Neurological – drowsiness, paraesthesia, blurred vision,
nystagmus and fits etc.
No proarrhythmic effects – no cardiotoxicity
• Uses: 50-100 mg bolus and 10-20 mg every 20 minutes
– Arrhythmia following acute MI and cardiac surgery to prevention of ventricular
tachycardia and prevent VF
– Digitalis toxicity – Dose not worsen AV block 22

23. ▪ In two multicentric trials ‘Cardiac Arrhythmia Suppression Trial I and
II’ (CAST I, II,) showed that post-MI patients randomized to receive
on a long-term basis encainide, flecainide, moricizine had higher
incidence of sudden death.
▪ Similar increased mortality has been reported by the “Mortality in the
survival with D-sotalol (SWORD) trial.
▪ Only the β blockers and amiodarone have been found to decrease
cardiac mortality in the long term.
23

24. CLASS II
• Drugs used are beta-blockers: Propranolol, Esmolol
• It suppress adrenergically mediated activity
• Propranolol - Membrane stabilizing effect like quinidine on heart at high doses
however Clinical doses (antiarrhythmic effect) - Block beta-1 receptor in heart
and decreases heart rate
• It decrease the slope of phase 4 depolarization and automaticity in SA
node, AVN and other ectopic foci (Adrenaline causes ventricular ES and
fibrillation by increasing the phase 4 depolarization.)
▪ Prolongation of ERP of AVN – impede AV conduction so no paradoxical
tachycardia. 24

25. Uses of Propranolol
• Arrhythmias associated with increased sympathetic activity – sinus
tachycardia, atrial extrasystoles provoked by emotion and exercise
• Less effective in PSVT than adenosine and verapamil
• Propranolol is used to treat sympathetically mediated arrhythmias
pheochromocytoma and halothane anaesthesia
▪ Sinus tachycardia, atrial and nodal extrasystole provoked by exercise
▪ Does not abolish AF or AFI but decreases ventricular rate
• Reduce mortality after MI – anti-ischaemic action
• Esmolol IV – quickly terminates AF and flutter and used in emergency
control of arrhythmia due to anaesthetics.
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26. CLASS III
▪ Class III drugs K+ channel blockers prolong repolarization (increase refractoriness)
by blocking outward potassium conductance.
▪ AP is widened and ERP is increased.
▪ Amiodarone- It have unusual iodine containing highly lipophilic long-acting
antiarrhythmic drug exerts multiple actions:
1. Block delayed rectifier K+ channel – prolongs APD and QT interval
2. Preferentially blocks inactivated Na+ channels (like lidocaine)– depresses
conduction in cells that are partially depolarized and longer APD
3. Partially inhibits myocardial Ca2+ channels, has noncompetitive β adrenergic
blocking property and alters thyroid function
Overall – Slowed conduction and supressed ectopic automaticity 26

27. ▪ Uses:
• Most tachyarrhythmia conditions – ventricular and supraventricular including PSVT
• Resistant VT and recurrent VF
• WPW syndrome
▪ Adverse effects:
• Photosensitization – skin pigmentation
• Peripheral neuropathy – weak shoulder and pelvic muscles
• Myocardial depression – bradycardia
• Pulmonary alveolitis and fibrosis – kept below 200 mg
• Corneal micro deposits – on long term use ,reversible on discontinuation
• Hypothyroidism, goitre – inhibition of T4 to T3
▪ Drug Interactions: Digoxin and warfarin (reduced renal clearance 27

28. ▪ On the basis of two clinical trials PALLAS and ATHENA,
the US-FDA in Dec 2011 issued a safety alert that
dronedarone should not be used in AF patients who cannot
and will not be converted to sinus rhythm (permanent AF),
because it doubles the rate of stroke, heart failure and
cardiovascular death in such patients.
28

29. CLASS IV
▪ The primary action of this class of drugs is to inhibit Ca2+ mediated slow
channel inward current.
▪ Verapamil
• Relatively selective AV nodal L-type calcium channel blockers – depression
of Ca++ mediated depolarization and delay recovery
• Phase-4 depolarization in SA node is reduced resulting in bradycardia
▪ Delayed after-depolarizations in PFs are dampened.
▪ Prolongation of A-V nodal ERP as result A-V conduction is markedly slowed
(P-R interval increases) and reentry involving A-V node is terminated.
▪ Verapamil has negative inotropic action 29

30. • Uses:
1. PSVT:
• For termination of attack – 5 mg IV over 2-3 minutes
(Risk of bradycardia, AV block, cardiac arrest and
hypotension)
• For prevention of attack 60-120 mg orally tds
2. Reduce ventricular rate in Atrial fibrillation (AF) and Atrial
flutter
3. Reentrant supraventricular and nodal arrhythmias are
susceptible to verapamil, but it is contraindicated in broad
QRS complex WPW tachycardia.
30

31. ADENOSINE
▪ It activates Ach sensitive K+ channels and causes membrane hyperpolarization
through interaction with A1 type of adenosine GPCRs on SA node .
▪ It indirectly reduces Ca2+ current in A-V node -depression of reentry in PSVT
▪ shortening of action potential in atrium and reduced excitability
▪ Adenosine has a very short t½ in blood (~10 sec) due to uptake into RBCs and
endothelial cells where it is converted to 5-AMP and inosine.
▪ ADR: chest tightness, dyspnea, fall in BP and flushing etc.
▪ Bronchospasm may be precipitated in asthmatics; verapamil is the drug of choice
for such patients.
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35. Anti-Arrhythmic SCREENING METHODS
• Aconitine Antagonism in Rats
• Digoxin-Induced Ventricular Arrhythmias in Anesthetized Guinea Pigs
• Strophanthin or Ouabain Induced Arrhythmia
• Ventricular Fibrillation Electrical Threshold
• Coronary Artery Ligation, Reperfusion Arrhythmia and Infarct Size in Rats
• Characterization of Anti-Arrhythmic Activity in the Isolated Right Ventricular
Guinea Pig Papillary Muscle
• Action Potential and Refractory Period in Isolated Left Ventricular Guinea Pig
Papillary Muscle 35

36. REFERANCE
Goodman and Gilman’s The pharmacological basis of
therapeutics; Laurence N Brunton 13th edition.
Essentials of Medical Pharmacology by KD Tripathi 8th edition.
Harrison’s Principal of Internal Medicine 20th edition.
Drug Discovery and Evaluation Pharmacological Assays Vogel
3rd Ed.
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37. Thank You
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