Anti-Arrhythmic agents in context to Medicinal Chemistry.

1. ANTI-
ARRHYTHMIC
AGENTS
PRESENTED TO
Dr. Riyaz
04/03/2023
PRESENTED BY
Tooba Mushtaq Dedmari
M.PHARM 1st Year
University Of Kashmir

2. Things
to discuss
Key takeaways:
Introduction
Classification
Synthesis
Mechanism of action
Properties
TOOBA DEDMARI-M.PHARM

3. CARDIAC
ARRHYTHMIA
Abnormality in the rate, regularity or site of
origin of the cardiac impulse or a
disturbance in conduction of impulse such
that the normal sequence of activation of
atria and ventricles are altered.
TOOBA DEDMARI-.M.Pharm
Cardiac arrhythmias are frequent problems in clinical
practice, occuring in upto 25%of patients treated with
digitalis,50%of anaesthetised patients, and over 8% of
patients with acute myocardial infarction.

4. BRADYCARDIA Tachycardia
Types Of
Arrhythmias
Sinus rates are below normal
range.
Sinus rates are above normal
range.
The normal sinus rhythm is
between 60-100beats per
minute.
Atrio-ventricular block
Extra systole
Paroxysmal supraventricular tachycardia
Atrial Flutter
Atrial Fibrillation
Ventricular Tachycardia
Torsades De-pointes
Ventricular Fibrillation

5. CAUSES OF
ARRHYTHMIA
Occurs when the SA node fails
to function normally,when other
pacemaker sites(eg. ectopic
pacemaker) trigger
depolarisation.
DISTURBANCES IN
IMPULSE FORMATION /
DISTURBANCES IN
IMPULSE CONDUCTION
OR BOTH
TOOBA DEDMARI-M.PHARM
01 02 03
Abnormal automaticity Abnormal Re-entry

6. ANTI-
ARRHYTHMIC
AGENTS
Antiarrhythmic drugs are those
that act upon the electrical
conduction system of the heart
in an attempt to maintain sinus
rhythm.
Anti-arrhythmic agents can modify impulse
generation and conduction or suppress abnormal
rhythms of the heart.

7. DIGOXIN

8. TOOBA DEDMARI-M.PHARM
CLASS 1: Blockade of fast sodium ion
channels by depressing phase of action
potential
1a. Moderate to marked sodium
channel blockade agents.
Disop

9. TOOBA DEDMARI-M.PHARM
1b.Mild to moderate
sodium channel
blockade agents
1c. Marked sodium
channel blockade
agents
P
Lid

10. TOOBA DEDMARI-M.PHARM

11. TOOBA DEDMARI-M.PHARM
Class 2:Beta
Adrenergic Antagonists
Class 3: Repolarisation
prolongators
Class4:Ca Channel blockers

12. DRUG PROFILE
AND
SYNTHESIS
The class I antiarrhythmic agents
interfere with the activity of Na+
channels. Thus, all of these drugs
can decrease the slope of phase 0
(Vmax). More frequently the
sodium channels open, greater will
be the blockade by these drugs
(use dependent blockade). These
agents block the specific channels
and decrease the threshold for
excitability. It decreases the
conduction velocity in fast
response tissues and increases
QRS duration.
These are further classified
according to action of these drugs
on K+ channels.
CLASS 1
CLASS 1A:
PROCAINAMIDE HCL(Pronestyl)
MOA: Apart from its action on sodium channels (block Na+ channel in open state), these drugs also block
cardiac K+ channels (thus delaying repolarisation resulting in prolonged action potential duration). Due to
prolongation of APD, these drugs can precipitate torsades de’pointes (prolonged QT interval). Agents in this
class also cause decreased conductivity and increased refractoriness. These drugs dissociate from the
sodium channels with intermediate kinetics. Time of recovery of sodium channels (τ) is 1-10 ms. Quinidine,
procainamide, and disopyramide are the important members of Class Ia.
:
Dose: The usual dose is 3 to 6 g orally at intervals of 6 to 8 h.
Dosage forms: Procainamide injection B.P., Procainamide tablets B.P.,
Procainamide HCl injection I.P.,
Procainamide HCl tablets I.P.

13. PROPERTIES
White crystalline powder
Odourless
Soluble in water, alcohol,
slightly soluble in chloroform,
very slightly soluble in ether.
More stable in water than
procaine.
It was developed in the course
of research for compounds
structurally similar to procaine.
SYNTHESIS:

14. CLASS1B:
MOA: Class Ib antiarrhythmic
agents (lignocaine, mexiletine,
tocainide and phenytoin) are
sodium channel blockers that
possess K+ channel opening
property. Class Ib agents have fast
onset and offset kinetics (τ < 1s),
meaning that they have little or no
effect at slower heart rates, and
more effects at faster heart rates.
These agents shorten the APD and
reduce refractoriness (because of
the opening of K+ channels). These
agents will decrease Vmax in
partially depolariSed cells with fast
response action potential. They
either do not change or decrease
the APD in non-depolarized tissues.
These drugs are used only for
ventricular arrhythmia.
MEXILETINE HCL:

15. PROPERTIES
White crystalline.
Soluble in water and alcohol.
It resembles lidocaine as it
possesses a xylyl moiety, but is
otherwise different chemically.
Most useful in suppressing
symptomatic ventricular
arrhythmias.
SYNTHESIS

16. CLASS 1C:
MOA: These agents have the most
potent sodium channel blocking
effects with negligible effect on K+
channels (therefore no effect on
APD). These have slow kinetics (τ >
10s). These drugs have maximum
pro- arrhythmic property,
therefore indicated only for the
resistant and life-threatening
ventricular tachycardia or
ventricular fibrillation and for the
treatment of refractory
supraventricular tachycardia.
Flecainide can be used for acute
treatment of Wolff Parkinson
White (WPW) syndrome.
[Treatment of choice for WPW
syndrome is radiofrequency
ablation of the aberrant pathway].
FLECAINIDE (Tambocar)
Dose: The usual dose is orally, 100 mg twice daily with an average
daily maintenance doses from 200 to
600 mg.
Dosage forms: Flecainide injection B.P., Flecainide tablets B.P.

17. PROPERTIES
White or almost white
crystalline powder.
very hygroscopic
soluble in water and in ethanol,
insoluble in dilute hydrochloric
acid and soluble in dilute acetic
acid.
Flecainide represents the first
fluorine containing newer
group of antiarrhythmic drugs.
It is indicated for use in
patients with life threatening
arrhythmias, such as sustained
ventricular tachycardia.
SYNTHESIS:

18. CLASS 2:
Class II agents are conventional beta
blockers. They act by blocking the effects of
adrenaline and nor-adrenaline at the β1
receptors, thereby decreasing the
sympathetic activity on the heart. These
agents are particularly useful in the treatment
of supraventricular tachycardia. These drugs
decrease the slope of phase 4 (responsible for
automaticity) and conduction through the AV
node. Dimensions of the ventricle and oxygen
consumption are decreased, and thereby
decreases the heart rate and aortic pressure.
Esmolol is the shortest acting beta blocker. It
can be used i.v. for the emergency control of
ventricular rate in atrial fibrillation or flutter.
ESMOLOL HCL (Cardesmo):
DOSE:A loading dose of 500 μg/kg/min is infused over 1 minute
followed by a maintenance dose of 50 μg/kg/min.

19. PROPERTIES
It is available as white crystals
It is used in the treatment of
supraventricular tachycardia.
SYNTHESIS

20. CLASS 3:
Class III agents predominantly block the
potassium channels, thereby prolonging
repolarization (prolongation of APD).
These drugs may precipitate torsades
de’pointes due to prolongation of QT
interval.
These drugs exhibit reverse use
dependent prolongation of the action
potential duration (Reverse use-
dependence). This means that the
refractoriness increases at lower heart
rates, therefore these are more
efficacious at preventing a
tachyarrhythmia than treating it. Because
of this property class III antiarrhythmic
agents may paradoxically be more
arrhythmogenic at low heart rates.
REPOLARISATION PROLONGERS AMIODARONE (Cardarone,Aldarone)
DOSE:The usual dose is 400 mg alternating with 600 mg daily for 1 to 3
weeks orally.
Dosage forms: Amiodarone intravenous infusion B.P., Amiodarone tablets
B.P.
(2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl) diethylamine

21. PROPERTIES
It is a white crystalline powder
Exhibits polymorphism.
Freely soluble in water, in
ethanol, and in methanol.
It is used as antiadrenergic,
antiarrythmic, and
antihypertensive agent.
SYNTHESIS:

22. CLASS 4:
TOOBA DEDMARI-M.PHARM
These drugs selectively block the slow inward current
carried by calcium. Administration of a
class IV drug causes a prolongation of the refractory
period in the AV
node and the atria, a decrease in AV conduction, and a
decrease in
spontaneous diastolic depolarization. These effects
block conduction of
premature impulses at the AV node and, thus, are very
effective in
treating supraventricular arrhythmias.
VERAPAMIL
PHENYL-ALKYL AMINES (VERAPAMIL),
BENZOTHIAZEPINES (DILTIAZEM)
2-(3,4-Dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-
(methyl)amino}-2-prop-2-ylpentanenitrile

23. PROPERTIES
It is a white crystalline powder
Soluble in water, freely soluble
in methanol, and spar- ingly
soluble in alcohol.
It is used in the treatment of
angina pectoris, arrhythmias
from ischaemic myocardial
syndromes, and
supraventricular arrhythmias.
SYNTHESIS (CONTD.)

24. TYPES OF ARRHYTHMIA DRUGS FOR Acute therapy
DRUGS FOR CHRONIC
THERAPY
REMARKS
F/AFL
Propanolol
Esmolol
Ibutilide Digoxin Amiodarone
Verapamil
Only ibutilide is indicated for conversion
to sinus rhythm, other drugs control
ventricular rate only
PSVT Adenosine
Verapamil Sotalol Propanolol
Amiodarone
Ventricular tachycardia
Lignocaine
Magnesium
Sotalol Amiodarone
Quinidine
Ventricular fibrillation
Lignocaine
Bretylium
Amiodarone Cardioversion is the treatment of choice
WPW syndrome Flecainide
Propanolol
Amiodarone
Laser ablation of aberrant pathway is
definitive treatment
Torsades de’ pointes
Magnesium (for both
congenital and acquired)
Propanolol (only congenital) Amiodarone should not be used
Digitalis induced ventricular
arrhythmia
Lignocaine
Phenytoin
Propanolol
For bradyarrhythmias atropine can be
used.
DRUG TREATMENT OF ARRHYTHMIAS