Antiarrytmic Drug New 3.pdf


The term arrythmia comes from the Greek
a- loss and rhthmos-rythm= loss of
rhythm.
A condition in which the heart beats with
an irregular or abnormal rhythm. Cardiac
arrythmia occur when electrical impulses
in the heart donot work properly. The
heart beat may be too slow or too rapid.
Dr. Anshu Chaudhary Dudhe 2
Arrythmia


Cardiac arrhythmia may occur due to
alteration in impulse generation or
abnormal automaticity (The ability to
spontaneous depolarize and generate
an action potential) and disturbance in
impulse conduction. A combination of
both these factors.


The rhythm of the heart normally is
determined by pacemaker called the SA
node. Which contain specialized cell that
under go spontaneous generation of
action potential at a rate of 60 to 100 action
potent (beasts)/min. The rhythm is
controlled by vagus nerve.
4


. The sinus rhythm normally controls
both atrial and ventricular rhythm.
Sinus rate below this range are termed
sinus bradycardia and sinus rate above
this range are termed “ Sinus
tachycardia”




Action potentials generated by the
SA node spread throughout the
atria, depolarizing this tissue and
causing atrial contraction. The
impulse then travels into ventricle
and cause ventricular contraction.


SA node→ AV node→ His-Purkinje
System →VENTRICLES
Trans membrane potential of cardiac cells
is determined by the concentrations of the
following ions: Sodium, Potassium ,
Calcium
The movement of these ions produces
currents that form the basis of the cardiac
action potential
ELECTRO-PHYSIOLOGY OF NORMAL
CARDIAC RHYTHM-




Effective refractory period (ERP)
It is also called absolute refractory period (ARP) :
•In this period the cell can’t be excited
•Takes place between phase 0 and 3


 The phases of cardiac action potential correspond to
the ECG.
 P wave reflect atrial depolarization (Phase 0)
 PR interval reflect the conduction velocity through
the AV node.
 The QRS complex reflect ventricular depolarization
(phase 0 in ventricular Action potential ( Non
pacemaker Action potential).
 T wave reflect ventricular repolarization.
 QT interval reflect the Action potential duration.
Corelation between cardiac action
potential and Electrocardiogram




 Palpitation
 Fatigue
 Breathlessness
 Heart failure
 Dizziness
 Chest discomfort
Features of Arrythmia


 Arrythmia occur due to
 Abnormality in impulse generation
 Abnormality in Impulse conduction
 Both
Mechanism of
Arrythmiogenesis




 Enhanced/Ectopic pacemaker activity- The
slope of phase-4 depolarization may be
increased pathologically in the automatic
fibres
Some of the more common arrhythmias are
termed as “ectopic” which occur when
electrical signal spontaneously arise in
regions other than the pacemaker and then
complete with normal impulses
Abnormal Generation of
impulses


B. After-depolarizations: These are
secondary depolarization accompanying a
normal or premature action potential.
Early after depolarization (EAD):
Repolarization during phase-3 is
interrupted and membrane potential
oscillates. If the amplitude is sufficient
large, adjacent tissue is activated and one
more extra impulses are propagated.


Delayed after-depolarization
(DAD): When attaining resting
membrane potential (RMP) a
secondary deflection occurs during
phase-4 and by that reach
threshold potential and initiate a
single premature AP.


Re-entry: It occur due to
abnormality of conduction, an
impulse may recirculate in the
heart and cause repetitive
activation without the need for any
new impulse to be generated.


Circus movement re-entry: It is happening in
an anatomically defined circuit. The
premature impulse, temporarily blocked in
one direction by refractory tissue, makes a
one-way direction. This type of re-entry is
often responsible for PSVT, atrial flutter and
atrioventricular reciprocal rhythm in WPW.




Microentry circuit in
ventricle




 Atrio-ventricular (A-V) block is Atrioventricular
block is a type of heart block that occurs when the
electrical signal traveling from the atria, or the upper
chambers of the heart, to ventricles, or the lower
chambers of the heart, is impaired.
 First degree A-V block: Slowed conduction resulting
in prolonged P-R interval.


Second degree :Second-degree AV
block occurs when the electrical
signal between the atria and
ventricles is even more impaired
than in a first-degree AV block.


Third degreeA -V block:Third-degree
AV block occurs when the signal
between the atria and ventricles is
completely blocked, and there is no
communication between the two. None
of the signals from the upper chambers
make it to the lower chamber.


Types of cardiac arrhythmias
100-150 Simple Tachycardia
60-100 Normal Heart beat
150-250 PSVT
250-350 ( Atrial and
Ventricular Flutter)
40-60 Mild Bradyarrhythmia
20-40 Moderate
Bradyarrhythmia
0-20 Mild Bradyarrhythmia
350-550 ( Atrial and
Ventricular Fibrillation)


Trsades de pointes: Torsades de pointes is a
specific form of polymorphic ventricular
tachycardia in patients with a long QT
interval. It is characterized by rapid, irregular
QRS complexes, which appear to be twisting
around the electrocardiogram


Antiarrhythmic agents are used in
prevention and treatment of
irregularities of cardiac rhythm. It may
be defined as drugs that are capable of
reverting any irregular cardiac rhythm
or rate to normal. They are used to
prevent or treat irregularities of cardiac
rhythms.
Antiarrhythmic drugs:


Antiarrythmic drug act by blocking
myocardial Na+, K+ or ca++ channel.
Vaughan Williams (1969) proposed 4
class system of antiarrytmic drugs.


1. Class-I (Membrane stabilizing agents):
A. Moderately decrease dv/dt of 0 phase:
Quinidine, Procainamide, Disopyramide
B. Little decrease in dv/dt of 0 phase:
Lidocane, Mexiletine, Tocainide,
phenytoin.
C. Marked decrease in dv/dt of 0 phase:
Propafenone, Flecainide, Lorcainide
Classification:


2. Class- II (Antiadrenergic agents) (β-
blockers): Propranolol, Esmolol, Sotalol
3. Class-III (Agents widening action
potential, K+ Channel Blocker):
Amiodarone, Dronedarone, Sotalol,
Dofetilide, Ibutilide.
4. Class-IV (Calcium channel blocker):
Verapamil, Diltiazem
Drug for PSVT- Adenosine, Digoxin




Class-I antiarrhythmic drugs, directly
interfere with the depolarization of
cardiac membrane (membrane stabilizing
agents). The drugs of this class slow the
rate of depolarization phase of the action
potential and moderately prolong the
repolarization phase eg. Quinidine,
Procainamide and Disopyramide.
Class-IA antiarrhytmic:


The primary mode of action of
these drug is blockde of Na+ and
K+ channel. The class I drug bind
easily to activated and /or
inactivated state of Na+ channel
but poorly to resting state.


Mode of Action of Class
I drug


Class IA Class IB Class 1C
Na+ channel Blocker .
Inhibit Na+ Channel in
open state and delay
channel recovery for 1-
10 Seconds
Closed state and
delay channel recovery
for less than 1 Seconds
open state and delay
channel recovery for
more than 10 second
K+ channel blocker (
significant) and
increase QT and APD
K+ channel opener
and decrease QT and
APD
K+ channel blocker (
Not significant) No
Change in QT interval
and APD.
Decrease conduction
velocity through AV
node so increase PR
Interval
No effect on PR -
Interval
Decrease conduction
velocity through AV
node so increase PR
Interval


 These drugs act on open or activated state of Na+
channel. They also moderately delay channel
recovery (channel recovery time: 1-10 sec), supress
AV conduction and increase refractoriness.
Mode of Action of Class I
drug


General Mode of Action of Class I drug


The alkaloid is obtained from the
bark of various species of Cinchona
bark ( cinchona officinalis)(Fam.
Rubiaceae) or prepared from quinine
which is a dextrorotatory
stereoisomer of quinine.
Quinidine Sulphate Or
Quinidine Bisulphate
N
OH
H
N
OCH3
H CH2
H
H2SO4. 2H2O
H


 Quinidine contains quinoline ring and bicyclic
quinuclidine ring system with hydroxyl methylene
group connecting these two component.
 In addition to Na+ Channel blockade , Quinidine
has cardiac antivagal action and prolong atrial ERP.
Qunidine slow AV conduction Therefore Quinidine
Increase P-R , widen QRS complex and increase
Action potential duration and QT interval


Mechanism of action:
Quinidine blocks myocardial Na+
channel in the open state and reduce
automaticity and rate of 0 phase
depolarization in a frequency
dependent manner.


Prolongation of APD is due to K+
channel block but lengthening of ERP is
caused by its moderate effect on
recovery of Na+ and K+ channels.
At high level it inhibit L type Ca++
channel and
It decreases automaticity, conduction
velocity and prolong repolarization.


Other action: Fall in B.P. due to
weak α- adrenergic blockade It also
has Muscarinic , Antimalarial and
antipyretic action.


Uses: Quinidine is a medication that acts as a
class I antiarrhythmic agent (IA) in the heart..
Quinidine is widely used for acute and
chronic treatment of ventricular and
supraventricular tachycardia. It is seldom
used now, because of risk of adverse effects,
including torsades depointe, sudden cardiac
arrest, angiodema, thrombocytopenia and
vascular collapse.


It is orally active amide derivative of local
anaesthetic drug procaine. It exert action
simillar to procaine.i.e. Slowing upstroke of
Action potential , Prolongation of QRS
complex, APD , ERP and Q-T interval.
Oral bioavailabity of procainamide is 75%. It is
metabolised in liver primarily by acetylation to
N-acetyl procainamide ( NAPA and prolong
APD and may be responsible for torsade de
pointes occuring in procainamide toxicity. 47
Procainamide hydrochloride:
H
N
N CH3
O
CH3
HCl
H2N


 Quinidine and Procainamide block myocardial
Na+ channel in the open state- reduces
automaticity and maximal rate of 0 phase
depolarization in a frequency dependant manner.
Prolongation of APD is due to K+ channel block
while lengthening of ERP is caused by it’s
moderate effect on recovery of Na+ and K+
channels. At high concentration it also inhibits L
type Ca++ channel.
 Procainamide is less effective in suppressing
ectopic automaticity than quinidine.Antivagal
action is absent and not α-blocker


 Antivagal action is absent
 Procainamide is less effective in supressing ectopic
automaticity than quinidine.
 Procainamide is not an alpha blocker and causes less
fall in B.P.
 Procainamide is weaker depressant of cardiac
contractality and A-V conduction.
Difference between Procainamide and Quinidine


 Uses of Procainamide: Procainamide is second line drug
to terminate VT and some supraventricular arrythmia.
Procainamide HCl is given for the treatment of
ventricular arrhythmias particularly those which are
resistant to Lidocaine and those following myocardial
infaraction. It also employed maintan sinus rhythm after
atrial fibrillation. Procainamide HCl may be given by i.m.
route.
 Preparation: Procainamide Injection, Procainamide
Tablets
 Brand name: Pronestyl, Procan, Procanbid 250 mg tab.
and 1 g/10 ml inj.


It is a qunidine like class- IA drug that has potent cardiac
depressant and anticholinergic action, but no α adrenergic
blocking property. Prolongation of P-R interval and QRS
widening are less marked. It is a second line antiarrhythmic
medication used in the treatment of ventricular tachycardia.
Disopyramide phosphate
N
O
H2N
N


 Disopyramide depresses the increase in sodium
permeability of the cardiac myocyte during Phase 0 of
the cardiac action potential, in turn decreasing the
inward sodium current. This results in an increased
threshold for excitation and a decreased upstroke
velocity. It may also be used for maintenance therapy
after cardioversion of AF or AFI and to treat vagally
mediated AF


 Adverse effect: It causes dry mouth, constipation,
Urinary retention and blurred vision and depression
of cardiac contractility is more prominent.
 Preparation: Disopyramide Phosphate capsule BP.
 Brand name: Norpace and Rythmodan, Regubeat
100, 150 mg tab and cap.


Synthesis of
Disopyramide


 Quinidine
 Quinidine is diastereomer of Quinine
 Despite Structure similarity, Quinidine is more effective
in cardiac muscle.
 It contain 2 ring with Nitrogen in both rings. Quinidine
Ring and Bicyclic quinuclidine ring.
SAR of Class 1A drug
N
OH
H
N
OCH3
H CH2
H
H2SO4. 2H2O
H


 Both Nitrogen are basic. Quinidine Nitrogen is used
as water soluble salt form(Sulphate salt)
 These salts are good orally Administered drug.
 Methoxy group at Quinoline and vinyl group at
quinuclidine ring help in metabolism of drug in
liver.


SAR of Procainamide
1) Procainamide is amide Biosters of Procaine
2) Replacement of Ester group with amide group in Procaine leads
to development of Procainamide
3) Amide group produces longer duration of action due to slow
hydrolysis and can be given orally.
4) Increasing the length of carbon chain may decrease the activity.
5) Disubstituted amino group is important for Antiarrytrhmic
activity of Procainamide .
H
N
N CH3
O
CH3
HCl
H2N
Procainamide
O
N C
H
3
O
C
H
3
H
C
l
H
2N
Procaine


 Unsubstituted Phenyl Ring is essential ring.
 Substitution on phenyl ring may reduced activity.
SAR of Dispyramide
N
O
H
2
N
N
D
is
o
p
y
ra
m
id
e


 Pyridine ring is essential for activity
 Replacement of amide group with other group result
in decrease in antiarrhythmic activity.
 Di isopropyl amino group is essential for activity.


 Subclass -IB: This class of drug block Na+ channels
more in the inactivated than in the open state, but
does not delay channel recovery( channel recovery
time < 1S). They don’t depress A-V conduction or
shorten APD, ERP and Q-T.


 It is 5,5-diphenylimidazolidine-2,4-dione. Phenytoin
has long been used to treat epilepsy and for some
time as an antiarrhythmic drug
Class IB drug: Phenytoin
sodium
N
H
H
N
C6H5
C6H5
ONa
O


 Phenytoin binds preferentially to the inactive form of the
sodium channel.
Prolong sodium channel inactivation and decrease Na+
entry
Slow down zero phase depolarization.
 Preparation: Phenytoin Injection, Phenytoin Tablets
 Brand name: Dilantin
Mode of Action of Phenytoin


 Tonic –Clonic Seizure
 Focal Seizure
 Myoclonic Seizure
 Status Epileptics
 Absence Seizure
 Ventricular and Atrial Tachycardia
 Cardiac Glycoside Toxicity.
Uses of Phenytoin


 It is a used as local anesthetic. It is safe if given by
slow i.v. injection. It is suppress VT and prevent VF.
It is ineffective in atrial arrhythmias.
Lidocaine hydrochloride OR Lignocaine
hydrochloride
CH3
CH3
O
H
N
C2H5
N
C2H5
.HCl. H2O


 Lidocaine is Blocker of Inactivated Sodium Channel more
than in open state.
 The cardiac action of lidocaine is suppression of
automaticity in ectopic foci.
 The rate of 0 phase depolarization and conduction
velocity is not decreased.
 It shorten phase 3 repolarization and decreases Action
potential duration and QT interval.
Mode of Action of lidocaine


 Therefore, lidocaine is suitable for infiltration, block,
and surface anaesthesia. Lidocaine is one of the most
commonly used local anaesthetics in dentistry.
 Lidocaine is also the most important class-1b
antiarrhythmic drug; it is used intravenously for the
treatment of ventricular arrhythmias (for
acute myocardial
infarction, digoxin poisoning, cardioversion,
if amiodarone is not available or contraindicated.
Uses of Lidocaine


 It comes in Subclass IB. Mexiletine is a drug used to
treat abnormal heart rhythms, chronic pain, and
some causes of muscle stiffness. It is a local
anaesthetic and as well as antiarrhythmic. It is
similar pharmacological action to Lidocane.
Mexiletine
hydrochloride
CH3
CH3
O
NH2
CH3
.HCl


 Mexiletine is Blocker of Inactivated Sodium Channel more than
in open state.
 The cardiac action of Mexiletine is suppression of automaticity
in ectopic foci.
 The rate of 0 phase depolarization and conduction velocity is
not decreased.
 It shorten phase 3 repolarization and decreases Action
potential duration and QT interval.
Mode of action of Mexiletine


It is used parentally in treatment of post infarction
sinister ventricular arrhythmias (PISVA) as alternative
to Lidocaine.
 Preparation: Mexiletine Capsules, Mexiletine
Injection
 Brand name: MEXITIL 50, 150 mg caps., 250 mg/10
ml inj.


 Tocainide is a class-Ib antiarrhythmic agent.
Tocainide is a primary amine analogue of lidocaine
with antiarrhythmic properties useful in the
treatment of ventricular arrhythmias.
Tocainide
hydrochloride
CH3
CH3
O
H
N
NH2
CH3
.HCl


 It exert action similar to Lidocaine.
 Tocainide is Blocker of Inactivated Sodium Channel
more than in open state. The cardiac action of Tocanide
is supression of automaticity in ectopic foci. The rate of
0 phase depolarization and conduction velocity is not
decreased. It shorten phase 3 repolarization and
decreases Action potential duration and QT interval


 General Structure
 Substituted phenyl ring is essential.
 Ortho methyl group on aromatic ring protect the
molecule from hydrolysis.
SAR of Class 1b
C
H
3
C
H
3
X C
H
2 N
H
H


 Amino group may be primary, Secondary and
Tertiary. Tertiary amine in Lidocaine and primary
amine in mexiletine
 X may be amide group (lidocaine, Tocainide) or
ether group ( Mexiletine)
C
H
3
C
H
3
O
N
H
2
C
H
3
.
H
C
l
M
e
x
i
l
e
t
i
n
e
h
y
d
r
o
c
h
l
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r
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t
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i
n
e
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r
g
r
o
u
p
a
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d
p
r
i
m
a
r
y
a
m
i
n
e
C
H
3
C
H
3
O
H
N
C
2
H
5
N
C
2
H
5
L
I
d
o
c
a
i
n
e
C
o
n
t
a
i
n
A
m
i
d
e
g
r
o
u
p
a
n
d
T
e
r
t
i
a
r
y
a
m
i
n
e


 These are the most potent Na+ channel blockers with
more prominent action on open state and the longest
recovery times (> 10S). They markedly delay
conduction, prolong P-R interval, broaden QRS
complex, but have variable effect on APD.
Subclass -1C


 Lorcainide is a Class-1C antiarrhythmic agent that is
used to help restore normal heart rhythm and conduction
in patients with premature ventricular contractions,
ventricular tachycardia and wolff-parkinson-white
syndrome.
Lorcainide hydrochloride
N N
O
Cl


 Lorcainide is given orally at a dose 50-100 mg 2-3
times/day after a meal; the drug can be also
administered as a slow intravenous injection at a
dose of 1-2 mg for 5-10 min and the dose can be
repeated every 8-12 h.
Lorcainide hydrochloride


 Lorcainide have a high affinity for open state Sodium
Channel (but not closed or inactive Na channel)
 reducing the fast Na+ influx and reduce The Channel
Recovery more than 10 Second
 slow the upstroke of ventricular myocytes’ action
potential and prolong the PR, QRS and QT intervals of
an ECG


 Class-III: This class of drug is prolongation of
repolarization (Phase-3). AP is widened and ERP is
increased.


Amiodarone is iodine containing highly
Lipophilic long acting anti-arrhythmic
drug. It exhibit multiple action (class I, II
,III and IV) action.
Amiodarone
hydrochloride:
O
O
H3C
I
O
N CH3
CH3
I
.HCl


It prolong Action potential duration and
Q-T interval due to block of myocardial
delayed rectifier K+ channel.
 It blocks inactivated Na+ channels like
lidocane with rapid rate of channel
recovery. It is more effective in depressing
conduction in cell that is partially
depolarize.


It is also partially inhibited
myocardial Ca++ channel
and non-competitive β
adrenergic blocking and
alters thyroid function.


Amiodarone is used to treat fatal
irregular heartbeat such as persistent
ventricular fibrillation/tachycardia. It is
used to restore normal heart rhythm and
maintain a regular, steady heartbeat. It is
effective in a wide range of ventricular
and supraventricular arrhythmias
including PSVT, nodal and ventricular
tachycardia.


SAR OF CLASS-III(AMIODARONE)
O
O
H3C
I
O
N CH3
CH3
I
.HCl
1)Butyl benzofuran and Diiodo benzene moiety were found to
essential for antiarrhythmic activity.
2)Tertiary amine is essential for activity. Tertiary amine when
converted to secondary amine activity will be same but
introduction of some toxicity.


 Replacement of Diethyl amine by larger alkyl group
resulting in to active compound Dronedarone.
Dronedarone shows faster activity, shorter half life,
reduced lipophilicity and toxicity.
O
O
H 3 C
O
N
C 4 H 9
C 4 H 9
N H
S
O
O
H 3 C
D r o n e d a r o n e


 Increasing the ethylene chain resulting in increase in
half life of drug.


 The primary action of class II drugs is to suppress
adrenergically mediated ectopic activity.
Class II Drug


 It is a nonselective β blocker having prominent Class III
action of prolonging repolarization by blocking cardiac
inward K+ channels. It is not a Na+ channel blocker—
does not depress conduction in fast response tissue, but
delays A-V conduction and prolongs its ERP. It exist in
two form d and l isomer
 d-Sotalol exert class III effect and l –sotalol exert Class III
and Beta Blocking action.
Sotalol
S
N
H
CH3
H
N CH3
OH
O
O
H3C


It Block sympathetic stimulation of β1- adrenergic
receptor and Slows firing of SA node and conduction
through AV-node.
Sotalol is effective in VT, some WPW arrhythmias
and for maintaining sinus rhythm in AF/AFl.
Due to prolongation of APD and Q-T,risk of dose-
dependent torsades de pointes is the major limitation.
It is contraindicated in patients with long Q-T
interval.


 Para substitution by methyl sulphonamide is
essential for activity
 Alpha carbon may be unsubstituted or substituted
with small alkyl group.
SAR of class II (Satalol)
S
N
H
CH3
H
N CH3
OH
O
O
H3C


 Hydroxyl group at beta carbon in R-configuration
gives maximum activity.
 Primary and secondary amine essential for activity.
Isopropyl chain help in selectivity and metabolism of
drugs.
 d isomer is K+ channel blocker. l isomer is both beta
and K+ channel blocker.

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