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Drugs used in Cardiac
Arrhythmias
Dr.V.V.Gouripur
What is an arrhythmia?
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The rhythm of the heart is normally generated and
regulated by pacemaker cells within the sinoatrial
(SA) node, which is located within the wall of the
right atrium.
SA nodal pacemaker activity normally governs the
rhythm of the atria and ventricles.
Normal rhythm is very regular, with minimal
cyclical fluctuation. Furthermore, atrial contraction
is always followed by ventricular contraction in the
normal heart.
When this rhythm becomes irregular, too fast
(tachycardia) or too slow (bradycardia), or the
frequency of the atrial and ventricular beats
are different, this is called an arrhythmia.
The term "dysrhythmia" is sometimes used and has
a similar meaning.
arrhythmia
Def'n:
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1. an abnormality of rate, regularity, or
site of origin of the cardiac impulse, or
2. a disturbance in conduction that causes
an alteration of the normal sequence of
activation of the atria and ventricles
NB: these may arise from abnormal impulse
generation, altered conduction, or both
Normal Cardiac excitation requires
 a pacemaker (normally the SA node)
and
 follower cells
• Conducting fibers &
• Myocardium.
Between the atria and ventricle is the
AV node which acts as a filter to
prevent too frequent activation of the
ventricles by supraventricular
tachyarrhythmias.
1.
2.
3.
Action potentials and conduction in the
conducting tissue, atria and ventricles
occur due to entry of extracellular
sodium through fast Na channels.
SA and AV nodes do not use fast Na
channels. Instead they rely solely on Ca
channels for action potentials and
conduction.
SA node is the dominant pacemaker
because it beats at a rate faster than the
AV node
4. Each SA nodal beat is accompanied by
one wave of activation affecting the atria,
AV node, Bundle branches, Purkinje fibers
and myocardium.
5. The heart then rests during diastole
before the next sinus beat occurs.
The normal cardiac action potential
in non conducting tissues (e.g.
ventricles)
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Phase 0-Due to opening of fast Na+ channels
(when the threshold potential (~ -70mV) is
reached)
There is a massive influx of Na+ into the
muscle cell, causing a rapid depolarisation
Phase 1- Partial repolarisation-Due to closure
of the Na+ channels
Phase 2-Plateau phase-Due to opening of slow
Ca2+ channels
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Phase 3- Repolarisation-Due to closure of
the Ca2+ channels and opening of the K+
channels, causing a massive loss ofK+ out
of the cell
Phase 4-Pacemaker potential
· This phase is unimportant in non
conducting heart tissues.
In conducting tissues (SA and AV nodes)
the pacemaker potential gradually
depolarises during diastole to reach the
threshold potential, resulting in a spike
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Conducting tissues always fire action
potentials, at varying frequencies (they
have intrinsic firing capacity). The SA node
fires the fastest and so assumes the role
of the pacemaker.
Non conducting tissues need a “jump
start” impulse from the conducting tissues
in order to depolarise (i.e. they are not
capable of intrinsically firing, unless under
pathological conditions)
Mechanism of Arrhythmia
 Enhanced
automaticity
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Triggered automaticity (normal action
potential is interrupted or followed by an
abnormal depolarization)

Reentry (abnormal impulse conduction)
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Sometimes the normal wave of
activation gets fractionated, giving rise
to multiple beats before the next sinus
beat comes.
This is called ‘reentry’
Re-entry
Purkinje fibre
Damage e.g.
thrombotic clot
causes muscle to
become ischaemic
Ventricular
muscle
Re-entry
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Caused by unidirectional block, usually in
diseased tissues
Probably the cause of many arrhythmias
Can occur in atria, ventricles and nodal
tissue
AP’s conducted only one-way, but
conduction is slower
Causes a constant loop of AP’s re-exciting
repeatedly (Circus Rhythm)
The tissue begins to beat independently of
input
Re-entry
1.
2.
3.
Reentry can occur in any part of the heart.
It can be stopped by making the
unidirectionally blocked tissue become
bidirectionally blocked.
It can also be blocked by converting
unidirectional conduction into bidirectional
conduction.
i) This can be done with drugs that block
Na channels directly or indirectly.
Two special cases of reentry in the AV
node are:
• Paroxysmal supraventricular
tachycardia - cause not clear & is
often short lasting
The other special cause of reentry in
the AV node is:
• Wolf Parkinson White Syndrome
where the normal slowly
conducting AV node is straddled by
a fast conducting Accessory fibre
which resembles atrial tissue.
ECTOPIC PACEMAKER
 SPONTANEOUS
(Purkinje Fiber)
 TRIGGERED
PACEMAKER
AUTOMATICITY
–Delayed afterdepolarisation
–Early afterdepolarisation
ECTOPIC PACEMAKER
DELAYED AFTERDEPOLARISATION
–Abnormal Oscillatory Ca Release from
SR
–Caused by Ca Overload
–Elevated Cytosolic Ca Causes
Increased Membrane Conductance to
Cations
–This leads to Oscillatory Depolarization
of Cell Membrane
ECTOPIC PACEMAKER
EARLY AFTERDEPOLARIZATION
–Sometimes caused by prolonged
action potential duration
–Due to oscillatory fluctuation of
delayed K+ channels
–May also be due to oscillatory
inactivation of calcium channels
What causes arrhythmias?
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coronary artery disease-When cardiac
cells lack oxygen, they become
depolarized, which lead to altered impulse
formation and/or altered impulse
conduction.
Changes in cardiac structure that
accompany heart failure (e.g., dilated
or hypertrophied cardiac chambers),
can also precipitate arrhythmias.
Finally, many different types of drugs
(including antiarrhythmic drugs) as well as
electrolyte disturbances (primarily K+ and
Ca++) can precipitate arrhythmias.
Types of Arrhythmias
(caused by the described mechanisms)
 Atrial flutter – atria beat rapidly at 250-350 beats
per min
 Supraventricular paroxysmal tachycardia – no
more than 200 beats per min. Trivial compared to the
other types
 Atrial fibrillation –350-600 beats per min. Irregular,
uncoordinated contractions, fragmentary, ventricles
beat at one fifth the rate of the atria, but not
regularly. If chronic, then the condition is serious
 Ventricular fibrillation – immediate cause of death
in many fatal causes of MI and electrocution.
Ventricles pump too fast. Use electric paddles in order
to disrupt contraction pattern and re-instate normal
rhythm
 Ventricular tachycardia – leads to a series of rapid
contractions called ventricular extrasystole
Clinical symptoms
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palpitation or fluttering sensation
in the chest.
a skipped beat -forceful contraction
and a thumping sensation in the
chest. .)
Patients may experience dyspnea
(shortness of breath), syncope
(fainting), fatigue,, chest pain or
cardiac arrest.
Treatment
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Reassurance is important. Most
cardiac arrhythmias cause no
symptoms, have no hemodynamic
importance, and have no prognostic
significance but may cause anxiety in
a patient who becomes aware of
them.
In rare cases, a precipitating factor
may be identified and modified
(eg, excessive intake of caffeine or
alcohol).
Drug treatment:
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Antiarrhythmic drug therapy is the
mainstay of management for most
important arrhythmias.
Classification of Antiarrhythmic Drugs
based on Drug Action( Table1)
CLASS
ACTION
I.
Sodium Channel Blockers
Moderate phase 0
depression and slowed
conduction (2+); prolong
repolarization
1A.
DRUGS
Quinidine, Procainamide,
Disopyramide
1B.
Minimal phase 0 depression
and slow conduction (0-1+);
shorten repolarization
Lidocaine
1C.
Marked phase 0 depression
and slow conduction (4+);
little effect on repolarization
Flecainide
II.
Beta-Adrenergic Blockers
Propranolol, esmolol
III.
K+ Channel Blockers
(prolong repolarization)
Amiodarone, Sotalol,
Ibutilide
IV.
Calcium Channel Blockade
Verapamil, Diltiazem
Mechanism of Action
of Antiarrhythmic
Drugs
 Stop
Automaticity
–Increase Membrane Threshold
for Activation
–Cause Membrane
Hyperpolarization
Mechanism of Action
of Antiarrhythmic
Drugs
Stop Reentry
 Convert
Unidirectional Block to
Bidirectional Block
 Abolish
Unidirectional Block
Mechanism of Action
of Antiarrhythmic
Drugs
 Improve Ventricular Function
 Slow ventricular rate
 Increase ventricular filling
 Increase cardiac output
Class I –
Blockers
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+
Na
Channel
Binds to Na+ channels and prevent conduction of
ions
Bind preferentially to the open channel state
(i.e. use-dependent)
The more the Na
channel
is used, the more drug is
+ CHANNEL BLOCKERS
bound
REST
OPEN
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REFRACTORY
Useful in conditions where channels open
frequently
Sub-classified into 3 groups: Ia, Ib and Ic
Quinidine (class Ia)
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This broad-spectrum drug is effective for the
suppression of VEBs and VT and for the
control of narrow QRS tachycardias, including
atrial flutter and fibrillation.
It is one of the few drugs that may convert AF
to sinus rhythm.
Elimination half-life (t1/2) is 6 to 7 h.
If an initial test dose of quinidine sulfate is
tolerated, the maintenance dosage is usually
200 to 400 mg po q 4 to 6 h.
Dosing should be adjusted so that QRS
Procainamide (class Ia)
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The main metabolite, N-acetyl procainamide,
also has antiarrhythmic effects and contributes
to procainamide's efficacy and toxicity.
It can be given cautiously IV as 100 mg over 1
to 2 min repeated q 5 min to a usual
maximum total dose of 600 mg (rarely up to 1
g) while monitoring BP and ECG.
Oral procainamide has a short elimination t1/2
(< 4 h), requiring frequent dosing or use of
sustained-release preparations. The usual oral
dosage is 250 to 625 mg q 3 or 4 h..
Adverse reactions
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QRS widening by 25% and QT prolongation
to 550 msec suggest toxicity.
Almost all patients receiving long-term
therapy (> 12 mo) develop serologic
abnormalities (notably a positive antinuclear
factor test), and
up to 40% have symptoms and signs of
hypersensitivity (arthralgia, fever, pleural
effusions
Disopyramide
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It has an elimination t1/2 of 5 to 7 h.
Oral dosing is usually 100 or 150 mg q 6 h.
Parenteral dosing, not available.
Disopyramide has powerful anticholinergic
effects that play only a minor role in arrhythmia
management but are responsible for urinary
retention and glaucoma;
less serious ADR (eg, dry mouth, problems of
accommodation, bowel upset, may contribute to
noncompliance.
Bradycardia may occur
Qunidine adverse reactions
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About 30% of patients develop.
GI problems (diarrhea, colic, flatulence) are
most common, but fever,
thrombocytopenia, and liver function
abnormalities also occur.
Quinidine syncope is a potentially
dangerous idiosyncratic and unpredictable
effect caused by torsade de pointes
TYPE 1A AGENTS
Procainamide
 Depresses
hemodynamics
 Effective
against atrial & ventricular
arrhythmia
 Paradoxical
tachycardia
PROCAINAMIDE
 Prolongation
of QRS complex
 Paradoxical tachycardia - prevented by
prophylactic digoxin
 Syncope - due to Torsade de pointes
 SLE-like Syndrome
–reversible & not associated with nephropathy
–Procainamide not good for therapy > 6
months
–greater toxicity in fast acetylators
 Bone
marrow depression
TYPE 1B AGENTS
Lidocaine Mexiletine Tocainide
 Suppress
automaticity
 Shorten action potential duration
 Prolong refractory period
 Decrease conduction (especially in
ischemic & therefore more depressed
tissue)
 Lesser hemodynamic depression
than with Procainamide
Lidocaine
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. It produces minimal myocardial depression
and has little effect on the sinus node, atria,
or atrioventricular node but acts powerfully
on His-Purkinje's and ventricular myocardial
tissue.
It can suppress the ventricular arrhythmias
that complicate MI (VEBs, VT) and reduce
the incidence of primary ventricular
fibrillation (VF) when given prophylactically
in early acute MI.
It is used only parenterally. The usual regimen
is 100 mg IV over 2 min followed by 50 mg IV
5 min later if the arrhythmia has not reverted.
An infusion of 4 mg/min (2 mg/min in patients
> 65 yr) should then be started. If it is
continued for > 12 h, toxic levels may be
reached.
Adverse effects;
 neurologic (tremor, convulsions) rather than
cardiac.
 Drowsiness, delirium, and paresthesias may
occur with too-rapid administration.
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Mexiletine, similar to lidocaine, has few cardiovascular adverse
effects, but GI (nausea, vomiting) and CNS (tremor,
convulsions) effects may limit its acceptability.
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Class Ic drugs are among the most
powerful antiarrhythmics but have
been associated with a significant risk
of proarrhythmia and depression of
cardiac contractility
LIDOCAINE
 Lidocaine
is effective mainly in ventricular
tachyarrhythmias
 Lidocaine is useless orally
–extensive first pass metabolism in the liver
–metabolite is proconvulsant & not antiarrhythmic
–Hence Lidocaine given IV
LIDOCAINE
 Useless
in any supraventricular arrhythmia
 Half life of lidocaine:
–distribution phase is 9 min &
–elimination phase is 100 min
 Therefore
it is given as a bolus combined
with infusion initially as well as with each
increase in dose
LIDOCAINE
 Lidocaine
is ideal in life-threatening
situations:
–Effective
–Rapid action
–Short duration
 Toxicity
–Cardiac depression
–CNS stimulation, tinnitus, convulsion, postictal depression
TYPE 1C AGENT
Propafenone Flecainide
Encainide
 Block
sodium entry and beta
receptors
 Minimal change in action potential
duration
 Suppress automaticity
 Very useful in WPW syndrome
 Decrease cardiac contractility (don’t
give is cardiac mechanical function is
poor)
 Metallic taste on prolonged use
TYPE 2 AGENTS
(b blockers)
Propranolol
Metoprolol
 Suppress
Esmolol
automaticity (decreased
sympathetics)
 Shorten action potential duration
 Decrease conduction in SA & AV
nodes
Class III - Drugs that prolong
repolarisation
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Prolonging the cardiac AP by increasing the
refractory period
Also have interactions with the ANS
Have a diverse pharmacology which is
poorly understood
Examples are bretyllium and amiodarone
Numerous side effects e.g. hepatic injury,
hypotension
Bretyllium only used for life-threatening
ventricular arrhythmias, amiodarone for
recurrent ventricular fibrillation
Class IV – Ca2+ channel blockers
Verapamil, diltiazem, nifedipine
 Block Ca2+ channels in the plasma
membrane especially L-type channels)
 Reduce slow inward current and force
of contraction
 Also slow conduction of AV node due
to calcium channel blockade
 Verapamil used in acute paroxysmal
tachycardia
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Classification of arrhythmias and drugs of choice
Atrial fibrillation and flutter･
･Digoxin is the drug of choice to slow ventricular
response･
･Alternative drugs that are widely used include
verapamil and propanolol･
･Digoxin, verapamil, and possibly beta-blockers may be
hazardous in patients with Wolf-Parkinson-White
syndrome (catheter ablation of extra-nodal pathways
in WPW is successful)･
･Subclass IA drugs (quinidine, procainamide,
disopyramide) have been used for long-term
suppression, but preliminary studies indicate higher
mortality than placebo･
･Class III (amiodarone) and Subclass IC (flecainide,
encainide, and propafenone) are also effective for
suppression, but may be associated with higher mortality
Supraventricular tachycardia
･Vagotonic maneuvers (carotid massage, Valsalva
maneuver, gagging) may be effective･
･Adenosine (short-lived) or verapamil (i.v.) are the drugs
of choice for termination･
･Verapamil is contraindicated in patients with congestive
heart failure, those receiving i.v. beta-blockers, and
should be used with caution in patients taking oral
quinidine･
･Esmolol (a beta-blocker) or digoxin are alternatives for
termination･
･Cardioversion or atrial pacing may be necessary for
some patients･
･Long-term suppression (possible increase in mortality):
Subclass IA, IC, Class II, Class IV, and digoxin･･
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Ventricular PVCs or non-sustained
ventricular tachycardia
No drug therapy for asymptomatic patients･･A
beta-blocker for patients with symptoms (syncope,
dizziness)･
data indicates higher mortality with encainide and
flecainide than placebo･
Sustained ventricular tachycardia
Cardioversion (safest and most effective therapy)
is preferred by most cardiologists in ventricular
tachycardia causing hemodynamic compromise･
･Lidocaine is drug of choice for acute treatment･･
Alternative drugs are procainamide and bretylium･
･Long-term suppression: Class II, Class III, Subclass
IA, and mexiletine (Class IB)･
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Ventricular fibrillation
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Defibrillation (with CPR) is the
treatment of choice;
Drugs are used for prevention of
recurrence･
Lidocaine is the drug of choice･･
Procainamide, amioradone, bretylium
are alternatives･
Cardiac glycoside-induced
ventricular tachyarrhythmias
･Lidocaine is drug of choice･
･Phenytoin, procainamide, or a beta-blocker
are alternatives･
･Digibind should be used in life-threatening
cases･
･Avoid cardioversion and bretylium except for
ventricular fibrillation or sustained
ventricular tachycardia･
･Beta-blockers and procainamide can make
heart block worse･
THE END