Active learning

Arrhythmias
Antiarrhythmic Drugs
 Arrhythmia or dysrhythmia means an abnormal
or irregular heart beat
Arrhythmias may originate in the atria, SA node
or AV node, whereby they are known as supra-
ventricular arrhythmias or in the ventricles
giving rise to the life-threatening ventricular
arrhythmias

Causes of Arrhythmias
 Arteriosclerosis
 Coronary artery spasm
 Heart block (mostly AV block)
 Myocardial ischemia
 ANTIARRHYTHMIC DRUGS
Cardiac arrhythmias are a frequent
problem in clinical practice. They commonly
occur in the presence of preexisting heart
disease. They are the most common cause of
death in patients with an
1.acute myocardial (80%) infarction or
2.terminal heart failure.
 They are also the most serious
manifestation of

1.digitalis toxicity (25%) and

2.are often associated with anesthesia

(50%)

3.hyperthyroidism and

4.electrolyte disorders.
 Background
Recall: to function efficiently, heart needs to contract
sequentially (atria, then ventricles) and in synchronicity

Relaxation must occur between contractions (not true for

other types of muscle [exhibit tetany  contract and hold
contraction for certain length of time])

Coordination of heartbeat is a result of a complex,

coordinated sequence of changes in membrane
potentials and electrical discharges in various heart
tissues
 Arrhythmia
Heart condition where disturbances in
 Pacemaker impulse formation
 Contraction impulse conduction
 Combination of the two

Results in rate and/or timing of contraction of

heart muscle that is insufficient to maintain
normal cardiac output (CO)

To understand how antiarrhythmic drugs work,

need to understand electrophysiology of
normal contraction of heart
 Pathophysiology

Sinoatrial (SA) node – the normal

initiation site of the action potential
(AP).
 Pathophysiology
Normal sinus rhythm (usually at a frequency
of 60–100 bpm), NSR is dependent on
1.generation of an impulse in the normal
sinoatrial (SA) node pacemaker and its
2.conduction through the atrial muscle,
through the atrioventricular (AV) node, through
the Purkinje conduction system, to the ventricular
muscle.
 Pathophysiology
Arrhythmias (dysrhythmias) – any
rhythm that is not normal sinus rhythm.

Arrhythmias may require the

treatment because too rapid, too slow, or
asynchronous contractions reduce
cardiac output.
Electrophysiology - resting potential
A transmembrane electrical gradient (potential) is
maintained, with the interior of the cell negative with
respect to outside the cell

Caused by unequal distribution of ions inside vs. outside

cell
 Na+ higher outside than inside cell
 Ca+ much higher “ “ “ “
 K+ higher inside cell than outside

Maintenance by ion selective channels, active pumps

and exchangers
Cardiac Na+ channels
 Contraction of
ECG (EKG) showing wave ventricles
segments

Repolarization of
Contraction of
ventricles
atria
 Mechanisms

Two major mechanisms for

arrhythmias are recognized:
abnormal automaticity

abnormal (reentrant) conduction.

 BASIC TERMS:

Abnormal automaticity – pacemaker

activity that originates anywhere other than in
the sinoatrial node.

Abnormal conduction – conduction of

an impulse that reenters tissue previously
excited.
 Cardiac Action Potential
Divided into five phases (0,1,2,3,4)
 Phase 4 - resting phase (resting membrane potential)
Phase cardiac cells remain in until stimulated
Associated with diastole portion of heart cycle

Addition of current into cardiac muscle (stimulation)

causes
 Phase 0 – opening of fast Na channels and rapid depolarization
Drives Na+ into cell (inward current), changing membrane potential
Transient outward current due to movement of Cl- and K+

 Phase 1 – initial rapid repolarization

Closure of the fast Na+ channels
Phase 0 and 1 together correspond to the R and S waves of the
ECG
Cardiac Action Potential (con’t)
Phase 2 - plateau phase
 sustained by the balance between the inward movement of Ca+ and
outward movement of K +
 Has a long duration compared to other nerve and muscle tissue
 Normally blocks any premature stimulator signals (other muscle tissue
can accept additional stimulation and increase contractility in a
summation effect)
 Corresponds to ST segment of the ECG.

Phase 3 – repolarization
 K+ channels remain open,
 Allows K+ to build up outside the cell, causing the cell to repolarize
 K + channels finally close when membrane potential reaches certain
level
 Corresponds to T wave on the ECG
Differences between nonpacemaker and
pacemaker cell action potentials

PCs - Slow, continuous depolarization during rest

Continuously moves potential towards threshold for a
new action potential (called a phase 4 depolarization)
 Mechanisms of Cardiac Arrhythmias

Result from disorders of impulse

formation, conduction, or both

Causes of arrhythmias
 Cardiac ischemia
 Excessive discharge or sensitivity to
autonomic transmitters
 Exposure to toxic substances
 Unknown etiology
Disorders of impulse formation
No signal from the pacemaker site

Development of an ectopic pacemaker

 May arise from conduction cells (most are capable of
spontaneous activity)
 Usually under control of SA node  if it slows down too much
conduction cells could become dominant
 Often a result of other injury (ischemia, hypoxia)

Development of oscillatory afterdepolariztions

 Can initiate spontaneous activity in nonpacemaker tissue
 May be result of drugs (digitalis, norepinephrine) used to treat
other cardiopathologies
Afterdepolarizations
 Disorders of impulse conduction
May result in
 Bradycardia (if have AV block)
 Tachycardia (if reentrant circuit occurs)

Reentrant
circuit
 Cardiac impulse
generation and
conduction
The electrical impulse for
contraction of the heart
originates in pacemaker
cells of the sinoatrial node
and spreads through the
atria, atrioventricular (AV)
node, and adjoining parts of
the His–Purkinje fiber system
to the ventricles.
 Reentrant arrhythmias
For reentry to occur, three conditions must
coexist:
(1) There must be an obstacle (anatomic or
physiologic) to homogeneous conduction,
thus establishing a circuit around which the
reentrant wave front can propagate.
(2) There must be unidirectional block at
some point in the circuit; that is, conduction
must die out in one direction but continue in
the opposite direction
(3) Conduction time must exceed the
effective refractory period.
 Mechanisms
Thus, dysfunction of impulse generation
or conduction at any of a number of sites in
the heart can cause an abnormality in
cardiac rhythm.
Therefore, the aim of therapy of the
arrhythmias is
1.to reduce pacemaker activity and
2.modify critically impaired conduction.
 Types of arrhythmias
A few of the clinically important arrhythmias are:

 atrial flutter;
 atrial fibrillation (AF);
 supraventricular tachycardia (SVT);
 premature ventricular beats (PVBs);
 ventricular tachycardia (VT);
 ventricular fibrillation (VF).
 Torsade de pointes –
It is now possible to define the
molecular basis of several congenital
and acquired cardiac arrhythmias.
The best example is the polymorphic
ventricular tachycardia known as
torsade de pointes, which is
associated with prolongation of the
QT interval (especially at the onset of
the tachycardia), syncope, and
sudden death.
 Torsade de pointes –
Torsade de pointes is a ventricular
arrhythmia of great pharmacologic
importance because it is often induced
by antiarrhythmic and other drugs that
change the shape of the action potential
and prolong the QT interval.
 REMEMBER!

Many of the antiarrhythmic

agents are now known to have
dangerous proarrhythmic action –
that is, to cause arrhythmias.
 Basic terms:
 Atrial fibrillation (AF) - Arrhythmia involvs
multiple ectopic foci of atrial cells, creating rapid
reentry and a chaotic movement of impulses
through the tissue of the atria. The ventricular
response is rapid (100-150 beats per minute) and
irregular. Cardiac output is decreased.

 Supraventricular tachycardia (SVT) - A

reentrant arrhythmia that travels through the AV
node; it may also be conducted through atrial
tissue as part of the reentrant circuit.
 Basic terms:
 Ventricular tachycardia (VT), ventricular fibrillation
(VF) - A very common arrhythmia, often associated with
myocardial infarction; Ventricular tachycardia is a
common cause of death in patients who have had a
myocardial infarction. Ventricular tachycardia may involve
abnormal automaticity or abnormal conduction, usually
impairs cardiac output, and may deteriorate into
ventricular fibrillation; for these reasons it requires prompt
management.

Ventricular, but not atrial, fibrillation is fatal if not

terminated within a few minutes.
 Thus,
Irregularities of heart rhythm can
interfere dangerously with cardiac
pumping function and may lead to death.
CLASSIFICATION OF ANTIARRHYTH MICS

The drugs used for arrhythmias fall

into five major groups (Vaughan Williams
classification):
Vaughan Williams classification
 Effect of antiarrhythmic drugs
Normal electrical cardiac function require normal
action potentials (AP), dependent on sodium – Na,
calcium – Ca, and potassium – K channel activity which
are under the appropriate autonomic control.
 Effect of antiarrhythmic drugs
Effect of drugs on automaticity
Most of the antiarrhythmic agents suppress
automaticity by blocking either Na+ or Ca2+ channels
to reduce the ratio of these ions to K+.
Effects of drugs on conduction abnormalities
Antiarrhythmic agents prevent reentry by slowing
conduction (class I drugs) and/or increasing the
refractory period (class III drugs), thereby converting
a unidirectional block into a bidirectional block.
Effective refractory period - The time that must pass
after the upstroke of a conducted impulse in a part of the
heart before a new action potential can be propagated in
that cell or tissue (period of inexcitability).
 ECG
ECG REFLECTS THE CHANGES IN CARDIAC
ELECTRICAL ACTIVITY
ECG is the body surface manifestation of the
depolarization and repolarization waves of the heart.
1.The P wave is generated by atrial depolarization,
2.the QRS - by ventricular muscle depolarization.
3.The PR interval is a measure of conduction time
from atrium to ventricle through the atrioventricular
(AV) node, and
4.the QRS duration indicates the time required for
all of the ventricular cells to be activated (ie, the
intraventricular conduction time).
5.The QT interval reflects the duration of the
ventricular action potential.
Active Learning: Antiarrythmic drugs

I.Sodium channel blockers;- Ahmed, Parikshit

II.Beta – adrenoceptor blockers;-Alia, Shivam

III.Potassium K-channel blockers;-Esther, Sojud

IV.Calcium channel blockers;- Madhumithra

V.Miscellaneous -adenosine, potassium ion,

magnesium ion. -Maite
 DRUG CLASSIFICATION

The antiarrhythmic drugs fall into 4 groups

or classes plus a miscellaneous group:
I.Sodium channel blockers;
II.Beta – adrenoceptor blockers;
III.Potassium K-channel blockers;
IV.Calcium channel blockers;
V.Miscellaneous – adenosine, potassium ion,
magnesium ion.
 Antiarrhythmic drugs
Biggest problem – antiarrhythmics can
cause arrhythmia!

 Example: Treatment of a non-life threatening

tachycardia may cause fatal ventricular
arrhythmia
 Must be vigilant in determining dosing, blood
levels, and in follow-up when prescribing
antiarrhythmics
 CLASS I ANTIARRHYTHMIC DRUGS
Class I antiarrhythmic drugs act by
blocking voltage-sensitive sodium (Na+)
channels via the same mechanism as local
anesthetics.
Sodium - channel blockers antiarrhythmic
drugs block channels in abnormal tissue more
effectively than channels in normal tissue. Thus,
these drugs have a selective depression.
Selective depression – the ability of certain
drugs to selectively depress areas of excitable
membrane that are most susceptible, leaving
other areas relatively unaffected.
 CLASS I ANTIARRHYTHMIC DRUGS
These agents slow the rate of rise of the
action potential (slowing conduction), increase
the ventricular effective refractory period.
The group 1 drugs are further subdivided
into three groups on the basis of their effects on
the duration of the AP (action potential).
Group 1A agents (procainamide) prolong
the AP.
Group 1B drugs (lidocaine) shorten the AP
in some cardiac tissues.
Group 1C drugs (flecainide) have no
effects on AP duration.
GROUP 1A DRUGS INCLUDE:

 Procainamide

 Quinidine

 Disopyramide.
 GROUP 1A DRUGS
Mechanism of action
They block INa(sodium) channels; some block IK(potassium)
channels. Therefore, they prolong AP duration and the
effective refractory period (ERP), in addition, to slowing
conduction velocity and ectopic pacemaker activity. The
increase in AP duration generates an increase in QT-interval.

CLINICAL APPLICATION
All types of arrhythmias: Atrial and ventricular
arrhythmias. (Procainamide – during the acute phase of
myocardial infarction)
 GROUP 1A DRUGS
Adverse effects:
Development of new arrhythmias (for example,
quinidine can actually precipitate arrhythmias such as
polymorphic ventricular tachycardia, which can
degenerate into ventricular fibrillation.
 GROUP 1A DRUGS
Adverse effects:
Hypotension
Lupus-like syndrome (reversible syndrome
– in 25-30% of patients)
Large doses – induce cinchonism (Quinidine
= headache, vertigo, tinnitus, blurred vision,
disorientation, psychosis)
Nausea, vomiting, diarrhea (quinidine).
Because of the toxic potential of quinidine,
calcium antagonists, such as amiodarone
and verapamil, are increasingly replacing this
drug in clinical use)
 
 DRUGS WITH GROUP 1B ACTIONS
Adverse effects:
CNS sedation (drowsiness, slurred
speech, paresthesia)
Excitation (convulsions, agitation,
confusion)
Allergy (rashes, anaphylaxis)
Cardiovascular depression
Cardiac arrhythmias (lidocaine)
Pulmonary fibrosis (tocainide).
 GROUPS 1C DRUGS:
 Flecainide

They block INa–channels and can

markedly slow conduction
velocity and pacemaker activity.

CLINICAL APPLICATIONS:
 Treatment of refractory
ventricular tachycardia
 Prevention of paroxysmal
atrial fibrillation/flutter.
 GROUPS 1C DRUGS
Adverse effects:

 Proarrhythmic effect

 CNS – toxicity (dizziness, headache)

 Flecainide has a negative inotropic effect

and can aggravate congestive heart failure
 Nausea

 Blurred vision
GROUP 2 ANTIARRHYTHMICS:
(Β-BLOCKERS)

 Propranolol (nonselective)

 Esmolol (short-acting β-
blocker)
 metoprolol
 CLINICAL USE:
Β-blockers
Thyrotoxicosis

As a prophylactic drug (prevention of

ventricular arrhythmias) in patients who
have had a myocardial infarction
Atrial flutter and fibrillation.
MECHANISMS, EFFECTS
Β-blockers
They block β-adreno-
ceptors and slow
pacemaker, thus, depress
automaticity, prolong AV
conduction, decrease
heart rate and contractility.
Class II agents are
useful in treating
tachyarrhythmias caused
by increased sympathetic
activity.
 Remember!
Β-blockers
These drugs provide a protective
effect against sudden death by
ventricular fibrillation for 2 years or
longer after the infarct. In contrast to the
sodium-channel blockers, β-blockers and
Class III compounds, such as sotalol and
amiodarone, are increasing in use.
 TOXICITIES:
Β-blockers
 Bronchospasm (propranolol)
 Cardiac depression
(depression of cardiac output)
 Atrioventricular block
 Hypotension
 Fatigue
 Hypoglycemia (drug-induced)
 Peripheral vasoconstriction
 GROUP 3 ANTIARRHYTHMICS

Potassium IK channel blockers:

 Amiodarone

 Sotalol

 Dofetilide

 Ibutilide

 Bretilium tosylate
 GROUP 3
ANTIARRHYTHMICS
Mechanism and effects
The hallmark of
group 3 drugs is
prolongation of the AP
(action potential)
duration and the
effective refractory
period (ERP). This
prolongation is caused
by strong blockade of IK
potassium channels.
 GROUP 3 ANTIARRHYTHMICS
Clinical uses:
 Severe refractory supraventricular and
ventricular tachyarrhythmias (!
amiodarone - has a broad spectrum of
therapeutic action – it blocks Na+, Ca2+, K+ -
channels and β-adrenoceptors. Thus,
amiodarone shows Class I, II, III and IV
actions. It is approved for use mainly in
arrhythmias that are resistant to other
drugs).
 Atrial flutter and fibrillation (treatment and
prophylaxis) – ibutilide, dofetilide, sotalol.
 Amiodarone has antianginal as well as
antiarrhythmic activity.
 GROUP 3 ANTIARRHYTHMICS
Side effects:
1. Syndrome of torsade de pointes
(sotalol, ibutilide, dofetilide)
2. Amiodarone causes
 thyroid dysfunction (hyper- or
hypothyroidism: amiodarone contains
iodine),
 paresthesias,
 liver toxicity, tremor,
 interstitial pulmonary fibrosis,
Side effects: Fotosensibility caused by long-
term use of amiodarone
 optic neuritis,
 micro crystalline
deposits in the
cornea and skin
(blue skin
discoloration,
caused by iodine
accumulation in the
skin),
 photosensitivity,
 neuropathy,
 muscle weakness.
 GROUP 4 ANTIARRHYTHMICS
(CALCIUM CHANNEL BLOCKERS):

 Verapamil

 Diltiazem
CALCIUM CHANNEL BLOCKERS
Mechanism and effects

These agents cause a selective

depression of calcium channels
and decrease conduction in AV
node and pacemaker activity. By
decreasing the inward current
carried by calcium, verapamil and
diltiazem slow conduction and
prolong the effective refractory
period in tissues that are dependent
on calcium currents, such as the AV
node.
The major effect of calcium –
channel blockers is on vascular
smooth muscle and the heart.
CALCIUM CHANNEL BLOCKERS
Clinicaluse
Calcium channel
blockers are effective
in AV nodal
arrhythmias, that
must traverse
calcium-dependent
cardiac tissues,
especially in
prophylaxis
(prevention).
Verapamil and diltiazem
are more effective
against atrial than
against ventricular
arrhythmias.
 Hypertension
 Angina pectoris
 MISCELLANEOUS ANTIARRHYTHMIC
DRUGS:
 Digoxin
 Adenosine
 Potassium ion (K+)
 Magnesium ion (Mg2+).
Potassium and magnesium ions have
depressant effects on digitalis-induced
arrhythmias, adenosine is effective in
abolishing AV nodal arrhythmias.
 TOXICITY:

Both hypokalemia and hyperkalemia are

associated with arrhythmogenesis. Severe
hyperkalemia causes cardiac arrest.
Therefore, when treating arrhythmias, serum
potassium should be measured and
normalized if abnormal.
 Potassium ions
Remember!
Pacemaker rate and arrhythmias
involving ectopic pacemaker cells appear
to be more sensitive to changes in serum
potassium concentration, compared with
cells of the sinoatrial node.
 Nondrug (nonpharmacologic)
treatment of arrhythmias
It should be noted that electrical methods of
treatment of arrhythmias have become very
important.
These methods include:
 External defibrillation (cardioversion);
 Implanted defibrillators;
 Implanted pacemakers;
 Radiofrequency ablation of arrhythmogenic
foci via a catheter.
 Therapeutic overview
Na+ channel blockade
β-adrenergic receptor blockade
Prolong repolarization
Ca2+ channel blockade

Adenosine
Digitalis glycosides
 Classification of antiarrhythmics
(based on mechanisms of action)

Class I – blocker’s of fast Na+ channels

 Subclass IA
Cause moderate Phase 0 depression
Prolong repolarization
Increased duration of action potential
Includes
 Quinidine – 1st antiarrhythmic used, treat both atrial and
ventricular arrhythmias, increases refractory period
 Procainamide - increases refractory period but side
effects
 Disopyramide – extended duration of action, used only
for treating ventricular arrthymias
 Classification of antiarrhythmics
(based on mechanisms of action)
 Subclass IB
Weak Phase 0 depression
Shortened depolarization
Decreased action potential duration
Includes
 Lidocane (also acts as local anesthetic) – blocks Na+
channels mostly in ventricular cells, also good for
digitalis-associated arrhythmias
 Mexiletine - oral lidocaine derivative, similar activity
 Phenytoin – anticonvulsant that also works as
antiarrhythmic similar to lidocane
 Classification of antiarrhythmics
(based on mechanisms of action)
 Subclass IC
Strong Phase 0 depression
No effect of depolarization
No effect on action potential duration

Includes
 Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart,
Also inhibits abnormal automaticity

 Propafenone
Also slows conduction
Weak β – blocker
Also some Ca2+ channel blockade
 Classification of antiarrhythmics
(based on mechanisms of action)
Class II – β–adrenergic blockers
 Based on two major actions
1) blockade of myocardial β–adrenergic receptors
2) Direct membrane-stabilizing effects related to Na+ channel blockade

 Includes
Propranolol
 causes both myocardial β–adrenergic blockade and membrane-
stabilizing effects
 Slows SA node and ectopic pacemaking
 Can block arrhythmias induced by exercise or apprehension
 Other β–adrenergic blockers have similar therapeutic effect
Metoprolol
Nadolol
Atenolol
Acebutolol
Pindolol
Stalol
Timolol
Esmolol
 Classification of antiarrhythmics
(based on mechanisms of action)

Class III – K+ channel blockers

 Developed because some patients negatively
sensitive to Na channel blockers (they died!)
 Cause delay in repolarization and prolonged
refractory period
 Includes
Amiodarone – prolongs action potential by delaying K+ efflux
but many other effects characteristic of other classes
Ibutilide – slows inward movement of Na+ in addition to
delaying K + influx.
Bretylium – first developed to treat hypertension but found to
also suppress ventricular fibrillation associated with
myocardial infarction
Dofetilide - prolongs action potential by delaying K+ efflux
with no other effects
 Classification of antiarrhythmics
(based on mechanisms of action)

Class IV – Ca2+ channel blockers

 slow rate of AV-conduction in patients with
atrial fibrillation

 Includes
Verapamil – blocks Na+ channels in addition to
Ca2+; also slows SA node in tachycardia
Diltiazem
 Pacemakers
Surgical implantation of electrical leads attached to a
pulse generator
Over 175,000 implanted per year
1) Leads are inserted via subclavicle vein and advanced to the
chambers on the vena cava (right) side of the heart
2) Two leads used, one for right atrium, other for right ventricle
3) Pulse generator containing microcircuitry and battery are
attached to leads and placed into a “pocket” under the skin
near the clavicle
4) Pulse generator sends signal down leads in programmed
sequence to contract atria, then ventricles
Pulse generator can sense electrical activity generated
by the heart and only deliver electrical impulses when
needed.
Pacemakers can only speed up a heart experiencing
bradycardia, they cannot alter a condition of
tachycardia
Implantation of Pacemaker