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Department of Pharmacology and Toxicology


Faculty of Pharmacy, Misr International University
Outline
I. Introduction (Pacemaker & myocardial Action
Potentials, ECG)
II. Definition and general classification of arrhythmia
III. Abnormal impulse conduction (bradyarrhythmias)
IV. Abnormal impulse generation (mechanism)
V. Classification of antiarrhythmic drugs
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Pacemaker
SA-node
Primary pacemaker
105 impulse/min
Sinus rhythm
AV-node
Secondary pacemaker
45-60 impulse/min
Nodal rhythm
Purkinje System
Tertiary pacemaker
25-40 impulse/min
Idioventricular rhythm
Inhibitory vagal
tone
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Pacemaker Potential
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Contractile myocardium action potential
Phase 0: rapid depolarization due to
rapid Na
+
influx
Phase 1: early partial repolarization
due to K
+
efflux
Phase 2: plateau prolonged
depolarization due to Ca
2+
influx
through slow Ca channels
(depolarizing Ca
2+
)
Phase 3: repolarization due to K
+
efflux without Ca
2+
influx
Phase 4: complete repolarization by
Na
+
/K
+
pump
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The absolute refractory period (ARP): The ventricles can not
respond to any stimuli
The relative refractory period (RRP): The ventricles can respond
to strong stimuli
Supernormal phase of excitability (SNP): The heart respond to
weaker stimuli
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Electrocardiogram (ECG)
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II. What is Arrhythmia?
Abnormal rate or rhythm of heart beats
Abnormal
Impulse Generation
Abnormal
Impulse Conduction
Tachyarrhythmia
Bradyarrhythmia
Heart Block
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III. Abnormal Impulse Conduction
Sinoatrial block (SA block)
No P-wave
Atrioventricular block (AV block)
1
st
degree (prolonged AV conduction)
so PR interval is long
2
nd
degree (regular & irregular)
3
rd
degree
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IV. Abnormal Impulse Generation
(Mechanism)
Ectopic foci: It occurs when cells in the
myocardium or conducting tissue develop a more
rapid phase 4 depolarization than the SA node e.g.
ischaemia
Re-entry circus movement: It occurs when the
impulse arrives at a part of the myocardium that is
refractory to the stimulus because of abnormally
slow repolarization
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Normal and re-entrant electrical pathways:
A. In normal impulse conduction, an impulse traveling down a pathway
arrives at point a, where it is able to travel down two alternate pathways, 1 and 2.
In the absence of re-entry, the impulses continue on and depolarize different areas
of the ventricle.
B. A re-entrant circuit can develop if one of the branch pathways is
pathologically disrupted. When the impulse arrives at point a , it can travel only
down pathway 1 because pathway 2 is blocked unidirectionally (i.e., the effective
refractory period of the cells in pathway 2 is prolonged to such an extent that
anterograde conduction is prohibited). The impulse conducts through pathway 1
and proceeds to point b . At this point, the cells in pathway 2 are no longer
refractory, and the impulse conducts in a retrograde fashion up pathway 2 toward
point a. When the retrograde impulse arrives at point a, it can initiate re-entry,
resulting in a sustained pattern of rapid depolarizations that trigger
tachyarrhythmias. This mechanism can occur over small or large regions of the
heart
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V. Classification of Antiarrhythmic Drugs
According to the effect on myocardial action potential
(Vaughan Williams Classifications):
Class-I: Sodium channel blockers
Class-II: Beta-adrenoceptor blocker
Class-II: Potassium channel blockers
Class-IV: Calcium channel blockers
Miscellaneous
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Class I: Sodium Channel Blockers
Blocking of Na channel rate of depolarization during
phase 0
The central concept in blocking Na channel is that of use-
dependent channel block
In general, the use-dependent characteristics enables
class I to block the high frequency excitation of the
myocardium without preventing the heart from beating at
normal frequencies
They have other function that have been proved by
electrophysiological studies e.g. K+ channel blocking
delay repolarization
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Class Examples Mechanism APD ARP AV
Conduction
Contractility
Ia
Quinidine
Block Na
+
(moderate
dissoc.) & K
+
channels

Procainamide
Disopyramide
Ib
Lignocaine
Mexiletine
Block Na
+
channel
(fast dissoc.) &
opening K
+
channel
- -
Ic
Flecainide
Propafenone
Block Na
+
channel
(slow dissoc.)
- -
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Sodium Channel Blockers (cont.)
Pharmacological effects:
Heart: direct myocardial depressant & atropine-like action
Automaticity: of automatic cells especially ectopic foci > nodal
cells by depressing the slope of phase 4
Rhythmicity (HR): Initial tachycardia due to atropine-like action then
HR by direct suppression of SA node
Excitability: They prolong the RP for all cardiac tissues (SA node,
atria & ventricles) especially ectopic foci
Conductivity: AV conduction at small dose (atropine-like action)
then AV conduction by prolonging the RP
Contractility: -ve inotroipc effect
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Sodium Channel Blockers (cont.)
ECG:
Prolongation of PR interval: AV conduction
QRS Widening: duration of ventricular
systole
If >50% of the original value toxicity
Prolongation of ST segment: Slow ventricular
repolarization
In case of toxicity Torsade de pointes
arrythmia
Abnormal T wave: inverted or depressed
BP:
Quinidine can depress vascular smooth muscle
tone, in part by -receptor blockade PR
and hypotension (at high dose)
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Sodium Channel Blockers (cont.)
Therapeutic uses:
Supraventricular arrhythmias: It is primarily used
chronically and prophylactically to prevent recurrences
of paroxysmal supraventricular tachycardia
Atrial flutter and fibrillation: Quinidine should not
be used without prior digitalization because its vagolytic
action may increase the frequency of impulse
transmission across the A-V node
Ventricular arrhythmias
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Sodium Channel Blockers (cont.)
Side effects and toxicity:
GIT disturbance including nausea, vomiting and anorexia
Quindinecan cause cinchonism
Mild symptoms include tinnitus, haring loss, vomiting and diarrhea
Severe symptoms include headache, diplopia, photophobia, altered perception of
color, confusion and psychosis
-ve inotropic producing hypotension particularly disopyramide
Cardiotoxicity
A-V block
Torsade de pointes arrythmia
CNS toxicity (drowsiness, tremor, confusion & convulsion)
Antimuscarinic effects (urinary retention, dry mouth & blurred vision)
Allergic reaction
Contraindications:
Heart block
Digitalis-induced arrhythmia
Idiosyncrasy hypersensitivity reaction
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Sodium Channel Blockers (cont.)
Class Examples ECG Clinical Uses Side Effects
Ia
Quinidine PR prolongation
QRS widening
QT prolongation
Supraventricular &
ventricular arrhythmia
(broad spectrum)
GIT disturbance
Cinchonism
Atropine-like effects
Hypotension
Allergic reaction
Cardiotoxicity
Procainamide
Disopyramide
Ib
Lignocaine No widening of QRS
Small reduction of
QT
IV only for ventricular
arrhythmia following MI
GIT disturbance
CNS toxicity
Ic
Flecainide
Propafenone
PR prolongation
QRS widening
Life threatening
ventricular arrhythmia
GIT disturbance
Hypotension
CNS toxicity
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Class II: - Blockers
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- Blockers
Pharmacological effects:
The mechanism in arrhythmias is primarily cardiac beta
blockade and reduction of cAMP, which results in the
reduction of Ca
2+
current and the suppression of
abnormal pacemakers
The A-V node is particularly sensitive to -blockers and
PR interval is prolonged
Certain -blockers block Na
+
channel (e.g. propranolol)
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- Blockers (cont.)
Effects on the Heart
1. Decreases S-A node automaticity
2. Decreases A-V node conduction velocity
3. Decreases myocardial contractility
Effects on ECG
Prolong P-R interval (due to decreased AV node
conduction to ventricle)
Therapeutic Use
Supraventricular tachycardia (above the AV
node)
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- Blockers (cont.)
Esmolol, a very short-acting -blocker for iv
administration, is used almost exclusively in acute
surgical arrhythmias
Propranolol, metoprolol and timolol are
commonly used as prophylactic drugs in patients
who have had a myocardial infarction (these drugs
provide a protective effect for two years or more
after the infarct)
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Class III: Potassium channel blockers
E.g. Amiodarone, Bretylium& Sotalol
Effects on the Heart
1. Delays repolarization
2. Prolongs action potential duration
3. Prolongs ARP
4. Also they have -blocking activity
Effects on ECG
Prolongs QT interval
Therapeutic Use
Ventricular tachycardia and
fibrillation
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Potassium channel blockers (cont.)
Amiodarone may be considered the most efficacious
antiarrhythmic drug
It has a broad spectrum: it blocks sodium, calcium and
potassiumchannels and beta adrenoceptors
Because of its toxicity, amiodarone must be reserved for use
in arrhythmias that are resistant to other drugs
Amiodarone causes thyroid dysfunction, microcrystalline
deposits in the cornea & skin, pulmonary fibrosis and
hepatotoxicity
Amiodarone rarely causes newarrhythmia
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Class IV: Calcium channel blockers
Effects on the Heart
1. Reduction of S-A node automaticity
2. Reduction of A-V node conduction velocity
3. Reduction of myocardial contractility (less Ca)
Effects on ECG
Prolongs PR interval
Therapeutic Use
Supraventricular tachycardia
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Calcium channel blockers (cont.)
e.g. Verapamil and Diltiazem
Verapamil was the drug of choice in treating atrioventricular
nodal reentry (also known as nodal tachycardia) until
discovering adenosine
Because of its effects on the A-V node, verapamil should not
be used in patients with A-V nodal dysfunction
Verapamil can depress myocardial contractility; therefore, it
is contraindicated in patients with CHF
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Miscellaneous antiarrhythmic drugs
Adenosine
It is a normal component of the body, but when it is
given in high doses as an IV bolus, the drug markedly
slows conduction in the atrioventricular node, probably
by reducing calcium current
Adenosine is extremely effective in abolishing A-V nodal
arrhythmia and, because of its very low toxicity, has
become the drug of choice for this arrhythmia
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Miscellaneous antiarrhythmic drugs (cont.)
Digitalis:
In atrial flutter or fibrillation, digitalis slows A-V
conduction sufficiently to protect the ventricles from
excessive high rates
The later applications of digitalis become less common
since the development of calcium channel blockers and
adenosine as antiarrhythmic drugs
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