Transcript ANTIARRHYTHMIC DRUGS

ANTIARRHYTHMIC DRUGS
• Arrhythmia/ 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
Mechnisms of Arrhythmogenesis
I. Abnormal Impulse
Generation
II. Abnormal Impulse
Conduction
A. Automatic rhythms:
- Enhanced normal
automaticity
- Abnormal automaticity
B. Triggered rhythms
-Early & Delayed afterdepolarisation
A. Conduction block
First-, second-, third–degree
block
B. Re-entry
- Circus movement
- Reflection
Normal To Pathologic cardiac Rythm
Specific Arrhythmias
 Supraventricular Arrhythmias
 Sinus tachycardia - high sinus rate of 100-180 beats/min
as occurs during exercise or other conditions that lead to
increased SA nodal firing rate
 Atrial tachycardia - a series of 3 or more consecutive
atrial premature beats occurring at a frequency
>100/min;
 Paroxysmal atrial tachycardia (PAT) of sudden onset,
disappearance
 Atrial flutter - sinus rate of 250-350 beats/min.
 Atrial fibrillation - uncoordinated atrial depolarizations.
 AV blocks - a conduction block within the AV node (or
occasionally in the bundle of His) that impairs impulse
conduction from the atria to the ventricles
 Ventricular premature beats (VPBs) - caused by
ectopic ventricular foci; characterized by widened QRS.
 Ventricular tachycardia (VT) - high ventricular rate
caused by aberrant ventricular automaticity or by
intraventricular reentry; can be sustained or nonsustained (paroxysmal); characterized by widened QRS;
rates of 100 to 200 beats/min; life-threatening.
 Ventricular flutter - ventricular depolarizations >200/min.
 Ventricular fibrillation - uncoordinated ventricular
depolarizations
Pharmacologic Rationale & Goals
The ultimate goal of antiarrhythmic drug therapy:
o Restore normal sinus rhythm and conduction
o Prevent more serious and possibly lethal
arrhythmias from occurring.
 Antiarrhythmic drugs are used to:
 decrease conduction velocity
 alter the excitability of cardiac cells by changing
the duration of the effective refractory period
 suppress abnormal automaticity
Pharmacologic Rationale
 Some drugs block fast sodium channels that determine how fast the
membrane depolarizes (slope of phase 0, Vmax) & conduction velocity
 Sodium channel blockers (Group I) reduce conduction velocity to
abolish tachyarrhythmias caused by reentry circuits
 Antiarrhythmic drugs affect cardiac refractoriness by changing
ERP/APD via potassium channels and delay repolarization of action
potentials (phase 3)
 This would inhibit reentry tachycardias
 Slow inward Ca channel blockers reduce SAnodal firing rate by
slowing the rate of rise of depolarizing pacemaker potentials (phase
4 depolarization)
 These drugs also reduce conduction velocity Ca-dependant tissue
including the AV & SA nodal cells
 Blockers of beta1-adrenoceptors can indirectly alter membrane ion
conductance, particularly calcium and potassium conductance
ANTIARRHYTHMIC DRUGS
• Most antiarrhythmic
drugs are proarrhythmic
• Only ß-blockers are
proved to reduce
mortality in postmyocardial infarction
patients
• They are classified
according to Vaughan
William into four
classes according to
their effects on the
cardiac action
potential
Class
I
Basic Mechanism/Actions
Na+ Channel blockade
IA
- moderate
Moderate reduction in phase 0
slope; increase APD/ERP.
IB
- weak
IC
- strong
II
β-ADR
blockers
Small reduction in phase 0
slope; reduce APD/ ERP
Pronounced reduction in phase
0 slope; no effect on APD/ERP
Block sympathetic activity;
reduce rate & conduction
III
K+-channel
blockade
IV
Delay re-polarization (phase 3),
increase APD/ERP
2+
Ca2+channel L-Ca channel blockade most
effective at SA & AV nodes;
blockade
reduce rate and conduction
1. Class I ANTIARRHYTHMIC DRUGS
Na+-Channels Blockers
• Drugs in this class are blockers of voltage-operated
fast Na+ channels in the myocardial membrane
• They show (class IA & IB) preferential selectivity to
Na+ channels in the open or inactivated closed states
• Hence, they have better degree of blockade in
tissues that are frequently depolarized or usedependent or state-dependent
• They decrease conduction velocity in non-nodal tissue
(atrial and ventricular muscle, purkinje conducting
system)
• Group IA drugs have additionally moderate K+
channel blockade
Class IA Drugs
Quinidine, Procainamide, Disopyramide
• Class IA agents slow the
phase 0/reduction of Vmax of
the cardiac action potential
(conduction velocity)
• They prolong muscle action
potential & ventricular
effective refractory period
(refractoriness)
• They decrease the slope of
Phase 4 spontaneous
depolarization, tending to
suppress enhanced normal
automaticity-induced
arrhythmias
Class IA Drugs
• They possess intermediate rate of association and
dissociation with sodium channels
• Pharmacokinetics:
• Procainamide has good oral bioavailability
• Procainamide is frequently used as IV slow route to
avoid hypotension
• Procainamide is metabolized into N-acetylprocainamide
(NAPA), an active class III meatbolite mailnly cleared via
the kidney, (dose adjustment in kidney failure)
• Quinidine has good oral bioavailability & metabolized
mainly in liver
Class IA Drugs Uses
• Class IA drugs are effective in treatment of both
supraventricular and ventricular arrhythmias
• Quinidine rarely used for supraventricular arrhythmias
• Oral quinidine/procainamide are used with class III
drugs in refractory ventricular tachycardia patients with
implantable defibrillator
• IV procainamide used for hemodynamically stable
ventricular tachycardia
• IV procainamide used for acute conversion of atrial
fibrillation including WPW syndrome
Class IA Drugs Toxicity
Quinidine
• A-V block at higher plasma levels
• At toxic levels, ventricular tachycardia
and torsade de pointes ventricular
arrhythmia
• Increasing digoxin plasma
concentration by displacing digoxin
from binding sites in addition to
decreased digoxin renal clearance
• Cinchonism occurs at large dose levels
(blurred vision, tinnitus, headache,
psychosis and gastrointestinal upset)
• Digoxin is administered before
quinidine to prevent the conversion of
atrial fibrillation or flutter into
paradoxical ventricular tachycardia.
Quinidine shortens of A-V nodal
refractoriness by atropine-like effects
Procainamide
 At high levels, asystole or induction of
ventricular arrhythmias
 Hypersensitivity reactions including drug fever
and rarely agranulocytosis.
 Systemic lupus erythromatosus (SLE)-like
(arthralgia, fever & pleural-pericardial
inflammation)
 The SLE is dose- and time-dependent, and
usually disappears upon drug stop
 It is most common in patients with slow hepatic
acetylation resulting in higher plasma level of
the parent drug
Disopyramide
• 1. Anticholinergic side-effects
• 2. Induction of ventricular arrhythmias in
patients with prolonged QT interval
• 3. Similar to quinidine, disopyramide may induce
ventricular arrhythmia if used alone in the
treatment of fibrillation
Class IB Drugs
• They shorten Phase 3
repolarisation and decreases
the duration of the cardiac
action potential
• They suppress arrhythmias
caused by abnormal
automaticity (c.f. quinidine
suppresses enhanced normal
automaticity-induced
arrhythmias)
 They show rapid association
& dissociation with Na+
channels with appreciable
degree of use-dependence
Agents of Class IB
Lidocaine
• It should be used by intravenous
route because of its extensive
first-pass metabolism
• Lidocaine is the drug of choice in
emergency treatment of
ventricular arrhythmias
Mexiletine and tocainide
• These are the oral analogs of
lidocaine
• Mexiletine is used for chronic
treatment of ventricular
arrhythmias associated with
previous myocardial infarction
• Tocainide is used for ventricular
tachyarrhythmias but its use is
limited by its pulmonary toxicity
that may lead to pulmonary
fibrosis
Uses
They are used in the treatment of ventricular arrhythmias arising during
myocardial ischemia or due to digoxin toxicity
They have little effect on atrial or AV junction arrhythmias
Class IC Drugs
• They markedly slow Phase 0 fast
depolarization
• They possess slow rate of association
and dissociation with sodium channels
• They markedly slow conduction in the
myocardial tissue
• They only have minor effects on
duration of action potential and
refractoriness
• They reduce automaticity by increasing
the threshold potential rather than
decreasing the slope of Phase 4
spontaneous depolarization
Class IC Drugs
• Agents of Class IC: Flecainide & propafenone
• Uses:
 They are broad-spectrum but only approved for refractory
ventricular arrhythmias
 Flecainide is a particularly potent suppressant of premature
ventricular contractions
• Toxicity and Cautions for Class IC Drugs:
 They are severe proarrhythmic drugs causing severe worsening of
a preexisting arrhythmia or de novo occurrence of lifethreatening ventricular tachycardia
 In patients with frequent PVCs following MI, flecainide increased
mortality compared to placebo
Notice: Class 1C drugs are particularly of low safety and have
shown even to increase mortality when used chronically after
MI
Class II ANTIARRHYTHMIC DRUGS
(β-adrenergic blockers)
Uses
β-Adrenergic blockers
produce both negative
• They are used in treatment
inotropic & chronotropic
of increased sympathetic
effects
activity-induced
arrhythmias such as stress• They diminish phase 4
and exercise-induced
spontaneous
arrhythmias
depolarization suppressing
automaticity and
• Treatment of atrial flutter
prolonging AV conduction
and fibrillation
• AV nodal tachycardia
Class II ANTIARRHYTHMIC DRUGS
• Propranolol: was proved to reduce the incidence of
sudden arrhythmatic death after myocardial infarction
• Metoprolol & Pindolol
 Metoprolol and other selective β1-adrenergic blockers
reduce the risk of bronchospasm
 Pidolol, having additional partial agonistic activity, may
decrease the frequency of cardiac failure
• Esmolol:
 Esmolol is a very short-acting β1-adrenergic blocker
that is used in the by intravenous route in acute
arrhythmias occurring during surgery or emergencies
Class III ANTIARRHYTHMIC DRUGS
• Class III antiarrhythmic drugs prolong phase 3
depolarization, without altering phase 0
upstroke or the resting membrane potential
• They prolong both the duration of the action
potential and the effective refractory period
(ERP)
• Their mechanism of action is still not clear but
it is thought that they block potassium
channels
Class III ANTIARRHYTHMIC DRUGS
• Drugs of Class III:
Sotalol, bretylium, amiodarone, ibulitide
• Uses:
They are used in the treatment of ventricular
arrhythmias, especially ventricular fibrillation or
tachycardia
Supra-ventricular tachycardia
Amiodarone usage is limited by its wide range
of side effects
Class III ANTIARRHYTHMIC DRUGS
Sotalol (Sotacor)
• Sotalol is a β-adrenergic blocker that also prolongs the duration of
action potential and refractoriness in all cardiac tissues
• Sotalol suppresses Phase 4 spontaneous depolarization and possibly
producing severe sinus bradycardia
• The β-adrenergic blockade combined with prolonged action
potential duration may of special efficacy in prevention of sustained
ventricular tachycardia
• It may induce the polymorphic torsade de pointes ventricular
tachycardia
Bretylium
• It is generally administered parenteraly because of poor GIT
absorption
• Long-term oral use is associated with painful parotid enlargement as
well as severe postural hypotension
Class III ANTIARRHYTHMIC DRUGS
Amiodarone (Cordarone)
• Amiodarone is a drug of multiple actions and not well understood
• It is extensively taken up by tissues, especially fatty tissues, and has a half-life of up
to 60 days
• Amiodarone antiarrhythmic effect is complex comprising class I, II, III, and IV
actions
• Prolongation of action potential duration and refractoriness is the main
• It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak βadrenergic blocker
• Amiodarone Toxicity
 Amiodarone has wide-spectrum toxicity
 Most common include GI intolerance, tremors, ataxia, dizziness, hyper-or
hypothyrodism
 Corneal microdeposits may be accompanied with disturbed night vision
 Other common side effects include liver toxicity, photosensitivity, gray facial
discoloration, neuropathy, muscle weakness, and weight loss
 The most dangerous side effect is pulmonary fibrosis which occurs in 2-5% of the
patients
Class IV ANTIARRHYTHMIC DRUGS
(Calcium Channel Blockers)
• Calcium channel blockers decrease inward Ca2+
currents resulting in a decrease of phase 4
spontaneous depolarization
• They slow conduction in Ca2+ currentdependent tissues like AV node
• Verapamil and diltiazem, but not nifedipine (or
the other dihydropyridine Ca2+ antagonists), are
representative of this class being more effective
on the heart than blood vessels
Class IV ANTIARRHYTHMIC DRUGS
• Verapamil and diltiazem bind only to open
depolarized voltage-operated Ca2+ channels, and
hence preventing re-polarization until the drug
dissociates from the channels.
• Therefore, they are use-dependent blocking rapidly
beating heart since in a normally-paced heart, Ca2+
channels have enough time to repolarize and the
drug to dissociate from the channel before the next
conduction cycle
• Verapamil and diltiazem slow conduction and
prolong effective refractory period in Ca2+ currentdependent tissues like AV node
Class IV ANTIARRHYTHMIC DRUGS
Verapamil & diltiazem are more effective in treatment
of atrial than ventricular arrhythmias.
They are used in treatment of supra-ventricular
tachycardia preventing the occurrence of ventricular
arrhythmias
They are used in treatment of atrial flutter and
fibrillation
Both drugs are contraindicated patients with preexisting depressed heart function because of their
negative inotropic activity
Both drugs may cause bradycardia, and asystole
especially when given in combination with β-adrenergic
blockers
Miscellaneous Antiarrhythmic Drugs
o
o
o
o
Adenosine
Adenosine activates A1-purinergic receptors
decreasing the SA nodal firing and automaticity,
reducing conduction velocity, prolonging effective
refractory period, and depressing AV nodal
conductivity
It is the drug of choice in treatment of paroxysmal
supra-ventricular tachycardia
It is used only by slow intravenous bolus
It has only low-profile toxicity being ultra-short
acting of 15 seconds duration
• Compare between class
IA, IB, and IC drugs as
regards effect on Na+
channel & ERP
• Sodium-channel blockade:
IC > IA > IB
• Increasing the ERP:
IA>IC>IB (lowered)