Download Antiarrhythmic Drugs

Arrhythmias
 These are drugs used to prevent or treat irregularities of cardiac rhythm.
 Arrhythmias are the most important cause of sudden cardiac death.
Types :
 extra beats (extrasystoles):
 premature atrial contractions
 premature ventricular contractions
 supraventricular tachyarrhythmias:
 atrial fibrillation (irregular heart rates of 350 to 700 bpm)
 atrial flutter( ’flutter waves’ at a regular rate of 240 to 440 bpm)
 paroxysmal supraventricular tachycardia (150-200 bpm)
 ventricular arrhythmias:
 ventricular fibrillation (fatal unless reverted within 2–5 min; the most
common cause of sudden cardiac death)
 ventricular tachycardia
 Torsades de pointes (twisting of points) is a life-threatening form of
ventricular tachycardia with rapid asynchronous complexes and an
undulating baseline on ECG. It is generally associated with long Q-T
interval.
 bradyarrhythmias
Phases of a cardiac action potential.
 The sharp rise in voltage ("0") corresponds to the influx of Na ions
 The decay ("1”) corresponds to the Na-channel inactivation, efflux
of K+ ions
 The plateau ("2") results from the opening of Ca2+channels.
 The decay ("3") corresponds to the repolarizing efflux of K+ ions.
Phases of a cardiac action potential
 Phase-0 - rapid depolarization
 Phase-1 – repolarization
 phase-2 - plateau phase
 Phase-3 - rapid repolarization
 Phase-4 – stable phase or resting membrane potential
Refractory period
 Effective refractory period (ERP) is the minimum
interval between two propagating APs or from the
beginning of phase 0 until phase 3, during which it is
impossible to evoke another action potential.
Mechanisms of cardiac arrhythmias
Enhanced/ectopic pacemaker activity
Ectopic impulse may be increased pathologically in the automatic fibres or
such activity may appear in ordinary fibres.
B. Triggered activity
These are secondary depolarizations accompanying a normal or premature
action potential (AP).
 Early after-depolarization
Repolarization during phase-3 is interrupted and membrane potential
oscillates. If the amplitude of oscillations is sufficiently large, neighbouring
tissue is activated and a series of impulses are propagated.
 Delayed after-depolarization
After attaining resting membrane potential (RMP) a secondary deflection
occurs which may reach threshold potential and initiate a single premature
AP.
A.
Mechanisms of cardiac arrhythmias
C. Re-entry
 Due primarily 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. These are called
reentrant arrhythmias.
 Class I: Fast Na-channel blockers
 Class II: Beta blockers(decreases slope of phase 4)
 Class III: K-channel blockers(prolongs phase 3)
 Class IV: Slow Ca-channel blockers(prolongs phase 2)
 Variable mechanism:
Adenosine
Digoxin
Magnesium sulf.
CLASS I
 Class I: Fast Na-channel blockers
 Ia -Quinidine, procainamide,
disopyramide (depress phase 0,
prolonging repolarization)
 Ib -Lidocaine, phenytoin, mexiletine
(depress phase 0 selectively in
abnormal/ischemic tissue, shorten
repolarization)
 Ic -Flecainide, propafenone,
moricizine (markedly depress phase
0, minimal effect on
repolarization)
See the phase 3 of the curve to
apply the mnemonic:
IB antiarrhytmics show the
line Before the (normal) face.
IA antiarrhytmics show the
line After the (normal) face.
IC antiarrhytmics show the
line Cara (spanish world of
face), because is the same as
normal in phase 3.
Clinical uses in cardiology
Ia
 Ventricular arrhythmias
 prevention of paroxysmal recurrent atrial
fibrillation (triggered by vagal overactivity)
 procainamide in Wolff-Parkinson-White
syndrome
 Increases QT interval
ADR
 Risk of torsades de pointes !!!
 neurological effects (ringing in ears, vertigo)
 Marked fall in BP
 Synergistic cardiac depression with β-blockers,
verapamil, K+ salts.
Clinical uses
Ib
 only for ventricular tachycardia (VT)
(inefficacy in atrial arrhythmias)
 treatment and prevention VT during and
immediately after myocardial infarction
ADR
 Proarrhythmic potential !!!
 neurological effects(paresthesias, blurred
vision)
Clinical uses
Ic
 prevents paroxysmal atrial fibrillation
 treats recurrent tachyarrhythmias of
abnormal conduction system.
 contraindicated immediately postmyocardial infarction.
ADR
 High proarrhythmic potential
 Sudden deaths
CLASS II
Class II agents include:
 Atenolol
 Esmolol
 Propranolol
 Metoprolol
Uses
 prevent and treatment of
supraventricular
tachyarrhythmias
 decrease myocardial
infarction mortality
They act by:
 blocking the β1-adrenergic
receptors,
 decreasing sympathetic
activity on the heart.
 decrease conduction
through the AV node.
CLASS III
Class III: Potassium (K) channel blockers
 Amiodarone (prolongs phase 3; also acts on
phases 1, 2, and 4)
 Sotalol (prolongs phase 3, decreases slope of
phase 4)
 Ibutilide (prolongs phase 3)
 Dofetilide (prolongs phase 3)
The characteristic action of this class is:
 prolongation of repolarization (phase-3);
 AP is widened
 ERP is increased.
Amiodarone
 Iodine containing highly lipophilic
Side effects:
long-acting antiarrhythmic drug
 Pulmonary fibrosis
exerts multiple actions: Amiodarone  Hypothyroidism
has Class I, II, III & IV activity
 Hyperthyroidism
 It accumulates in muscle and fat.
 Corneal micro-deposits
 The duration of action is
 Blue-grey discoloration of
exceptionally long: t½ 3–8 weeks
the skin
 It is useful both in supraventricular
 Photosensitization
arrhythmias and ventricular
 Peripheral neuropathies
arrhythmias (e.g. ventricular
fibrillation, ventricular tachycardia,  Possible association
atrial fibrillation)
between amiodarone and
an increased risk of cancer
 Fall in BP
 Bradycardia
 Myocardial depression
CLASS IV
Calcium (Ca) channel blockers
 Verapamil (prolongs phase 2)
 Diltiazem (prolongs phase 2)
 They decrease conduction through the AV node
 They thus reduce the contractility of the heart, so may
be inappropriate in heart failure.
 Poor /no efficacy in ventricular arrhythmias
Uses:
 paroxysmal supraventricular tachycardia
 reduce ventricular rate in patients with atrial fibrillation.
ADR
 bradycardia, A-V block, cardiac arrest and hypotension
Class V / Other agents
Digoxin
 decreases conduction of electrical impulses through
the AV node and increases vagal activity.
Adenosine
 Is used intravenously for terminating supraventricular
tachycardias (PSVT).
Magnesium sulfate
 an antiarrhythmic drug, but only against very specific
arrhythmias which has been used for torsades de
pointes.
Adenosine
 Very short t½ ~ 10 sec
Uses :
 Termination of attack of PSVT
Advantages of adenosine:
 Efficacy equivalent to or better than verapamil.
 Action lasts < 1 min
adverse effects are transient.
 Can be given to patients with hypotension, CHF or
those receiving β blockers. Verapamil is
contraindicated in these situations.
 Effective in patients not responding to verapamil.
ADR
 Transient dyspnoea, chest pain, fall in BP, cardiac
arrest
Digoxin
Indications:
 atrial fibrillation
 atrial flutter
 By slowing down the conduction in the AV node and
increasing its refractory period, digoxin can reduce the
ventricular rate.
 The arrhythmia itself is not affected, but the pumping
function of the heart improves, owing to improved
filling.
Clinical classification of antiarrhythmic drugs
Bradyarrhythmias and A-V Block
Treatment of chronic heart block - implanted cardiac
pacemaker.
For acute/transient A-V block :
 Atropine
Atropine abbreviates A-V node ERP and increases
conduction velocity in bundle of His.
 Adrenomimetics (Adr, isoprenaline)
 These drugs may overcome partial heart block by
facilitating A-V conduction and shortening ERP of
conducting tissues.
 They may also be used in complete heart block to maintain
a sufficient idioventricular rate (by increasing automaticity
of ventricular pacemakers) till external pacemaker can be
implanted.