Download CVS 4 Anti arrhy

ANTIARRHYTHMIC
DRUGS
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INTRODUCTION
• The heart contains specialized cells that exhibit
automaticity; that is, they can generate rhythmic
action potentials in the absence of external stimuli
• This phenomenon of automaticity is carried out by
the “pacemaker” cell that spreads the
depolarization from the SA node → AV node →
Bundle of His → Purkinje cells
• Dysfunction of impulse generation or conduction at
any level in the heart can cause an abnormality in
cardiac rhythm called Arrhythmia
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Types OF Arrhythmia
• Altered Rate
• Premature beats
• Altered Conduction
• http://www.cvpharmacology.com/clinical%20topi
cs/arrhythmias-2
• http://www.skillstat.com/tools/ecg-simulator
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Reentry
For reentry to occur, certain
conditions must be met that
are related to the following:
1) the presence of a
unidirectional block within
a conducting pathway
2) critical timing
3) the length of the effective
refractory period of the
normal tissue
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CONSEQUENCES OF ARRHYTHMIA
• Cause the heart to beat too slowly
• To beat too rapidly (vent tachycardia, atrial
flutter
• To respond to impulses originating from sites
other than the SA node
• To respond to impulses traveling along
accessory pathways that lead to deviant
depolarization
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Action Potential in cardiac &HisPurkinje system
Plateau Phase (Opening of Ca-Na Channels
and Decrease K permeability)
+ 20 mV
Depolarization Phase
(Opening of Fast Na
Channels)
- 80 mV
Repolarization Phase
(Opening of K Channels)
0.2 to 0.3 sec
Resting Membrane Potential
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PHASES OF AP in Fast fibers
• Phase 0 - depolarization - opening of Na channels(
fast sodium current)
• Blocked by class I drugs
• phase 1 – Inactivation of Na channels,
• phase 2 – Plateau phase -- slow but prolonged
opening of Ca channels balanced by late outward K⁺
current.
• Phase 3 – Final repolarization – closure of Ca
channels and rapid K efflux.
• Blocked by class III drugs
• Phase 4 ---- return of membrane to resting potential
by the activity of Na⁺/K⁺-ATPase
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Three ion channel
mechanisms contribute to
the pacemaker potential –
The first is a progressive
reduction in potassium
permeability.
Second is presence of
funny channels.
Third is presence of
T-type calcium channels
(T transient).
ANS Regulation of Heart Rate
• SA & AV nodes are innervated by both PANS &
SANS fibers activating M2 & b1 receptors
respectively.
• Phase 4 slope increased by increase cAMP (b1
activation) & slowed by decrease cAMP (M2
activation).
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CLASSES OF DRUGS
• CLASS I ANTIARRHYTHMIC DRUGS
• CLASS II ANTIARRHYTHMIC DRUGS
• CLASS III ANTIARRHYTHMIC DRUGS
• CLASS IV ANTIARRHYTHMIC DRUGS
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Class I – (Na CHANNEL
BLOCKERS)
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Effects on depolarization
Effects on repolarization
Effects on automaticity
Indirect vagal effects
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Na+ Channel Blockers - Class IA
• Decrease Vmax(phase 0) via block of fast Na
channels in the open or activated state
• Increase APD & Effective Refractory Period
(ERP)
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QUINIDINE
• Increase HR & AV conduction due to
its muscarinic blockade
• Vasodilation due to blockade of alpha
receptor → hypotension
• orally effective
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THERAPEUTIC USES
• WIDE RANGE
• A-Fib, Ventricular tachyarrhythmias
• MAINTAIN NORMAL RHYTHM AFTER
CARDIOVERSION
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Adverse effects
• nausea & vomiting,
• cinchonism (GI, tinnitus, ocular dysfunction,
CNS excitation),
• syncope due to prolongation of QT interval
(torsades), AV & SA block
• At toxic doses: ventricular tachycardia.
• Interactions: hyperkalemia increases its
cardiotoxicity; enhances digoxin toxicity;
Decrease effects of AChE inhibitors in
myasthenia.
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PROCAINAMIDE
• CLASS 1A
• DERIVATIVE OF LOCAL ANAESTHETIC
PROCAINE
• ADVANTAGES
• LESS ANTIMUSCARINIC EFFECTS
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Pharmacokinetics
• Well absorbed via oral route
• Short half-life
• Metabolized via N-acetyltransferase to Nacetyl procainamide (NAPA), an active
metabolite
• NAPA is eliminated via the kidney
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SIDE EFFECTS
• SLE LIKE SYNDROME, Hematotoxic
• CNS effect: DEPRESSION, HALLUCINATIONS, &
PSYCHOSIS.
• CVS: TORSADES
• Toxic dose: ASYSTOLE, ventricular arrhythmia
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DISOPYRAMIDE
• CLASS I A
• NEGATIVE IONOTROPIC
• ANTI MUSCARINIC EFFECT – GREATER
• SIDE EFFECTS
• ANTICHOLINERGIC EFFECTS
• NOT FIRST LINE DRUG. USED AS AN ALTERNATIVE TO OTHER
CLASS 1A DRUGS
• CI: in patients with heart failure
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Na+ Channel Blockers - Class IB
• Decrease Vmax –
• block fast Na+ channels in the
inactivated state - preference for
tissues partly depolarized
(ischemic or hypoxic tissues)
• Decrease APD( blockade of slow
Na⁺ window current in the
plateau)
• (SHORTENS PHASE 3
REPOLARISATION)
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• ROUTE – I.V.
• EXTENSIVE FIRST PASS METABOLISM preclude
oral use.
• USES : arrhythmias during an MI, & DOC (Drug
Of Choice) for arrhythmias following
attempted cardioversion.
• MC : VENTRICULAR ARRHYTHMIAS
• Digoxin toxicity
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Lidocaine
• Adverse effects: CNS toxicity culminating in
seizures.
• Least cardiotoxic of conventional
antiarrhythmics.
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OTHER CLASS 1 B
• MEXILETINE
• TREATMENT OF VEN. ARRHY. MOSTLY WITH
PAST H/O OF MI.
• Side effects:
• Epigastric burning:
• nausea (common)
• Neurologic side effects:
– diplopia, vertigo, slurred speech, tremor
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CLASS 1B
• TOCAINIDE - VTA
• SIDE EFFECTS
• fatal bone marrow aplasia
• pulmonary fibrosis.
• RARELY USED
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Na+ Channel Blockers - Class IC
• Decrease Vmax - block fast Na+ channels in all
states
• No effect on APD
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CLASS 1 C - FLECAINIDE
•
•
•
•
•
Na channel blocker at all states
SLOWS PHASE O
NEGATIVE IONOTROPIC EFFECT
CI : HEART FAILURE-CAN INDUCE V TAC (proarrhythmic)
SIDE EFFECTS : DIZZINESS, BLURRED VISION
• USES : reserved for management of life-threatening
arrhythmias or refractory VA
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CLASS II ( BETA BLOCKERS)
• Decrease SA & AV nodal activity
• Decrease slope of phase 4 (diastolic currents)
of AP in pacemakers
• prevent b1 adrenoceptors activation which
would normally increase cAMP
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• Propranolol (non-selective) &
• cardioselective drugs –
acebutolol,
metoprolol
esmolol
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• Rx uses:
• prophylaxis post-MI & in SVTs & Atrial
arrhythmias;
• esmolol (IV) is used in acute SVTs.
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Class III (K+ Channel Blockers)
• Increase APD & ERP especially in Purkinje &
ventricular tissues
• Decrease IK (delayed rectifier current) slowing
phase 3 of AP.
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CLASS III ( K CHANNEL BLOCKERS)
• AMIODARONE
• Dofetilide
• SOTALOL
• PROLONGS PHASE 3 REPOLARIZATION
• BLOCKS K OUTLFOW, ↑ APD & ERP
• All class III drugs prolong QT-interval except
Amiodarone
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SOTALOL
• β₁ blocker but acts as a K⁺ channel blocker
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USES:
Treatment of life threatening arrhythmia
SUPPRESS ECTOPIC BEATS
DECREASES rate of sudden death following
an acute MI & IN PTS with SUSTAINTED
VENT. TACHYCARDIA.
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AMIODARONE
• Both antianginal & antiarrhythmic activity.
• Shows actions of class I, II, III, IV .
• Does not prolong the QT-interval
• Use:
• in treatment of severe refractory Supraventricular and
VTA.
• SE: GI intolerance , photosensitivity, ataxia, blue skin
discoloration, tremor, dizziness, liver toxicity, pul.
Fibrosis hepatotoxicity, hypo/hyperthyroidism.
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CLASS IV (Ca Channel blockers)
• Verapamil
• Diltiazem
• Decrease the influx of Ca²⁺ – decrease the
rate of phase 0 depolarization and phase 4
spontaneous depolarization
• Decrease conduction velocity
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USES
• Used in treatment of atria than ventricular
arrhythmia
• SVTs of nodal arrhythmias
• They also have effect on the vascular smooth
muscle and the heart.
• So can be used in treatment of hypertension
also.
• CI: in pts with depressed heart function
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SE:
• GI distress: CONSTIPATION
• dizziness
• flushing
• Hypotension
• AV block
• Interaction: Verapamil displaces digoxin from
binding sites
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Other drugs: ADENOSINE
1. Activates adenosine receptor
2. Gi-coupled decreasing cAMP
• Decrease SA and AV nodal activity
• USES:
• Used mainly for the abolishing paroxysmal
Supraventricular tachycardia( IV route )
• AV nodal arrhythmia
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• Possible side effects - flushing, sedation &
dyspnea , bronchospasm
• Antagonized by theophylline.
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• DIGOXIN
• Prolongs ERP
• Diminishes conduction velocity in purkinje
fibers.
• Can be used in atrial fib and flutter.
• Toxic dose: results in ventricular tachycardia
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