antiarrhythmic drugs
TRANSCRIPT
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ANTIARRHYTHMIC DRUGS
Dr. Kunal A. Chitnis1st Year Resident
TNMC, Mumbai
17th September 2010
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SA Node fires at 60-100 beats/sec
Spreads through atria
Enters the AV Node(Delay of 0.15 sec)
Propagates through His Purkinje system
Depolarizes ventricles beginning from endocardial surface of apex to
epicardial surface of base
Normal Sinus Rhythm
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Movement of ions across cell membrane
• Ions move across in response to electrical and concentration gradients
• Pass through specific ion channels or transporters
• The Equilibrium/Reversal potential is given by the
Nerst equation:
Eion= - 61Log(Ci/Ce)
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• The Resting Membrane Potential of the cell is -95mV
• The cell maintain this transmembrane ionic gradient by
1. Active mechanisms like the Na+ pump and Na+/K+ ATPase (Electrogenic)
2. Fixed anionic charges within the cell
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No Net movement
Net movement inside the cell
EK -94 ENa +65
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Phase 0:RapidDepolarisation
(Na+ influx)
Phase 1:Early Repolarisation(Inward Na+ current
deactivated,Outflow of K+):
Transient Outward Current
Phase 2:Plateau Phase
(Slow inward Ca2+ Current balanced by outward delayed rectifier K+ Current)
Phase 3:Late Repolarisation
(Ca 2+current inactivates,K+ outflow)
Action Potential of Cardiac Muscle
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Action Potential of SA Node
RMP not stable and full repolarisation at -60mV
Spontaneous Depolarisation occurs due to:
• Slow, inward Ca2+ currents• Slow, inward Na+ currents called “Funny Currents”
-50mV T-type Ca2+ channels
-40mV L-type Ca2+ channels
-35mV
Phase 3:Repolarisation
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Action Potential in AV Node
• Very similar to SA Node
• Causes delay of conduction
• It gives time for atrial contraction and filling of the ventricles.
• Site of action of many antiarrhythmics
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Regulation by autonomic toneParasympathetic/Vagus Nerve stimulation:
• Ach binds to M receptors, releasing G protein βγ subunits
• Activate Ach dependent K+ current
• ↓ slope of Phase 4
Sympathetic stimulation:
• Activation of β1 receptors
• Augmentation of L-type Ca2+ current and funny currents
• ↑ slope of Phase 4
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Refractoriness
• Effective/Absolute Refractory period: During this period, depolarization on adjacent cardiac muscles does not produce a new depolarization.
• Protective mechanism and keeps the heart rate in check, prevents arrhythmias and coordinates muscle contraction
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• During the plateau phase, max Na+ channels are in inactivated state, therefore refractory
• Upon repolarisation, recovery occurs from the inactivation state to closed state
• Only channels in closed state can be depolarised• It extends from phase 0 uptill sufficient recovery
of Na channels. • Changes in the ERP:
1. Altered recovery from inactivation
2. Action Potential Duration alteration
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ERP of Fast responsive tissue
• Dependent on Na+ channels recovery
• Voltage dependent
ERP of Slow Responsive/ Nodal tissue
• Dependent on Ca2+ channels recovery
• Time dependent/ decremental response
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Cardiac Arrhythmias
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Arrhythmia means an Abnormal heart rhythm
Results from the abnormalities of:
Impulse generation (Rate or Site of origin)
Conduction Both
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Classification of Arrhythmias1. Characteristics:
a. Flutter – very rapid but regular contractionsb. Tachycardia – increased ratec. Bradycardia – decreased rated. Fibrillation – disorganized contractile activity
2. Sites involved:
a. Ventricularb. Atrialc. SA Noded. AV Node
Supraventricular
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Mechanisms of Cardiac Arrhythmias
(A) Enhanced Automaticity:
• In cells which normally display spontaneous diastolic depolarization (SA Node, AV Node, His-Purkinje System)
• Automatic behavior in sites that ordinarily lack pacemaker activity
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A normal cardiac action potential may be interrupted or followed by an abnormal depolarization
Reaches threshold & causes secondary upstrokes
2 Major forms:
1. Early Afterdepolarization2. Late Afterdepolarization
(B) Afterdepolarization and Triggered Automaticity
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1. Early Afterdepolarization
•Phase 3 of repolarization interrupted
•Result from inhibition of Delayed Rectifier K+ Current
•Marked prolongation of Action Potential
•Slow heart rate, ↓ Extracellular K+, Drugs prolonging APD
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2. Late Afterdepolarizations
•Secondary deflection after attaining RMP
•Intracellular Ca2+ overload
•Adrenergic stress, digitalis intoxication, ischemia-reperfusion
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(C) Re-entrant Arrhythmia
Defined as circulation of an activation wave around an inexitable object
3 requirements for Re-entrant Arrhythmia:
1. Obstacle to conduction
2. Unidirectional block
3. CT>ERP
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Unidirectional Block
Establishment of Re-entrant circuit
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Requirement to treat an arrhythmia:
1. ↓ CO:• Slow contractions (bradyarrhythmias)• Fast contractions (tachyarrhythmias)• Asynchronous contractions (V Tach, V Fib)
2. Convert to serious Arrhythmias:• Afl → VTach, V Tach → VF
3. Thrombus formation:• AF→ Stasis in Atrium→ Thrombus formation→ Embolism
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Management Of Arrhythmias
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Management
• Acute Management• Prophylaxis
• Non Pharmacological• Pharmacological
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Non Pharmacological• Acute1. Vagal Maneuvers
2. DC Cardioversion
• Prophylaxis1. Radiofrequency Ablation
2. Implantable Defibrillator
• Pacing (Temporary/ Permanent)
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Pharmacological Approach
Drugs may be antiarrhythmic by:
• Suppressing the initiator mechanism• Altering the re-entrant circuit
1. Terminate an ongoing arrhythmia
2. Prevent an arrhythmia
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Drugs may ↓ automatic rhythms by altering:
A. ↓ Phase 4 slope
B. ↑ Threshold potential
C. ↑ Max diastolic potential
D. ↑ Action Potential Duration
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Vaughan Williams Classification
Phase 4
Phase 0
Phase 1
Phase 2
Phase 3
0 mV
-80mV
II
IIII
IV
Class I: block Na+ channels Ia (quinidine, procainamide, disopyramide) (1-10s)Ib (lignocaine) (<1s)Ic (flecainide) (>10s)
Class II: ß-adrenoceptor antagonists (atenolol, sotalol)
Class III: block K+ channels (amiodarone, dofetilide,sotalol)
Class IV: Ca2+ channel antagonists (verapamil, diltiazem)
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Class I: Na+ Channel Blockers
• IA: Ʈrecovery moderate (1-10sec)
Prolong APD
• IB: Ʈrecovery fast (<1sec)
Shorten APD
• IC: Ʈrecovery slow(>10sec)
Minimal effect on APD
Trecovery is time required to complete approximately 63% of an exponentially determined process to complete
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Effect of Na+ channel block on ERP:
The point at which sufficient no. (25%) of Na+ channels recovered from inactivation is prolonged.
↑ ERP thus blocking early extrasystoles
At times, post repolarization refractoriness.
Drug
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State Dependent Block of Na+ channels
• Na+ channel blockers binds to channels in open &/or inactivated state, poorly/ not at all to resting state
• Dissociate during diastole • Results in phasic changes in extent of block during AP
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Effect of increased heart rate on the Na+ channel block
↑ Na+ channel block as time spent in diastole ↓→↑ERP
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Drugs having ↓ Rate of Recovery
Slow dissociation Rate→ ↑ Na+ Channel block→ ↑ ERP
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Effect of RMP on Na+ channel Block
• At RMP of -85mV: block is rapidly reversed during diastole
• As RMP↑ : more no. of channels remain in inactivated state→↑ block
• Marked drug binding, conduction block & loss of excitability. Thus sick tissue is selectively inhibited
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Ectopic Pacemaker
↓ Upstroke
↑ Threshold↓ Slope phase 4
Block INa
Vm
(mV)
-80mV
0mV
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Effect on Re-entrant Arrhythmia
Effect of Class I drugs:
1. ↓ Vmax: Extinguishing of propagating re-entrant wavefront
2. ↑ERP: CT<ERP
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Ia Ib IcModerate Na+ channel blockade
Mild Na+ channel blockade
Marked Na+ channel blockade
Slow rate of rise of Phase 0
Limited effect on Phase 0
Markedly reduces rate of rise of phase 0
Prolong refractoriness by blocking several types of K+ channels
Little effect on refractoriness as there is minimal effect on K+ channels
Prolong refractoriness by blocking delayed rectifier K+ channels
Lengthen APD & repolarization
Shorten APD & repolarization
No effect on APD & repolarization
Prolong PR, QRS & QT
QT unaltered or slightly shortened
Markedly prolong PR & QRS
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Procainamide (Class Ia)
• Blocks open Na+ channels & Non specific blockade of K+ channels • Ganglion blocking properties, thus can cause hypotension on iv use
• Risk of excessive prolongation of QT interval & torsades de pointes
• Drug induced Lupus Syndrome
• N-acetylprocainamide (NAPA) an active metabolite has class III activity
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• NAPA causes APD prolongation but no drug induced lupus
• Fast acetylators: QT prolongation common Slow acetylators: Drug induced Lupus common
• Effective in most atrial & ventricular arrhythmias
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Quinidine (Class Ia)
• Diastereomer of antimalarial quinine
• Similar to procainamide
• Cardiac antimuscarinic (vagolytic)
• Risk of torsades due to QT prolongation
• Nausea, diarrhoea, vomiting, cinchonism (headache, dizziness & tinnitus)
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Disopyramide (Class Ia)
• Cardiac antimuscarinic effects more marked than quinidine (blurred vision, dry mouth, urinary retention)
• Risk of torsades
• Maintain sinus rhythm in AF/Afl
• To prevent VTach/VF
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Lidocaine (Class Ib)
• Highly effective in arrhythmias associated with AMI
• Blocks activated & inactivated Na+ channels with rapid kinetics
• The inactivated channel block ensures greater effects on cells with long action potentials like purkinje fibres & ventricular cells
• Selective depression in depolarized &/or rapidly driven cells
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• S/E Seizures, tremors, dysarthria, altered consciouness, nystagmus
• Action terminated by rapid redistribution (t1/2 8mins) & hepatic metabolism(t1/2120mins)
• Given only i.v.
• Termination of ventricular arrhythmias, prevention VF after cardioversion
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Mexiletine (Class Ib)
• Orally acting congener of Lidocaine
• Electrophysiological & antiarrhythmic actions similar to Lidocaine
• Other uses: Relieving pain due to diabetic neuropathy & nerve injury
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Flecainde (Class Ic)
• Potent blocker of Na+ & K+ channels with slow unblocking kinetics
• Blocks K+ channels but does not prolong APD & QT interval
• Maintain sinus rhythm in supraventricular arrhythmias
Cardiac Arrhythmia Suppression Test (CAST Trial):When Flecainide & other Class Ic given prophylactically to patients convalescing from Myocardial Infarction it increased mortality by 21/2 fold. Therefore the trial had to be prematurely terminated
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Propafenone (Class Ic)
• Properties similar to flecainide
• Weak β blocking activity
• Used for supraventricular arrhythmias
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Moricizine (Class Ic)
• Phenothiazine analogue
• Chronic treatment of ventricular arrhythmias
CAST II Increased mortality shortly after a myocardial
infarction & did not improve survival during long term therapy
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Class II: β Adrenoreceptor Blocking Drugs
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β Adrenergic Stimulation β Blockers
↑ magnitude of Ca2+ current & slows its inactivation
↓ Intracellular Ca2+ overload
↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate
↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediated automaticity
Epinephrine induces hypokalemia (β2 action)
Propranolol blocks this action
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Other Actions:• ↑ AV Nodal conduction time & prolong its
refractoriness (↑PR interval)
Useful in re-entrant arrhythmias involving AV node & controlling ventricular response in Afl/AF
• Controlling arrhythmias associated with physical or emotional stress
(blocking β mediated actions of catecholamines)
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• Clinical trials suggest that they significantly reduce incidence of re-
infarction & sudden death after an MI ↓ Size of infarct & arhhythmiasIncrease energy required to defibrillate the
heart↓ chances of subsequent MI
• Includes Propranolol, Esmolol, Timolol, Metoprolol, Atenolol, Bisoprolol
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Selected β Adrenergic Receptor blockersPropranolol:• Exert Na+ channel blocking (membrane stabilizing)
effects at high concentrations• Clinical significance is unknown
Acebutolol:• Suppresses ventricular ectopics
Esmolol:• β1 selective metabolized by RBC esterases• t1/2 9 mins
• Rate control of rapidly conducted AF
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Class III: K+ Channel Blockers
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Prolong action potential by blocking K+ currents usually Ikr
Enhance inward current also through Na+ channels
Prolong Repolarization→ QT Prolongation
Thereby ↓ Automaticity & inhibit Re-entry (↑ ERP)
Other actions: ↓ Defibrillation energy requirement, ↑ contractility & inhibition of VF owing to ischemia
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Vm
(mV)
-80mV
0mV
↑ APD
Ectopic Pacemaker
Block IK
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Reverse Use Dependence:
Action potential prolongation is least marked at fast rates & most marked at slow rates Thus risk of torsades
Toxicity:These drugs have a risk of torsades as they prolong cardiac action potentialMore common in women
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Amiodarone
• Blocks variety of channels: IKr , IKs , IKto , IKir
• Also blocks inactivated Na channels, ↓Ca current, adrenergic blocker
• Thus Class I,II,III,IV effects
•↓abnormal automaticity, prolongs APD, ↓ conduction velocity
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PK:
• Oral bioavailability 30%
• Distributed in lipids
• Undergoes hepatic metabolism by CYP3A4 to desethyl-amiodarone (active metabolite)
• Effect maintained over 1-3 months after discontinuation
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Adverse effects:
• Hypotention • Torsades• Pulmonary fibrosis (CXR, PFT)• Corneal microdeposits• Hypo/hyper thyroidism• Peripheral neuropathy, proximal weakness• Photosensitivity• Hepatic dysfunction
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Uses
• Oral→ chronic arrhythmias, iv→acute life threatening arrhythmias
• Prevention of Recurrent VTach/VF
• Maintain sinus rhythm in AF
• Acute termination of VTach/VF
• Wolf-Parkinson-White syndrome
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Dronedarone
• Structural analogue of amiodarone without iodine
• Blocks IKr, IKs, ICa, INa & β receptors
• No thyroid & pulmonary toxicity
• Maintain sinus rhythm in paroxysmal/persistent AF/Afl
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Dofelitide
• Potent & Pure IKr blocker
• Slow rate of recovery
• PK: 100% bioavailability, excreted unchanged by kidneys
• S/E: torsades viz dose dependent
• Used to maintain sinus rhythm in AF/Afl
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Ibutilide
• IKr blocker & activates INa
• Rapid iv infusion used for immediate conversion of Afl/AF to sinus rhythm
• Efficacy Afl>AF
• PK: undergoes extensive 1st pass metabolism. Thus not used orally. t1/2 6hrs
• S/E: torsades
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Sotalol
• IKr blocker and non selective β receptor blocker • Class II,III actions
• ↑ APD, ↓ automaticity, slows AV Nodal conduction & prolong AV Nodal refractoriness
• Prolongs QT interval
• S/E: EAD’s & torsades
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• PK: 100% bioavailable, excreted unchanged in urine • Uses: Ventricular arrhythmias, maintenance of sinus rhythm AF, used in pediatric age-group
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Vernakalant (RSD1235)
• Investigational multichannel ion blocker
• Blocks IKr, IKur, IKAch, Ito
Thus prolong atrial repolarization & ERP. Less action potential prolongaton in ventricle
• Rate dependent Na channel block (Recovery is fast)
• Slows conduction of AV node
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• S/E: dysgeusia, cough, paraesthesia, hypotension
• PK: metabolized in liver by CYP2D6, t1/2 2hrs • Use: Converting recent onset AF to sinus rhythm
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Class IV: Ca2+ Channel Blocking Drugs
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• Block L-Type Ca 2+ channels in slow- response tissues & depress Phase 3 & 4
• Slows SA Node by its direct action
• AV Node conduction time & effective refractive period increased (Prolongs PR interval)
• Important effect on upper & middle parts of AV Node
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• Shorten plateau of action potential & reduce force of contraction
• Suppress both Early & Late Depolarization
• May have a particular value in blocking one limb of re-entry circuit
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His Bundle
Normal ERP
PrematureAtrial Beat
Atrium“Dispersion of Refractoriness”
Normal ERP
βIschemic Area Long ERP
PSVT: •140-220 min -1• sudden onset• palpitations,dizziness
AV Node Re-entry
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Ischemic Area
Verapamil/ Diltiazem
Normal ERP
Long ERP
β
Long ERP
ERP>CT
Effect of ClassIV Drugs on AV Nodal Reentrant Arrhythmia
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• Parental verapamil & diltiazem approved for rapid conversion of PSVT to sinus rhythm & temporary control of rapid ventricular rate in AF/Afl
• C/I in WPW syndrome
• Oral verapamil in conjugation with digoxin to control ventricular rate in chronic AF/AFl
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Verapamil
• Blocks both activated & inactivated Ca2+ channels
• Given orally with a t1/2 8hrs
• extended release formulation available
• If used with digoxin, then dose is reduced
• S/E constipation, lassitude, peripheral edema
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Diltiazem
• Similar in efficacy to verapamil
• Undergoes a high first pass metabolism
• Relatively more smooth muscle relaxing action
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Miscellaneous
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Adenosine
• Naturally occurring nucleoside
• Acts on specific G protein-coupled adenosine receptors
• Activates IKAch channels in SA node, AV node & Atrium Shortens APD, hyperpolarization & ↓ automaticity
• Inhibits effects of ↑ cAMP with sympathetic stimulation
↓ Ca currents
↑AV Nodal refractoriness & inhibit DAD’s
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Vm
(mV)
-80mV
0mV
↓ APD
Hyperpolarization
Adenosine
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PK:
• Carrier mediated uptake & metabolism by deaminase in most cells
• t1/2 few seconds
• Given as iv bolus
• Theophylline & caffeine→ block adenosine receptors
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Adverse effects:
• flushing, shortness of breath, chest burn
Use:
• DOC for acute termination of re-entrant supraventricular arrhythmia
•Rare cases of DAD mediated VTach
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Digitalis
• Acts by blocking Na+/K+ATPase→ +ve Inotropic effect • Antiarrhythmic actions exerted by AV Nodal Refractoriness by: Vagotonic actions→ inhibit Ca2+ currents in AV node
• Activation of IKAch in atrium: hyperpolarization & shortening of APD in atria
• ↑ Phase 4 slope→ ↑ Rate of automaticity in ectopic pacemakers
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• ECG: PR prolongation, ST segment depession
• Adverse Effects:
Non cardiac: Nausea, disturbance of cognition, yellow vision
Cardiac: Digitalis induced arrhythmias
• PK: Digoxin- 20-30% protein bound, slow distribution to effector sites, loading dose given, t1/2 36hrs, renal elimination
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Digitoxin- hepatic metabolism, highly protein bound, t1/2 7daysToxicity results with amiodarone & quindine (↓ clearance) Thus dose has to be decreased
• Used in terminating re-entrant arrhythmia involving AV Node & controlling ventricular rate in AF
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Magnesium
• Its mechanism of action is unknown but may influence Na+/K+ATPase, Na+ channels, certain K+ channels & Ca2+ channels • Digitalis induced arrhythmias if hypomagnesemia present • Torsade de pointes even if serum Mg2+ is normal • Given 1g over 20mins
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Bradyarrhythmias
Resting heart rate of <60/min
Classified as Atrial/AV Nodal/Ventricular
Management:
• Acute→ iv atropine
• Permanent→ Pacemakers
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Toxicities
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Class IConduction slowing can account for toxicity
Afl 300/min
Slowing of conduction with Na+ channel blocker
AV Node permits greater no of impulses
(Drop in Afl 300/min with 2:1 or 4:1 AV conduction to 220/min with 1:1 conduction HR 220beats/min)
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• Re-entrant VTach after MI can ↑ frequency & severity arrhythmic episodes
• Slowed conduction allows the re-entrant wave front to persist within tachycardia circuit
• Difficult to treat
• Na+ infusion may be beneficial
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Class II
• Bradycardia & exacerbation of CCF in patients with low ejection fraction
Class Ia & Class III
• Excessive QT prolongation & torsades de pointes
• ‘‘Twisting of points”
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• Rapid, polymorphic ventricular tachycardia •Twist of the QRS complex around the isoelectric baseline
• Fall in arterial blood pressure
• Can degenerate into Ventricular fibrillation
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Treatment:
• Withdrawal of offending drug •Magnesium sulphate
•Phenytoin
•Isoproterenol infusion/Pacing
•Defibrillation
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Digitalis Induced Arrhythmias
• Can cause virtually any arrhythmia• DAD related tachycardia with impairment of SAN & AVN• Atrial tachycardia with AV block is classic• Ventricular bigeminy• Bidirectional ventricular tachycardia• AV junctional tachycardia• Various degrees of AV block• Sever intoxication: Severe bradycardia with hyperkalemia
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Treatment
• Sinus bradycardia & AV block: Atropine
• Digitalis induced tachycardia responds to Mg2+
• Antidigoxin (DIGIBIND) binds to digoxin & digitoxin thereby enhancing their renal excretion
• SA & Node AV Node dysfunction may require temporary pacing
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TRIALS
• Cardiac Arrhythmia Suppression Trial (CAST)
• Cardiac Arrhythmia Pilot Study (CAPS)
• Antiarrhythmics Versus Implantable Defibrillators (AVID)
• Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM)
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Therapeutic Drug Monitoring
• Important as these drugs have narrow therapeutic index
• Class IA & Digoxin- Most important for drug monitoring
• Amiodarone- TDM has limited role
• TDM less important for Class II, III & IV drugs
• TDM no value for Lignocaine & Procainamide due to Active metabolites (GX, MEGX & NAPA)
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Evaluation of Antiarrhythmic Drug Action
Ex-Vivo Models:
• Guinea pig muscle strips
In-Vivo Models:
• Atrial Arrhythmias
1. Atrial Rapid Pacing Model
2. Afl with Anatomical Obstacle Model
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• Ventricular Arrhythmias
1. Digitalis-induced Ventricular Arrhythmia
2. Halothane adrenaline Arrhythmia
3. Canine two stage coronary ligation Arrhythmia
4. Programmed electrical stimulation induced re-entry Arrhythmia
5. Coronary artery occlusion/reperfusion Arrhythmia
• Genetic Models:
1. Homozygous null connexin 40 vulnerability to atrial arrhythmias
2. Transgenic mouse model→ Over expresses a constitutively active form of TGF-b1
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Clinical Evaluation:
Two designs commonly used:
1. Evaluating antiarrhythmic agents in pts with ICDOutcome parameter – number of defibrillator discharge
2. Evaluating antiarrhythmic agents in target populationMortality rates could be assessedLarge sample size required
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Newer Advances
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ZP123-Rotigaptide • Prevents uncoupling of connexin 43 mediated gap junction communication during acute metabolic stress• Selective for atrial electrophysiology• ↓ AF vulnerability in MR
Tedisamil • Class III antiarrhythmic• Blocks Ito, IKATP, IKr, IKs, IKur
• Prolongs APD atria>ventricles• Could be used for AF, Afl
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Azimilide • Class III antiarrhythmic• Blocks IKr & IKs
• Converts and maintains sinus rhythm in patients with atrial arrhythmias• Reduces frequency and severity of ventricular arrhythmias in patients with implanted cardioverter-defibrillators
AVE0118 • Blocks IKur & Ito
• Prolongs atria ERP• May be useful in atrial arrhythmis
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AZD 7009• Inhibition of IKr, Ito, IKur and INa, a mixed ion channel blockade• Promising drug for converting AF to sinus rhythm• Phase II trial
AP-792 • Cardioselective Ca2+ channel blocker • Suppresses the ventricular arrhythmias Encainide (MJ9067)• Probably has effects on Phase 2• Can be effective in suppressing ventricular ectopics
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BRL32872
• Blocks IKr & L-type Ca2+ channels• Prolongs APD• May possibly prevent torsades de pointes
Piboserod• Functional 5-HT4 receptor antagonist• Could be used for AF
Nifekalant• Class III antiarrhythmic• Blocks IKr
• Approved in Japan• Ventricular tachycardia
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Conclusion
• Precipitating factors (ischemia, electrolyte imbalance, drugs) should be eliminated
• Drugs acting on particular mechanism of arrhythmia should be used
• Some arrhythmias should not be treated
• Risk benefit ratio assessed (drug provoked arrhythmias)
• Patient specific contraindications (disopyramide→CCF, amiodarone→pulmonary disease)
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