Download - Antiarrhythmic drugs
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Antiarrhythmic drugs
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Antiarrhythmics ????
– In a textbook Interesting but sedative.• Try it if you have insomnia
– In the lecture Confusion ??????????• As always
– In the exam hall Panic! • Don’t worry rarely asked
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• A-RHYTHM –IA• Defn- Arrhythmia is deviation of heart from
normal RHYTHM.
• RHYTHM1) HR- 60-1002) Should origin from SAN3) Cardiac impulse should propagate through normal conduction pathway with normal velocity.
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• CLASSIFICATION OF ARRHYTHMIAS
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100
60
Normal range
150 Simple tachyarrythmia
200 Paroxysmal TA
350 Atrial flutter
. 500 Atrial fibrillation
40 Mild bradyarrhythmias 20 moderate BA
Severe BA
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ARRHYTHMIAS
Sinus arrythmia
Atrial arrhythmia
Nodal arrhythmia(junctional)
Ventricular arrhytmia
SVT
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Electrophysiology of cardiac tissue
• Impulse generation and transmission • Myocardial action potential • Depolarization and repolarization waves as
seen in ECG
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Types of cardiac tissue (on the basis of impulse generation)
• AUTOMATIC/ PACEMAKER/ CONDUCTING FIBRES (Ca++ driven tissues)
Includes SA node, AV node, bundle of His, Purkinje fibres
Capable of generating their own impulseNormally SA node acts as Pacemaker of heart
• NON-AUTOMATIC MYOCARDIAL CONTRACTILE FIBRES (Na+ driven tissues)Cannot generate own impulse Includes atria and ventricles
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Impulse generation and transmission
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Myocardial action potential
In automatic tissues In non-automatic tissues
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Action potential in Non automatic myocardial contractile tissue
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+30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
21
K+ Ca++ K+
Atp
K+Na+
K+
Ca++
Na+
K+
Na+
Resting
open
Inactivated
Phase zero depolarization
Early repolarization Plateau phase
Rapid Repolarization
phase
Phase 4 depolarization
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Action potential in nodal tissues
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+30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
21
K+ Ca++ K+
Atp
K+Na+
K+
Ca++
Na+
K+
Cardiac action potential.mp4
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Fast channel Vs slow channel AP
Fast channel AP• Occurs in atria, ventricles, PF• Predominant ion in phase-0
is Na+• Conduction velocity more • Selective channel blocker is
tetradotoxin , LA
Slow channel AP• Occurs in SA node, A-V node• Predominant ion in phase-0
is Ca2+
• Less • Selective channel blockers
are calcium channel blockers
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Common terms
• Automaticity – Capacity of a cell to undergo spontaneous diastolic
depolarization• Excitability – Ability of a cell to respond to external stimulus by
depolariztion• Threshold potential – Level of intracellular negativity at which abrupt
and complete depolarization occurs
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Common terms
• Conduction velocity of impulse– Determined primarily by slope of action potential
and amplitude of phase-0, any reduction in slope leads to depression of conduction
• Propagation of impulse– Depends on ERP & Conduction velocity
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Refractory period
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Depolarization &
Repolarization waves seen in
ECG
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ECG is used as a rough guide to some cellular properties of cardiac tissue
• P wave: atrial depolarization • PR-Interval reflects AV nodal conduction time• QRS DURATION reflects conduction time in
ventricles• T-wave: ventricular repolarization • QT interval is a measure of ventricular APD
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Mechanisms of cardiac arrythmia
• Abnormal impulse generation:• Depressed automaticity• Enhanced automaticity
• Triggered activity (after depolarization):• Delayed after depolarization • Early after depolarization
• Abnormal impulse conduction:• Conduction block • Re-entry phenomenon • Accessory tract pathways
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a) Enhanced automaticityAutomatic behavior in sites ordinarily lacking pacemaker activityCAUSES: Ischaemia/digitalis/catecholamines/acidosis/ hypokalemia/stretching of cardiac cells
Nonpacemaker nodal tissues: membrane potential comes to -60mv
Increased slope of phase 4 depolarisation
Become ECTOPIC PACEMAKERS.(AV nodal rhythm, idioventricular rhythm, ectopic beats)
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Less negative RMP
More negative TP
Ectopic pacemaker activity encouraged by
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b) Trigerred automaticity
+30 mV
0 mV
-80 mV
-90 mV
Early After Depolarisation
(EAD)
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b) Trigerred automaticity+30 mV
0 mV
-80 mV
-90 mV
Delayed After Depolarisation
(DAD)
Intracellular cal. Overload (Ischemia reperfusion, adr.stress, digitalis intoxication or heart failure)
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c. Abnormal impulse conduction
• Conduction block– First degree block – Second degree block – Third degree block
• Re-entry phenomenon • Accessory tract pathways
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INEXCITABLE TISSUE
Re-entry
1 2
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Re-entry
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Counterclockwise right atrial reentry
LA is passively activated
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Requirements for re-entry circuit
• Presence of anatomically defined circuit • Region of unidirectional block • Re-entry impulse with slow conduction
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Anatomical: Wolff-Parkinson-White syndromeFunctional: Fibrillation
Accessory tract pathways
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WPW: Initiation of SVT
Supraventricular tachycardia• initiated by a
closely coupled premature atrial complex (PAC)
• blocks in the accessory pathway
• but conducts through the AV node
• retrograde conduction via accessory pathway
• inverted P wave produced by retrograde conduction visible in the inferior ECG leads
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Regulation by autonomic toneParasympathetic/Vagus Nerve stimulation:
• Ach binds to M2 receptors
• Activate Ach dependent outward K+ conductance (thus hyperpolarisation)
• ↓ phase 4 AP
Sympathetic stimulation:
• Activation of β1 receptors
• Augmentation of L-type Ca2+ current
• Phase 4 AP more steeper
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+30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
21
K+ Ca++ K+
Atp
K+Na+
K+
Ca++
Na+
Na+ Ca++ K+
RATE
SLOPE
Effective Refractory PeriodRMP
THRESHOLD POTENTIAL
Possible MOA of antiarrythmic agents
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Classification of Anti-Arrhythmic Drugs (Vaughan-Williams-Singh..1969)
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: prolong action potential and prolong refractory period (amiodarone, dofetilide, sotalol)
Class IV: Ca2+ channel antagonists (verapamil, diltiazem)
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Classification based on clinical use
• Drugs used for supraventricular arrhythmia`s– Adenosine, verapamil, diltiazem
• Drugs used for ventricular arrhythmias – Lignocaine, mexelitine, bretylium
• Drugs used for supraventricular as well as ventricular arrhythmias– Amiodarone, - blockers, disopyramide,
procainamide
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Na+ channel blocker• Bind to and block Na+ channels (and K+ also)• Act on initial rapid depolarisation (slowing effect)• Local Anaesthetic (higher concentration): block
nerve conduction• Do not alter resting membrane potential
(Membrane Stabilisers)• At times, post repolarization refractoriness.• Bind preferentially to the open channel state • USE DEPENDENCE : The more the channel is in
use, the more drug is bound
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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 unaltered or slightly shortened
Markedly prolong PR & QRS
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Class I: Na+ Channel Blockers
• IA: Ʈrecovery moderate (1-10sec)
Prolong APD
• IB: Ʈrecovery fast (<1sec) Shorten APD in some heart
tissues
• IC: Ʈrecovery slow(>10sec) Minimal effect on APD
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Class IA
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Quinidine
• Historically first antiarrhythmic drug used. • In 18th century, the bark of the cinchona plant
was used to treat "rebellious palpitations“
pharmacological effects threshold for excitability automaticity prolongs AP
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Quinidine
• Clinical Pharmacokinetics• well absorbed • 80% bound to plasma proteins (albumin)• extensive hepatic oxidative metabolism• 3-hydroxyquinidine,• is nearly as potent as quinidine in blocking
cardiac Na+ channels and prolonging cardiac action potentials.
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Quinidine
• Uses
• to maintain sinus rhythm in patients with
atrial flutter or atrial fibrillation
• to prevent recurrence of ventricular
tachycardia or VF
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QuinidineAdverse Effects-
Non cardiac• Diarrhea, thrombocytopenia,• cinchonism & skin rashes. cardiac marked QT-interval prolongation &torsades de
pointes (2-8% ) hypotension tachycardia
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Drug interactions
• Metabolized by CYP450 • Increases digoxin levels• Cardiac depression with beta blockers • Inhibits CYP2D6
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Disopyramide• Exerts electrophysiologic effects very similar to
those of quinidine.• Better tolerated than quinidine• exert prominent anticholinergic actions• Negative ionotropic action.• A/E-• precipitation of glaucoma,• constipation, dry mouth, • urinary retention
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Procainamide
• Lesser vagolytic action , depression of contractility & fall in BP
• Metabolized by acetylation to N-acetyl procainamide which can block K+ channels
• Doesn’t alter plasma digoxin levels• Cardiac adverse effects like quinidine • Can cause SLE not recommended > 6 months • Use: Monomorphic VT, WPW Syndrome
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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 unaltered or slightly shortened
Markedly prolong PR & QRS
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Class IB drugs
Lignocaine, phenytoin, mexiletine
Block sodium channels also shorten repolarization
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Class Ib
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Lignocaine • Blocks inactivated sodium channels more than
open state • Relatively selective for partially depolarized
cells • Selectively acts on diseased myocardium • Rapid onset & shorter duration of action • Useful only in ventricular arrhythmias ,
Digitalis induced ventricular arrnhythmias
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• Lidocaine is not useful in atrial arrhythmias???
• atrial action potentials are so short that the
Na+ channel is in the inactivated state only
briefly compared with diastolic (recovery)
times, which are relatively long
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Pharmacokinetics
• High first pass metabolism • Metabolism dependent on hepatic blood flow • T ½ = 8 min – distributive, 2 hrs – elimination • Propranolol decreases half life of lignocaine • Dose= 50-100 mg bolus followed by 20-40 mg
every 10-20 min i.v
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Adverse effects
• Relatively safe in recommended doses • Drowsiness, disorientation, muscle twitchings• Rarely convulsions, blurred vision, nystagmus • Least cardiotoxic antiarrhythmic
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• Local anaesthetic • Inactive orally • Given IV for antiarrhythmic action • Na+ channel blockade which occurs• Only in inactive state of Na+ channels • CNS side effects in high doses • Action lasts only for 15 min• Inhibits purkinje fibres and ventricles but • No action on AVN and SAN so • Effective in Ventricular arrhythmias only
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Mexiletine
• Oral analogue of lignocaine • No first pass metabolism in liver • Use: – chronic treatment of ventricular arrhythmias
associated with previous MI – Unlabelled use in diabetic neuropathy
• Tremor is early sign of mexiletine toxicity • Hypotension, bradycardia, widened QRS ,
dizziness, nystagmus may occur
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Tocainide
• Structurally similar to lignocaine but can be administered orally
• Serious non cardiac side effects like pulmonary fibrosis, agranulocytosis, thrombocytopenia limit its use
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Class I C drugs Encainide, Flecainide, Propafenone
Have minimal effect on repolarization Are most potent sodium channel blockers
• Risk of cardiac arrest , sudden death so not used commonly • May be used in severe ventricular arrhythmias
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Class Ic
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Propafenone class 1c
• Structural similarity with propranolol & has -blocking action
• Undergoes variable first pass metabolism • Reserve drug for ventricular arrhythmias, re-
entrant tachycardia involving accesory pathway
• Adverse effects: metallic taste, constipation and is proarrhythmic
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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 2½ fold. Therefore the trial had to be prematurely terminated
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Class II: Beta blockers • -receptor stimulation: • ↑ automaticity, • ↑ AV conduction velocity, • ↓ refractory period
• -adrenergic blockers competitively block catecholamine induced stimulation of cardiac - receptors
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Beta blockers • Depress phase 4 depolarization of pacemaker
cells, • Slow sinus as well as AV nodal conduction :– ↓ HR, ↑ PR
• ↑ ERP, prolong AP Duration by ↓ AV conduction
• Reduce myocardial oxygen demand• Well tolerated, Safer
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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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Use in arrhythmia
• Control supraventricular arrhythmias • Atrial flutter, fibrillation, PSVT
• Treat tachyarrhythmias caused by adrenergic • Hyperthyroidism Pheochromocytoma,
during anaesthesia with halothane• Digitalis induced tachyarrythmias• Prophylactic in post-MI• Ventricular arrhythmias in prolonged QT
syndrome
+
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Esmolol• β1 selective agent• Very short elimination t1/2 :9 mins• Metabolized by RBC esterases• Rate control of rapidly conducted AF• Use:• Arrythmia associated with anaesthesia• Supraventricular tachycardia
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Class III drugs
↑APD & ↑RP by blocking the K+ channels
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Vm
(mV)
-80mV
0mV
↑ APDBlock IK
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Amiodarone • Iodine containing long acting drug • Mechanism of action: (Multiple actions) –Prolongs APD by blocking K+ channels –blocks inactivated sodium channels –β blocking action , Blocks Ca2+ channels –↓ Conduction, ↓ectopic automaticity
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• Pharmacokinetics:–Variable absorption 35-65%–Slow onset 2days to several weeks –Duration of action : weeks to months
• Dose – Loading dose: 150 mg over 10min –Then 1 mg/min for 6 hrs –Then maintenance infusion of 0.5 mg/min
for 24 hr
Amiodarone
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Amiodarone
• Uses:– Can be used for both supraventricular and ventricular
tachycardia• Adverse effects:– Cardiac: heart block , QT prolongation, bradycardia,
cardiac failure, hypotension – Pulmonary: pneumonitis leading to pulmonary fibrosis – Bluish discoloration of skin, corneal microdeposits – GIT disturbances, hepatotoxicity– Blocks peripheral conversion of T4to T3 can cause
hypothyroidism or hyperthyroidism
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• Antiarrhythmic • Multiple actions • Iodine containing• Orally used mainly• Duration of action is very long (t ½ = 3-8 weeks) • APD & ERP increases • Resistant AF, V tach, Recurrent VF are indications • On prolonged use- pulmonary fibrosis • Neuropathy may occur • Eye : corneal microdeposits may occur
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• Bretylium: – Adrenergic neuron blocker used in resistant
ventricular arrhythmias • Sotalol:– Beta blocker
• Dofetilide, Ibutilide :– Selective K+ channel blocker, less adverse events – use in AF to convert or maintain sinus rhythm– May cause QT prolongation
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Newer class III drugs
• Dronedarone • Vernakalant • Azimilide • Tedisamil
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Calcium channel blockers (Class IV)
• Inhibit the inward movement of calcium ↓ contractility, automaticity , and AV conduction.
• Verapamil & diltiazem
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Verapamil
• Uses:– Terminate PSVT– control ventricular rate in atrial flutter or
fibrillation• Drug interactions: – Displaces digoxin from binding sites – ↓ renal clearance of digoxin
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Other antiarrhythmics
• Adenosine :– Purine nucleoside having short and rapid action – IV suppresses automaticity, AV conduction and
dilates coronaries – Drug of choice for PSVT – Adverse events: • Nausea, dyspnoea, flushing, headache
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Vm
(mV)
-80mV
0mV
↓ APD
Hyperpolarization
Adenosine
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Adenosine • Acts on specific G protein-coupled adenosine receptors • Activates AcH sensitive K+ channels 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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• Atropine: Used in sinus bradycardia • Digitalis: Atrial fibrillation and atrial flutter • Magnesium SO4: digitalis induced arrhythmias
Other antiarrhythmics
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Magnesium
• Its mechanism of action is unknown but may influence Na+/K+ATPase, Na+ channels, certain K+ channels & Ca2+ channels
• Use: Digitalis induced arrhythmias if hypomagnesemia present, refractory ventricular tachyarrythmias, Torsade de pointes even if serum Mg2+ is normal
• Given 1g over 20mins
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Drugs of choices
S. No
Arrhythmia Drug
1 Sinus tachycardia Propranolol2 Atrial extrasystole Propranolol,3 AF/Flutter Esmolol, verapamil ,digoxin 4 PSVT Adenosine ,esmolol 5 Ventricular Tachycardia Lignocaine , procainamide ,
Amiodarone 6 Ventricular fibrillation Lignocaine, amiodarone 7 A-V block Atropine , isoprenaline