anti arrhythmic drug thereapy
TRANSCRIPT
ANTI ARRHYTHMIC DRUG THERAPY
Contents
• Electrophysiology of Heart
• Arrhythmia: Definition, Types, Mechanisms
• Antiarrhythmic drugs: Class I, II , III , IV
• Treatment of arrhythmia : Guidelines
Electrophysiology of Heart
Introduction
Normal conduction pathway
SA node Generates
action potential AV node
Delivers the impulse to
purkinje fibersPurkinje fibers
Conduct the impulse to the
ventricles
SAN
AVN
Impulse conductionNormal conduction pathway
Impulses originate regularly at a frequency of 60-100 beat/ min
Cardiac Action Potential
Divided into five phases (0,1,2,3,4) Phase 4 - Resting phase (resting membrane potential)
Associated with diastole portion of heart cycle Addition of current into cardiac muscle
(stimulation) causes Phase 0 –Opening of fast Na channels
Drives Na+ into cell, changing membrane potential Transient outward current due to movement of Cl- and
K+ Phase 1 – Initial rapid repolarization
Closure of the fast Na+ channels Phase 0 and 1 together correspond to the R and S
waves Keating MT, Sanguinetti MC: Molecular & Cellular Mechanisms of cardiac arrhythmia. Cell 2001;104;569
Cardiac Action Potential (contd) Phase 2 - Plateau phase
Sustained by the balance between the inward movement of Ca+ and outward movement of K +
Long duration compared to other nerve and muscle tissue
Corresponds to ST segment of the ECG Phase 3 – Repolarization
K+ channels remain open, Outward K+ movement, repolarization of cell Closure of K + channels when membrane
potential reaches certain level Corresponds to T wave on the ECG
-100
-80
-60
-40
-20
0
20
Phase 0
Phase 1
Phase 2
Phase 3
Phase 4
Na+ ca++
ATPase
mv Cardiac Action Potential
Resting membrane Potential
Na+m
Na+Na+Na+Na+Na+
hK+
ca++
K+K+K+
ca++ca++
(Plateau Phase)
K+K+K+ Na+
K+
Dep
ola
riza
tio
n
-100
-80
-60
-40
-20
0
20
Phase 0
Phase 1
Phase 2
Phase 3
Phase 4
Na+ ca++
ATPase
mv Cardiac Action Potential
R.M.P
Na+m
Na+Na+Na+Na+Na+
hK+
ca++
K+K+K+
ca++ca++
(Plateau Phase)
K+K+K+ Na+
K+
Dep
ola
riza
tio
nAP curve in pacemaker
Cells
Effective refractory period (ERP) Also called Absolute Refractory Period
(ARP) Period in which cells can’t be excited Takes place between phase 0 and 3
Duan D et al; Functtional role of ion channels in cardiac disease; Acta Pharmacol Sin 2005; 26;265
Arrhythmias
Variation in either the site or rate of cardiac impulse formation, and/or a variation in the sequence of cardiac impulse propagation
Causes: Arteriosclerosis Coronary artery Spasm Heart block Myocardial ischemiaHume RJ, Grant AO, Cardiac arrhythimia ; Katzung Basic & clinical pharmacology, Lange
Medical Publishers,12th ed,2012,pg227-250
Normal heartbeat & Arrhythmia
Normal rhythm
Arrhythmia
AV septum
Mechanisms of Arrhythmogenesis
1 -Abnormal Impulse Generation
Automatic rhythms
Triggered rhythms
Enhanced normal
automaticityEctopic focus
Delayed after daepolarizati
on
Early after depolarizati
on
↑AP from SA node
AP arises from sites other than SA node
Mechanisms of Arrhythmogenesis
2-Abnormal conduction
Conduction block
Reentry
1st degree
2nd degree
3rd degree
Circus moveme
nt
Reflection
When impulse is not conducted
from the atria to the ventricles
Mechanisms of Arrhythmogenesis
Mechanisms of bradycardias: Sinus bradycardia: D/t abnormally slow
automaticity Bradycardia due to AV block: Abnormal
conduction within the AV node or the distal AV conduction system
Mechanisms of tachycardias : - Accelerated automaticity. - Triggered activity - Re-entry (or circus movements)
Mechanisms of Arrhythmogenesis ACCELERATED AUYOMATICITY D/t increase in rate of diastolic
depolarization or changing threshold potential
Can occur in virtually all cardiac tissues and may initiate arrhythmias
Thought to produce sinus tachycardia, escape rhythms and accelerated AV nodal (junctional) rhythms
Mechanisms of Arrhythmogenesis TRIGGERED ACTIVITY Myocardial damage → oscillations of
transmembrane potential → 'after depolarizations’ → threshold potential → Arrhythmia
Can be exaggerated by pacing, catecholamines, electrolyte disturbances, and some medications
Examples : Digoxin toxicity → causes Atrial tachycardias Ventricular arrhythmia in the long QT syndrome
Mechanisms of Arrhythmogenesis
RE-ENTRY (OR CIRCUS MOVEMENT) Occurs when 'ring' of cardiac tissue surrounds
inexcitable core Tachycardia initiated if an ectopic beat finds one
limb refractory (α) resulting in unidirectional block and the other limb excitable
Circus movement will be maintained If: Time to conduct around the ring > Recovery
times (refractory periods) of the tissue within the ring
Majority of regular paroxysmal tachycardias are produced by this mechanism
Reentry Arrhythmias
Normal
Re-enterant
Tachycardia
Mechanisms of Arrhythmogenesis
ABNORMAL ANATOMIC CONDUCTION Bundle of
Kent
•Present only in small populations•Lead to reexcitation Wolf-Parkinson-White Syndrome (WPW)
Types of Arrhythmia
Sinus Tachycardia:
High sinus rate of 100-180 beats/min
Occurs during exercise or other conditions that lead to increased SA nodal firing rate
Atrial Tachycardia:
Series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min
Paroxysmal Atrial Tachycardia (PAT):
Tachycardia which begins and ends in acute manner
Types of Arrhythmia
Atrial Flutter: Sinus rate of 250-350 beats/min.
Atrial Fibrillation: Uncoordinated atrial depolarizations.
AV blocks Conduction block within the AV node ,
occasionally in the bundle of His → impairs impulse conduction from the atria to the ventricles.
Types of Arrhythmia
Ventricular Premature Beats (VPBs): Ectopic ventricular foci; characterized by
widened QRS. Ventricular Tachycardia (VT):
High ventricular rate caused by abnormal ventricular automaticity or by intraventricular reentry
Can be sustained or non-sustained (paroxysmal);
Characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening.
Types of Arrhythmia
Ventricular Flutter:
Ventricular depolarizations >200/min.
Ventricular Fibrillation:
Uncoordinated ventricular depolarizations
Management of Arrhythmia
Management of Arrhythmia
Pharmacological therapy (Antiarrhythmic Drugs)
Cardioversion
Pacemaker therapy
Surgical therapy e.g. aneurysmal excision
Interventional therapy “ablation”
Antiarrhythmic Drugs
Pharmacologic rationale & Goal The ultimate goal of antiarrhythmic
drug therapy: Restore normal sinus rhythm and
conduction Prevent more serious and possibly lethal
arrhythmias from occurring. Antiarrhythmic drugs are used to:
Decrease conduction velocity Change the duration of the effective
refractory period (ERP) Suppress abnormal automaticity
Shrivatsa U, Wadhani M, Singh AB; Mechanisms of antiarrhythmic drug action & their clinical relevance for controlling disorders of cardiac rhythm; Curr Cardiol Rep 2002;4;401
Classification of Antiarrhythmic Drugs
Classified a/c to Vaughan William into four classes
Class Mechanism Action Notes
INa+
channel blocker
Change the slope of phase 0
Can abolish tachyarrhythmia
caused by reentry circuit
II β blocker ↓heart rate and conduction velocity
Can indirectly alter K and Ca conductance
III K+ channel blocker
1. ↑action potential duration (APD) or
effective refractory period (ERP).
2. Delay repolarization.
Inhibit reentry tachycardia
IVCa++
channel blocker
Slowing the rate of rise in phase 4 of SA node(slide
12)
↓conduction velocity in SA and AV node
Classification of Antiarrhythmic Drugs
Phase 0
Phase 1
Phase 2
Phase 3
Phase 4
R.M.P
(Plateau Phase)
Class I:
Na + channel blockers.
- Pacemaker potential
--
-
Class III:K + channel blockers
-Class IV:
Ca ++ channel blockers
Class II:Beta blockers
Classification of Anti-Arrhythmic Drugs
Treatment of tachyarrhythmias:
Class I drugs (Membrane stabilizing drugs) :
Mechanism: Class I drugs block fast Na+ channels, thereby
Reducing the rate of phase 0 depolarization Prolonging the effective refractory periodIncreasing the threshold of excitability Reducing phase 4 depolarization
These drugs also have local anesthetic properties
Woosely RL. Antiarrhythmic drugs. Hurst’s The Heart (Ed. Fuster V, Alexander RW, O’Rourke RA, et al.) 10th edition.2001;1:899–924
Class IA
1. Quinidine Alkaloid – cinchona , dextro isomer of quinine. Blocks sodium channel & potassium channel
also Anti-muscarinic and Alpha blocking action Administered orally & is rapidly absorbed from
gastrointestinal tract Hydroxylated in the liver t1/2 of approximately 5—12 hours, longer in
hepatic or renal disease & in heart failure Bitter and irritant Inhibitor of CYP P450 system.
1. Quinidine
↑↑ plasma conc of digoxin by displacing it from tissue binding sites & decreasing its renal & biliary clearance.
Uses: Atrial fibrillation Ventricular tachycardia
Adverse effects : GIT : Diarrhea, nausea, vomiting and
cinchonism Thrombocytopenia Precipitate torsade de pointes by
prolonging QT interval
1. Quinidine
Drug interactions Increases digoxin plasma levels &risk of
digitalis toxicity t1/2 reduced by agents that induce drug-
metabolizing enzymes (phenobarbital, phenytoin)
May enhance the activity of coumarin anticoagulants & other drugs metabolized by hepatic microsomal enzymes
Cardiotoxic effects exacerbated by hyperkalemia
2. Procainamide
Like quinidine, but Safer to use intravenously Produces fewer adverse GI effects
Acetylated in liver to N-acetylprocainamide (NAPA)
Eliminated by the kidney (t ½ -3 – 5 hrs) More likely than quinidine to produce
severe or irreversible heart failure Adverse effects
SLE like syndrome consisting of arthralgia and arthritis specially in slow acetylators
3. Disopyramide
Prominent anti-cholinergic activity Eliminated by the kidney (t ½ - 4 – 10 hrs) Approved only for ventricular arrhythmia &
Atrial fibrilllation (not a first line) Adverse Events:
Proarrhythmic Urinary retention, Blurred vision, Dry
mouth ( Parasympatholytic) Mild negative ionotrophy
Class IB
1. Lidocaine: Least cardiotoxic : (t ½ - 1.5 - 2 hrs) Block inactivated Na channels : preferred
for partially depolarized cells in ischemic area
High first pass metabolism – not given orally
Used in: Ventricular arrhythmia Digoxin induced arrhythmia
Main toxicity:Neurological – drowsiness, nystagmus &
seizures
2. Mexiletine and Tocainide
Similar in action to lidocaine Can be administered orally T ½ - Mexiletine – 10-12 hrs - Tocanide – 11-23 hrs Used for long-term treatment of
ventricular arrhythmias associated with previous Myocardial Infarction
Adverse events: Mexiletine : Ataxia, dizziness, tremors Tocainide : Blood dyscrasias, pulmonary
fibrosis, GI and neurological symptoms
Moricizine
Phenothiazine
Has properties of class IB, IA, and IC antiarrhythmics,
Use should be limited to life-threatening ventricular arrhythmias
Class IC
Class of potent Na channel blocker
Drugs of this class have negative inotropic effect
High pro-arrhythmogenic potential – sudden death
Class IC
1.Flecainide Orally active antiarrhythmic Metabolized by microsomal enzymes (t ½ -
20 hrs) Used for ventricular tachyarrhythmias &
maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter & WPW
C/I in pts with structural heart disease Adverse events :
Heart failure, dizziness, headache , Blurred vision
2. Propafenone
Spectrum of action similar to that of quinidine Possesses β-adrenoceptor antagonist activity Metabolized by hepatic microsomal enzymes T ½ - 2 – 10 hrs Approved for treatment of supraventricular
arrhythmias and suppression of life-threatening ventricular arrhythmias
C/I in structural heart disease Adverse events:
Nausea, Vomitting, altered taste
Class II
They Are β-adrenoceptor antagonists, including propranolol
Act by reducing sympathetic stimulation Inhibit phase 4 depolarization Depress automaticity Prolong AV conduction Decrease
Heart rate Contractility
Class II
Major drugs Propranolol, a nonselective β-adrenoceptor antagonist
Acebutolol & esmolol, more selective β1-adrenoceptor antagonists
Used to treat ventricular arrhythmias
Propranolol, metoprolol, nadolol, and timolol frequently used to prevent recurrent MI
Class II
Absorption and elimination: Propranolol: oral, iv Esmolol: iv only (very short acting T½, 9
min) Cardiac effects
APD and refractory period in AV node to slow AV conduction velocity
decrease phase 4 depolarization (catecholamine dependent)
Class II
Uses: Treating sinus and catecholamine
dependent tachyarrhythmias Converting reentrant arrhythmias in AV Protecting the ventricles from high atrial
rates Side effects:
Bronchospasm Hypotension Don’t use in partial AV block or
ventricular failure
Class III
Class III drugs: Prolong action potential duration Prolong effective refractory period
Act by: interfering with outward K+
currents or slow inward Na+ currents
Class III
1. Amiodarone
Structurally related to thyroxine. Net effect:
Increases refractoriness Depresses sinus node automaticity Slows conduction.
Long half-life (14—100 days) ↑ risk of toxicity Plasma conc not well correlated with its effects After parenteral administration:
Electrophysiologic effects →within hours Effects on abnormal rhythms may not be seen
for several days
1. Amiodarone
Antiarrhythmic effects may last for weeks or months after the drug is discontinued
Uses: Refractory life-threatening ventricular arrhythmias in preference to lidocaine
T/t of atrial and/or ventricular arrhythmias
Adverse effects Pulmonary fibrosis Skin pigmentation Corneal deposits Interferes with the thyroid function
2. Ibutilide
Administered by intravenous infusion Pure Ikr channel blocker
Also activates inward Na+ current Net result in APD Causes QT Uses :
Conversion of atrial fibrillation and flutter Side effects :
Torsades de pointes
3. Sotalol
Prolongs the cardiac action potential Increases the duration of the refractory period Has nonselective β-adrenoceptor antagonist
activity Uses:
Atrial arrhythmias or life-threatening ventricular arrhythmias
Treatment of sustained ventricular tachycardia Adverse effects:
Proarrhythmic actions, dyspnea, and dizziness
4. Dofetilide
Administered orally APD and refractory period Potent inhibitor of K+-channels Used in T/t of atrial fibrillation or atrial
flutter Adverse effects:
Serious arrhythmias, Torsades de pointes
5.Bretylium Also has some direct antiarrhythmic
action. Has properties of class II drugs Used for T/t of Ventricular arrhythmia
after lidocaine failure
Class IV
Mechanism
Class IV drugs selectively block L-type calcium channels.
These drugs prolong nodal conduction and effective refractory period and have predominate actions in nodal tissues
Class IV
Verapamil
Phenylalkylamine that blocks both activated and inactivated slow calcium channels.
Tissues that depend on L-type calcium channels are most affected
Has equipotent activity on the AV and SA nodes and in cardiac and vascular muscle tissues
Useful in: Supraventricular tachycardia Atrial flutter and fibrillation
Verapamil
Adverse effects:
Negative inotropic action that limits its use in damaged hearts;
Can lead to AV block when given in large doses or in patients with partial blockage.
Can precipitate sinus arrest in diseased patients
Causes peripheral vasodilation.
Miscellaneous Antiarrhythmic Drugs Adenosine
Acts through specific purinergic (P1) receptors. Causes an increase in potassium efflux and
decreases calcium influx. This hyperpolarizes cardiac cells and decreases
the calcium-dependent portion of the action potential.
Drug of choice for the treatment of paroxysmal supraventricular tachycardia, including those associated with Wolff-Parkinson-White syndrome
Digoxin
Mode of action: Na-K ATPase inhibition Positive inotrope Vagotonic
T ½ - Premature (61hrs), Neonate (35hrs), Infant (18hrs), Child (37hrs), Adult (35-48hrs )
Uses: Supraventricular Tachycardia
Digoxin
Interactions: Coumadin- ↑ PT ↑ Digoxin level Quinidine, amiodarone, verapamil ↓ renal function/renal tubular excretion
(Spironolactone) Worse with ↓ K+, ↓ Ca++
Digoxin Toxicity
Proarrhythmic Causes nausea/vomiting, lethargy,
visual changes Metabolic
Hyper K+, Ca++
Hypo K+, Mg++
Hypoxemia Hypothyroidism
Investigational Drugs
Analogs of Amiodarone are being developed such as: ATI-2001 Dronedarone SR-33589
Dronedarone: Resonable safety profile Well characterized pharmacokinetic &
pharmacodynamic profile Effective in doses lower than 2000 mg/dayWolbrette D et al ; Dronedarone for the treatment of atrial fibrillation and atrial flutter: Approval and efficacy ; Vasc Health Risk Manage 2010;6;517
Investigational Drugs
Azimilide : Potassium-channel blocking properties Prolongs cardiac AP & refractory periods Found to be effective in patients with
symptomatic tachyarrhythmias and ICDs therapies in recent studies
Other drugs, such as Ambasilide, are also in clinical development
Chromanol 293B is in preclinical testing
Reynolds RM, Josephson ME. Sustained ventricular tachycardiain ischemic cardiomyopathy : current management. ACC Current Journal Review 2005;14:63-71
Treatment of bradyarrhythmias
Atropine Blocks the effects of acetylcholine. Elevates sinus rate and AV nodal and
sinoatrial (SA) conduction velocity, & decreases refractory period
Used to treat bradyarrhythmias that accompany MI
Adverse effects: Dry mouth, mydriasis, and cycloplegia; May induce arrhythmias.
Treatment of bradyarrhythmias Isoproterenol
Stimulates β-adrenoceptors Increases heart rate and contractility. Uses: Maintain adequate heart rate and
cardiac output in patients with AV block Adverse effects:
Tachycardia, Anginal attacks Headaches, Dizziness Flushing, and tremors
T/t of Atrial Flutter/Fibrillation1. Reduce thrombus formation by using
anticoagulant warfarin2. Prevent the arrhythmia from converting to
ventricular arrhythmia First choice: class II drugs:
After MI or surgery Avoid in case of heart failure
Second choice: class IV drugs Third choice: digoxin
Only in heart failure of left ventricular dysfunction
T/t of Atrial Flutter/Fibrillation3. Conversion of the arrhythmia into normal
sinus rhythm Class III: IV ibutilide, IV/oral amiodarone, or oral sotalol Class IA: Oral quinidine + digoxin (or any drug from the
2nd step) Class IC: Oral propaphenone or IV/oral flecainide Use direct current in case of unstable
hemodynamic patient Fuster V et al; ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. Circulation 2006;114;700
T/t of Ventricular Arrhythmia Premature ventricular beat (PVB) First choice: class II
IV followed by oral
Early after MI
Second choice: amiodarone
Avoid using class IC after MI ↑ mortality
T/t of Ventricular Tachycardia First choice: Lidocaine IV
Repeat injection if needed
Second choice: procainamide IV
Adjust the dose in case of renal failure
Third choice: class III drugs
Especially amiodarone and sotalol
Grant AO, Recent advances in the treatment of arrhythmia. Circ J 2003;67;651
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