Antiarrhythmic drugs
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Transcript of Antiarrhythmic drugs
HEART
ashfaq
Pumping blood
Details??
Cardiac Function
Rate & Rhythm
Contraction
Contraction
•Chambers ( coordination)
Recall
• Contraction with
– Rhythm & Rate
– Coordinated• (alternate Contraction (systole) & (Diastole)
How comes ???
Specialsed Conducting System
The Conducting System of the Heart
DISTINGUISHED FEATURES OF CARDIAC MUSCLE FROM OTHER EXCITABLE TISSUE
Pacemaker Activity (automaticity) Absence of fast Na+ current in SA & AV node Ca++ current initiates action potential. Long action potential (Plateau) & Refractory
period Influx of Ca+ during Plateau
Normal Cardiac Rhythm
Parts of a Normal Typical ECG
0.1- 0.22
< 0.12
< 0.10
0.44 – 0.46
Ionic Basis of
Membrane Electrical Activity
During Cardiac Cycle: Ions ( Na+, K+, Ca+ & Cl- ) moves across cell membranes in response to their concentration gradients only when their channels open. Ionic movement produces currents responsible for the cardiac action potential.
Diastolicchannelcurrents
Inward Na+ Current
m (activation) gate: their opening for Na+ ions leads to depolarization from threshold to action potential voltage.h (inactvation) gate: closure occurs after this brief opening of m gates
- 85
influx
eflux
Absolute Refractory Period
Relative R.P.
E after depolarizationD
Threshold
Phase 0: Depolarization; Rapid Sodium Influx;Resting voltage has become positive.
Phase 1:Early Repolarization; brief K+ & Cl- eflux
Phase 2:Plateu phase; Ca++ influx
Phase 3:Rapid repolarization; K+ & Cl- eflux
Phase 4 ( automaticity ): Ratio of Na+/K+ permeability; cellularelectrolyte balance is slowly restored. Slow Diastolic Depolarization;Until the threshold potential is reached.
Early & Delayed - after depolarization may occur during relative refractory periodbefore the phase 4, due to myocardial damage, so leading to arrhythmias.
Early & Delayed depolarizations interrupt Phase 3
T-type Ca++ opens
K+ closedNa+ unchanged
L-typeCa++
K+ opens
Myocardial Action Potential
I b = background inward sodium current,
If = ‘funny current’,
I cat= transient or ‘T’ type calcium current, opening of channels leads to threshold
I cal = slow responding ‘ L’ type calcium channels,
I k = delayed rectifier potassium current,
Threshold
Ical
Slow Responding Fibers; Ca++ role; as at -55 mV Na+ channels close
SA Node & AV Node or Damaged fibers
I k1= inward rectifier current,
I Na= Fast responding inward sodium current, ( Na channels closes at -55 to -70 mv at which however Ca channel opens ) so in ischemic damage, fast responding fibers are changed into slow responding fibers
I to = transient outward potassium current,
I cal = ‘L’ type calcium channel,
I k = delayed rectifier potassium current,
Upstroke
-85 resting potential
O -
Fast Responding Fibers; Na+ Role
the only conduction pathway
Body Surface Manifestations of the Depolarization and
Repolarization Waves of the heart.
The only conduction pathway
delay of 0.15 sec.
at
to allow blood
to enter from atria to Ventricles
AV node
Normal Sinus Rhythm P waves preceding each QRS complex
Normal
12 leads
Electrocardiogram
The Main Factors affecting Heart Rate
Gender
ANS activity ( Sympathetic/Parasympathetic)
Age
Circulating Hormones ( Adrenaline, Thyroxin)
Physical Activity
Temperature
Baroreceptors Reflex
Emotional States
Arryhthmia
Dysrhythmia
Cardiac Arrhythmia is an abnormality in:
Rate, Rhythm, Site of origin & the conduction of cardiac impulse.
Arrhythmias occur in:
Myocardial Infarction ( >80% )
Anesthetized Patients ( Up To 50% )
Digitalized Patients ( Up To 25% )
(All Antiarrythmics are Arrhythmogenic )
Arrhythmias are caused by:• abnormal pacemaker activity or • abnormal impulse propagation & conduction
• Shift of pacemaker function from SA to other part of the Heart
• Block transmission in the Heart• Abnormal pathway in the heart• Spontaneous generation of Impulses in the heart
There is a normal relationship between “refractory period and conduction velocity”.
Any change in this relationship may lead to arrhythmias
Factors Affecting Rhythm:
Automaticity,
Conduction & its Velocity,
Excitability,
Responsiveness,
Refractoriness & ERP.
Factors Precipitating Arrhythmias
1. Ischemia: Myocardial Infarction, Coronary Vessels Disease,2. Hypoxia : Chronic Cor-pulmonale, Shock, Severe Anemia, 3. Acidosis : Pneumonia, Ketoacidosis, Lactic Acodosis,4. Alkalosis: Respiratory, Metabolic ( K+/Cl- Depletion ), 5. Electrolyte Abnormalities: Hypokalemia, Hypocalcemia,6. Excessive Catecholamines: Sympathetic Stimulation,
Exercise, Hypertension, Thyrotoxicosis, Pheochromocytoma,7. Autonomic Influences: Vasovagal Induced and
Postprandial Arrhythmias, Caffeine, Smoking, Recreational Drug Use, Alcohol Abuse,8. Drug Toxicities: Digoxin, Amiodarone, Β – Blockers,9. Diseases of Cardiac Fibers: Cardiomyopathy, Fibrosis of
His Purkinje System, Post - Cardiac Surgery,
Mechanism of Arrhythmias
• A). Disturbances of Impulse Formation:
1. Changes in Automaticity:
2. Triggered Activity:
• B). Disturbances of Impulse Conduction;
1. Abnormal Regulation of the Heart Beat by
sympathetic, vagal activity or re-entry
• C). Molecular & Genetic Basis of Arrhythmias
A). Disturbances of Impulse Formation:
a). Increase or decrease in pacemaker rate: due to increased or decreased depolarization of Pace Maker Cells;
slope 4: if decreased i.e., more negative leads to slow normal
pace maker rate,
e.g., Vagal discharge, β-receptor Blockers
b). Latent Pace Makers: ( Some Purkinje Fibers; Quiescent Atrial & Ventricular Cells )
they show normally slow phase 4 depolarization and are more prone to acceleration thus may show repetitive pace maker activity esp. in hypokalemia
D
1. Changes in Automaticity:
a). Afterdepolarizations: EADs, DADs ( early or delayed after depolarization )
2. Triggered Activity:
Early After Depolarization's: are usually produced & exacerbated at slow heart rates and
contribute to the development of long QT – related arrhythmias.
Delayed After Depolarization's: occur when intracellular calcium is increased and are exacerbated by
fast heart rates and usually responsible for arrhythmias related to digitalis / catecholamine & to myocardial ischemia
a. Increased slope of phase 4 depolarization as in hypokalemia, β stimulation, etc. leads to early completion of diastolic depolarization, ↑Pace Making
b. Reduced Threshold Potential --- early completion of diastolic depolarization.
“Triggered Activity”: stimulating during relative refractory period so getting action potential earlier than normal.E. Early after depolarization, arises almost from the plateau.D. Delayed after depolarization, arises from the resting potential.
a b
accelerated automaticity e.g.,in sympathetic stimulation
Threshold
Normal or Reduced
Pace Maker Depolarization=Durations of Action Potential & Diastolic Interval )
Four Basic Mechanisms CAUSING Disturbed rhythm
• Delayed after Depolarization• Re-Entry• Ectopic pace maker• Heart Block
B). Disturbances of Impulse Conduction;Abnormal Regulation of the Heart Beat
1). In A / B: Effects of sympathetic stimulation & Nor epinephrine.
Sympathetic stimulation increases the heart rate by increasing the slope of the pacemaker potential
2). In C / D: depressed conduction due to increased vagal activity (AV nodal block, bundle branch block)
C D
Vagal stimulation decreases the atrial force of contraction by marked shortening of action potential;
also increased K+ permeability & reduced Ca++ current both contribute to block AV conduction
3). Re - entry (circus movement tachycardia): if an ectopic beat finds one limb refractory
Impulse passes down
both limbs at equal speed
Retrograde Impulse will pass
When: the refractory period is shorter
than
the conduction time
or on recovery
it passes if the other side is slowly excited
esp. at AV node, Atrial or Ventricular Walls
Normal Damaged
C). Molecular & Genetic Basis of Arrhythmias
as in several congenital & acquired cardiac arrhythmias; there is either increased inward current
or
decreased outward current during the plateau,
Types of Arrhythmias
TACHYARRHYTHMIA
• Atrial– Supraventricular Tachycardia
• (Pulse Rapid, Regular, Ectopic Beats)
– Atrial Fibrillation• Ventricle
– Ventricular Tacharrhythmia– Ventricular Fibrillation
Brady-arrhythmias: ( rate < 60 beats/min.),
Tachy-arrhythmias: ( rate >100 beats/min.),
Sinus Bradycardia may be due to: hypothermia, hypothyroidism, cholestatic jaundice, raised intracranial pressure, β-blockers, digitalis etc., IHDs, sick sinus syndrome- fibrosis of the atrium & sinus node.
Heart Block • conduction block at any level in the conducting system; Prolongation of PR interval > 0.22 s & then gradually P waves don’t conduct. ( 1st – 3rd degree block ) • block lower than the Bundle of His produces Bundle Branch Block; widening of QRS complex up to 0.11 s ( N: < 0.10 s) .
Sick Sinus Syndrome sinus arrest & junctional escape beats (J). P waves are inverted in the cavity leads
Complete Heart Block
Congenital Complete Heart Block: QRS complex is narrow
with rate 52 beats/min.
Acquired Complete Heart Block: QRS complex is broad with rate 38 beats/min.
Tachy-arrhythmias: ( rate >100 beats/min.), may be due to Exercise, Emotion, Pain, Fever, Infection, Acute Myocardial Infarction, Acute Heart Failure, Acute Pulmonary Embolism, Hypovolemia, Pregnancy, Anemia, Hyperthyroidism, Pheochromocytoma, Excess Sympathetic or Reduced Parasympathetic Stimulation, etc.
Tachycardias are more symptomatic if the arrhythmia is fast & sustained
Supraventricular Tachycardia: Sinus Tachycardia, Atrial Fibrillation, Atrial Flutter, Ventricular Tachyarrhythmias: Ventricular Tachycardia, Ventricular Fibrillation, The Brugada syndrome, Torsades de pointes, Ventricular Premature Beats.
ECG (Ambulatory Record )
Supra Ventricular Tachycardia
Supra-Ventricular Tachycardiaat atrium or AV junction e.g.,
Atrial Premature Beats conducts to the ventricles with a slightly prolonged PR interval
Premature P waves are different from the sinus P waves
A prolonged QT interval
in
Supra-ventricular Tachycardia
P waves= Atrial rate is 150/min. R-waves=Ventricular rate is 75/min.
Atrial Tachycardia with IInd Degree AV. Block
F= flutter waves; flutter rate= 240/min.Every fourth F wave is transmitted to the ventricles;
Ventricular rate= 60/min.
Atrial Flutter
Atrial Fibrillation ( Irregular Rhythm Atrial Rate 300 To 600 /Min.)
Ventricular Rate Depends On Atrial Regularity At Av Node Entry
Atrioventricular Junctional Tachycardia
AV Nodal re-entry TachycardiaQRS complex are narrow & P waves not visible
Atrioventricular re-entry TachycardiaAfter narrow QRS complexes the tachycardia P waves are clearly seen.
During sinus rhythm of WPW Syndrome short PR interval & δ waves ( arrow )
Atrial Fibrillation in the WPW Syndrome.Tachycardia with broad QRS complexes with fast & irregular ventricular rate
Familial Atrial Fibrillation:
there is increased inward current of potassium
mutation of the gene for subunits of the slow delayed rectifier potassium
current,
Ventricular EctopicsVentricular Ectopics of different morphology
A pair of PVCs
Frequent PVCs
Following PVCs, non -sustained, a brief run of Ventricular Tachycardia
Ventricular Fibrillation( Post Myocardial Infarction )
Ventricular Ectopic followed by fibrillation
Torsade de pointes ( which is associated with syncope and sudden death ) decreased outward current of
Potassium due to: mutation in gene of potassium
channels leading to decreased repolarization & long QT subtypes 1, 2, 5 & 6.
Torsade de pointes
( a short lived atypical ventricular tachycardia which arises when ventricular repolarization is greatly prolonged - long QT syndrome: may be due to decreased K+, Mg+, Ca++ or drugs ) may be dangerous if resulting in ventricular fibrillation.
a brief period of idioventricular rhythm
The Brugada Syndrome:
( which is characterized by ventricular fibrillation & sudden
death ) increased outward current of Sodium due to: mutation in gene of sodium channels leading to congenital long QT subtype 3 syndrome
The Brugada Syndrome
( an inheritable condition )
Idiopathic Spontaneous Ventricular Fibrillation
with ST - Elevation in V1 – V3 Right Bundle Branch Block
Holter Recording: sudden increase in heart rate at 11:00 & 13:00 0 clock
Ambulatory ECG
ST depression with silent myocardial ischaemia
Treatment of arrhythmia
Why arrhythmias should be treated?
Arrhythmias may cause: Sudden Death, Stroke ( emboli )
Syncope, Heart Failure, Dizziness, Palpitation, or Asymptomatic at all.
because
Asymptomatic or
Minimally Symptomatic Arrhythmias
are usually not treated
because anti-arrhythmic drugs themselves can precipitate lethal arrhythmias;
Treatment of arrhythmias
is needed only if
• cardiac output is reduced, or if• some arrhythmias can precipitate serious / lethal rhythm disturbances e.g., ventricular fibrillations.
Cardiac Output is decreased
due to:
Increased rate of contraction
Decreased rate of contraction
Asynchronised rate of contraction
The major anti-arrhythmic mechanisms
1. Sodium Channel Blockade 2. Sympathetic Blockade at heart 3. Prolongation of Effective Refractory Period
4. Calcium Channel Blockade
Thanks for patience Listening
Anti-arrhythmic Drugs
Dr. Ashfaq Ahmad
1. DRUGS: ClassificationClass I ( Na Channel Blockers -Membrane-depressants ): Sub-Class
Ia: Disopyramide- Ventriculr DysrhymiaProcainamid - Paroxysmal atrial Fibrillation due to
Quinidin vagal overactivity
Ib: Lidocaine Tocainid Ventricular Tachycardia & Fibrillation Mexilitine immidiate after MIPhenytoin
Ic: Flecainide - Paroxysmal atrial Fibrillation
Propofenone - Recurrent Tacharrhythmias ( wolff Moricizine Parkin-son white syndrome)
Class II ( Beta Blockers ):AtenololMetoprololPropranololAcebutolEsmolol
Class III ( K+ Channels Blockers ) Prolong Action Potential
AmiodaroneSotalBretyliumIbutilideDofetil
Class IV ( Ca Channel Blockers )VerapamilDiltiazemBepridil
Class V ( Miscellaneous ): Adenosine Magnesium sulphate Digoxin Isoprenaline Atropine
2. Catheter Ablation:
3. Implantable Cardioversion Defibrillator ( ICD ):
Pharmacological Properties
Pharmacokinetics:
Bioavailability (>80%):
Digitalis, Quinidine, Ia drugs, Ib except Lidocaine, SotalolFirst-pass metabolism:
Lidocaine, Moricizine, Ic, Beta blockers
Routes of administration: Only Oral: Disopyramide, Acebutalol, Propofenone, Moricizine, Tocainide, Sotalol, Mexilitine, Flecainide.
Only Parenteral: Lidocaine, Esmolol, Ibutilide, Bretylium, Adenosine, MgSO4
Oral + Parenteral: Ia, Amiodarone, Propranolol, Ca-Blockers, Digitalis
Half-Life:
Short: Lidocaine (2hrs), Adenosine(<10 sec), Esmolol (10 min)
Long: Digoxin (36hrs), Phenytoin (<42hrs), Amiodarone (weeks).
Intermediate (4 - 20 hrs): All Others
Active Metabolites of: Quinidine, Procainamide, Propofenone, Adenosine
Mechanism of Action
Aim of the Treatment is
to make the depolarized tissues silent
- 85
influx
eflux
Absolute Refractory Period
Relative R.P.
E after depolarizationD
Threshold
Phase 0: Depolarization; Rapid Sodium Influx;Resting voltage has become positive.
Phase 1:Early Repolarization; brief K+ & Cl- eflux
Phase 2:Plateu phase; Ca++ influx
Phase 3:Rapid repolarization; K+ & Cl- eflux
Phase 4 ( automaticity ): Ratio of Na+/K+ permeability; cellularelectrolyte balance is slowly restored. Slow Diastolic Depolarization;Until the threshold potential is reached.
Early & Delayed - after depolarization may occur during relative refractory periodbefore the phase 4, due to myocardial damage, so leading to arrhythmias.
Early & Delayed depolarizations interrupt Phase 3
The anti-arrhythmic drugs:
a). Decrease: automaticity, Conduction,& Ecitability
The automaticity of ectopic sites more than at SA Node
by1) reducing the ratio of sodium & potassium
permeability so the membrane-potential during phase 4
stabilizes closer to potassium equilibrium at which K+ movement is stopped
2) or by
increasing the threshold ( making more positive ),
ii). the conduction & excitability of depolarized tissues
by reducing: excitatory currents to a level below for propagation,
due to decreased available ‘un blocked channels’
b). Increase: the refractory period more at
depolarized tissues than in normally polarized tissues by prolongation of recovery time of the channels
which are still able to reach the rested state thusextra-systoles are unable to propagate at all;
later impulses propagate more slowly and are subject to bidirectional block in re-entry arrhythmias.
Na Blockade (mainly):
Ia, Ib, Ic, Phenytoin, Amiodarone, Na Blockade (Some): Beta-blockers, Ca blockers
Beta-Blockade (Mainly):
Esmolol, PropranololBeta-Blockade (Some): Bretylium, Sotalol, Propofenone, Amiodarone (irreversible)
Beta Blockers, Na+ & Ca++ Blockers
Phase 4 slope decreased
K+ Channel Blockade:
Amiodarone, Sotalol, Bretylium, Ibutilide
K+ Blockers,Adenosine,Na+ Blockers
Increased duration of Action Potential
Ca-Blockade (mainly): Verapamil, Diltiazem Ca-Blockade (some): Amiodarone, Procainamide, Disopyramide, MgCl
Cardiac Effects
Pacemaker Activity Depressed (SA node/ Ectopic Sites): Ia (except Disopyramide),
Ib, Ic, II, III (except Ibutilide),
IV, Adenosine (No effect)
Action Potential (Prolonged duration): Ia, III
Refractory period Atrial / Ventricular (prolonged): Ia, Ib, II, III (except Bretylium) (some): Ic, IV AV Node (Prolonged): II, III, IV, Adenosine, AV Node (some): Ib, Ic, Bretylium, Ibutilide PR-Interval (Prolonged): II, III (except Bretylium, Ibutilide)
QRS Duration (Prolonged): Ia, Ib
QT Interval (Prolonged): Ia, III
Other Effects
Anti-muscarinic: Quinidine, Disopyramide
Cholinomimetic: Digitalis
Sympathomimetic: Bretylium
Alpha-blocking: Quinidine
Beta-blocking (Mainly): Esmolol, Propranolol, Sotalol, Bretylium
Some: Adenosine, Amiodarone, Quinidine, Procainamide, Ca-blockers
Ganglion blocking: Procainamide, Bretylium,
USES:
1. To relieve symptoms due to: • AV node re-entry tachycardia,• WPW syndrome,• Atrial fibrillation or flutter or • tachycardia. ( Class Ic or Class III ; Anticoagulants if needed, Catheter
Ablation )
2. To prevent sudden death in:• Life-threatening ventricular tachyarrhythmias, • Congenital long QT, • Ventricular Tachycardia.
( Beta-blockers +/- pacemaker, Calcium Channel Blockers, Catheter Ablation, or ICD )
3. Supra-ventricular (Only or mainly): IV, I, Adenosine (Some)
4. Ventricular (Only or Mainly): I, II, Bretylium
5. Both (equally): III (except Bretylium)
Adverse EffectsQuinidine: GIT, Cinchonism, Idiosyncracy
Procainamide: SLE, GIT, Allergic
Disopyramide: Atropine like
Lidocaine: CNS
Propofenone: Taste, constipation, Arrhythmias
Amiodarone: Vasodilatation, Accumulation in heart, liver, skin, tears
Bretylium: Ganglion blockade
Sotalol: Beta blockers like
Adenosine: Vasodilatation, Broncho-spasm, Heart Block
Contra Indications
CCF: Disopyramide, Flecainide, Beta blockersSA Node/AV node Dysfunction: Beta blockers, Ca Channel blockers, DigoxinMyocardial Infarction: FlecainideProlonged QT Interval:
Quinidine, Procainamide, Disopyramide, Sotalol, Bretylium, Amiodarone, Ibutilide
2. Catheter AblationThree or four electrode - catheters are placed into the heart chambers to record and pace from various sites.
Radio – frequency catheter ablation is frequently employed for symptomatic tachy – arrhythmias like:
AV re-entry tachycardia or with WPW syndrome: first line therapy to avoid the risk of sudden death .
Ventricular & Atrial Tachycardia ( in normal hearts ): easily cured by catheter ablation.
Atrial flutter:If not easily managed medically; 90 – 95 % effective.
Atrial fibrillation: After AV node ablation & pacemaker implantation a marked symptomatic improvement occurs but anticoagulants are still required. ( successful in 60 – 80 % cases )
Complications: Pulmonary vein stenosis, thrombosis, stroke.
X-Ray of a dual-chamber Implantable Cardioverter-defibrillator( IUD ) in a left pectoral position with atrial & ventricular leads
3.CARDIOVERTER DEFIBRILLATOR
Termination of ventricular fibrillationby the direct current shock after detecting it correctly
Electrogram recorded internally from the ventricular lead of an ICD shows chaotic ventricular activity consistent with ventricular fibrillation
The ICD recognizes ventricular tachycardia or fibrillation and automatically delivers pacing or a shock to the heart to cause
cardioversion to sinus rhythm
ECG – Body manifestation of
Depolarization and Repolarization Wavesof the Heart
Β - agonistsPacemaker potential (Phase 4)
Rapid depolarization
(Phase 0)
Plateau (Phase 2)
Repolarisation (Phase 3)
Class II
Class I
Class IV
Class III (and Ia)
The Conducting System of the Heart
PR Interval: Conduction Time From Atria to Ventricles
QRS Duration: Ventricular Conduction Time
QT Interval: Duration of Ventricular Action Potential
QRS Complex: Ventricular Depolarization
P – Wave: Atrial Depolarization
T – Wave: Ventricular Repolarization
Standard Leads (bipolar)
Augmented leads (augmented bipolar)
Chest Leads (uni-polar)
The
connections
& directions
of the
current flow
Cardiac Vectors: a). The hexaxial Reference System e.g., lead l is O0, lead ll is 600, lead lll is + 1200.
b). Direction of the vector: e.g., in lead lll positive & negative deflections are equal, so the mean QRS vector is perpendicular to lead lll