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