Electrophysiology of the heart

Arrhythmia: definition, mechanisms, types

Drugs :class I, II, III, IV, others

Guide to treat some types of arrhythmia

Normal conduction pathway:

1- SA node generates action

potential and delivers it to the atria and the AV

node

2- The AV node delivers the impulse to

purkinje fibers

3- purkinje fibers conduct the

impulse to the ventricles

Action potential of the heart:

In the atria, and ventricles the AP

curve consists of 5 phases

In the SA node , AV node and purkinje

AP curve consists of 3 phases

Non-pacemaker action potential

Phase 0: fast upstroke

Due to Na+ influx

Phase 3: repolarizati

onDue to K+

efflux

Phase 4: resting

membrane potential

Phase 2: plateu

Due to Ca++ influx

Phase 1: partial repolarizationDue to rapid efflux of K+

N.B. The slope of phase 0 = conduction velocityAlso the peak of phase 0 = Vmax

Pacemaker Action Potential

Phase 4: pacemaker potential

Na influx and K efflux and Ca

influx until the cell reaches

threshold and then turns into

phase 0

Phase 0: upstroke:

Due to Ca++ influx

Phase 3: repolarization:

Due to K+ efflux

Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously

Effective refractory period (ERP)

It is also called absolute refractory period (ARP) :

•In this period the cell can’t be excited

•Takes place between phase 0 and 3

If the arrhythmia arises from

the ventricles it is called ventricular arrhythmia

If the arrhythmia arises from

atria, SA node, or AV node it is

called supraventricular arrhythmia

Delayed afterdepolarizat

ion

Early afterdepolarizat

ion

↑AP from SA node

AP arises from sites other than SA node

Refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity).

The discharge rate of normal or abnormal pacemakers may be accelerated by drugs, various forms of cardiac disease, reduction in extracellular potassium, or alterations of autonomic nervous system tone

AED –AP occurs during repolarization

CausesCongenital defective of K

channelProlong QT syndrome

Abn Na Channel- fast recovery to resting state

K channel blockers drugHypokalemia eg: use of

diureticBradycardia prolong

Action potential duration

DAD –AP occurs once repolarization complete

caused by intracellular Ca / Na overloadAdrenergic stimulation

(Ca & Na overload)Digitalis (- Na K APTase,

red Na effux, >NA intra cellular, + Na Ca exchanger ,

Miocardia Ischaemia/ infaction( reduce O2, reduce ATP production, reduce Na K ATPase activity

arrhythmias that arise as a result of afterdepolarizations (abnormal depolarizations that interrupt phase 2, phase 3, or phase 4 ) which on depends of the prior impulse (or series of impulses)

This is when the impulse is not

conducted from the atria to the

ventricles

1-This pathway is blocked

2-The impulse from this pathway

travels in a retrograde

fashion (backward)

3-So the cells here will be

reexcited (first by the original

pathway and the other from the

retrograde)

Reexcitation of cardiac tissue by return of the same cardiac impulse using a circuitous pathway

Due to imbalance of conduction and refractories

Mech of PVCVT and VFSVT,AF,flutter

Here is an accessory

pathway in the heart called

Bundle of Kent

•Present only in small populations

•Lead to reexcitation Wolf-Parkinson-White Syndrome

(WPW)

Abnormal anatomic conduction

In case of abnormal generation:

Decrease of phase 4 slope (in pacemaker cells)

Before drug

after

phase4

Raises the threshold

In case of abnormal conduction:

↓conduction velocity

(remember phase 0)

↑ERP(so the cell won’t be

reexcited again)

Tachydysrhythmias

Regular Irregular

Narrow complex Wide complex Narrow complex Wide complex

Sinus TachycardiaAtrial Tachycardia

Atrial FlutterAVNRT/AVRT

Ventricular tachycardiaPacer-mediated

tachycardiaSVT with pre-existing BBB

SVT with rate-dependent BBB

MATAtrial Fibrillation

Atrial Flutter with variable block

Torsade des PointesVentricular fibrillation

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

classmechanismactionnotes

INa+ channel

blockerChange 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 & conduction

velocity

↓conduction velocity in SA and

AV node

•Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia)•They are classified according to Vaughan William into four classes

according to their effects on the cardiac action potential

They ↓ conduction velocity in non-nodal tissues (atria, ventricles, and

purkinje fibers)They act on open Na+ channels or inactivated only

Have moderate K+ channel blockade

So they are used when many Na+

channels are opened or

inactivated (in tachycardia only) because in normal

rhythm the channels will be at rest state so the drugs won’t

work

Slowing of the rate of rise in phase 0 ↓conduction velocity

↓of Vmax of the cardiac action potential

prolong muscle action potential & ventricular (ERP)

↓ the slope of Phase 4 spontaneous depolarization (SA node) Decreased pacemaker activity

They make the slope more horizontal

Intermidiate interection with sodium channel blocker Pharmacokinetics:

Supraventricular and ventricular arrhythmias Quinidine –prevent recurrent supraventricular

tachydysrhythmias & suppress ventricular premature contraction

Oral quinidine/procainamide are used with class III drugs in refractory ventricular tachycardia patients with implantable defibrillator

IV procainamide used for hemodynamically stable ventricular

tachycardia for acute conversion of atrial fibrillation including

Wolff-Parkinson-White Syndrome (WPWS)

Systemic lupus erythromatosus (SLE)-like symptoms: arthralgia,

fever, pleural-pericardial inflammation.

Symptoms are dose and time dependent

Common in patients with slow hepatic acetylation

Notes:Torsades de pointes: twisting of the point .

Type of tachycardia that gives special characteristics on ECG

At large doses of quinidine cinchonism occurs:blurred vision, tinnitus, headache, psychosis and gastrointestinal

upsetQuinidine has anti vagal action accelerate AVN

conduction Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into

paradoxical ventricular tachycardia

Adverse effect of Disopyramide --Negetive inotropic effect , CI in Cardiac failure or AV block

-Urinary retension,dry mouth,blurred vision & precipitated glaucoma (anticholinergic activity)

- Sinus Node depression& Prolong QTVentricular reentry arrythmia, VF, TDP

They shorten Phase 3 repolarization

↓ the duration of the cardiac action potential

Suppress arrhythmias caused by abnormal automaticity

Show rapid association & dissociation (weak effect) with Na+ channels with appreciable degree of use-dependence

Min change on conduction velocity

Lidocaine Used IV because of

extensive 1st pass metabolism

Clearence is related to hepatic blood flow, liver fx,microsomal activity-prolong in liver dis, heart failure, elderly

Propanolol , cimetidine, halothane dec hepatic clearence of lignocaine

Mexiletine

Oral analogs of lidocaine

Used for chronic treatment of ventricular arrhythmias associated with previous myocardial infarction

UsesThey are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicityThey have little effect on atrial or AV junction arrhythmias (because they have min effect on conduction velocity)

Adverse effects:1 -neurological effects

2 -negative inotropic activity

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0

Death

Ventricular Arrest

Cardiac ArrhythmiaRespiratory arrest

Myocardial depression

Plasma lidocaine concentration µg/ml

Coma

Loss of conciousness

Convulsion

Muscle twitching

Visual disturbances

Lightheadness, tinnitus, circumoral & tongue numbness

Positive inotropy, anticonvulsant, antiarrythmic

CNS excitation

Markedly slow Phase 0 fast depolarization

Markedly slow conduction in the myocardial tissue

They possess slow rate of association and dissociation (strong effect) with sodium channels

Have only minor effects on the duration of action potential and refractoriness

Reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization.

Clinical use Refractory ventricular

arrhythmias. particularly potent

suppressant of premature ventricular contractions (beats)

Dosage :Orally :100 – 200 mg bdIV :2 mg/kg up to 150

mg over 10-30 mins Infusion : 1.5 mg/kg/h for 1 hour,

Then 0.1 – 0.25 mg/kg/hTherapeutic plasma

con. : 0.2-1.0 ug/ml

PharmacokineticsRapid and complete

absorbed after oral: bioavailability-90%

40-50% protein bindingVd: 5-10 L/kg

Metabolized in liver25% excreted unchanged

by the kidneysElimination half life: 7-15

hElimination decrease in ;

CCF , renal failure

Drugs interactionFlecainide increase the

plasma concentrations of digoxin and propanolol

Toxicity and Cautions for Class IC Drugs: Potentially serious proarrhythmogenic effect

causing: severe worsening of a preexisting arrhythmia

(ventricular arrhythmia aggravated in 5-12 % patient)

In patients with frequent premature ventricular contraction (PVC) following MI, flecainide increased mortality compared to placebo.

CNS effect comman- diziness, visual disturbance, GIT upset

Notice: Class 1C drugs are particularly of low safety and have shown even increase mortality when used

chronically after MI

Compare between class IA, IB, and IC drugs as regards effect on Na+ channel

& ERP

Sodium channel blockade:   IC > IA > IB

Increasing the ERP:IA>IC>IB (lowered)

Because of K+

blockade

Mechanism of action Negative inotropic

and chronotropic action.

Prolong AV conduction (delay)- prolong PR interval

Diminish phase 4 depolarization suppressing automaticity(of ectopic focus)

Clinical UsesTreatment of increased

sympathetic activity-induced arrhythmias such as stress- and exercise-induced arrhythmias

Atrial flutter and fibrillation.

AV nodal tachycardia.

Reduce mortality in post-myocardial infarction patients

Protection against sudden cardiac death

Clinical useShort term

management of tachycardia and hypertension in peri-operative period, acute SVT

No intrinsic sympathomimetic activity or membrane stabilizing properties

Adverse effectCardiac

precipitate heart failure

Non cardiac act B2-

adrenoreceptor antagonism at high dose – caution in asthmatics

Irritant to veins and extravasations - tissue necrosis

PharmacokineticProtein bound – 60%Rapid metabolized by red blood cell esterase to inactive acid metabolism and methyl alcoholHalf-life 10 minute

Oral dose: 10 to 80mg every 6-8

hr ( Chronic suppression

of ventricular dysrhythmia)

IV: 1 mg per minute, total dose3 to 6mg

(emergency suppression of cardiac dysrythmia)

Adverse effectsBradycardia,hypotension,

myocardial suppression and bronchospasm, acccentuate CCF

cross placenta readily. Fetal bradycardia, hypoglycaemia, hyperbilirubinaemia and intrauterine growth retardation (IUGR) are concerns.

Most reports have not shown significant adverse fetal effects but beta-blockers are probably best avoided in known IUGR

Propranolol was proved to reduce

the incidence of sudden arrhythmatic

death & reinfact after myocardial infarction

Prolongation of phase 3 repolarization without altering phase 0 upstroke or the resting membrane potential

prolong both the duration of the action potential and ERP

Clinical Uses: Wide spectrum activity against refractory

supraventricular and ventricular tachyarrhythmia

Pulseless ventricular tachycardia and fibrillation resistant to defibrillation

Effective for suppression of tachyarrhythmia a/w WPWS

Sotalol (Sotacor) non selective B adrenergic blockade

prolongs the duration of action potential and refractoriness in all cardiac tissues (by action of K+ blockade) – class 111 action

suppresses Phase 4 spontaneous depolarization possibly producing severe sinus bradycardia (by β blockade action)

β-adrenergic blockade combined with prolonged action potential duration may be of special efficacy in prevention of sustained ventricular tachycardia

Most dangerous S/ E: the polymorphic torsades de pointes ventricular tachycardia because

it increases ERP, prolong QT interval

Ibutilide Used in atrial fibrillation or flutter Only drug in class three that possess pure K+ blockade

Slow repolarization by enhance influx Na, blocked Prolong cardiac action potensials K channel

IV administration May lead to torsade de pointes

A Benzoflurance derivative, resembles thyrosineAmiodarone is a drug of multiple actions ,complex comprising

class I, II, III, and IV actionsDominant effect: Prolongation of action potential duration and

refractorinessIt slows cardiac conduction, works as Ca2+ channel blocker,

and as a weak β-adrenergic blocker

Dose and administrationVF/VT unresponsive to CPR, shock and vasopressor

IV: 300 mg (5mg/kg) bolus

Life threatening arrhythmiasMax dose: 2.2 g IV over 24HRapid Infusion 150 mg over 10 minutes , Slow infusion: 360 mg

over 6H, Maintenance Infusion: 540 mg over 18HTherapeutic blood level: 1.0 – 3.5 mcg/ml

PharmacokineticsPoorly absorbed from gut,oral bioav. 50-70%Highly protein-bound >95%Vd 2-70 l/kg

Elimination half-life 20-100 days

Hepatic metabolism produces desmethylamiodarone – antiarrhythmic activity

Not removed by hemodialysis

Drug interaction effect of other highly protein bound drugs

(phenytoin, warfarin) are increase – dose should adjust

Plasma level of digoxin may rise when amiodarone added

Toxicity Common with patient chronic treatment

Most common include GI intolerance, tremors, ataxia, dizziness, and hyper-or hypothyrodism (2-4 %)

Cardiac – bradycardia and hypotension. Prolonged QT interval (inc ventricular tachyarrrythmia including Torsade de points)

Corneal microdeposits may be accompanied with disturbed night vision

Others: liver toxicity, photosensitivity & rash (10 %) , gray facial discoloration, neuropathy, prox muscle weakness, and weight loss

The most dangerous side effect is pulmonary fibrosis which occurs in 2-5% of the patients

can be irreversible and life threatening -unusual at doses used for atrial fibrillation (200 mg/day)

10% fatal, most reversible

Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization (SA node)

They slow conductance in Ca2+ current-dependent tissues like AV node.

Examples: verapamil & diltiazemBecause they act on the heart

only and not on blood vessels.

Dihydropyridine family are not used because they only act on blood vessels

Prevents influx of Ca through slow (L) channel in SA and AV node – reduce their automaticity

They prolong ERP of AV node ↓conduction of impulses from the atria to the ventricles

Coronary artery dilatation

Clinical Uses More effective in treatment of atrial than ventricular arrhythmias.Treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmiasTreatment of atrial flutter and fibrillation

Dose5 – 10 mg IV bolus over 1-3 min

Infusion 5 mcg/kg

Verapamil

PhamacokineticOrally and IV90% absorbed from gut,

oral bioav.25% d/t high first-pass metabolism

90% bound to plasma protein

Metabolized in liverExcreted in urineVd 3-5 l/kgElimination half-life 3-7

hrs

Adverse effectCardiac

SVT with WPW syndromeverapamil precipitate VT

Pt with poor LV functionprecipitate cardiac failure

With agent that slow AV conduction (digoxin,B-blocker, halothane) precipitate serious

bradycardia and AV blockIncrease serum level of

digoxinNon cardiac

cerebral artery dilatation, constipation

CI- Sick sinus syndrome. heart block, poor left

ventricular failure

AdenosineEndogenous nucleoside slows conduction of cardiac impulses

through the AVN and accessory pathways

usesEffective for stable narrow complex SVTEffective in terminating those due to

reentry involving AV node or sinus nodeRegular and monomorphic wide-complex Not effective in AF, flutter or VT

Mechanism of actionIts stimulates cardiac

adenosine 1 receptors to increase K+ currents

shorten the action potential duration

hyperpolarize cardiac cell membranes.

In addition, Adenosine decrease cAMP concentration

PhamacokineticIts short-lived cardiac

effectsElimination half

time : 10 seconds by carrier-mediated cellular uptake

Dosage IV : 6mg iv rapid

bolus (over 1-3 second followed by NS bolus) , followed by a dose of 12mg if necessary

Drug interactionInhibit by

theophyllinePotentiated by

adenosine uptake inhibitors such as dipyridamole

Side effectsFacial flushing ,

Headache

Dyspnea, Chest discomfort

NauseaTransient

atrioventricular heart block, asystole

Rare – bronchospasm

Pharmacologic effects of adenosine are antagonized by methyxanthines (theophylline, caffeine) and potentiated by dipyridamole

Contraindication 2nd or 3rd degree heart

block & Sick sinus syndrome

Mode of actionCo-factor for membrane

enzyme Na+/K+ ATPaseLack of magnesium may

lead to intracellular K+ depletion

Slow the conduction trough AV node and prolong the refractory period in atria & ventricles– similar class 111

Clinical useTorsade de pointesVentricular arrhythmias

ass with digitalis toxicityMultifocal atrial

tachycardia

Dose: 1-2 g (2-4 ml of

50% solution) dilute in 50 ml D5 over 1h ( poorly absorbed from gut)

Mg is excreted by kidneys and accumulate in renal failure

Adverse effect Hypotension

Mode of actionDirect –

bind and inhibit cardiac Na+/K+ ATPase increase intracellular Na+ and decrease intracellular K+

Raised intracellular Na+ increased exchanged with extracellular Ca2+ resulting increase availability of intracellular Ca2+ positive inotopic effect, increasing excitability and force of contraction

Indirect- release of Ach at cardiac muscarinic receptors – slow

conduction and prolong refractory period in AV node and bundle of HIS

Clinical useTreatment of atrial

fibrilation or flutter

DoseLoading dose 1 – 1.5

mg, divided dose over 24h

Maintenance dose 125 – 500 mcg/day

Therapeutic range 1-2 mcg/l

Adverse effectCardiac

PVC, bigemini, all form of AV block

ECG – prolonged PR interval, ST segment depression, T wave flattening and short QT interval

Non cardiacAnorexia, nausea and

vomiting, diarrhoe and lethargy,

visual disturbance, headache and gynecosmatia

Toxicity – plasma conc >2.5 mcg/l

Treatment of digoxin toxicityStop digoxin adm. Gastric lavage, actvated

charchoalCorrect precipitating factor – K+SVT – propanololAV blockade – pacing, atropine,

isoprenalineVentricular arrhythmias – phenytoin,

lignocaine, pacingDigoxin – specific Fab a/body fragments

classECG QTConduction velocity

Refractory period

IA++↓↑

IB0no↓

IC+↓no

II0↓In SAN and AVN↑ in SAN and AVN

III++No↑

IV0↓ in SAN and AVN↑ in SAN and AVN

1st: Reduce thrombus formation by using anticoagulant warfarin

2nd: 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

digoxin•Only in heart failure of left ventricular dysfunction

3rd: Conversion of the arrhythmia into normal sinus rhythm:Class III:IV ibutilide, IV/oral amiodarone, or oral sotalol

Class IA: ( no longer recommended except vagally mediated AF coz More effective drug available , extra cardiac side effect & proarrythmia effect)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

Address precipitating factors :

hyperthyroidism, heart failure & etc