II. Mechanisms for Arrhythmias

8/14/2019 II. Mechanisms for Arrhythmias

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II. MECHANISMS FORARRHYTHMIAS

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A. Definition of Arrhythmias

-abnormality in rate, regularity, site oforigin, and/or sequence of activation

-they range in severity.

B. Abnormalities of Impulse Generation

1. Altered Normal Automaticity

2. Triggered Impulses (afterdepolarizations)

C. Abnormality of Conduction - Re-entryMechanisms


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1. Altered Normal Automaticity- change in spontaneous phase 4 depolarization

Affects primarily SA node and His-Purkinje fibers but in disease states, suchas from ischemia, ventricular cells can also spontaneously depolarize.

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1. Altered Normal Automaticity

Favor RAPID phase 4Depolarization

Sympathetic nervous system

Catecholamines

Hypokalemia

Cell damage

ischemia

myocardial stretch

trauma

Drugsatropine

cardiac glycosides

(His-Purkinje)

Favor SLOW phase 4Depolarization

Parasympathetic nervous

system Acetycholine

Hyperkalemia

DrugsClass 1 antiarrhythmics -

quinidine

verapamil

propranolol


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2. Triggered Impulses

normal action potential is interrupted orfollowed by an abnormal depolarization.Early and delayed afterdepolarizations.

a. Early afterdepolarizations (EAD)

b. Delayed afterdepolarizations (DAD)


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b. Delayed Afterdepolarizations (DAD)

- secondary depolarizations that occur after full repolarizationhas developed.

1) Phase 0 carried by sodium with fast conduction.2) Factors associated with DAD include:

- High intracellular Ca2+ load (ischemia, cardiac glycosides)- Increased SNS activity high catecholamines.- fast heart rates


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secondary depolarizations that occur before repolarization

is complete.1) Phase 0 may be carried by Ca2+, Na+ or mixture

of the two.2) Factors associated with EAD include:

- Increased SNS activity - high catecholamines- Cell damage (hypoxia, mycocardial stretch)- slow heart rate- hypokalemia- More likely with Purkinje cells

** - Prolonged QT interval (delayed repolarization)(increased in slowed HR and prolonged AP)(drug-induced including antiarrhythmics.

antihistamines, antidepressants, others)- Markedly prolonged QT interval predisposes to

torsade de pointes (a form of ventriculartachycardia)

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Electrocardiogram from a patient with the long QTsyndrome during two episodes of torsade depointes.


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is complete.1) Phase 0 may be carried by Ca2+, Na+ or mixture

of the two.2) Factors associated with EAD include:


** - Prolonged QT interval (delayed repolarization)(increased in slowed HR and prolonged AP)(drug-induced including antiarrhythmics.

antihistamines, antidepressants, others)- Markedly prolonged QT interval predisposes to


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secondary depolarizations that occur before repolarizationis complete.

1) Phase 0 may be carried by Ca2+, Na+ or mixtureof the two.

2) Factors associated with EAD include:


** - Prolonged QT interval (delayed repolarization)(increased in slowed HR and prolonged AP)

(drug-induced including antiarrhythmics.antihistamines, antidepressants, others)

- Markedly prolonged QT interval predisposes totorsade de pointes (a form of ventriculartachycardia)


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is complete. 1) Phase 0 may be carried by Ca2+, Na+ or mixtureof the two.

2) Factors associated with EAD include:

- Increased SNS activity - high catecholamines

- Cell damage (hypoxia, mycocardial stretch)- slow heart rate- hypokalemia- More likely with Purkinje cells

** - Prolonged QT interval (delayed repolarization)(increased in slowed HR and prolonged AP)

(drug-induced including antiarrhythmics.antihistamines, antidepressants, others)- Markedly prolonged QT interval predisposes to


Hereditary longQT Syndromes

Acquired longEAD -> long QT

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C. Abnormality of Conduction - Re-entry

II. MECHANISMS FOR ARRHYTHMIAS

A. Definition of ArrhythmiasB. Abnormalities of Impulse Generation

1. Altered Normal Automaticity2. Triggered Impulses (EAD and DAD)


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Requires an abnormal conduction pathway to form a

self-propagating circuit

1. Common properties of Re-entry arrhythmias

a. A divided conduction path (anatomical, pathologicalor functional) which would normally extinguish itself

b. Decremental conduction in one path with completeloss of conduction.

c. Re-activation of the extinguished pathway in thereverse direction by the remaining and unopposedpathway.

d. Correct timing of the conduction rate in the active

pathway and the refractory period of the cells in theextinguished pathway.

Responsible for many cardiac arrhythmias.

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Re-entry 1

Wave fronts meet and extinguish


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Re-entry 2

(Ischemic) area with decremental conduction(i.e., an area where conduction velocityprogressively slows to zero and then dies out.)


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Re-entry 3 Re-entry current when the unopposedwavefront crosses the same area out

of the refractory period



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Re-entry 3 Re-entry current when the unopposedwavefront crosses the same area out

of the refractory period


Whydoesntthe re-entrycurrent dieout too?


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Re-entry 4

Antiarrhythmic

drugs break are-entry circuitby causing abidirectionalblock.

They do thisby directly orindirectlymodifying therefractory

period of thearea ofdamaged cells

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Requires an abnormal conduction pathway to form aself-propagating circuit





d. Correct timing of the conduction rate in the activepathway and the refractory period of the cells in the

extinguished pathway.



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Re-entry: Common mechanism for Arrhythmias

1. Regions of anatomically-split pathways affected byischemia or other injury

2. Re-entry in AV node [paroxysmal supraventriculartachycardia (PSVT)]

3. Developmental pathologies (Wolff-Parkinson-White Syndrome, where an accessory pathwaybridges atria and ventricle in a way that can shortcircuits the AV node).

4. Areas of ischemic injury (MI)

5. Functional re-entry circuit in torsade de pointeinitiated by an EAD.

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IV. ANTIARRHYTHMIC DRUGS

Class 1

Sodium Channel

Blockers

Class 2

Beta Adrenergic

Blockers

Class 3

Prolong Refractory

Period (Potassium

Channel Blockers)

Class 4

Calcium

Channel

Blockers

Other

A Quinidine

Procainamide

Disopyramide

Propranolol*

Acebutolol

Esmolol

Others

Amiodarone

Bretylium

Sotalol

Ibutilide

Verapamil

Diltiazem Adenosine

Atropine

Digoxin

B Lidocaine

Phenytoin

Mexiletine

C Flecainide

Propafenone

Moricizine

*additional mechanisms at higher concentrations (Class 1B effects)


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Class 1 Antiarrhythmic Drugs

Class 1A Quinidine (Procainamide, Disopyramide)

Class 1B Lidocaine (Phenytoin, Mexiletine).

Class 1C Flecainide (Propafenone, Morcizine).

Sodium Channel Blockers

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Class 1A Depress phase 0 depolarization (conductionvelocity) in fast response cells and decreasesautomaticity;prolong action potential duration and increaserefractory period. Moderate effects on conduction inNORMAL cells.

Class 1B Depress phase 0 depolarization (conductionvelocity) in fast response cells and can decreaseautomaticity. No significant effect on action potentialduration. Minimal effects on conduction in NORMAL cells

Class 1C Depress phase 0 depolarization (conduction

velocity) in fast response cells and can decreaseautomaticity. Minimal effect on action potential duration.Marked effects on conduction in NORMAL cells.


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Class 1 Antiarrhythmic DrugsClass 1A Depress phase 0 depolarization (conductionvelocity) in fast response cells and also can depressautomaticity; prolong action potential duration and increaserefractory period. Moderate effects on conduction inNORMAL cells.

Class 1B Depress phase 0 depolarization (conductionvelocity) in fast response cells and can decreaseautomaticity. No significant effect on action potential

duration. Minimal effects on conduction in NORMAL cells

Class 1C Depress phase 0 depolarization (conductionvelocity) in fast response cells and can decreaseautomaticity. Minimal effect on action potential duration.Marked effects on conduction in NORMAL cells.

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Class 1A Depress phase 0 depolarization (conductionvelocity) in fast response cells and also can depressautomaticity; prolong action potential duration and increaserefractory period. Moderate effects on conduction inNORMAL cells.

Class 1B Depress phase 0 depolarization (conductionvelocity) in fast response cells and can decreaseautomaticity. No significant effect on action potential

duration. Minimal effects on conduction in NORMAL cells

Class 1C Depress phase 0 depolarization (conductionvelocity) in fast response cells and can decreaseautomaticity. Minimal effect on action potential duration.

Marked effects on conduction in NORMAL cells.


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A. Class 1 - Sodium Channel Blockers

2. Comparison of Lidocaine, Quinidine and Flecainide on Normal Cells

Drug State-Dependence tau Recovery (seconds)

Quinidine (1a) Open 3

Lidocaine (1b) Inactive > Open 0.1

Flecainide (1c) Open 11

The different subgroups of class 1 drugs bind to differentchannel states or have different binding kinetics.

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3. Action Potentials -

Basis for conductionfrom cell to cell.

Algebraic sum ofvoltage over timeyields ECG.

PR Interval =

primarily AV nodeconduction time

QT Interval = ventricular depolarization-> repolarization time


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A. Class 1 - Sodium Channel Blockers

2. Comparison of Lidocaine, Quinidine and Flecainide on Normal Cells

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Class 1A - Sodium Channel Blockers

MechanismQUINIDINE

1. Predominant action

- blocks voltage gated sodium channels;

binds preferentially to open state of channel.

Selectivity for: a) cells at higher heart rate;

b) cells at less negative RMP;

Effect on cells is to:

decrease rate of phase 0increase threshold for excitability;decrease automaticity in His-Purkinjecells (but not SA cells).


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Therapeutic Uses

QUINIDINE

1. Use has declined but is still used for -2. Variety of supraventricular and ventricular tachyarrhythmias.

2. Blocks potassium channels - prolongs refractory period.increase phase 3 and prolongs the QT interval

3. Alpha-adrenergic blockade

4. Atropine-like effect (anticholinergic)

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Side Effects

Other Considerations

QUINIDINE

1. Prolongation of QT interval - increased risk oftorsades de pointes (2-8%; form of ventriculartachycardia which can culminate in ventricularfibrillation).

2. Hypotension due to alpha-adrenergic blockade.3. High incidence of diarrhea (30-50%)

1. Drug interaction with digoxin - increases latter'sserum level.2. Still widely used despite side effects.


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Related Drugs(Similar to quinidine but different pharmacokinetics)

QUINIDINE

PROCAINAMIDE (Pronestyl, Procan) -

lacks vagolytic and alpha-adrenergic blockade;60-70% become ANA positive;25-50% develop a lupus-like syndrome

DISOPYRAMIDE (Norpace)

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Class 1B - Sodium Channel Blockers

Mechanism LIDOCAINE (Xylocaine)

Predominant action - blocks voltage gated sodiumchannels; binds preferentially to inactivated state ofchannel. Selectivity for:

a) ventricular cells over atrial cells;b) cells with fast rate over cells with slow rate;

c) cells with less negative RMP > more negative RMP.

Sodium channel blockade leads to increased thresholdfor excitability; decreased automaticity.


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Therapeutic Uses

Side Effects

LIDOCAINE (Xylocaine)

1. Acute suppression of ventricular arrhythmias. (nolonger the first choice for recurrent sustained V-tachor V-fib.)

2. Must be given parentally because of extensive firstpass effect - often as intravenous bolus and infusion.Latter modified with liver disease and heart failure.

1. Central nervous system symptoms - seizures (very

rapid administration) and drowsiness, dysarthriaand dysesthesia (more gradual increase in serumlevels).

2. Depression of cardiac function.

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Other Considerations

Related Drugs(Lidocaine variants not susceptible to first-pass metabolismand can be given orally, and tend to be less selective forsick cells.)

LIDOCAINE (Xylocaine)

Also used at local anesthetic.

MEXILETINE (Mexitil)TOCAINIDE


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Class 1C - Sodium Channel Blockers

Mechanism

Therapeutic Uses

FLECAINIDE (Tambocor)

1. Predominant action - blocks voltage gated sodium

channels; Selectivity for cells at high heart rate butgreater depression at normal rates than class 1A and1B.

2. Can block potassium channels (but much less ornegligible effect on QT interval ).

1. Variety of supraventricular tachycardias.

2. Life-threatening ventricular arrhythmias.

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Class 1C - Sodium Channel Blockers

Side Effects

Related Drugs

FLECAINIDE (Tambocor)

1. Proarrhythmic - especially in presence ofsevere heart disease -> increase mortality

2. Depression of left ventricular function.

PROPAFENONE (Rythmol)


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Class 2

Effects primarily due to blocking beta adrenergic influenceson conducting system.

(Beta - blockers)

Propranolol

AcebutololEsmolol

Others

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Class 2 - Beta Adrenergic Blockers

MechanismPROPRANOLOL (Inderal)

1. Predominant action - blockade of beta adrenergicreceptors (1 in myocardium).

Therapeutic Uses

1. Beta blockers reduce mortality in early period andsubsequently after acute myocardial infarction.

2. Chronic ventricular arrhythmias.

3. Control of ventricular rate in atrial flutter or fibrillation.

4. Paroxysmal supraventricular tachycardia (PSVT).


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Class 2 - Beta Adrenergic BlockersPROPRANOLOL (Inderal)

Therapeutic Uses

5. Symptomatic sinus tachycardia.

6. Catecholamine-related ventricular arrhythmias.

See lecture on "Autonomic DrugsSide Effects

Related Drugs

Esmolol Very short half-life / used i.v.

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Major effect is to prolong duration of action potentialsand, thus, increase refractory period.

(Potassium Channel - blockers)Class 3

Amiodarone

Bretylium

SotalolIbutilide


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Class 3 - Potassium Channel Blockers

2. Therapeutic Uses

AMIODARONE (Cordarone)

a. FDA recommendation - only for life-threatening ventriculararrhythmias refractory to all other available forms of therapy.

b. Powerful inhibitor of pacemaker automacitiyc. Long-term (oral) use

1. trial fibrillation and atrial flutter2. Supraventricular tachycardia3. Life-threatening (sustained) ventricular tachycardia

d. i.v. use:

1. Ventricular fibrillation2. Sustained ventricular tachycardia

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3. Side Effects (most minimized at low doses)

AMIODARONE (Cordarone)

a. Hypotensionb. AV blockc. Arrhythmias (2%)

d. Blue-gray skin discoloratione. Pulmonary fibrosis (potentially fatal)f. Thyroid abnormalities (from iodine content)g. Corneal deposits

h. Blurred visioni. Photosensitivity

j. GI disturbances


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Related DrugsAMIODARONE (Cordarone)

Ibutilide

Sotalol

K channel blockerNa channel activatorUses -> atrial fibrillation

K channel blockerNonselective blocker

Uses -> ventricular and atrial arrhythmiasDose-dependent torsade de pointes

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Class 4Depresses slow response action potentials in AV andSA nodes where depolarization is mediated primarily bycalcium influx.

(Calcium Channel - blockers)

Verapamil

Diltiazem


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Class 4 - Calcium Channel Blockers

Mechanism

Therapeutic Uses

Side Effects

Related Drugs

VERAPAMIL (Isoptin, Calan)

1. Predominant action - blocks voltage-gated L-typecalcium channels.

1. Control of ventricular rate in atrial flutter and fibrillation.2. Paroxysmal supraventricular tachycardia (PSVT) due to

reentry involving the AV node.

1. Cardiac depression.2. Hypotension.

3. Constipation (most common).

DILTIAZEM (Cardizem, Dilacor)

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Other Antiarrhythmics

Mechanism ADENOSINE (Adenocard)

1. Predominant action - acts through A1 adenosinereceptors to activate potassium channels and inhibiteffects of increased cyclic AMP. This in turn leads to:

a) hyperpolarization and slowing of SA node firing;b) shortening of action potential of atrial cells;c) depression of conduction velocity through AV node.

These actions break the reentry circuit allowingresumption of normal sinus rhythm.


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Other Antiarrhythmics

Therapeutic Uses

Side Effects

ADENOSINE (Adenocard)

1. Acute conversion of paroxysmal supraventriculartachycardia (PSVT) due to reentry involving the AV

node. Highly effective.

2. Given as intravenous bolus in central line. Effectstransient (maximal within 10-20 sec).

1. Transient facial flushing, dyspnea and chest pressure.

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Mechanism

Therapeutic Uses

Side Effects

Other AntiarrhythmicsATROPINE

1. Predominant action - muscarinic blockade;decreases acetylcholine-induced activation ofpotassium channels through M2 receptors;increases spontaneous phase 4 depolarization of

SA node.

1. Sinus bradycardia (e.g., acute myocardial infarction)

See lecture on "Cholinergic Systems"


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Mechanism

Therapeutic Uses

Side Effects

Other AntiarrhythmicsDIGOXIN (Lanoxin)

See lecture on "Drug Therapy of Congestive Heart FailureIncreases vagal tone and suppresses AV node activity.

Control of ventricular rate in atrial flutter and fibrillation.

See lecture on "Drug Therapy of Congestive Heart Failure"

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II. Mechanisms for Arrhythmias

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