Cardiac Rhythm Disorders With Rmp and Inactivcating Sodium Channels

8/3/2019 Cardiac Rhythm Disorders With Rmp and Inactivcating Sodium Channels

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Chapter 8: Antiarrhythmic Agents

Table of Contents

ElectrophysiologyMembrane Potential: Ionic

Dependencies

Cardiac Rhythm

Cardiac Electrophysiology

Transmembrane Potential

Sodium

Potassium

Spontaneous Depolarization

Channel Activation

Phasesof the cardiac action potential andionic and electrophysiological changes are

associated with normal cardiac rhythm

Resting membrane potential and conduction

velocity

Pathophysiology

Introduction: Arrhythmias & Drug TherapyAbnormalities of Cardiac Impulse Initiation

Mechanism of Action of Antiarrhythmic

Agents

Antiarrhythmic Drug Classes

Antiarrhythmic Drugs

Membrane Potential: Ionic Dependencies

(Simulation)

Electrophysiology and Cardiac Arrhythmias

Cardiac Rhythm

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Normal rate: 60-100 beats per minute

Impulse Propagation: sinoatrial node to the atrioventricular (AV node) to the His-Purkinje

followed by distribution throughout the ventricle

Normal AV nodal delay (0.15 seconds) -- sufficient to allow atrial ejection of blood into the ventricles

Definition: arrhythmia -- cardiac depolarization different from above sequence --

abnormal origination (not SA nodal)

abnormal rate/regularity

abnormal conduction characteristics

Cardiac Electrophysiology

Transmembrane potential -- determined primarily by three ionic gradients:

Na+, K+, Ca 2+

water-soluble, -- not free to diffuse through the membrane in response to concentration or electricalgradients: depended upon membrane channels (proteins)

Movement through channels depend on controlling "molecular gates"

Gate-status controlled by:

Ionic conditions

Metabolic conditions

Transmembrane voltage

Maintenance of ionic gradients:

Na+/K+ ATPase pump

termed "electrogenic" when net current flows as a result of transport (e.g., three Na+ exchange for

two K+ ions)

Initial permeability state -- resting membrane potential


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sodium -- relatively impermeable

potassium -- relatively permeable

Cardiac cell permeability and conductance:

conductance: determined by characteristics of ion channel protein

current flow = voltage X conductance

voltage = (actual membrane potential - membrane potential at which no current would flow, even

with channels open)

Sodium

Concentration gradient: 140 mmol/L Na+ outside: 10 mmol/L Na+ inside;

Electrical gradient: 0 mV outside; -90 mV inside

Driving force -- both electrical and concentration -- tending to move Na+ into the cell.

In the resting state: sodium ion channels are closed therefore no Na+ flow through the membrane

In the active state: channels open causing a large influx of sodium which accounts for phase 0

depolarization

Cardiac Cell Phase 0 and Sodium Current

Note the rapid "upstroke" characteristic

of Phase 0 depolarization.

This abrupt change in membrane

potential is caused by rapid, synchronous

opening of Na+ channels.

Note the relationships between the the

ECG tracing and phase 0

Potassium:

Concentration gradient (140 mmol/L K+ inside; 4 mmol/L K+outside)

Concentration gradient -- tends to drive potassium out

Electrical gradient tends to hold K+ in.

Some K+ channels ("inward rectifier") are open in the resting state -- however, little K+

current flows because of the balance between the K+ concentration and membrane electrical


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gradients

Cardiac resting membrane potential: mainly determined

By the extracellular potassium concentration and

Inward rectifier channel state

Spontaneous Depolarization (pacemaker cells)-- phase 4 depolarization

Spontaneous Depolarization occurs because:

Gradual increase in depolarizing currents (increasing membrane permeability to sodium

or calcium)

Decrease in repolarizing potassium currents (decreasing membrane potassium

permeability)

Both

Ectopic pacemaker: (not normal SA nodal pacemakers) --

Facilitated by hypokalemic states

Increasing potassium: tends to slow or stop ectopic pacemaker activity

Channel Activation Sequence:

Depolarization to threshold voltage--Na+

m gate activation (activation gate); assuming inactivation (h) gates are not closed then

sodium permeability dramatically increased; intense sodium current

depolarization

h gate closure; Na+ current inactivation

Ca2+ --

Ca2+: Channel Activation Sequence similar to sodium; but occurring atmore positive membrane potentials (phases 1 and 2)

Following intense inward Na+ current

(phase 0), Ca2+currents:

Phases 1 & 2, are slowly inactivated.

(Ca2+channel activation occurred later

than for Na+)


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Channel Inactivation, Re-establishing the Resting Membrane Potential

Final repolarization (phase 3):

complete Na+ and Ca2+ channel

inactivation

Increased potassium permeability

Membrane potential approaches K+

equilibrium potential -- which

approximates the normal resting

membrane potential

Five Phases: cardiac action potential associated with HIS-purkinje fibers or ventricular

muscle


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Phase 0 corresponds to Na+ channel activation.

The maximum upstroke slope of phase 0 is proportional to the sodium current.

Phase 0 slope is related to the conduction velocity in that the more rapid the rate

of depolarization the greater the rate of impulse propagation.

Phase 1 corresponds to an early repolarizing K+ current.

rapidly inactivated.

Phase 2 is the combination of an inward, depolarizing Ca2+ current balanced by

an outward, repolarizing K+ current (delayed rectifier).

Phase 3 is also the combination of Ca2+ and K+ currents.

Phase 3 is repolarizing because the outward (repolarizing) K+ current increases

while the inward (depolarizing) Ca2+ current is decreasing.

Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by

a balance between outward Na+ current and inward K+ current.

As a result, the resting membrane potential would normally be flat.

In disease states or for other cell types (SA nodal cells) the membrane potential

drifts towards threshold.

This phenomenon of spontaneous depolarization is termed automaticity and has

an important role in arrhythmogenesis.

Influence of Membrane Resting Potential on Action Potential Properties

The extent and synchrony of sodium channel activation is dependent on the resting membrane

potential.

Inactivation gates of sodium channels close in the membrane potential range of -75 to -55 mV (less

channels available for sodium ion inward current)

For example: less intense sodium current if the resting potential is - 60 mV compared to -80 mV

Consequences of reduced sodium activation due to reduced membrane potential (less negative)

reduced of velocity upstroke (Vmax) [phase 0] (maximum rate of membrane potential change)

reduced excitability

reduced conduction velocity-- a significant cause of arrhythmias

prolongation of recovery:-- an increase in effective refractory period


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Plateau Phase:

Plateau phase -- Na channels mostly inactivated

Repolarization (h gates reopen)

"Refractory period": time between phase 0 and phase 3 -- during this time the stimulus does not result in a

propagated response

Altered refractoriness may cause or suppress arrhythmias

Factors that reduce the membrane resting potential & reduce conduction velocity

Hyperkalemia

Sodium pump block

Ischemic cell damage

Conduction in severely depolarized cells

With decreased membrane potentials (e.g., -55 mV), sodium channels are inactivated

Under some circumstances, increased calcium permeability or decreased potassium permeability

allow for slowly conducted action potentials with slow upstroke velocity

Ca2+-inward current-mediated action potentials are normal for the specialized conducting SA

nodal and AV nodal tissues, which have resting membrane potentials in the -50 to-70 mV range.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in

Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange,

1998, pp 216-241.

Factors that may precipitate or exacerbate arrhythmias

Ischemia

Hypoxia

Acidosis

Alkalosis

Abnormal electrolytes

Excessive catecholamine levels

Autonomic nervous system effects (e.g., excess vagal tone)

Excessive catecholamine levels

Autonomic nervous system effects (e.g., excess vagal tone)


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Drug effects: e .g., antiarrhythmic drugs may cause arrhythmias)

Cardiac fiber stretching (as may occur with ventricular dilatation in congestive heart failure)

Presence of scarred/diseased tissue which have altered electrical conduction properties

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and

Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241

Pathophysiology

Arrhythmias develop because of abnormal impulse generation, propagation or both.

Abnormalities of Cardiac Impulse Initiation

Factors that influence heart rate (altered frequency of pacemaker cell firing rate)

Heart rate determined (interval between pacemaker firing) by the sum of: Action potential duration +

Diastolic duration interval

More important -- Diastolic duration interval: determined by 3 factors:

Maximum diastolic potential (most negative membrane potential reached during diastole

Slope of phase 4 depolarization: (increased slope: threshold is reached quicker causing a

faster heart rate; decreased slope: longer to reach threshold resulting in a slower heart rate

Threshold Potential (membrane potential at which in action potential is initiated)

Decreased Heart Rate:--

Vagal Effects: (cholinergic influences on the heart rate)

more negative maximum diastolic potential (the membrane potential starts farther away from

the threshold potential)

reduced slope of phase 4 depolarization (takes longer to reach threshold potential)

Increased Heart Rate:-

Adrenergic Effects: (sympathetic/sympathomimetic influences on heart rate)

Beta adrenergic receptor blockers (reduced phase 4 depolarization slope)

Factors that can increase automaticity:

hypokalemia

cardiac fiber stretch

beta-adrenergic receptor activation


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injury currents

acidosis

Latent Pacemakers -- cells not normally serving pacemaker function, but exhibits s low phase 4

depolarization: conditions favoring latent pacemaker activity noted above

All cardiac cells (including normally inactive atrial/ventricular cells) may show pacemaker activity,

particularly in hypokalemic states

Failure of impulse initiation can lead to excessively slow heart rate,bradycardia .

If an impulse fails to propagate through the conduction system from the atrium to the ventricle, heart block

may occur.

An excessively rapid heart rate, tachycardia, is also encountered clinically


Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241.

Introduction: Arrhythmias and Drug Therapy

Atrial fibrillation may result in a high ventricular following rate.

Accordingly, drugs which may reduce ventricular rate by reducing AV nodal conduction include:

calcium channel blockers (verapamil (Isoptin, Calan), diltiazem (Cardiazem))

beta-adrenergic receptor blockers (propranolol (Inderal)), and

digitalis glycosides.

Treatment of atrial fibrillation: Verapamil (Isoptin, Calan) & Diltiazem (Cardiazem)

Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.

Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular ratessecondary to atrial flutter or fibrillation.

Major adverse effect (i.v. administration) is hypotension. Heart block or sinus bradycardia can also occur.

Treatment of atrial fibrillation: Propranolol (Inderal)

Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade.

Normally, sympathetic drive results in increased in Ca2+ ,K+ ,and Cl- currents.


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Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and

increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated

arrhythmias.

These effects are blocked by beta-adrenergic receptor blockers.

Beta-adrenergic receptor blockers increase AV conduction time (takes longer) and increase AV

nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

Beta-adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and

fibrillation, again by acting at the AV node.

Adverse effects of beta blocker therapy can lead to fatigue, bronchospasm, depression, impotence, and

attenuation of hypoglycemic symptoms in diabetic patients and worsening of congestive heart failure.

Drugs assist in restoring and maintaining normal sinus rhythm include quinidine and procainamide

Quinidine {Quinidine gluconate (Quinaglute, Quinalan)}

Although classified as a sodium channel blocker, quinidine also blocks K+ channels.

Most antiarrhythmic agents have such multiple actions.

Sodium channel blockade results in

an increased threshold

decreased automaticity.

Potassium channel blockade results in action potential (AP) prolongation (width increases).

Quinidine gluconate-Clinical Use:

Maintains normal sinus rhythm in patients who have experienced atrial flutter or fibrillation.

Prevents ventricular tachycardia or fibrillation.

Quinidine gluconate (Quinaglute, Quinalan) administration results in vagal inhibition (anti-muscarinic)

and alpha-adrenergic receptor blockade.

Adverse effects include cinchonism (headaches and tinnitus), diarrhea.

Quinidine is also associated with torsades de pointes, a ventricular arrhythmias associated withmarked QT prolongation.

This potentially serious arrhythmia occurs in 2% - 8% if patients, even if they have a therapeutic or

subtherapeutic quinidine blood level.

Procainamide (Procan SR, Pronestyl-SR)

Quinidine and Procainamide similar: electrophysiological properties.

By contrast to quinidine, procainamide does not exhibit either vagolytic or alpha-adrenergic blocking


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activity.

Useful in acute management of supraventricular and ventricular arrhythmias.

Long term use is associated with side effects, including a drug-induced lupus syndrome which

occurs at a frequency of 25% to 50%.

In slow acetylators the procainamide-induced lupus syndrome occurs more frequently and earlier in

therapy than in rapid acetylators.

The red dot highlights the AV node

Paroxysmal supraventricular tachyarrthymias (PSVT) may be managed, depending upon clinical

presentation, by increasing the vagal tone at the AV node

Valsalva maneuver

Alpha-adrenergic receptor agonist administration

digoxin administration

by administration of drugs that reduce AV transmission:

Adenosine (Adenocard), verapamil (Isoptin, Calan), diltiazem (Cardiazem), esmolol

(Brevibloc) or DC cardioversion.

Adenosine (Adenocard)

Effects mediated through G protein-coupled adenosine receptor.

Activates acetylcholine-sensitive K+ current in the atrium and sinus and A-V node.

Decreases action potential duration, reduces automaticity

Increases A-V nodal refractoriness

Rapidly terminates re-entrant supraventricular arrhythmias (I.V)

Verapamil (Isoptin, Calan) & Diltiazem (Cardiazem)

Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV

nodes.

Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular


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rates secondary to atrial flutter or fibrillation.

Major adverse effect (i.v. administration) is hypotension. Heart block or sinus

bradycardia can also occur.

Esmolol (Brevibloc)

Esmolol is a very short acting, cardioselective beta-adrenergic receptor

antagonist.

i.v. administration is used for rapid beta-receptor blockade in treatment of

atrial fibrillation with high ventricular following rates.

Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally

sympathetic drive results in increased in Ca2+ ,K+and Cl- currents.

Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up),

and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization)

mediated arrhythmias. These effects are blocked by beta-adrenergic receptor

blockers.

Beta-adrenergic receptor blockers

increase AV conduction time

increase AV nodal refractoriness, thereby helping to terminate nodal

reentrant arrhythmias.

Three mechanisms have been associated with many tachyarrhythmias

Enhanced Automaticity

Enhance automaticity is associatied with an increase in the slope of phase 4 depolarization results in

As a result of the increase in phase 4 slope the cell reaches threshold more often per minute

resulting in higher heart rate.

Factors that increase automaticity include

mechanical stretch

beta-adrenergic stimulation

hypokalemia

Ischemia can induce abnormal automaticity, i.e. automaticity that occurs in cells not

typically exhibiting pacemaker activity.

Triggered Automaticity

Triggered automaticity occurs when a second depolarization occurs prematurely.


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One type of triggered automaticity is a delayed afterdepolarization (DAD).

If this late depolarization reaches threshold (a) second beat(s) may occur.

Factors that predispose to delayed afterdepolarizations include:

excessive adrenergic activity

digitalis toxicity

high intracellular Ca2+

A second type of triggered automaticity is Early Afterdepolarization (EAD) which is associated with

significant prolongation of the action potential duration.

In this case, during a prolonged phase 3 repolarization, the repolarization is interrupted by a

second depolarization.

Factors that predispose to Early Afterdepolarizations include

bradycardia

low extracellular K+

certain drugs, including some antiarrhythmics

Torsades de pointes, a polymorphic ventricular arrhythmia- associated with

Prolongation of cardiac repolarization (prolonged Q-T interval)

Possibly induced by early afterdepolarizations.

The antiarrhythmic drug quinidine gluconate (Quinaglute, Quinalan) can cause this arrhythmia. Many

other drugs can also cause this effect.

Reentry is the most common cardiac conduction abnormality leading to arrhythmias.

PF: Branched Purkinje Fiber terminating on ventricular muscle (VM).


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Shaded Area: Depolarized region with unidirectional (one-way) block (Decremental conduction,

impulse slowly dies out)

slowed conduction may be due to depression of Na + or Ca2+ currents (e.g. AV node)

Retrograde impulses (wavy line) propagate slow enough such that cells in branch 1 are no longer

refractory and can be activated by the re-entry potential.

Drugs that terminate reentry may further depress conduction, converting the "unidirectional" block toa "bidirectional" block

A reentrant circuit involves a pathway that bifurcates into two branches.

One pathway is blocked to anterograde conduction, but can be excited in a retrograde

manner by the impulse that traversed the unblocked path.

Retrograde conduction occurs until excitation of now non-refractory tissue re-initiates the

process.

return to Table of Contents

How do Antiarrhythmic Drugs Work?

Although for a given arrhythmia in a patient the mechanism may not be known, there are certain general

explanations for the action of anti-arrhythmic agents. Anti-arrhythmic drugs may work by:

(a) Suppressing initiation site (automaticity/after-depolarizations) and/or

(b) Preventing early or delayed afterdepolarizations and/or

(c) By disrupting a re-entrant pathway.

(a) Automaticity: Automaticity may be diminished by:

(1) increasing the maximum diastolic membrane potential

(2) decreasing the slope of phase 4 depolarization

(3) increasing action potential duration

(4) raising the threshold potential

All of these factors make it take longer or make it more difficult for the membrane

potential to reach threshold.

(1) The diastolic membrane potential may be increased by adenosine and acetylcholine.

(2) The slope of phase 4 depolarization may be decreased by beta receptor blockers


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(3) The duration of the action potential may be prolonged by drugs that block cardiac K+

channels

(4) The membrane threshold potential may be altered by drugs that block Na+ or Ca2+

channels.

(b) Delayed or Early Afterdepolarizations:

Delayed or early afterdepolarizations may be blocked by factors that

(1) prevent the conditions that lead to afterdepolarizations.

(2) directly interfere with the inward currents (Na+, Ca2+) that cause afterdepolarizations.

(c) Reentry

For anatomically-determined re-entry such as Wolf-Parkinson-White syndrome (WPW) drugs the

arrhythmia can be resolved by blocking action potential (AP) propagation. (In WPW syndrome, an

accessory conduction pathway, linking atria and ventricles and bypassing the atrioventricular node, is the

structure responsible for the arrhythmia)

In WPW-based arrhythmias, blocking conduction through the AV node may be clinically effective.

Drugs that prolong nodal refractoriness and slow conduction include: Ca2+ channel blockers, beta-

adrenergic blockers, or digitalis glycosides.

For functional (non-anatomical) reentrant circuits, prolongation of refractoriness is the

electrophysiological change most likely to terminate the reentry arrhythmia.

Prolongation of tissue refractoriness can be accomplished by those antiarrhythmic drugs that block Na + channels.

Sodium channel blockers reduces the percentage of recovered channels (following inactivation by

depolarization) at any given membrane potential.

Examples of antiarrhythmic drugs classified as sodium channel blockers include lidocaine, quinidine, and

tocainide.

"Although any type of arrhythmia can occur in a patient with WPW, the two most common are CMTs

(circus

movement tachycardias) and atrial fibrillation (AFib). CMT is the more common arrhythmia of the two

Treatment of CMTs associated with WPW is similar to treating PSVT

In a stable patient, adenosine (6 mg rapid IV push; if unsuccessful, 12 mg rapid IV push)

should be the first-line treatment in any regular tachycardia, regardless of whether the complex is

wide or narrow

Treatment of AFib associated with WPW is necessarily different than for a patient with a normal heart.

AFib is an irregular rhythm as opposed to the regular rhythm seen in CMTs.

The basic treatment principle in WPW AFib is to prolong the anterograde refractory period


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of the accessory pathway relative to the AV node. This slows the rate of impulse transmission

through the accessory pathway and, thus, the ventricular rate.

If AFib were treated in the conventional manner by drugs that prolong the refractory period of the

AV node (eg, calcium channel blockers, beta-blockers, digoxin), the rate of transmission through the

accessory pathway likely would increase, with a corresponding increase in ventricular rate.

This could have disastrous consequences, possibly causing the arrhythmia to deteriorate into V fib.

Procainamide (17 mg/kg IV infusion, not to exceed 50 mg/min; hold for hypotension or 50% QRSwidening) blocks the accessory pathway, but it has the added effect of increasing transmission

through the AV node. Thus, although procainamide may control the AFib rate through the accessory

pathway, it may create a potentially dangerous conventional AFib that may require treatment with

other medications. Prompt cardioversion of patients with WPW and AFib is recommended.

Medical management may be a viable option in some patients, but it may have

unpredictable results. Note that cardioversion is always the treatment of choice in unstable

patients."----*From emedicine (http://www.emedicine.com/EMERG/topic644.htm) Authored by

Mel Herbert, MD, MBBS, Assistant Professor of Medicine and Nursing, Department of Emergency

Medicine, Olive View-University of California at Los Angeles Medical Center

Antiarrhthmic Drug Classes

Class I Antiarrhythmic Drugs

Class I: Sodium Channel Blockers

Sodium channel blocking antiarrhythmic drugs are classified as use-dependent in that they bind to open

sodium channels.

Their effectiveness is therefore dependent upon the frequency of channel opening.

There are three classes or types of sodium channel blockers:

Type Ia: prototype: quinidine gluconate (Quinaglute, Quinalan). Type Ia drugs slow the rate of

AP rise and prolong ventricular effective refractory period.

Quinidine

Overview

dextroisomer of quinine; quinidine gluconate (Quinaglute, Quinalan) also has antimalarial and

antipyretic effects

Pharmacokinetics:

80%-90%: bound to plasma albumin

Rapid oral absorption; rapid attainment of peak blood levels (60-90 minutes)

Elimination half-life: 5-12 hours


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IM injection, possible but not recommended due to injection site discomfort

IV administration: limited due to myocardial depression & peripheral vasodilation

Metabolism:

Hepatic: hydroxylation to inactive metabolites; followed by renal excretion

20% excreted unchanged in urine

Impaired hepatic/renal function: accumulation of quinidine and metabolites

Sensitive to enzyme induction by other agents--

decreased quinidine blood levels with phenytoin, phenobarbital, rifampin

Mechanism of antiarrhythmic action-- primarily activated sodium channel blockade which results in:

Depression of ectopic pacemaker activity

Depression of conduction velocity

may convert a one-way conduction blockade to a two-way (bidirectional) block --

terminating reentry arrhythmias

Depression of excitability (particularly in partially depolarized tissue)

Recovery from sodium channel blockade is slower in depolarized tissue (compared to normal

tissue):

This is the basis for relative selectivity of quinidine action in depolarized tissue compared to

normal tissue, (i.e. lengthened refractory period, depressed conduction velocity, reducedexcitability observed in depolarized tissue to greater extent the normal tissue)

Although classified as a sodium channel blocker, quinidine also blocks K+ channels.

Most antiarrhythmic agents have such multiple actions.

Effect on the ECG: QT interval lengthening

Basis: quinidine-mediated reduction in repolarizing outward potassium current

Result:

Longer action potential duration

Increased effective refractory period

Reduces reentry frequency; reduced rate in tachyarrhythmias

Sodium channel blockade results in

an increased threshold


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decreased automaticity.

Quinidine Uses

Used to manage nearly every form of arrhythmia especially acute and chronic

supraventricular dysrhythmias

Ventricular tachycardia

Frequent indications:

Prevent recurrence of supraventricular tachyarrhythmias

Suppression ventricular premature contractions

Approximately 20% of patients with atrial fibrillation will convert to normal sinus rhythm following

quinidine treatment

Supraventricular tachyarrhythmia due to Wolff-Parkinson-White syndrome -- effective suppression

by quinidine

Digitalization prior to quinidine administration:

Quinidine sulfate (Quinidex,Quinora)/quinidine gluconate (Quinaglute, Quinalan) may cause a

paradoxical increase in ventricular response due to quinidine's vagolytic effect at the AV node

(antimuscarinic action increases AV nodal throughput, allowing more SA nodal impulses to reach the

ventricle)

Vagotonic effects on digitalis prevents this paradoxical increase by increasing vagal tone

at AV node

Quinidine sulfate (Quinidex,Quinora) administration results in vagal inhibition (anti-

muscarinic) and alpha-adrenergic receptor blockade.

Quinidine Side Effects

Cardiovascular--at (high) plasma concentrations (> 2ug/ml)

Prolongation (ECG) of PR interval, QRS complex, QT interval

Heart block likely with 50% increase in QRS complex duration (reduced dosage)

Quinidine syncope: may be caused by delayed intraventricular conduction, resulting in

ventricular dysrhythmia

Patients with preexisting QT interval prolongation or evidence of existing A-V block

(ECG): probably should not be treated with quinidine

Hypotension -- primarily following IV administration

Mechanism: peripheral vasodilation secondary to alpha-adrenergic receptor blockade

Increased hypotension risk associated with quinidine +verapamil treatment


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Effects on heart rate:

increase secondary to either quinidine's antimuscarinic effect and/or reflex increase in

sympathetic activity

Quinidine is associated with Torsades de pointes, a ventricular arrhythmias associated with

marked QT prolongation.

Torsades de pointes: Electrophysiological Features

ventricular origin

wide QRS complexes with multiple morphologies

changing R - R intervals

axis seems to twist about the isoelectric line

This potentially serious arrhythmia occurs in 2% - 8% if patients, even

if they have a therapeutic or subtherapeutic quinidine blood level.

Other quinidine adverse effects include:

cinchonism

blurred vision, decreased hearing acuity, gastrointestinal upset,headaches

and tinnitus.

Nausea, vomiting, diarrhea (30% frequency)

Drug-drug interaction:quinidine gluconate (Quinaglute, Quinalan)-digoxin (Lanoxin,

Lanoxicaps)

Quinidine increases digoxin plasma concentration; may cause digitalis toxicity in

patients taking digoxin or digitoxin

Effects on neuromuscular transmission:

Quinidine gluconate (Quinaglute, Quinalan) interferes with normal neuromuscular

transmission; enhancing the effect of neuromuscular-blocking drugs

Recurrence of skeletal muscle paralysis postoperatively may be

associated with quinidine administration


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Procainamide

Overview:

Local anesthetic (procaine) analog

Long-term use avoided because of lupus-related side effect

Metabolism:

Elimination: renal excretion & hepatic metabolism; by contrast to procaine, procainamide is

highly resistant to hydrolysis by plasma esterases.

40%-60% excreted unchanged (renal)

Renal dysfunction requires procainamide dosage reduction

Hepatic metabolism -- acetylation

cardioactive metabolite: N-acetylprocainamide (NAPA);

NAPA accumulation may lead to Torsades de pointes

Quinidine and Procainamide similar: electrophysiological properties.

Possibly somewhat less effective in suppressing automaticity; possibly more effective in

sodium channel blockade in depolarized cells

Useful in acute management of supraventricular and ventricular arrhythmias .

Drug of second choice for management of sustained ventricular arrhythmias (in

the acute myocardial infarction setting)

Effective in suppression of premature ventricular contractions & paroxysmal

ventricular tachycardia rapidly following IV administration

Most important difference compared quinidine: procainamide does not exhibit

vagolytic (antimuscarinic) activity.

Procainamide is less likely to produce hypotension, unless following rapid IV

infusion

Ganglionic-Blocking Activity

Side Effects/Toxicities

Long term use is associated with side effects, including a drug-induced, reversible lupus

erythematosus-like syndrome which occurs at a frequency of 25% to 50%.


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Consists of serositis, arthralgia & arthritis

Occasionally: pluritis, pericarditis, parenchymal pulmonary disease

Rare: renal lupus

Vasculitis not typically present (unlike systemic lupus erythematosus)

Positive antinuclear antibody test is common; symptoms disappear upon drug discontinuation

In slow acetylators the procainamide-induced lupus syndrome occurs more frequently and

earlier in therapy than in rapid acetylators.

Nausea, Vomiting -- most common early, noncardiac complication


Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241;

Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in

Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Disopyramide (Norpace)Overview:

Very similar to quinidine gluconate (Quinaglute, Quinalan)

Greater antimuscarinic effects (in management of atrial flutter & fibrillation, pre-treatment with a drug

that reduces AV conduction velocity is required)

Approved use (USA): ventricular arrhythmias

Metabolism:

Dealkylated metabolite (hepatic); less anticholinergic, less antiarrhythmic effect compared apparent

compound50% -- excreted unchanged, renal

Electrophysiological effects similar to quinidine gluconate (Quinaglute, Quinalan)

Similar to quinidine gluconate (Quinaglute, Quinalan) in effective ventricular and atrial

tachyarrhythmia suppression

prescribed to maintain normal sinus rhythm in patients prone to atrial fibrillation and flutter and is also

used to prevent ventricular fibrillation or tachycardia.

Side Effects/Toxicity

Adverse side-effect profile: different from qunidine's in that disopyramide (Norpace) is not

an alpha-adrenergic receptor blocker but is anti-vagal.

Most common side effects: (anticholinergic)

dry mouth

urinary hesitancy

Other side effects: blurred vision, nausea

Cardiovascular:

QT interval prolongation (ECG)

paradoxical ventricular tachycardia (quinidine-like)

Negative inotropism (significant myocardial depressive effects)--undesirable with preexisting left

ventricular dysfunction (may promote congestive heart failure, even in patients with no prior evidence

of myocardial dysfunction)

Disopyramide is not a first-line antiarrhythmic agent because of its negative inotropic effects


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If used, great caution must be exercised in patients with congestive heart failure

Can cause torsades de pointes, a ventricular arrhythmia


Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-

241;Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in


Type Ib:

Class Ib agents are often effective in treating ventricular arrhythmias. Example: lidocaine. Type

Ib agents exhibit rapid association and dissociation from the channel.

Mexiletine (Mexitil) (Class IB, Sodium Channel Blocker)

Overview

Amine analog of lidocaine (Xylocaine), but with reduced first-pass metabolism.

Suitable for oral administration

Similar electrophysiologically to lidocaine

Clinical Use:

Chronic suppression of ventricular tachyarrhythmias

Combination with a beta adrenergic receptor blocker or another antiarrhythmic drug (e.g.

quinidine gluconate (Quinaglute, Quinalan) or procainamide (Procan SR, Pronestyl-SR)):

synergistic effects allow:

reduced mexiletine dosage

decreased side effect incidence

Possibly effective: decreasing neuropathic pain when alternative medications have proven

ineffective-- applications (on-label use):

diabetic neuropathy

nerve injury

Side effects:

Epigastric burning: usually relieved by a taking drug with food

nausea (common)

Neurologic side effects:

diplopia, vertigo, slurred speech (occasionally), tremor


23/37

Lidocaine (Xylocaine) (Class Ib, Sodium Channel Blocker)

Overview/Pharmacokinetics:

Local anesthetic administered by i.v. for therapy of ventricular arrhythmias

Extensive first-pass effect requires IV administration

Half-life: two hours

Infusion rate: should be adjusted based on lidocaine plasma levels

Factors influencing loading and maintenance doses:

Congestive heart failure (decreasing volume of distribution and total body clearance)

Liver disease: plasma clearance -- reduced; volume of distribution -- increased; elimination

half-life substantially increased (3 X or more)

Drugs that decrease liver blood flow (e.g. cimetadine, propranolol), decreased lidocaine

clearance (increased possible toxicity)

Metabolism

Hepatic;some active metabolites

Cardiovascular Effects:

Site of Action: Sodium Channels

Blocks activated and inactivated sodium channels (quinidine blocks sodium channels only in

the activated state)

During diastole, in normal tissue, as membrane potential returns to normal resting levels (-90

mV) lidocaine rapidly dissociates from the channel (low affinity for the channel resting state)

During diastole, in ischemic tissue, the membrane potential does not return to

normal resting levels but remains partially depolarized and lidocaine remains bound

(higher affinity, longer time constant for unblocking that at less negative resting

potentials)

Therefore, lidocaine is more effective in suppressing activity in depolarized, arrhythmogenic

cardiac tissue but has little effect on normal cardiac tissue -- the basis for this drug's

selectivity.

Very effective antiarrhythmic agent for arrhythmia suppression associated with

depolarization (e.g., digitalis toxicity or ischemia)

Comparatively ineffective in treating arrhythmias occurring in normally polarized issue

(e.g., atrial fibrillation or atrial flutter)


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No significant effect on QRS or QT interval or on AV conduction (normal doses)

Lidocaine (Xylocaine) decreases automaticity by reducing the phase 4 slope and by

increasing threshold.

Clinical Uses:

Suppression of ventricular arrhythmias (limited effect on supraventricular

tachyarrhythmias)

Suppression of reentry-type rhythm disorders:

premature ventricular contractions (PVCs)

ventricular tachycardia

May reduce incidence of ventricular fibrillation during the initial time frame

following acute myocardial infarction; no evidence to support prophylactic use and

myocardial infarction

Side Effect/Toxicities

Overdosage:

vasodilation

direct cardiac depression

decreased cardiac conduction -- bradycardia; prolonged PR interval; widening QRS

on ECG

Major side effect -- neurological

Large doses, rapidly administered can result in seizure.

Factors that reduce se izure threshold for lidocaine:

hypoxemia, hyperkalemia, acidosis

Otherwise: CNS depression, apnea.

Tocainide (Class I, Sodium Channel Blocker)

Amine analog of lidocaine, similar to mexiletine, orally active --but with reduced first-pass metabolism.

Used for chronic suppression of ventricular tachyarrhythmias

Electrophysiologically similar to lidocaine

Similar to mexiletine: tocainide + if beta-adrenergic receptor blocker or another antiarrhythmic drug:

synergism


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e.g.--Combination with quinidine may increase efficacy and diminish adverse effects.

Side Effects:

Profile similar to mexiletine

suitable for oral administration, but RARELY USED due to possibly fatal bone marrow aplasia and

pulmonary fibrosis.

tremor and nausea are major dose-related adverse side effects

Excreted by the kidney, accordingly dose should be reduced in patients with renal disease



Phenytoin

Overview

Effective in suppression of ventricular arrhythmias associated with digitalis toxicity

Less effective than quinidine, procainamide, or lidocaine, in treatment of ventricular

arrhythmias due to other etiologies

Pharmacokinetics:

Routes of administration: oral, or IV

Normal saline preferred -- phenytoin may precipitate in 5% dextrose in water

Slow IV injection into large peripheral or central vein preferable-- decreased chance of:

discomfort

thrombosis at injection site

Hepatic Metabolism --hydroxylation and conjugation (glucuronidation):

Elimination half-life: approximately 24 hours

Impaired hepatic function may cause excessive phenytoin blood levels

Mechanism of Action/Cardiac Effects:

Electrophysiological e ffects on automaticity and conduction velocity--somewhat like

lidocaine

Shortens QT interval more than any other antiarrhythmic agent

No significant effect on ST-T waves or QRS complex

No significant myocardial depression


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Improvement in AV Node Conduction;

Depression of SA Nodal Activity

Drug-Drug Interaction:

Significant SA nodal depression may occur when combining those volatile anesthetics that depress

SA nodal activity and phenytoin

Drugs that lower phenytoin levels:

barbiturates (mechanism:metabolizing enzyme induction)

Drugs that increase phenytoin level (inhibit metabolism):

warfarin, phenylbutazone, isoniazid

Side effect/Toxicities:

Primary Toxicity: CNS disturbance (particularly cerebellar-- dose correlated > 18 ug/ml--

exceeding this concentration is unlikely to improve cardiac rhythm)

CNS symptoms:

ataxia, vertigo, slurred speech, sedation, nystagmus, confusion

Partial inhibition of insulin secretion: enhances blood glucose levels in hyperglycemic patients



Type Ic: Type Ic drugs slowly dissociate from resting sodium channels

Flecainide (Tambocor)--( Na+ and K+ Channel Blocker)

Overview:

Fluorinated local anesthetic analog of procainamide (Procan SR, Pronestyl-SR)

More effective than quinidine gluconate (Quinaglute, Quinalan) or disopyramide (Norpace

in:

suppressing ventricular tachycardia

suppressing ventricular premature contractions

Pharmacokinetics:

oral absorption: excellent

long elimination half-time (approximately 20 hours)


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25% flecainide: excreted unchanged (kidneys)

Hepatic metabolism: weakly active metabolites

Factors reducing flecainide elimination:

congestive heart failure

renal failure

Cardiac Effects/Clinical Use:

Suppression ventricular tachycardia & ventricular premature contractions

Effective in management of atrial tachyarrhythmias

Effective in tachyarrhythmias associated with Wolff-Parkinson-White syndrome (suppression of

conduction bypass tracts)

Chronic flecainide (Tambocor) treatment following myocardial infarction not

recommended:

increased incidence of sudden death in treated patients

In CAST, flecainide increased mortality in patients recovering from

myocardial infarction.

Flecainide: should be reserved for management of life-threatening arrhythmias

Slight/moderate negative inotropic property

Proarrhythmic effects in patients with preexisting left ventricular function deficiency

Electrophysiology:

Prolongation of PR interval (ECG)

Prolongation of QRS complex (> 25%)

Sinoatrial nodal depression (similar to beta-adrenergic blockers and calcium channel blockers)

Side-Effects/Toxicities

Most common:vertigo and difficulty in visual accommodation

Most serious of adverse effects is induction of potentially lethal arrhythmias such as

reentrant ventricular tachyarrhythmias.



Amiodarone (Cordarone) (Class I and III Channel Blocker)


28/37

Overview:

A benzofurane derivative, 37% iodine by weight, structurally similar to thyroxine

may cause hypothyroidism or hyperthyroidism (frequency: 2%-4%)

Insidious development

Patients with previous thyroid dysfunction: more likely to develop amiodarone-

mediated thyroid effects

Hyperthyroidism: most readily evidenced by increased plasma level of triiodothyronine

Secondary to iodine release from parent drugs;

Often refractory to conventional treatment

intolerant of beta-adrenergic receptor blockade (because of underlying

cardiac disease)

Following failed medical management: surgical thyroidectomy is appropriate

bilateral superficial cervical plexus block has been used for anesthetic

management of subtotal thyroidectomy in this patient group

Hypothyroidism: most readily evidenced by increased plasma level of thyroid-

stimulating hormone (TSH)

may interfere with certain radiologic procedures (Iodine accumulation)

Approved for use only in treatment of serious ventricular arrhythmias (USA)

also used for refractory supraventricular arrhythmias

Numerous adverse effects.

Metabolism & Excretion

Long elimination halftime: 29 days

Minimal renal excretion

Principal metabolite (desmethylamiodarone) -- longer elimination halftime compared to amiodarone

Extensive protein binding

Amiodarone concentrated in the myocardium (10-50 times plasma concentration)

Cardiovascular Properties and Uses:

Used in patients with ventricular tachycardia or fibrillation resistant to treatment with

other drugs.


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Effective inhibitor of abnormal automaticity.

Oral administration, preoperatively, reduces likelihood of atrial fibrillation following cardiac surgery.

Suppresses tachyarrhythmias associate with Wolff-Parkinson-White syndrome

secondary to depression of conduction in the AV node and accessory bypass tracts.

Similar to beta-blockers (unlike most class I antiarrhythmics), amiodarone decreases

mortality after myocardial infarction

Antiarrhythmic effectiveness begins within 72 hours following initiation of oral treatment; nearly

immediate effect following IV administration

Following discontinuation of chronic oral therapy: pharmacological effects may last up to two

months (long elimination half-time)

Mechanism of Action

Blocks sodium and potassium channels and prolongs action potential duration.

Prolongs effective refractory period in:

SA node

AV node

ventricle

atrium

His-Purkinje system

accessory bypass tracts (Wolff-Parkinson-White syndrome)

Vascular Effects

Noncompetitive alpha and beta adrenergic receptor blocker

Systemic vasodilation

Antianginal properties, secondary to coronary vasodilation

Side Effects

Pulmonary:

Most serious adverse effect seen in long-term therapy is a rapidly progressive pulmonary

fibrosis which may be fatal

Frequency: 5%-15% treated patients

Mortality rate: 5% to 10%


30/37

Cause: unknown (possibly related to amiodarone-mediated generation of free oxygen

radicals in the lung)

Two types of amiodarone-pulmonary toxicity clinical presentations:

More common: Slow, insidious, progressive dyspnea, cough, weight loss,

pulmonary infiltration (chest x-ray)

Acute onset: dyspnea, cough, arterial hypoxemia.

Anesthetic Implications: pulmonary

Suggested restriction of inspired oxygen concentration in patients receiving

amiodarone and undergoing general anesthesia close level possible while retaining

adequate systemic oxygenation

Postoperative pulmonary edema has been reported in patients treated with

amiodarone chronically-- resembles acute onset form of amiodarone toxicity.

In patients with preexisting amiodarone-cause pulmonary damage are at increasedrisk for adult respiratory distress syndrome following surgery requiring

cardiopulmonary bypass.

Cardiovascular Effects:

Prolongation of QT interval (ECG); increased incidence of ventricular tachyarrhythmias

(including torsades de pointes)

Bradycardia (atropine-resistant)

Catecholamine responsiveness: diminished due to alpha and beta-receptor blockingactivity

Hypotension; A-V block (following IV administration)

Anesthetic Implications: cardiovascular

With general anesthesia -- enhanced antiadrenergic action, presentation as:

A-V block, sinus arrest, decrease cardiac output, hypotension

Sinus arrest more likely in the presence of anesthetics that inhibit SA nodal automaticity

(e.g. lidocaine, halothane)

Consideration should be given for temporary ventricular pacemaker and

sympathomimetic administration (e.g. isoproterenol) for patients taking amiodarone and

scheduled undergo surgery.

Ocular and other Side Effects:

Corneal microdeposits-- common;usually no visual impairment


31/37

Photosensitivity, rash: 10% frequency

Rare: cyanotic discoloration (slate-gray facial pigmentation)

Neurological:

peripheral neuropathy; sleep disturbance, headache, tremor, some skeletal muscle weakness

Drug-drug interaction

Potent inhibitor of hepatic metabolism or renal elimination of many drugs.

Warfarin, quinidine gluconate (Quinaglute, Quinalan), procainamide (Procan SR, Pronestyl-

SR) and digoxin (Lanoxin, Lanoxicaps) are examples of drugs which may require dosage

reduction during amiodarone (Cordarone).

Amiodarone (Cordarone) displaces digoxin (Lanoxin, Lanoxicaps) from protein binding

sites

Digoxin (Lanoxin, Lanoxicaps) levels may increase as much as 70%

Digoxin (Lanoxin, Lanoxicaps) dose should be decreased as much as 50% when amiodarone

is administered concurrently

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical

Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241; Stoelting, R.K., "Cardiac

Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven

Publishers, 1999, 331-343

Class II: Beta-Adrenergic Antagonists

-adrenoceptor blockers:

Decrease the slope of phase IV depolarization slowing the heart

Depressing automaticity.

Conduction time through AV node is increased while contractility is diminished.

Class II Antiarrhythmic drugs

Propranolol (Inderal)

Metoprolol (Lopressor) (beta-1 "specific")

Pindolol (Visken) (partial agonist)

Esmolol (Brevibloc)(very short acting)

Propranolol


32/37

Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally,

sympathetic drive results in increased in Ca2+ ,K+ ,and Cl- currents.

Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and

increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated

arrhythmias. These effects are blocked by beta-adrenergic receptor blockers.

Beta-adrenergic receptor blockers increase AV conduction time and increase AV nodal

refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

Beta-adrenergic receptor blockade can also help reduce ventricular following rates in atrial

flutter and fibrillation, again by acting at the AV node.

Adverse effects of beta blocker therapy can lead to fatigue, bronchospasm, depression,

impotence, and attenuation of hypoglycemic symptoms in diabetic patients and worsening of

congestive heart failure.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical

Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241

Esmolol (Brevibloc)

Esmolol (Brevibloc) is a very short acting, cardioselective beta-adrenergic receptor antagonist.

i.v. administration is used for rapid beta-receptor blockade in treatment of atrial fibrillation with

high ventricular following rates.

Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally, sympathetic drive

results in increased in Ca2+ ,K+and Cl- currents.

Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD

(delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias. These effects are

blocked by beta-adrenergic receptor blockers.

Beta-adrenergic receptor blockersincrease AV conduction time

increase AV nodal refractoriness, thereby helping to terminate nodal reentrant

arrhythmias.






Class III: Potassium Channel Blockers


33/37

Blockade of potassium channels delay repolarization and prolong the action potential. As a result, the

effective refractory period is increased.

Bretylium (Bretylol)

Overview:

Initially released as an antihypertensive agent.

Orthostatic hypotension may occur following chronic use

Inhibits neuronal catecholamine release, following an initial direct early release of

norepinephrine from adrenergic nerve terminals (transient hypertension)

Direct antiarrhythmic properties

Pharmacokinetics:

IV or IM Route of Administration

Following rapid IV administration: nausea & hypotension

After the first doses: bretylium-mediated norepinephrine release causes:

transient hypertension

increased ventricular irritability (particularly in patients also receiving digitalis)

Renal elimination: 8-12 hour halftime

Dosage reduction required in patients with renal dysfunction

Hepatic metabolism: not demonstrated

Cardiac Actions:

Antiarrhythmic effect due to prolongation of the cardiac action potential and inhibition of

norepinephrine reuptake by sympthetic nerves

Increased ventricular (not atrial) action potential duration and effective refractory period

Somewhat selective for ischemic cells which have shortened action potential durations

Bretylium may reverse shortening of action potential duration due to ischemia

Possesses anti-fibrillatory activity; independent of sympatholytic action

Initial catecholamine release (prior to inhibition of release), results in some positive

inotropic effect; however, this action may induce ventricular arrhythmias (catecholamines

generally are pro-arrhythmogenic).

Inhibition of catecholamine release may result in bradycardia.


34/37

Clinical Use:

Management of serious ventricular arrhythmias refractory to lidocaine or procainamide

Possible initial drug for treatment of ventricular fibrillation--Rationale:

Increases ventricular fibrillation threshold;

Prolongs action potential duration;

Prolongs effective refractory period

Amiodarone (Cordarone)

Overview:

A benzofurane derivative, 37% iodine by weight, structurally similar to thyroxine

May cause hypothyroidism or hyperthyroidism (frequency: 2%-4%)

Insidious development

Patients with previous thyroid dysfunction: more likely to develop amiodarone-

mediated thyroid effects

Hyperthyroidism: most readily evidenced by increased plasma level of triiodothyronine

Secondary to iodine release from parent drugs;

Often refractory to conventional treatment

intolerant of beta-adrenergic receptor blockade (because of underlyingcardiac disease)

Following failed medical management: surgical thyroidectomy is appropriate

bilateral superficial cervical plexus block has been used for anesthetic

management of subtotal thyroidectomy in this patient group

Hypothyroidism: most readily evidenced by increased plasma level of thyroid-

stimulating hormone (TSH)

May interfere with certain radiologic procedures (Iodine accumulation)

Approved for use only in treatment of serious ventricular arrhythmias (USA)

Also used for refractory supraventricular arrhythmias

Numerous adverse effects.

Metabolism & Excretion

Long elimination halftime: 29 days


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Minimal renal excretion

Principal metabolite (desmethylamiodarone) -- longer elimination halftime compared to amiodarone

Extensive protein binding

Amiodarone concentrated in the myocardium (10-50 times plasma concentration)

Cardiovascular Properties and Uses:

Used in patients with ventricular tachycardia or fibrillation resistant to treatment with

other drugs.

Effective inhibitor of abnormal automaticity.

Oral administration, preoperatively, reduces likelihood of atrial fibrillation following cardiac surgery.

Suppresses tachyarrhythmias associate with Wolff-Parkinson-White syndrome

secondary to depression of conduction in the AV node and accessory bypass tracts.

Similar to beta-blockers (unlike most class I antiarrhythmics), amiodarone decreases

mortality after myocardial infarction

Antiarrhythmic effectiveness begins within 72 hours following initiation of oral treatment; nearly

immediate effect following IV administration

Following discontinuation of chronic oral therapy: pharmacological effects may last up to two

months (long elimination half-time)

Mechanism of Action

Blocks sodium and potassium channels and prolongs action potential duration.

Prolongs effective refractory period in

SA node

AV node

ventricles

atrium

His-Purkinje system

accessory bypass tracts (Wolff-Parkinson-White syndrome)

Vascular Effects

Noncompetitive alpha and beta adrenergic receptor blocker

Systemic vasodilation


36/37

Antianginal properties, secondary to coronary vasodilation

Side Effects

Pulmonary:

Most serious adverse effect seen in long-term therapy is a rapidly progressive

pulmonary fibrosis which may be fatal

Frequency: 5%-15% treated patients

Mortality rate: 5% to 10%

Cause: unknown (possibly related to amiodarone-mediated generation of free oxygen

radicals in the lung)

Two types of amiodarone-pulmonary toxicity clinical presentations:

More common: Slow, insidious, progressive dyspnea, cough, weight loss,

pulmonary infiltration (chest x-ray)

Acute onset: dyspnea, cough, arterial hypoxemia.

Anesthetic Implications: pulmonary

Suggested restriction of inspired oxygen concentration in patients receiving

amiodarone (Cordarone) and undergoing general anesthesia to as low a level as

while retaining adequate systemic oxygenation

Postoperative pulmonary edema has been reported in patients treated with

amiodarone (Cordarone) chronically-- resembles acute onset form of amiodarone

toxicity.

In patients with preexisting amiodarone-caused pulmonary damage are at increased

risk for adult respiratory distress syndrome following surgery requiring

cardiopulmonary bypass.

Cardiovascular:

Prolongation of QT interval (ECG); increased incidence of ventricular tachyarrhythmias

(including torsades de pointes)

Bradycardia (atropine-resistant)

Catecholamine responsiveness: diminished due to alpha and beta-receptor blocking activity

Hypotension; A-V block (following IV administration)

Anesthetic Implications: cardiovascular

With general anesthesia -- enhanced antiadrenergic action, presentation as:

A-V block, sinus arrest, decrease cardiac output, hypotension


37/37

Sinus arrest more likely in the presence of anesthetics that inhibit SA nodal

automaticity (e.g. lidocaine, halothane)

Consideration should be given for temporary ventricular pacemaker and

sympathomimetic administration (e.g. isoproterenol) for patients taking

amiodarone and scheduled undergo surgery.

Ocular and other Side Effects & Drug-drug interaction: As above





Class IV: Calcium Channel Blockers

These drugs block the inward calcium current and therefore slow conduction through the AV node and decreasethe slow of phase 4 depolarization.

Calcium channel blockers are especially active at vascular smooth muscle and at the heart.

Verapamil (Isoptin, Calan) (main action on the heart)

Nifedipine (Procardia, Adalat) (main action on vascular smooth muscle (anti-hypertensive effect))

Diltiazem (Cardiazem) (action on both the heart and vascular smooth muscle)

Adenosine (Adenocard)

Effects mediated through G protein-coupled adenosine receptor.

Activates acetylcholine-sensitive K+ current in the atrium and sinus and A-V node.

Decreases action potential duration, reduces automaticity

Increases A-V nodal refractoriness

Rapidly terminates re-entrant supraventricular arrhythmias (I.V)


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Cardiac Rhythm Disorders With Rmp and Inactivcating Sodium Channels