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ONACRUZ,MD,MHPED,FPOGS

Anti-arrhythmics

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OVERVIEW

PHYSIOLOGY OF CARDIAC CONTRACTION DRUGS: CLASSES I

ARRHYTHMIAS ANTI-ARRHTYMIC

IV
OTHER ANTI-ARRHYTHMICS

ADENOSINE DIGOXIN
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CARDIAC ACTION POTENTIALS

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Action Potential in SA Nodal Cells

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ACTION POTENTIAL OF VENTRICULAR MYOCYTES

Phase O: FAST UPSTROKE

Cell Membrane

Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ OUTSIDE CELL
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Na+ Na+ Na+

INSIDE CELL

Phase I: Partial Repolarization

Cell Membrane

Na+ K+ K+ K+ K+

OUTSIDE CELL
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INSIDE CELL

Phase 2: Plateau
Cell Membrane Ca++ Ca++ Ca++

K+

K+ K+ K+

OUTSIDE CELL
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INSIDE CELL

Phase 3: Repolarization
Cell Membrane

Ca++ K+ K+ K+ K+

OUTSIDE CELL
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INSIDE CELL

Phase 4: Forward Current

Increasing

depolarization results from gradual increase in permeability to sodium membrane potential is restablished

Resting

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Determination of Firing Rate

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Specialized conduction system

SA NodeAV

native pacemaker

Node- latent pacemaker of His-latent pacemaker pacemaker

Bundle

Purkinje-latent

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Factors Determining Firing Rate

1.Rate of spontaneous depolarization in phase 4 2.Threshold potential 3.Resting membrane potential

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What are arrhythmias?

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Dysfunctions ofImpulse Impulse

formation and/or conduction

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Disturbance in impulse formation

Altered

automaticity (increased activity of pacemakers) (EADs. DADs)

Triggered Activity

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Altered automaticity
Physiologic Pathologic

latent pacemakers takeover escape, ectopic beats direct tissue injury

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Triggered Activity
Afterdepolarizations:

occur when a normal action potential triggers an EXTRA depolarization

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Afterdepolarizations

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Disturbances of Impulse Conduction

Simple

block or circus movement Tracts

Reentry

Accessory

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Accessory Tract Pathways

Bundle

of Kent

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Basic Pharmacology

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MECHANISM of Action
1. 2. 3. 4.

Sodium channel blockade Blockade of sympathetic autonomic effects in the heart Prolongation of effective refractory period Calcium channel blockade

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State-dependent ion channel block

Ion

channels can change into various conformational states in membrane permeability to a particular ion is mediated by conformational changes in the channels through which that ion passes

Changes

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State-dependent ion channel block

Antiarrhythmic

agents often have different affinities for different conformational states of the ion channel

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Antiarrhythmics preferEctopic

pacemakers tissues, ischemic tissues

Depolarized Activated

channels (phase 0) or inactivated channels (phase 2)- use or state dependent drug action

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Drug Action in cells with abnormal automaticity

Reduction Increase

of phase 4 slope by blocking sodium or calcium threshhold of positive chronotropic action of norepinephrine in the heart (beta blockers)

Blockade

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Drug action in reentry

Slows

conduction by:

1. steady state reduction of available unblocked channels 2. prolongation of recovery time of channels that are able to reach rested and available state (increased refractory period)

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Drug-induced arrhythmia
As

dose of antiarrhythmics are increased, they begin to suppress conduction in normal polarized tissue of the heart concentrations may also be proarrhythmic in settings of fast heart rates, acidosis, hyperkalemia, ischemia

Therapeutic

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Specific Antiarrhythmics

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Class I : SODIUM Channel Blockers

SA NODAL

EFFECTS:

decreases automaticity by increasing threshold potential and decreasing slope of phase 4 depolarization

Ventricular Myocyte effects:

decreases upstroke velocity (slope) of phase 0, for some also prolongs repolarization (increases ERP) 4/22/12

Sodium Channel Blockers

Generally

decrease reentry and prevent arrhythmia by: 1.decreasing conduction velocity 2.increasing the refractory period

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Sodium Channel Blockers

Although

all three subclasses have similar effects on action potential in the SA node, there are important differences in their effects on ventricular action potential

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Class IA
Moderate Prolongs Prolongs Increases

sodium channel blockade (Moderate reduction in slope of phase 0) repolarization in both SA node and ventricles action potential duration Effective Refractory Period

duration
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Class IB
Weak

sodium channel blockade (Small reduction in phase 0 slope) action potential duration in some tissues of the heart effective refractory period

Shortens

Decreases

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Class IC
Strong

sodium blockade reduction in slope of phase 0

Pronounced No

effect on APD or ERP

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Na Channel Blockers
Sodium

Blockade

IC>IA>IB
ERP

IA-increase, IB-shortens, IC-no effect

Action

Potential Duration (K+ repolarization current) IA > IB IC-no effect

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Classs IA: procainamide

Slows

phase 4 depolarization thereby decreasing abnormal automaticity threshold for excitation in atrium and ventricles- direct depressant actions

Increases

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procainamide
EXTRACARDIAC

EFFECTS

ganglion blocking propertiesreduces peripheral vascular resistance* hypotension (esp.IV)

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Procainamide toxicity
CARDIAC

excessive slowing of conduction as precipitation of new arrhythmias such torsades de pointes* syncope

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Procainamide toxicity
EXTRACARDIAC

lupus-like syndrome nausea and diarrhea rash fever hepatitis agranulocytosis

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Procainamide : Pkinetics
IV,IM, NAPA Liver Half

PO(good absorption) metabolite- Class III activity*

metabolism and renal excretion

life is 3-4 h (frequent dosaging)

Dose

reduction in renal failure and heart failure

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Procainamide:Uses
Atrial

and ventricular arrhythmias

Sustained

ventricular arrhythmias with acute MI (second choice)

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Class IA Quinidine
CARDIAC

EFFECTS

similar to procainamide more cardiac antimuscarinic effects than procainamide Cardiac toxicities- excessive QT interval prolongation, torsades de pointes, excessive slowed conduction
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quinidine
EXTRACARDIAC

EFFECTS

diarrhea, nausea, vomiting cinchonism (headache, dizziness, tinnitus) thrombocytopenia hepatitis angioneurotic edema
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fever

Quinidine: Pkinetics
Rapid Binds

absorption after oral intake to albumin and alpha glycoprotein metabolism

Hepatic Half

life 6-8 hrs release formulations

Slow

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Quinidine: Uses
Occasional:

atrial flutter/fib

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Class IA: Disopyramide

CARDIAC

EFFECTS

similar to procainamide and quinidine greater cardiac antimuscarinic effect than quinidine*

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Disopyramide
CARDIAC

TOXICITIES

similar to quinidine precipitation of heart failure*

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disopyramide
EXTRACARDIAC

TOXICITIES

ATROPINE-LIKE EFFECTSurinary retention dry mouth blurred vision constipation glaucoma worsening
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Disopyramide: Pkinetics, Use

Oral Reduced

dose in renal failure arrhythmias

Ventricular

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Class IB: Lidocaine

Low

incidence of toxicity effective for arrhythmias in acute

Highly

MI
IV

use only

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lidocaine
CARDIAC

EFFECTS

greater effects on purkinje and ventricular cells than atrial Selective depression of conduction in depolarized and not in resting cells

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Lidocaine: Toxicity
CARDIAC

least cardiotoxic among class I uncommon proarrhythmic effects hypotension in large doses (heart failure cases)*

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Lidocaine: toxicity
EXTRACARDIAC

Neurologic* paresthesia, tremor, nausea lightheadedness, hearing disturbances slurred speech, seizures

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Lidocaine: Pkinetics
Extensive Parenteral Half-life Higher

first pass hepatic metabolism* (infusion)

1-2h (can be as short as 20 mins)

concentration may be needed in some cases of MI or other acute illness**

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Lidocaine: Pkinetics
Doses Drug

are decreased in those with heart failure, liver disease interaction:* propranolol cimetidine

(Renal disease has no effect)

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Lidocaine: Use
DOC-

tx for ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in acute MI

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Class IB: Mexiletine

Oral

active congener of lidocaine

Adverse

effects are dose-related and frequently occur at therapeutic doses (neurologic)* Elimination half-life is 8-20 h*

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Mexiletene: Use
Ventricular Chronic

arrhythmias

pain conditions

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Class IC: Flecainide

Potent Does Well

sodium and potassium blocker*

not prolong APD or QT interval 20h

absorbed orally metabolism, renal elimination

Half-lifeHepatic No

antimuscarinic effects

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Flecainide
TOXICITY:

severe arrhythmia exacerbation*

USE: Supraventricular arrhythmias,PVCs

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Class IC: Propafenone

With

weak beta blocking action similarity: propranolol of action: Quinidine

Structural Spectrum Liver

metabolism

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propafenone
TOXICITY:

metallic taste constipation arrhythmia exacerbation

USE: supraventricular arrhythmias

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Class IC: Moricizine

Potent

sodium channel blocker prolongation

No APD Many

metabolites*

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Moricizine
TOXICITY:

Dizziness Nausea Arrhythmia exacerbation

USE:

ventricular arrhythmias
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Class II: Beta Blockers

Cardiac

Effects: anti-arrhythmic

beta receptor blockade direct membrane effects

Well tolerated but less effective than sodium channel blockers*

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Beta blockers
Propranolol Esmolol Sotalol*

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Class 3: Potassium Channel Blockers

Drugs

that prolong effective refractory period via prolongation of action potential K+ channel or enhance inward currents of sodium dependence*

Blocks

reverse-use

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Class 3: Amiodarone
CARDIAC

EFFECTS:

marked prolongation of the APD and QT interval by blocking Ik blocking effect occurs in all ranges of heart rates*-the exception broad range of actions- Class I-IV actions
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Amiodarone
CARDIAC

EFFECTS

slows heart rate and AV node conduction highly efficacious, low risk of torsades even if QT is prolonged

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Amiodarone
EXTRACARDIAC

EFFECTS

Peripheral vasodilatation*

USES ventricular arrhythmias, tachycardia supraventricular arrhythmias (atrial fib)

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Amiodarone
Accumulates

in many tissues (heart, lung, liver, skin, tears)

TOXICITY:
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CARDIAC

symptomatic bradycardia and heart block*

Amiodarone
TOXICITY:EXTRACARDIAC

dose-related pulmonary fibrosis abnormal liver function tests and hepatitis photodermatitis, gray blue discoloration of exposed skin asymptomatic corneal microdeposits

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amiodarone
KINETICS

bioavailability 35-65% hepatic metab: desethylamiodarone* elimination half-life 50% rapid component (3-10days) 50% slow (weeks) *effects are maintained up to 3 months

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amiodarone
KINETICS

drug interaction increase with cimetidine decrease with rifampicin increases levels of warfarin and digoxin

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Class 3: Bretylium
Direct

antiarrhythmic effect and inhibitor of neuronal catecholamine release EFFECTS

CARDIAC

lengthens ventricular* APD and ERP esp. in ischemic tissues- reverses shortening of APD due to ischemia
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bretylium
CARDIAC

EFFECTS

initial positive inotropic effect*

EXTRACARDIAC EFFECTS postural hypotension** nausea and vomiting

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bretylium
KINETICS

available for IV use

USES (rare)

emergency- resuscitation from ventricular fibrillation after failure of lidocaine and cardioversion (amiodarone preferred)
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Class 3: Sotalol
Class

3 (APD prolongation) and Class 2 (beta blocker) actions mixture:

Racemic

*Beta blocking effect is in the l-isomer APD prolongation in d- and l-isomers

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Sotalol
KINETICS

100% bioavailability excreted unchanged in the kidneys half-life of 12 h few direct drug interactions

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sotalol
CARDIAC

TOXICITIES

torsades des pointes* further depression of LV function**

USES life threatening ventricular arrhythmias maintaining sinus rhythm in atrial fib supraventricular and ventricular

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Class 3: Dofetilide
Dose

dependent blockade rapid component of delayed rectifier potassium current Ikr* (esp. in hypokalemia) to block is independent on stimulation frequency due to slow rate of recovery from the blockade*

Ability

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dofetilide
KINETICS

100% bioavailability Drug interactionVerapamil* Cimetidine** 80% excreted renally unchanged 20% excreted as inactive metabolites
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dofetilide
Contraindication:

baseline QT interval of > 450ms, intraventricular delay, bradycardia of <50 beats, hypokalemia

USE:

maintenance or restoration of normal sinus rhythm in atrial fibrillation

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Class 3: Ibutilide
Blockade

of rapid component of delayed rectifier potassium current and activation of slow inward sodium current

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Ibutilide
KINETICS

rapid by hepatic metabolism renal excretion half-life 6 h

USES

acute conversion of atrial fibrillation and flutter

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ibutilide
CARDIAC

TOXICITY

extreme prolongation of QT interval torsades des pointes

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Class 4: Calcium Channel Blocker

Initially

introduced for management of angina pectoris

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Class 4: Verapamil
CARDIAC

EFFECTS

blocks activated and inactivated L-type calcium channels especially in rapidly firing tissues, less completely polarized at rest, those whose activation depends more on calcium channels* SA and AV NODES
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verapamil
CARDIAC

EFFECTS

suppression of EAD and DAD

EXTRACARDIAC EFFECTS Peripheral vasodilatation

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verapamil
TOXICITY:

CARDIAC*

hypotension and ventricular fibrillation when given for a misdiagnosed SVT** negative inotropic effect AV block sinus arrest
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verapamil
TOXICITY:

EXTRACARDIAC

constipation lassitude nervousness peripheral edema

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verapamil
KINETICS

half life 7 h extensive liver metabolism 20% bioavailability

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verapamil
USES

SVT (also adenosine) reduction of ventricular rate in atrial fib or flutter Ventricular arrhythmias (occasional)

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Class 4: Diltiazem
Similar

to verapamil

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Miscellaneous: ADENOSINE
Naturally Half

occuring nucleoside

life 10 mins

Activates

inward K+ rectifier current and inhibits Ca current: marked hyperpolarization and suppression of calcium dependent action potentials

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adenosine
Bolus

inhibits AV node conduction and increases AV node refractory period* prompt conversion of paroxysmal SVT to sinus rhythm

DOC-

Interactions caffeine, theophylline dipyridamole

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adenosine
TOXICITY:

flushing in 20% shortness of breath, chest burning in 10% brief AV block atrial fibrillation
headache, hypotension, nausea, paresthesias
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Miscellaneous: Magnesium
Effects

on Na+/K+ ATPase, sodium channels, calcium channels

USES:

Digitalis-induced arrhythmias in hypomagnesemic patients Torsades des pointes

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Miscellaneous: Potassium

Hypokalemia and hyperkalemia are both arrhythmogenic Therapeutic goal: normalization of potassium gradients and pools in the body

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