AGENTS USED IN

CARDIAC
ARRHYTHMIAS

ELMER A. LINAO, MD, MBA, FPCC,

FA s C C
BCCM, Legaspi City
February 5 2019
 Cardiac arrhythmias are a common
problem in clinical practice

 Up to 25% of patients treated with

digitalis,

 50% of anesthetized patients and over

 80% of patients with acute myocardial

infraction
 Arrhythmias may require treatment
because rhythms that are too rapid, too
slow or asynchronous can reduce cardiac
output

 Some arrhythmias can precipitate more

serous or even little driven disturbances
 Early premature ventricular depolarization
can precipitate ventricular fibrillation.

 The hazards or antiarrhythmic drugs and

in particular the fact they can precipitate
lethal arrhythmias in some patients.
Arrhythmias can be treated with:

1. Drugs discussed in this chapter

2. nonpharmacologic therapies such as
pace makers, cardioversion, catheter
ablation and surgery
SPECIFIC ANTIARRHYTHMIC AGENTS

1. CLASS 1 ACTION IS SODIUM

CHANNEL BLOCKADE

• Subclasses of this action reflect effects on the

action potential duration (APD) and the kinetics
of sodium blockade.
• Drugs with class 1A action prolonged the APD
and dissociate from the channel with
intermediate kinetics
 Drugs with class 1B action shorten the
APD in some tissues of the heart and
dissociate from the channel with rapid
kinetics

 Drugs with class 1C action have minimal

effects on the APD and dissociate from
the channel with slow kinetics
2. CLASS 2 ACTION IS SYMPHATOLYTIC

 Drugs with this action reduce beta-

adrenergic activity in the heart

3. CLASS 3 ACTION MANIFESTS AS

PROLONGATION OF THE APD.

 Most drugs with action block the rapid

component of the delayed rectifier potassium
current Ikr
4. CLASS 4 ACTION IS BLOCKADE OF
THE CARDIAC CURRENT

 This action slows conduction in regions

where the action potential upstroke is
calcium dependent, eg., the SA and AV
nodes
SODIUM CHANNEL-BLOCKING DRUGS
(Class 1)

Drugs with local anesthetic action blocks

sodium channels and reduce the sodium
current, INA

They are the oldest group of anti-

arrhythmic drugs and are still widely used.
CARDIAC EFFECTS

 Blocking sodium channels, procainamide

slows the upstroke of the action potential,
slows conduction and prolongs the QRS
duration of the ECG

 The APD (Class 3 action) by nonspecific

blockade of potassium channels.
 Procainamide has direct depressant
actions on SA and AV nodes, an these
actions are only slightly counterbalance
by drug – induced vagal block
EXTRACARDIAC EFFECTS

 Procainamide has ganglion-blocking

properties

 Reduces peripheral vascular resistance

and cause hypotension, particularly with
intravenous use
TOXICITY

 Procainamide’s cardiotoxic effects include


A)excessive action potential prolongation,
B) QT-interval prolongation, and
C)induction of torsades de pointes arrhythmia
D)syncope.

 A trouble adverse effect of long-term

procainamide therapy is a syndrome
resembling lupus erythematosus and
usually consisting arthralgia, and arthritis
 In some patients, pleuritis, pericarditis or
parenchymal pulmonary disease also
occurs

 Renal lupus is rarely induced by

procainamide

 Other adverse effects include nausea and

diarrhea (10% of cases), rash, fever,
hepatitis (<5%), and agranulocytosis
(approximately 0.2%)
Pharmacokinetics & Dosage

 Procainamide can be administered safely by

intravenous and intramuscular routes and is
well absorbed orally.

 NAPA has class 3 activity

 Procainamide is eliminated by hepatic

metabolism to NAPA by renal elimination. It’s
half-life is only 3-4 hours.

 Is eliminated by the kidneys. Thus

procainamide must be reduced in patients
with renal failure.
 The risk of gastrointestinal (GI) or cardiac
toxicity rises at plasma concentrations
greater than 8 mcg/ml or NAPA
concentrations greater that 20 mcg/ml

 To control ventricular arrhythmias, a total

procainamide dosage of 2-5 g/d is usually
required.
 Therapeutic Use

 Procainamide is effective against most

atrial and ventricular arrhythmias.

 Procainamide is the drug of second or

third choice ( after lidocaine or
amiodarone) in the most coronary care
units for the treatment of sustained
ventricular arrhythmias associated with
acute myocardial infarction.
QUINIDINE (SUBGROUP 1A)

 Cardiac Effects

 Quinidine has actions similar to those of

procainamide:
A) it slows the upstroke of the action potential,
B) slows conduction, and
C) prolongs the QRS duration of the ECG, by
blockade of sodium channels.

 It’s toxics cardiac effects include excessive

QT-interval prolongation and induction of
torsades de pointes arrhythmia.
 Extra Cardiac Effects

 Adverse GI effects of diarrhea, nausea,

and vomiting are observed in one third to
one half of patients.

 A syndrome of headache, dizziness, and

tinnitus ( cinchonism) is observed at toxic
drug concentrations.
 Idiosyncratic or immunologic reactions,
including thrombocytopenia, hepatitis,
angioneurotic edema, and fever, are
observed rarely.

 Pharmacokinetics & Therapeutics Use

 Quinidine is readily absorb from the GI

tract and eliminated by hepatic
metabolism.
DISOPYRAMIDE (SUBGROUP 1A)

Cardiac Effects
 The effects of disopyramide are very similar
to those of procainamide and quinidine.
 Its cardiac antimuscarinic effects are even
more marked than those of quinidine.
 Slows AV conductions should be administered
with disopyramide when treating atrial flutter
or fibrillation.
TOXICITY

Disopyramides atropine-like activity

accounts for most of its automatic adverse
effects:
A) urinary retention (most often, but
exclusively, in male patients with
prostatic hyperplasia),
B) dry,
C) blurred vision,
D) constipation, and
E) worsening of preexisting coma.
 Pharmacokinetics & Dosage

 Disopyramide is only available for oral

use.

 The typical dosage of Disopyramide is

150 mg three times a day.
LIDOCAINE (SUBGROUP 1B)

 Arrhythmias associated with acute

myocardial infarction based only by the
intravenous route.
 Cardiac Effects
 Lidocaine blocks activated and
inactivated sodium channels with kinetics.
TOXICITY

 Lidocaine is one of the least cardiotoxic of

the currently used sodium channel
blockers.
 Proarrhythmic effects, including
 A) SA node arrest
 B) worsening of impaired conductions,
and
 C) ventricular arrhythmias, are
uncommon with lidocaine use.
 In large doses, especially in patients with
preexisting heart failure, lidocaine may
cause hypotension-partly by depressing
myocardial contractility.
 Lidocaine most common adverse effects-like
those of other local anesthetics-are
neurologic:
 A) paresthesias
 B) tremor,
 C)nausea of central origin,
D)lightheadedness,
 E)hearing disturbances,
 F) slurred speech and
 G) convulsions.
 The effects are dose-related and usually
short-lived; seizures respond to
intravenous diazepam.
PHARMACOKINETICS & DOSAGE

 Extensive first- pass hepatic metabolism,

only 3% of orally administered Lidocaine
appears in the plasma.

 Lidocaine must be given parenterally.

 Half-life of 1-2 hours

 In adults a loading dose of 150-200 mg

administered over about 15 minutes (as a
single infusion or as a series of slow
boluses)

 Maintenance infusion of 2-4 mg/min to

achieve a therapeutic plasma level of 2-6
mcg/mL.
 Increased plasma,

 ờ- acid glycoprotein, in an acute-phase

reactant protein that binds Lidocaine, making
less free drug available to exert its
pharmacologic effects.

 Steady state concentrations may be

achieved in 8-10 hours in normal patients

 patients with heart failure, 24-36 hours may

be required in those with liver disease.
Therapeutic Use

 Lidocaine is the agent of choice for

termination of ventricular tachycardia and
prevention of ventricular fibrillation after
cardioversion in the setting of acute
ischemia.
 MEXILETINE (SUBGROUP 1B)

 Mexiletine is an orally active congener of

lidocaine.

 Mexiletine is used in the treatment of

ventricular arrhythmias.

 The elimination half-life is 8-20 hours and

permit administration two or three times
per day.
.
 Significant efficacy in relief chronic pain,
especially pain due to diabetic neuropathy
and injury.

 The usual dosage is 450-750 mg/d orally.

 The usually daily dosage of Mexiletine 600-
1200 mg/d.

 Dose related adverse effects are seen

frequently therapeutic dosage.

 These are predominantly neurologic, include

a) tremor,
b) blurred vision, and
c) lethargy
FLECAINIDINE (SUBGROUP 1C)

 Flecainide is a potent blocker of sodium

and potassium chart with slow unblocking
kinetics.

 It is currently used for patients with

other normal hearts who have
supraventricular arrhythmias.

 Flecainide is very effective in suppressing

premature ventricular contractions.
 It may cause severe exacerbation of
arrhythmia even when normal doses are
administered to patients preexisting
ventricular tachyarrhythmias and those
with a previous myocardial infraction and
ventricular ectopy.
 Half-life of approximately 20 hours.

 Elimination is by hepatic metabolism and

by the kidney.

 The usual dosage of flecainide is 100-200

mg twice a day.
PROPAFENONE (SUBGROUP 1C)

 Propafenone has some structural

similarities to propanolol.

 It possesses weak Beta blocking activity.

 Propafenone is metabolized in the liver,

with the average half-life of 5-7 hours.
 The usual daily dosage of Propafenone is
450-900 mg/d in three divided doses.

 The drug is used primarily for

supraventricular arrhyhthmias.

 Most common adverse effect are

a. Metallic taste
b. Constipation
c. arrhythmia exacerbation
MORICIZINE (SUBGROUP 1C)

 Moricizine is antiarrhythmic
phenothiazine derivative that was used for
treatment of ventricular arrhythmias.

 Sodium channel blocker that does not

prolong action potential duration.
BETA-ADRENOCEPTOR-BLOCKING DRUGS
(CLASS 2)

• Propranolol and similar drugs have

antiarrhythmic properties by virtue of their Beta-
receptor-blocking action and direct membrane
effects.
• Have selectivity for Cardiac Beta-1
receptor,

• Some have intrinsic sympathomimetic

activity

• Some have marked direct membrane

effects

• Some prolong the cardiac action potential.

• The relative contribution of the Beta-
Blocking and direct membrane effects to
the antiarrhythmic effects of these drugs
are not fully known.

• Efficacy for suppression of ventricular

ectopic depolarization is lower than that of
sodium channel blockers
 Although Beta blockers are fairly well
tolerated, their efficacy for suppression of
ventricular ectopic depolarizations is lower
than that of sodium channel blockers.

 Esmolol is a short acting Beta Blocker

used primarily as an antiarrhythmic drug
for intraoperative and other acute
arrhythmias.
 Drugs That Prolong Effective Refractory
Period By Prolonging the Action Potential
(Class 3)

 Prolong action potentials, usually

blocking potassium channels in cardiac
muscle or by enhancing inward current,
eg, through sodium channels.
ESMOLOL is a short acting beta-blocker
used primarily as an antiarrhythmic drug
for intraoperative and other acute
arrhythmias.
DRUGS THAT PROLONG EFFECTIVE
REFRACTORY RERIOD BY PROLONGING
THE ACTION POTENTIAL (Class 3)

• These drugs prolong action potentials

usually by blocking potassium channel in
cardiac muscle or by enhancing inward
current , eg., thru sodium channels
AMIODARONE

 Amiodarone is approved for oral and

intravenous use to treat serious
ventricular arrhythmias.

 Highly effective in the treatment of

Supraventricular arrhythmias such as
atrial fibrillation.

 Has an unusual pharmacokinetics and

important extracardiac adverse effects.
 As a result of its broad spectrum of
antiarrhythmic action, it is very
extensively used for a wide variety of
arrhythmias.

 Dronedarone an analog that lacks iodine

atoms, recently received FDA approval for
the treatment of atrial flutter and
fibrillation.
 Celivarone is another noniodinated
benzofuran derivative similar to
dronedarone that is currently undergoing
clinical trials for the prevention of
ventricular tachycardia recurrence.
Cardiac Effects

 Amiodarone markedly prolongs the action

potential duration (and the QT interval on
the ECG) by blockage of Iks

 During chronic administration, Iks is also

blocked.

 A class 3 agent, amiodarone also

significantly blocks inactivated sodium
channels.
 Amiodarone also has weak adrenergic
and calcium channel-blocking actions.

 The broad spectrum of actions may

account for its relatively high efficacy and
its low incidence of torsades de pointes
despite significant QT-interval
prolongation.
Extracardiac Effects

 Amiodarone causes peripheral

vasodilation.

 Action is prominent after intravenous

administration and may be related to the
action of the molecule.
Toxicity

 Amiodarone may produce symptomatic

bradycardia and heart block in patients
with preexisting sinus or AV node disease.

 Drug accumulates in many tissues,

including the heart (10-50 times more so
than in plasma), lung, liver and skin and
is concentrated in tears.
 Low dose of 200 mg/d or less, fatal
pulmonary fibrosis may be observed in
1% of patients.

 Hypersensitivity hepatitis may be develop

during amiodarone treatment and liver
function test should be monitored
regularly.

 Halos develop in the peripheral visual

fields of some patients.
 Amiodarone blocks the peripheral
conversion of thyroxine (T₄) to
triiodothyronine (T₃).

 It is also a potential source of large

amounts of inorganic iodine.

 Amiodarone may result in hypothyroidism

or hyperthyroidism.
PHARMACOKINETICS

 Amiodarone is variably absorbed with a

bioavailability of 35-65%.

 Hepatic metabolism, and the major

metabolite, desethylamiodarone, is a
bioactive.
 Half-life is complex, with a rapid component
of 3-10 days (50% of the drug).

 Discontinuation of the drug effects are

maintained for 1-3 months.

 Measurable tissue levels may be observed

up to 1 year after discontinuation.
 Loading dose of 10g is usually achieved
and with 0.8-1.2 g daily doses.

 The maintenance dose is 200-400 mg

daily.

 Pharmacologic effects may be achieved

rapidly by intravenous loading.
 QT-prolonging effect is modest with this
route of administration, whereas brady-
cardia and AV block may be significant.

 Amiodarone is a substrate for liver

cytochrome CYP3A4.

 The histamine H₂ blocker cimetidine.

 Drugs that induce CYP3A4, eg, rifampin,
decrease amiodarone concentration when
co administered.

 P450 enzymes and may result in high

levels of many drugs, including statins,
digoxin and warfarin.
 Warfarin should be reduced by one third
to one half following initiation of
amiodarone.

 Prothrombin time should be closely

monitored.
Therapeutic Use

 Low doses (100-200_ mg/d of

amiodarone are effective in maintaining
normal sinus rhythm in patients with atrial
fibrillation.

 The drug is effective in the prevention of

recurrent ventricular tachycardia.

 Associated with an increase in mortality

in patients with coronary artery disease or
heart failure.
Dronedarone

 Dronedarone is a structural analog of

amiodarone in which the iodine atoms
have been removed from the phenyl ring
and a methanesulfonyl group has been
added to the benzofuran ring.

 Dronedarone elimination is primarily

nonrenal.
 Tubular secretion of creatinine, resulting
in a 10-20% increase in serum creatinine;

 Dronedarone restores sinus rhythm in a

small percentage of patients (<15%) with
atrial fibrillation.

 It produces a 10 to 15 bpm reduction of

the ventricular rate compared to placebo.
SOTATOL

 Sotalol has both Beta-adrenergic receptor-

blocking (class 2) and action potential-
prolonging (class 3) actions.

 The drug is formulated as a racemic mixture

of D- and L- sotalol.

 Beta-adrenergic blocking activity resides in

the L-isomer

 the D- and L-isomers share action potential

prolonging effects.
 Sotalol is well absorbed orally with
bioavailability of nearly 100%.

 Metabolized in the liver and is not bound
to plasma proteins.

 Excretion is predominantly by the

kidneys in the unchanged form with a
half-life of approximately 12 hours.
 Torsades de pointes that approaches 6%
at the highest recommended daily dose.

 Sotalol is approved for the treatment of

life-threatening ventricular arrhythmias
and the maintenance of sinus rhythm in
patients with atrial fibrillation.
DOFETILIDE

 Dofetilide has class 3 action potential

prolonging action.

 Dose-dependent blockade of the rapid

component of the delayed rectifier
potassium current (Ikr) and the blockade
of Ikr increases in hypokalemia.
 Dofetilide is 100% bioavailable.

 Verapamil increases peak plasma

dofetilide concentration by increasing
intestinal blood flow.

 QTс of greater than 450 ms (500 ms in

the presence of an intraventricular
conduction delay)

 Bradycardia of less that 50 bpm

 Hypokalemia are relative contraindications
to its use.

 Dofetilide is approved for the

maintenance of normal sinus rhythm in
patients with atrial fibrillation.
Ibutilide

 Ibutilide, like dofetilide, shows cardiac

repolarization by blockade of the rapid
component of the delayed rectifier potassium
current.

 Slow of inward sodium current.

 Ibutilide is rapidly cleared by hepatic

metabolisim and the elimination half-life
averages 6 hours

 The metabolites are excreted by the kidney.

CALCIM CHANNEL-BLOCKING DRUGS
(CLASS 4)

 Which verapamil is the prototype, were

first introduced as anti-anginal agents and
are discussed in greater detail.
VERAPAMIL

Cardiac Effects
 Verapamil blocks both activated and
inactivated L-type calcium channels.

 Marked in tissues that fire frequently, those

that are less completely polarized at rest and
those in which activation depends exclusively
on the calcium current as the SA and AV
nodes
 Verapamil usually slows the SA node by
its direct action, but its hypotensive action
may occasionally result in a small reflex
increase of SA rate.

 Can suppress early and delayed after

depolarization and may antagonize slow
responses in severely depolarized tissue.
Extracardiac Effects

 Verapamil cause peripheral vasodilation,

which may be beneficial in hypertension
and peripheral vasospastic disorders.

 Its effects on smooth on muscle produce

a number of extracardiac effects.
Toxicity

 Verapamil’s cardiotoxic effects are dose-

related and usually avoidable.

 Verapamil’s negative inotropic effects

may limit its clinical usefulness in
diseased hearts
 Verapamil can induce AV block when used in
large doses or in patients with AV nodal
disease.

 This block can be treated with atropine and

Beta-receptor stimulants.

 Adverse extracardiac effects:

a. constipation
b. lassitude
c. Nervousness
d. peripheral edema.
Pharmacokinetics & Dosage

 Half-life of Verapamil is approximately 4-7

hours.

 Metabolized by the liver

 after oral administration, its bioavailability is

only about 20%.

 Verapamil must be administered with

caution in patients with hepatic dysfunction
or impaired hepatic perfusion.
 Verapamil dosage is an initial bolus of 5 mg
administered over 2-5 minutes, followed a
few minutes later by a second 5 mg bolus if
needed.

 Doses of 5-10 mg can be administered every

4-6 hours, or a constant infusion of 0.4
mcg/kg/min may be used.

 Effective oral dosages are higher that

intravenous dosage because of first-pass
metabolism and range from 120 mg to 640
mg daily, divided into three or four doses.
Therapeutic Use

 Supraventricular tachycardia is the major

arrhythmia indication for verapamil.

 Adenosine or verapamil are preferred over

older treatments(propranolol, digoxin,
edrophonium, vasoconstrictor agents, and
cardioversion) for termination.
 Verapamil can also reduce the ventricular
rate in atrial fibrillation and flutter (“rare
control”).

 Verapamil is occasionally useful in ventricular

arrhythmias.

 Intravenous verapamil in a patient with

sustained ventricular tachycardia can cause
hemodynamic collapse.
DILTIAZEM

 Diltiazem appears to be similar in efficacy

to Verapamil in the management of
supraventricular arrhythmias, including
rate control in atrial fibrillation.
ADENOSINE

Mechanism & Clinical Use

 Adenosine is a nucleoside that occurs

naturally throughout the body.

 Half-life in the blood is less than 10

seconds.
 Mechanism of actions involves of an
inward rectifier K† current and inhibition
of calcium current.

 Inhibits AV nodal conduction and

increases the AV nodal refractory period
but has lesser effects on the SA node.
 Adenosine is currently the drug of choice
for prompt conversion of paroxysmal
supraventricular tachycardia to sinus
rhythm of paroxysmal rhythm because of
its high efficiency (90-95%) and very
short duration of action.
 Bolus dose of 6 mg followed, if
necessary, by a dose of 12 mg.
 Drug is less effective in the presence of
adenosine receptor blockers such as
theophylline or caffeine
 Its effects are potentiated by adenosine
uptake inhibitors such as dipyridamole.
The Nonpharmacologic Therapy of Cardiac
Arrhythmias

 Radiofrequency catheter ablation or

extreme cold, cryoablation.

 Implantable cardioverter-defibrillator
(ICD), a device that can automatically
detect and treat potentially fatal
arrhythmias such as ventricular
fibrillation.
Toxicity

 Adenosine causes flushing in about 20% of

patients and shortness of breath or chest
burning (perhaps related to bronchospasm)
in over 10%.

 Induction of high grade AV block may occur

but is very short lived.

 Atrial Fibrillation may occur

 Less common toxicities include headache,

hypotension, nausea, and paresthesias.
IVABRADINE

 Localized expression of the “funny” current

If in the SA node and its important role in
pacemaker activity provides an attractive
therapeutic target for heart rate control.

 Selective blocker of If is not complete.

 It reduces heart rate without affecting

myocardial contractility in ventricular
repolarization, or intracardiac conduction.
 Patients with left ventricular dysfunctions
and heart rates greater than 70bpm,
ivabradine reduced mean heart rate and
the composite end points of
cardiovascular mortality hospitalization.

 Drug is administered in doses of 5-10 mg

as needed. Visual disturbances
attributable to the block of If channels in
the retina have been described.
Ranolazine

 Ranolazine was originally developed as

an antianginal agent.

 Ranolazine also blocks the rapid

component of the delayed rectifier K†
current Ikr the blockade of both Inal and
Ikr results in opposing effects on the APD;

 Ranolazine had been shown to have

antiarrhythmic properties in both atrial
and ventricular arrhythmias.
MAGNESIUM

 With digitalis-induced arrhythmias who were

hypomagnesemic, magnesium infusion has
been found to have antiarrythmic effects in
some patients with normal serum magnesium
levels.

 Recognized to influence sodium potassium

ATPase sodium channel and potassium
channel and calcium channels
 Magnesium therapy appears to be indicated
in patients with digitalis induced arrhythmia

 Also indicated in some patients with torsades

de pointes even if serum magnesium is
normal

 The usual dosage is 1g given IV over 20

minutes
POTASSIUM

 Resting potential depolarizing action and (2)

a membrane potential stabilizing action,

 Increased potassium permeability

 Hypokalemia results in an increased risk of

early and delayed after depolarizations, and
ectopic pacemaker activity, especially in the
presence of digitals.

 Hyperkalemia depresses ectopic pacemakers

(severe hyperkalemia is required to suppress
the SA node) and slows conductions.
PRINCIPLES IN THE CLINICAL USE OF
ANTIARRHYTHMIC AGENTS

 Pretreatment Evaluation
1. Eliminate the cause.
2. Make a firm diagnosis
3. Determine the baseline condition
• Class 1C drugs in patient with
ischemic heart disease.
4. Question the need for therapy.
Benefits & Risks

 Reduction of arrhythmia-related
symptoms , such as palpitations, syncope
or cardiac arrest; and reduction in long-
term mortality in asymptomatic patients.
Thank You!!!!