Antiarrhythmic Drugs 2

Associate Professor
Dr. Col. Azmat Ali
Sitara-e-Imtiaz (Military)
 Classification of supraventricular
tachyarrhythmias
• Automatic arrhythmias
• Some atrial tachycardias associated with acute medical conditions
• Some multifocal atrial tachycardias
• Reentrant arrhythmias
• SA nodal reentrant tachycardia
• Intra-atrial reentrant tachycardia
• Atrial flutter and atrial fibrillation
• AV nodal reentrant tachycardia
• Macroreentrant (bypass-mediated) reentrant tachycardia
• Triggered arrhythmias (probable mechanism)
• Digitalis-toxic atrial tachycardia
• Some multifocal atrial tachycardias
• SA, sinoatrial; AV, atrioventricular.
 Classification of ventricular
tachyarrhythmias
• Automatic arrhythmias
• Some ventricular tachycardias associated with
acute medical conditions
• Acute myocardial infarction or ischemia
• Electrolyte and acid–base disturbances or
hypoxia
• High sympathetic tone
 Reentrant arrhythmias
• Ventricular tachycardia and fibrillation
associated with some chronic heart diseases
• Previous myocardial infarction
• Dilated cardiomyopathy
• Hypertrophic cardiomyopathy
• Channelopathies
 Triggered arrhythmias (probable
mechanism)
• Pause-dependent torsades de pointes (EADs)
associated with drugs that prolong QT interval
• Catechol-dependent torsades de pointes
(DADs) associated with digitalis toxicity or
idiopathy
• Brugada syndrome and SUNDS.
 Antiarrhythmic Therapy
• Antiarrhythmic drug therapy can have two
goals:
• termination of an ongoing arrhythmia
• or prevention of an arrhythmia.
• Unfortunately, antiarrhythmic drugs not only
help to control arrhythmias but also can cause
them, especially during long-term therapy.
• .
Vaughan-Williams classification system
of antiarrhythmic drugs

• Class I: Sodium-channel-blocking drugs

Class IA: Moderately slow conduction and
moderately prolong action potential
duration
Quinidine
Procainamide
Disopyramide
• Class IB: Minimally slow conduction and
shorten action potential duration
Lidocaine
Mexiletine
Tocainide
Phenytoin
• Class IC: Markedly slow conduction and
minimally prolong action potential
duration
Flecainide
Encainide
Propafenone
Moricizine*
• Class II: Beta-blocking drugs.
• Esmolol
• Mtoprolol
• Propraolol
• Class III: Prolong action potential duration
Amiodarone
Sotalol
Ibutilide
Dofetilide
 .
• Class IV: Calcium-channel-blocking drugs
• Diltiazem
• Verapamil
 Other anti arrhythmic Drugs
• Adenosine
• Digoxin
 Sicilian Gambit scheme

• In 1990, a group of eminent electrophysiologists retreated to

Taormina, Sicily, to consider the issue of the classification of
antiarrhythmic drugs because of the well-recognized limitations of
the Vaughan-Williams scheme:
• the oversimplification of concepts about antiarrhythmic drugs,
• the common grouping of drugs with dissimilar actions,
• the inability to group certain drugs accurately,
• and the
failure to take into account many actions of antiarrhythmic drugs
that became recognized only long after the Vaughan-Williams
system had been proposed.
SICLIAN –GAMBIT SCHEME
SICLIAN –GAMBIT SCHEME
 QUINIDINE
• Quinidine) is the dextroisomer of quinine and was one of
the first clinically used antiarrhythmic agents.
• Due to the high incidence of ventricular proarrhythmia.
and numerous equally efficacious agents, quinidine is now
used sparingly.
• Quinidine shares all of the pharmacological properties of
quinine, including anti-malarial, antipyretic, oxytocic, and
skeletal muscle relaxant actions.
 Electrophysiological
action
• SA node and atrial tissue
• At low concentrations a slight increase in heart rate results from the
anticholinergic effects while at higher concentrations spontaneous diastolic
depolarization is
slowed.
• Quinidine slows the Vmax of phase 0 slowing conduction through all tissue.
• Quinidine also has “local anesthetic” properties.
AV node:
• The anti-cholinergic effect of quinidine enhances conduction through the AV node.

• Quinidine’s direct electrophysiological actions on

the AV node decreases conduction
• His-Purkinje system and ventricular muscle:
Quinidine decreases the slope of phase 4
depolarization, inhibiting automaticity.
• Depression of automaticity in the His-Purkinje system
is more pronounced than depression of SA node
pacemaker cells.
• Quinidine also prolongs repolarization in ventricular
muscle resulting in an increase in the duration of the
action potential and QT interval on ECG a result of
blocking the delayed rectifier potassium channel (IKr).
 Electrocardiographic Changes.

• Quinidine prolongs the PR, QRS, and QT intervals.

• QRS and QT prolongation is more
pronounced than with other antiarrhythmic
agents.
• The magnitude of prolongation is directly related
to the plasma concentration of the drug.
• Hemodynamic Effects. Myocardial depression is not a
problem in patients with normal cardiac function while
patients with compromised myocardial function may
experience a decrease in cardiac function.
• Quinidine relaxes vascular smooth muscle
direct ly as well as indirectly by inhibition of alpha-1-
adrenoceptors.
• Pharmacokinetics. Quinidine has nearly
complete oral bioavailability with an onset
of action within 1–3 hours,
• and peak effect within 1–2 hours.
• The plasma half-life is 6 hours with primarily
hepatic metabolism.

• Therapeutic serum concentrations are 2–

4 µg/mL
 CLinical Uses
• The use of quinidine is limited by the poor side effect
profile and the availability of equally or more efficacious
agents.
• Quinidine may be used in combination with other agents
such as mexilitine for the control of ventricular,arrhythmias.
.
• Since Currently, the inclusion of quinidine
should be limited to patients with ICDs due to
the significant risk of pro-arrhythmia.
• More recently, it may be useful in the patients with
short QT syndrome
• Adverse Effects. The most common adverse
effects are diarrhea, upper-gastrointestinal
distress, and light-headedness.
• Other relatively common adverse effects include
fatigue, palpitations, headache, angina-like
pain, and rash.
• These adverse effects are dose-related and
reversible with cessation of therapy.
• Thrombocytopenia may also occur
• The cardiac toxicity of quinidine includes AV and
intraventricular block, ventricular
tachyarrhythmias, and depression
of myocardial contractility.
• Ventricular proarrhythmia with loss of
consciousness, referred to as “quinidine
syncope,” is more common in women and may
occur at therapeutic or subtherapeutic plasma
concentrations
• Large doses of quinidine can produce
a syndrome known as cinchonism,which is
characterized by ringing in the ears, headache,
nausea, visual disturbances or blurred vision,
disturbed auditory acuity, and vertigo.
• Larger doses can produce confusion, delirium,
hallucinations, or psychoses.
• Quinidine can also
cause hypoglycemia
• Contraindications. One absolute contraindication is
• complete AV block with junctional or idioventricular escape rhythm
that may be suppressed leading to cardiac arrest.
• Persons with congenital QT prolongation may develop torsades de
pointes and should not be exposed to quinidine.
• Owing to the negative inotropic action of quinidine, the drug is
contraindicated in congestive heart failure and
hypotension.
• Digitalis intoxication and hyperkalemia accentuate the effect of
quinidine on conduction velocity.
• The use of quinidine and quinine should be avoided in patients who
previously have previously shown evidence of quinidine-induced
thombocytopenia.
 Drug Interactions
• . Quinidine increases the plasma concentrations of digoxin,
requiring a downward adjustment in the
digoxin dose.
• Drugs that inhibit the hepatic metabolism of quinidine and
increase the serum concentration include acetazolamide,
certain antacids (magnesium hydroxide and
calcium carbonate),
• Cimetidine. Phenytoin, rifampin, and barbiturates increase
the hepatic metabolism of quinidine and reduce
its plasma concentrations.
 PROCAINAMIDE-Cardic Effects
• By blocking sodium channels, procainamide slows the upstroke of the
action potential,
• slows conduction,
• and prolongs the QRS duration of the ECG.
• The drug also prolongs the APD (a class 3 action) by nonspecific blockade
of potassium
channels.
• The drug may be somewhat less effective than quinidine in suppressing
abnormal ectopic pacemaker activity but more effective in blocking
sodium channels in depolarized cells.
• Procainamide has direct depressant actions on SA and AV nodes, and
these actions are only slightly counterbalanced by
drug-induced vagal block.
 Extracardiac Effects

• Procainamide has ganglion-blocking properties. This

action reduces peripheral vascular resistance and can
cause
hypotension, particularly with intravenous use.
However, in therapeutic concentrations, its peripheral
vascular effects are
less prominent than those of quinidine. Hypotension is
usually associated with excessively rapid procainamide
infusion or
the presence of severe underlying left ventricular
dysfunction.
 Toxicity

• Procainamide’s cardiotoxic effects include

excessive action potential prolongation,
• QT-interval prolongation,
• Induction of torsades de pointes arrhythmia and
syncope.
• Excessive slowing of conduction can also occur.
• New arrhythmias can be precipitated.
• A troublesome adverse effect of long-term procainamide therapy is a syndrome
resembling lupus erythematosus and
usually consisting of arthralgia and arthritis.
• In some patients, pleuritis, pericarditis, or parenchymal pulmonary disease also
occurs.
• Renal lupus is rarely induced by procainamide.
• During long-term therapy, serologic abnormalities (eg,
increased antinuclear antibody titer) occur in nearly all patients, and in the
absence of symptoms, these are not an indication
to stop drug therapy.
• Approximately one third of patients receiving long-term procainamide therapy
develop these
reversible lupus-related symptoms.
• Other adverse effects include nausea and diarrhea (in about 10% of cases), rash,
fever, hepatitis (< 5%), and agranulocytosis (approximately 0.2%).
 Pharmacokinetics

• Procainamide can be administered safely by intravenous and intramuscular routes

and is well absorbed orally.
• A metabolite (N-acetylprocainamide, NAPA) has class 3 activity.
• Excessive accumulation of NAPA has been implicated in
torsades de pointes during procainamide therapy, especially in patients with renal
failure.
• Some individuals rapidly acetylate procainamide and develop high levels of NAPA.
• Half-life is only 3–4 hours,
• NAPA is eliminated by the kidneys. it is important to measure plasma levels
of both procainamide and NAPA, especially in patients with circulatory or renal
impairmen
 DOSAGE
•
If a rapid procainamide effect is needed, an intravenous
loading dose of up to 12 mg/kg can be given at a rate of 0.3
mg/kg/min or less rapidly.
• This dose is followed by a maintenance dosage of 2–5
mg/min, with careful monitoring of plasma levels. The risk
of gastrointestinal (GI) or cardiac toxicity rises at plasma
concentrations greater than 8 mcg/mL or NAPA
concentrations greater than 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.
• However, many clinicians attempt to avoid longterm
therapy because of the requirement for frequent dosing
and the common occurrence of lupus-related effects.
Procainamide is the drug of second or third choice (after
lidocaine or amiodarone) in most coronary care units for
the treatment of sustained ventricular arrhythmias
associated with acute myocardial infarction.
 LIDOCAINE (SUBGROUP 1B)

• Lidocaine has a low incidence of toxicity and a

high degree of effectiveness in arrhythmias
associated with acute myocardial infarction.
• It is used only by the intravenous route.
 Electrophysiological Actions

• SA node and atrium: At therapeutic doses (1–5 mg/kg),

lidocaine has no effect on the sinus rate and weak effects
on atrial tissue.
AV node: Lidocaine has minimal effects on
the conduction velocity and ERP of the AV node.
His-Purkinje system and ventricular muscle: Lidocaine
reduces membrane responsiveness and decreases
automaticity.
• Lidocaine in very low concentrations slows phase 4
depolarization in Purkinje fibers.
• In higher concentrations, automaticity may be suppressed,
and phase 4 depolarization eliminated.
 Electrocardiographic Changes.

• The PR, QRS, and QT intervals are usually

unchanged, although the QT interval may be
shortened in some patients.
• The paucity of electrocardiographic changes reflects
lidocaine’s lack of effect on healthy myocardium and
conducting tissue.
• Hemodynamic Effects. At usual doses,
lidocaine does not depress myocardial function, even in the
face of CHF.
 Toxicity

• Lidocaine is one of the least cardiotoxic of the currently

used sodium channel blockers. Proarrhythmic effects,
including SA node arrest, worsening of impaired
conduction, and 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.
•
 Neurological
• Paresthesias, tremor, nausea of central origin,
lightheadedness, hearing disturbances, slurred
speech, and convulsions.
• These occur most commonly in elderly or
otherwise vulnerable patients or when a bolus of
the drug is given too rapidly.
• The effects are dose-related and usually short-
lived; seizures respond to intravenous diazepam.
• In general, if plasma levels above 9
mcg/mL are avoided, lidocaine is well tolerated.
 Pharmacokinetics & Dosage

• Because of its extensive first-pass hepatic metabolism, only 3% of

orally administered lidocaine appears in the plasma.
Thus, lidocaine must be given parenterally
• Lidocaine has a 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) should be followed by a
maintenance infusion of 2–4 mg/min to achieve a therapeutic
plasma level of 2–6 mcg/mL.
• Determination of lidocaine plasma levels is of great value in
adjusting the infusion rate. Occasional patients with myocardial
infarction or other acute illness require (and tolerate) higher
concentrations. This may be due to increased plasma α1-acid
glycoprotein, an acute phase reactant protein that binds lidocaine,
making less free drug available to exert its pharmacologic effects.
 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.
• However, routine prophylactic use of lidocaine in this setting may actually
increase total mortality, possibly by increasing the incidence of asystole,
and is not the standard of care.
• Lidocaine’s use has decreased as amiodarone
is frequently being used primarily for post-
operative ventricular ectopy.
 Contraindications.

• Contraindications
include hypersensitivity to local anesthetics
of the amide type (a very rare occurrence),

• severe hepatic dysfunction or

• a previous history of grand mal seizures due to lidocaine.
• Care must be used in the presence of
second- or third-degree heart block as it may
increase the degree of block and abolish all
idioventricular pacemakers.
 Drug Interactions.

• Ranitidine, may cause an increase in the

plasma concentration of lidocaine.
• The myocardial depressant effect of lidocaine
is enhanced by phenytoin administration.
 AMIODARONE

• Cardiac Effects

Amiodarone markedly prolongs the action

potential duration (and the QT interval on the
ECG) by blockade of IKr. During chronic
administration, IKs is also blocked.
• The action potential duration is prolonged
uniformly over a wide range of heart rates; that
is, the drug does not have reverse use-dependent
action
• In spite of its present classification as a class 3 agent,
amiodarone also significantly blocks inactivated sodium
channels.
• Its action potential prolonging action reinforces this effect.
• Amiodarone also has weak adrenergic and calcium channel
blocking actions.
• Consequences of these actions include slowing of the
heart rate and atrioventricular node conduction.
• The broad spectrum of actions may account for its
relatively high efficacy and low incidence of torsade de
pointes despite significant QT interval prolongation.
 Extracardiac Effects

• Amiodarone causes peripheral vasodilation.

This action is prominent following intravenous
administration and may be related to the
action of the vehicle.
 Toxicity
cardic
• Amiodarone may produce symptomatic
bradycardia and heart block in patients with
preexisting sinus or atrioventricular node disease.
EXTRACARDIAC
Amiodarone accumulates in many tissues,
including the heart (10-50 times greater than
plasma), lung, liver, and skin, and is concentrated
in tears. Dose-related pulmonary toxicity is the
most important adverse effect. Even on a low
dose of £ 200 mg/d, fatal pulmonary fibrosis may
be observed in 1% of patients
• Abnormal liver function tests and hepatitis may
develop during amiodarone treatment.
• The skin deposits result in a photodermatitis and a
gray-blue skin discoloration in sun-exposed areas, eg,
the malar regions.
• After a few weeks of treatment, asymptomatic corneal
microdeposits are present in virtually all patients
treated with amiodarone.
• Halos develop in the peripheral visual fields of some
patients.
• sssssssssssssssssssssssRarely, an optic neuritis may
progress to blindness.
• 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
CLASS III: POTASSIUM CHANNEL BLOCKERS

• Drugs that prolong effective refractory period by

prolonging action potential
• Prolong AP by blocking K+ channels in cardiac
muscle (↑ inward current through Na+ & Ca++
channels)
• Quinidine & Amiodarone → prolong AP duration
• Bretylium & Sotalol → prolong AP duration & refractory
period
• Ibutilide & Dofetilide → “pure” class III agents
• Reverse use-dependence
CLASS III: POTASSIUM CHANNEL BLOCKERS

BRETYLIUM
• Antihypertensive
• Interferes with neuronal release of catecholamines
• With direct antiarrhythmic properties
• Lengthens ventricular AP duration & effective refractory
period
• Markedly ↑ strength of electrical stimulation needed to
induce V.fib. & delays onset of fibrillation after acute
coronary ligation
• (+) inotropic action
CLASS III: POTASSIUM CHANNEL BLOCKERS

BRETYLIUM
• Intravenous administration
• Dosage: 5 mg/kg
• Tptic Use: ventricular fibrillation
• In emergency setting, during attempted resuscitation
from ventricular fibrillation when lidocaine &
cardioversion have failed
• S/E: postural hypotension***
ppt. ventricular arrhythmia
nausea & vomiting
CLASS III: POTASSIUM CHANNEL BLOCKERS

SOTALOL
• Nonselective beta-blocker that also slows repolarization
& prolongs AP duration
• Effective antiarrhythmic agent
• Used in supraventricular & ventricular arrhythmias in
pediatric age group
• Renal excretion
• Dosage: 80 – 320 mg bid
• Toxicity: torsades de pointes
beta-blockade symptoms
CLASS III: POTASSIUM CHANNEL BLOCKERS

IBUTILIDE
• Slows repolarization
• Prolong cardiac action potentials
• MOA: > enhance inward Na+ current
> by blocking Ikr-
> both
• routes: Oral, IV (1 mg over 10min)
• Clin. Uses: atrial flutter, atrial fibrillation
• Toxicity: Torsades de pointes
CLASS III: POTASSIUM CHANNEL BLOCKERS

DOFETILIDE

• A potential Ikr- blocker

• Dosage: 250-500 ug bid
• Clin. Uses: Atrial flutter & fibrillation
• Renal excretion
• Toxicity: Torsade de pointes
CLASS IV: CALCIUM CHANNEL BLOCKERS

VERAPAMIL
• Blocks both activated & inactivated calcium channels
• Prolongs AV nodal conduction & effective refractory
period
• Suppress both early & delayed afterdepolarizations
• May antagonize slow responses in severely depolarized
tissues
• Peripheral vasodilatation → HPN & vasospastic disorders
CLASS IV: CALCIUM CHANNEL BLOCKERS

VERAPAMIL
• Oral administration → 20% bioavailability
• t½ = 7 hrs
• Liver metabolism
• Dosage:
IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/min
Oral: 120-640 mg daily, divided in 3-4 doses
• Tptic use: SVT, AF, atrial fib, ventricular arrhythmias
• Toxicity: AV block, can ppt. sinus arrest
constipation, lassitude, nervousness,
peripheral edema
CLASS IV: CALCIUM CHANNEL BLOCKERS

DILTIAZEM & BEPRIDIL

• Similar efficacy to verapamil in
supraventricular arrhythmias & rate
control in atrial fibrillation
• Bepridil
AP & QT prolonging action→ ventricular
arrhythmias but may ppt. torsade de pointes
Rarely used → primarily to control refractory
angina
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

DIGITALIS

• Indirectly alters autonomic outflow by

increasing parasympathetic tone &
decreasing sympathetic tone
• Results in decreased conduction time &
increased refractory period in the AV node
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

ADENOSINE

• A nucleoside that occurs naturally in the body

• t½ ≈ 10 seconds
• MOA: enhances K+ conductance & inhibits cAMP-
induced Ca++ influx → results in marked
hyperpolarization & suppression of Ca++-dependent AP
• IV bolus: directly inhibits AV nodal conduction & ↑ AV
nodal refractory period
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

ADENOSINE
• DOC for prompt conversion of paroxysmal SVT to sinus
rhythm due to its high efficacy & very short duration of
action
• Dosage: 6-12 mg IV bolus
• D/I:
theophylline, caffeine – adenosine receptor
blockers
Dipyridamole – adenosine uptake inhibitor
• Toxicity: flushing, SOB or chest burning, atrial
fibrillation, headache, hypotension, nausea,
paresthesia
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

MAGNESIUM

• Effective in patients with recurrent

episodes of torsades de pointes (MgSO4 1
to 2 g IV) & in digitalis-induced arrhythmia
• MOA: unknown → influence Na+/K+
ATPase, Na+ channels, certain K+ and
Ca++ channels
 MISCELLANEOUS ANTIARRHYTHMIC AGENTS

POTASSIUM
• Therapy directed toward normalizing K+ gradients & pools in
the body
• Effects of increasing serum K+:
1. resting potential depolarizing action
2. membrane potential stabilizing action
• Hypokalemia:
 ↑ risk of early & delayed afterdepolarization
 ↑ ectopic pacemaker activity esp if (+) digitalis
• Hyperkalemia:
 Depression of ectopic pacemakers
 Slowing of conduction
 Principles in the Clinical Use of Antiarrhythmic Agents

Pretreatment Evaluation:
1. Eliminate the Cause
2. Make a firm Diagnosis
3. Determine the baseline conditions
4. Question the need for therapy
Benefits and Risks:
1. Reduction of arrhythmia related symptoms such as
palpitation, syncope or cardiac arrest.
2. Reduction in long term mortality in asymptomatic patients.
Conduct of Antiarrhythmic Therapy:
 TORSADE DE POINTES
Treatment

• Discontinue causative medication

• Correct hypokalemia & hypomagnesemia
• Give magnesium 1-2 grams IV
• To prevent subsequent episodes, increase
heart rate until cause of TdP is corrected
and/or cleared from the body
– Temporary pacemaker
– Isoproterenol
Cardioversion is only indicated when patient
becomes hemodynamically compromised
 TORSADE DE POINTES
Cardiovascular Agents

Type IA
– Quinidine
– Procainamide
– Disopyramide
Type III
– Sotalol
– Dronedarone
– Ibutilide
– Dofetilide
Ranolazine
TORSADE DE POINTES
Antimicrobials

Pentamidine
Macrolides
– Erythromycin & Clarithromycin
Ketolides
– Telithromycin
Fluoroquinolones
– Moxifloxacin
 TORSADE DE POINTES
Non-Cardiovascular Agents
Antipsychotics Methadone
Antidepressants Chloral hydrate
Vasopressin Triptans
Tacrolimus Cyclobenzaprine
Droperidol Apomorphine
Tamoxifen Vardenafil
Posaconazole
 TORSADE DE POINTES
Discontinued Agents

Terfenadine/Astemizole
Cisapride
Gatifloxacin/Grepafloxacin/Sparfloxacin
Probucol
Bepridil
 TORSADE DE POINTES
Treatment

• Discontinue causative medication

• Correct hypokalemia & hypomagnesemia
• Give magnesium 1-2 grams IV
• To prevent subsequent episodes, increase
heart rate until cause of TdP is corrected
and/or cleared from the body
– Temporary pacemaker
– Isoproterenol
Cardioversion is only indicated when patient
becomes hemodynamically compromised