ANTIARRHYTHMIC DRUGS

Professor Dr Nor Azizan Abdullah

ELECTROPHYSIOLOGY OF THE HEART

Ganong’s Review of Medical Physiology, 23rd Edn.

ELECTROPHYSIOLOGY OF THE HEART

ECG: Guide to some cellular properties of

cardiac tissue

HR reflects SA node automaticity

PR-interval reflects atrial depolarisation
and AV nodal conduction time (120-200
msec.) mostly taken by this, (delayed)

QRS duration reflects ventricle
depolarisation and atrial repolarisation
(60-100 msec.)

QT interval is a measure of ventricular
depolarisation plus ventricular
repolarisation (ventricular AP duration,
360-440 msec.)
Waves of the ECG

Ganong’s Review of Medical Physiology, 23rd Edn.

 SA Node Pacemaker Potential

Phase 4: spontaneous
depolarization or pacemaker
potential

Phase 0: depolarization
• primarily caused by Ca2+
conductance (movement of Ca2+
is slow so the rate of
depolarization is slower than in
other cardiac cells)

sodium goes to

Phase 3: Repolarization the slow sodium channel

• K+ channels open
• ↑ in the outward hyperpolarizing K+ currents, at
the same time the L-type Ca2+ channels close
 Cardiac Action Potential
Phase 2 (Plateau Stage)
Phase 1(Initial Repolarization)
Cardiac cell less

Inactivation of fast Na+ permeable to Na+
channels
Ca2+ influx through slow Phase 3 (Rapid repolarization)

↑ K+ efflux Ca2+ channels
Na+ gates closed

K+ begins to leave cell
K+ efflux

Inactivation of slow Ca2+
channels

Phase 0 (Rapid Depolarization)

Phase 4

Rapid depolarization

Resting Membrane

Opening of fast Na+ Potential
channels → Na+ rushes in,
depolarization occurs
 ARRHYTHMIAS
abnormal rhythm

Abnormalities of cardiac rhythms

Rhythms that are too rapid, too slow, or asynchronous

May be clinically significant if they interfere with cardiac
function

Arrhythmias may originate in the atria, SA node or AV node →
supraventricular arrhythmias

Arrhythmias that originate from the ventricles can give rise to
life threatening ventricular arrhythmias
 ARRHYTHMIAS
Mechanisms of cardiac arrhythmias:
1. ABNORMAL IMPULSE GENERATION:
• Automatic rhythms
• enhanced normal automaticity
• abnormal automaticity (when electrical impulses arises anywhere
other than SA node, it is an abnormal or ectopic focus)
• Triggered rhythms (due to excessive Calcium)
• early-after depolarizations (abnormal upstrokes in phase 3
repolarisation)
• delayed-after depolarizations (secondary upstrokes after full
repolarisation)

2. ABNORMAL IMPULSE CONDUCTION:

• Reentry
 Antiarrhythmic Drugs

Classified according to Vaughan Williams into four classes
according to their effects on cardiac action potential

Some of the antiarrhythmic drugs are pro-arrhythmic

• to reduce ectopic pacemaker

activity/enhanced automaticity
Aim of therapy
• to modify conduction or
refractoriness in reentry circuits
 SBPC

Vaughan Williams Classification

CLASS • MAJOR ACTION

• Na+ channel blockers e.g. quinidine,

I procainamide, lignocaine, flecainide

• β-adrenoceptor antagonists e.g. propranolol,

II metoprolol (Beta blocker)

• K+ channel blockers e.g amiodarone, sotalol

III

• Calcium channel blockers, block L-type Ca2+

IV channel e.g. verapamil, diltiazem
 Class I: Sodium Channel Blocking Drugs

Slow conduction velocity membrane-stabilising effect

Prolong refractoriness and decreases formation

Decrease automaticity & conduction of electrical
for conduction problem impulses
 Class I: Sodium Channel Blocking Drugs

Block high-frequency excitation of the myocardium that occurs in
tachyarrhythmias

Bind to Na+ channels most strongly when they are in either the
open or the refractory state (inactivated): use-dependent channel
block, hence tend to block tissues that are frequently depolarised
depolarisation

Activation gate: m
Inactivation gate: h
Class I: Sodium Channel Blocking Drugs

Class 1A • Large block of open Na+ and K+

(quinidine, channels
procainamide) • Prolong APD (QT interval)
action potential duration

• High affinity for open & more so the

inactivated Na+ channels with rapid
Class 1B unbinding during diastole
(lignocaine) • Slightly shorten APD due to blocking
LA of small Na+ plateau current
• Large block of open Na+ channels
Class 1C with very slow unbinding during
diastole
(flecainide) • Minimal effects on APD
Class I: Sodium Channel Blocking Drugs

x block potassium channel,

so x prolong
 Class IA: Sodium Channel Blocking Drugs
Quinidine and Procainamide

pharmacologically similar

fallen out of favour

effect on action potential (AP) :
• Na+ channel block slows the
upstroke of the cardiac AP, slows
conduction velocity in fast response
tissues and prolongs the QRS
duration of the ECG
• also prolongs the AP duration by
blockade of K+ channels → prolong
effective refractory period
• Na+ channel–blocking properties
also result in an ↑ threshold for
excitability & ↓ automaticity
 Class IA: Sodium Channel Blocking Drugs
Therapeutic Uses:

Have a broad spectrum of anti-arrhythmic effects

Clinically available but infrequently used

Quite effective in suppressing atrial and ventricular
arrhythmias but their toxicity is quite significant
 Class IA: Sodium Channel Blocking Drugs
Quinidine

produces α-adrenergic receptor blockade and vagal inhibition
(i.v. quinidine is associated with marked hypotension and sinus
tachycardia)

Pharmacokinetics:
• well absorbed
• 80% bound to plasma proteins
• t1/2∼ 6 hr
• undergoes extensive hepatic oxidative metabolism;
3-hydroxyquinidine (active metabolite)
• potent inhibitor of hepatic CYP2D6 → drug interactions
eg: Beta blocker
 Class IA: Sodium Channel Blocking Drugs
Quinidine

Adverse effects:
Noncardiac:
• GI symptoms are most common (nausea, abdominal pain,
diarrhoea)
• immunological reaction (thrombocytopenia)
• cinchonism (headache, tinnitus) – related to elevated plasma
concentration
Cardiac:
• marked QT-interval prolongation and torsades de pointes
(occurs at therapeutic or subtherapeutic plasma
concentrations)- patients with a history of long QT, torsades, or
hypokalemia should not be treated with quinidine
 Class IA: Sodium Channel Blocking Drugs

Procainamide

Pharmacokinetics:
• available in oral & IV forms
• eliminated rapidly (t1/2, 3–4 hours) by both
(i) renal excretion of unchanged drug
(ii) hepatic metabolism - conjugation by N-acetyl transferase to
N-acetyl procainamide
 Class IA: Sodium Channel Blocking Drugs
Procainamide

Adverse effects:
• hypotension & marked slowing of conduction - major
adverse effects of high concentrations (>10 µg/mL)
• agranulocytosis
• nausea when level of N-acetyl
• torsades de pointes procainamide is high
• lupus syndrome, typically rash and arthralgias in slow-
acetylators
 Class IB: Sodium Channel Blocking Drugs

Lignocaine

blocks cardiac open Na+ channels but more so the
inactivated Na+ channels

recovery from block is very rapid at normal resting
potential more inactivated Na+ channels

exerts greater effects in depolarized (e.g. ischaemic)
and/or rapidly driven tissues

Other class IB drugs: mexilitine, tocainide
 Class IB: Sodium Channel Blocking Drugs
Lignocaine

Pharmacokinetics:
• given by i.v. infusion (not active orally because of extensive first
pass metabolism in liver)
• rapid onset of action (1-2 min) & short duration of action
• plasma t1/2 is normally ∼ 2 hr
• elimination is slowed if hepatic blood flow is ↓

Adverse effects:
• neurologic: (most common) paresthesias, tremor, nausea,
lightheadedness, hearing disturbances, slurred speech,
convulsions
• least cardiotoxic amongst Na+ blockers - proarrhythmic effects
are uncommon
 Class IB: Sodium Channel Blocking Drugs
Lignocaine

Therapeutic uses:
• Treatment of ventricular arrhythmias arising during myocardial
ischaemia or due to digoxin toxicity
• Other uses: local anaesthesia
Class IC: Sodium Channel Blocking Drugs
Flecainide, Propafenone

Potent Na+ channel blockers

Markedly slow phase 0 fast depolarization markedly slow
and slow conduction in myocardial tissue
purkinje fibre & bundle of his

Prolong PR interval

Minor effects on AP duration &
refractoriness

Reduce automaticity by increasing
threshold potential
Class IC: Sodium Channel Blocking Drugs

Propafenone has mild β-blocking properties as well

Both flecainide & propafenone are hepatically cleared

Both can cause hepatitis, nausea, emesis, altered taste

Are used in the management of atrial arrhythmias
 Class II: β-Adrenoceptor Antagonists
Adrenaline can cause arrhythmias by

↑ pacemaker current (thereby ↑ sinus rate)

↑ the slow inward Ca2+ current

Thus, β-adrenergic receptor antagonists

reduce HR

prolong AV nodal refractoriness, slow AV nodal
conduction

decrease intracellular Ca2+ overload, & inhibit
after-depolarization-mediated automaticity
 Class II: β-Adrenoceptor Antagonists
Propranolol

non-selective β-adrenoceptor antagonist

also exert Na+ channel–blocking effects at high
concentrations

Metoprolol

Selective β1-adrenoceptor antagonist
 Class II: β-Adrenoceptor Antagonists

Adverse effects:
• worsening of bronchospasm in patients with asthma,
negative inotropic effect, bradycardia, fatigue
prolong AVN refactory

Therapeutic uses:
• terminate reentrant arrhythmias that involve the AV node
• control ventricular response in atrial fibrillation or flutter high HR
• useful for preventing arrhythmias and decreasing mortality in
post-myocardial infarction patients
Class III: Action Potential Prolongation

prolong APD by blocking K+
channels involved in cardiac
repolarization →
i. seen as an increase in QT
interval on ECG
ii. increase in refractoriness
(therefore should be an
effective way of treating
reentrant tachycardias)

can paradoxically also have
proarrhythmic effects: torsade de
pointes (polymorphic form of
ventricular tachycardia)
 Class III: Action Potential Prolongation
Amiodarone

also decreases Ca2+ current & blocks inactivated Na+ channels

potently inhibits abnormal automaticity & decreases conduction
velocity

Pharmacokinetics:
• variably absorbed with a bioavailability of 35–65%
• extensively bound in tissues
• metabolized by CYP3A4 to an active metabolite (desethyl-
amiodarone)
• drug interactions: gastritis
• cimetidine inhibits CYP3A4
TB drug
• rifampicin induces CYP3A4
• long elimination t1/2 (10-100 days); ∴ need loading dose
• accumulates in the body during repeated dosing
 Class III: Action Potential Prolongation

Amiodarone
Adverse effects:
• skin rashes & slate-grey/bluish discoloration in sun-exposed
areas
• thyroid abnormalities (hypo- or hyper)
• abnormal liver function tests & hepatitis
• corneal microdeposits (after few weeks of treatment)
• fatal pulmonary fibrosis (slow in onset but may be
irreversible)
• IV amiodarone: hypotension owing to vasodilation &
depressed myocardial performance
 Class III: Action Potential Prolongation
Amiodarone

Therapeutic uses:
• broad spectrum efficacy against a wide range of
supraventricular & ventricular arrhythmias
• tachycardia associated with Wolff-Parkinson-White
syndrome
• oral therapy to maintain sinus rhythm in A-Fib or atrial
flutter
• oral therapy for patients with recurrent ventricular
tachycardia or fibrillation resistant to other drugs; but many
centres use cardioverter-defibrillator (ICD)
• i.v. for acute termination of ventricular tachycardia or
fibrillation
 Class III: Action Potential Prolongation
Sotalol

Has both potassium channel-blocking and β-blocking
activity and activity

Renal excretion

Adverse effects: associated with β-blockade,
dysrhythmogenic effects

Therapeutic uses:

prevention or management of ventricular tachycardia and
fibrillation

maintenance of sinus rhythm in patients with atrial
fibrillation similar to Amiodarone
Class IV: Calcium Channel-Blocking Drugs
Verapamil & Diltiazem

block voltage-sensitive L type Ca2+
channels (both activated and
inactivated), ∴ slow conduction in SA &
AV nodes

AV nodal ERP is prolonged & AV
conduction is slowed (PR interval ↑)

↓ Ca2+ reduces afterdepolarizations in PF
PFs purkinje fibre

Other effect: block of Ca2+ channels in

vascular smooth muscle results in
hypotension (diltiazem has relatively
more smooth muscle-relaxing effect)
 Class IV: Calcium Channel-Blocking Drugs

Pharmacokinetics:

Verapamil
• L-verapamil is a more potent calcium channel blocker than is
D-verapamil
• administration: normally by oral, IV
• plasma t1/2 ∼ 6-8 hr.
• L-enantiomer undergoes more extensive first-pass hepatic
metabolism

Diltiazem
• also undergoes extensive first-pass hepatic metabolism
 Class IV: Calcium Channel-Blocking Drugs
Verapamil & Diltiazem

Adverse effects:
• hypotension (major adverse effect, particularly with bolus
administration)
• constipation (oral verapamil)

• high doses: AV block or suppression of SA node, particularly

when used in combination with β-blockers, digoxin or other
drugs that inhibit the SA and AV nodes
 Class IV: Calcium Channel-Blocking Drugs

Therapeutic uses: Paroxysmal supraventricular tachycardia

• oral verapamil to prevent recurrence of PSVT

• I.V. verapamil or diltiazem to terminate PSVT; however
adenosine is safer
• reduce ventricular rate in atrial flutter/fibrillation provided
they do not have Wolff-Parkinson-White disorder (worsen
the arrhythmia by facilitating antegrade conduction thru’
accesory pathway/ ancillary tract leading to V-Fib)

• verapamil's negative inotropic effects limit its clinical

usefulness in diseased hearts, ∴C/I in heart failure, impaired
LV function, sick sinus syndrome, heart block
 Antiarrhythmic Drug Unclassified in the
Vaughan Williams System
Adenosine

activates Ach sensitive K+ channels & causes membrane
hyperpolarisation thru’ stimulation of A1 (G-protein coupled)
adenosine receptors →
• on SA node: slows the rate of rise of the pacemaker potential →
bradycardia
• on AV node (prolong ERP → slowing conduction)

also inhibits Ca2+ current → increase AV nodal refractoriness and
inhibits DADs elicited by sympathetic stimulation

Pharmacokinetics injection
• rapid bolus dose for efficacy
• elimination t1/2 ∼ seconds, by carrier-mediated uptake in most cell
types & subsequent metabolism by adenosine deaminase
 Antiarrhythmic Drug Unclassified in the
Vaughan Williams System
Adenosine

Adverse effects:
• short-lived
• transient asystole (lasts < 5 sec)
• flushing, sense of chest fullness & dyspnoea, dizziness &
nausea

Drug interactions:
• methylxanthines (theophylline, caffeine) block adenosine
receptors
• dipyridamole (a vasodilator & antiplatelet) blocks nucleoside
uptake mechanism, potentiating adenosine & prolonging its
adverse effects
 Antiarrhythmic Drug Unclassified in the
Vaughan Williams System

Adenosine

Therapeutic use:
• intravenously to terminate SVT (has largely replaced
verapamil)