Antiarrhythmic drugs

Question 1

What is the electrophysiology involved in the heart?

Answer 1

The myocardium is electrophysiologically distinct from other excitable tissues:

 The specialized cells of the SA node are capable of
spontaneous depolarization (automaticity) and
generation of action potentials (AP) that spread
throughout the heart (“pacemaker” activity).

 The generation and conduction of AP in SA and AV is
mainly dependent on slow Ca++ ion channels.
Absence of fast Na+ currents.

Question 2

What are the different phases of the action potential?

Answer 2

 Phase 0: rapid depolarization
- The rapid influx of Na+ through voltage-gated ion channels

 Phase 1: Rapid initial repolarization
- Rapid inactivation of the sodium channels

 Phase 2: Plateau
- The influx of Ca++ through the slow Ltype ion channel

 Phase 3: Repolarization
- Efflux of K+ from the cells

 Phase 4: Spontaneous diastolic depolarization

• Slow Na+ channels
• Influx of Ca++ through the slow Ltype ion channel

Question 3

What is the action potential in the SA node?

Answer 3

 Phase 4: Spontaneous diastolic
depolarization:
 Opening of slow Na+ channels -
"funny" currents: initiation of
depolarization
 -50mV opening of T-type Ca
channels: continuation of
depolarization
 -40 mV opening of L-type Ca
channels: continuation of
depolarization

 Phase 0: Depolarization (at
-35mV)
 Mainly caused by the influx of Ca2+
through L-тип Ca2+ канали
 The current through these channels
is slow and that is why the
depolarization is slower than in other
cardiac cells

Question 4

What are the types of action potentials in the heart?

Answer 4

Two types of AP based
on the mechanism of
depolarization:

 Dependent on “slow”
Ca++ channels (L type):
 SA node
 AV node

 Dependent on “rapid”
Na+ channels:
 Atria
 His-Purkinje fibers
 Ventricles

Question 5

What are cardiac arrhythmias?

Answer 5

 Clinically, arrhythmias are classified
according to:

- The site of their origin –
supraventricular (atrial, junctional) and
ventricular
- Whether the heart rate is increased
(tachycardia) or decreased
(bradycardia)

Question 6

What are the causes of arrhythmias?

Answer 6

 Changes in the
pacemaker activity of SA
node

 Block in the conduction of
impulses

 Ectopic foci, causing
abnormal AP favored by
 Digitalis excess
 Catecholamines
 Ischemia
 Electrolite disbalance
 Drug toxicity

 Re-entry mechanism
(“circus movement”)
 Abnormal conductance
(WPW)

Question 7

How are antiarrhythmic drugs classified? (Vaughan William’s classification)

Answer 7

Class I (sodium channel-blocking drugs)
 IA: Prolongation of repolarization
 Quinidine
 IB: Shortening of repolarization
 Lidocaine
 Phenytoin
 IC: No effect on repolarization
 Propafenone

 Class II (BABs)
 Propranolol, Metoprolol, etc.

Class III (drugs prolonging the AP) – Block K+
outward currents
 Amiodarone, Sotalol

Class IV (Non-DHP type CCBs)
 Verapamil, Diltiazem

Question 8

What are Na+ channel states?

Answer 8

resting -> activated -> inactivated

Na+ channel block:

Higher affinity of the drugs to activated and inactivated than to resting states of the channels -> selective action

Question 9

What is an example of a class IA antiarrhythmic drug? what are its clinical uses?

Answer 9

Effect of Class I on the fast cardiac action potential =
Slope of phase 0

 Quinidine
 Binds to Na+ channels; intermediate dissociation from the
channels
 Prolongs repolarization due to a certain blockade of K+
channels

Clinical use:

 Ventricular arrhythmias
 Prevention of recurrent paroxysmal atrial fibrillation
triggered by vagal overactivity
 It is now seldom used because of side effects:
 Cardiac, incl. pro-arrhythmic (QRS)
 Anti-cholinergic
 GI
 Allergic
 CNS – ‘cinchonism’

Question 10

What is an example of a class IB antiarrhythmic drug and what are its PK, PD, clinical use, and tolerability?

Answer 10

Lidocaine: the most widely used class I AAD

 PK:
 Significant first-pass metabolism
 Only given by IV bolus or infusion
 Plasma half-life ~ 2 hrs

 PD:
 Binds to Na+ channels in the open and inactivated states;
shows fast dissociation from the channels
 Only marginally affects conduction velocity; shortens AP
duration
 Effective in aborting ventricular ectopic beats, especially
in ischemia

 Clinical use: i.v. ventricular tachycardia in acute
myocardial infarction (AMI).

 Tolerability profile: safe
 CNS: drowsiness, disorientation, convulsions
 Low pro-arrhythmic potential

Question 11

What is an example of a class IC antiarrhythmic drug and what are its uses?

Answer 11

 Propafenone

 Binds to Na+ channels
 Does not influence AP duration

 Used in:
 supraventricular arrhythmias (paroxismal atrial
fibrillation)
 recurrent tachyarrhythmias associated with abnormal
conducting pathways (e.g. Wolff-Parkinson-White
syndrome).

 Side effects:
 Меtal taste, constipation
 Cardiac: pro-arrhythmic (QRS)

Question 12

What drugs affect the pacemaker activity?

Answer 12

β agonist

M-agonist, BAB, Adenosine

Question 13

What are some clinical uses of class II AADs?

Answer 13

Class II AADs (propranolol, metoprolol)
reduce mortality in patients recovering
from myocardial infarction, and should
always be considered in this setting.

 Used for prophylaxis against recurrent
tachyarrhythmias (e.g. paroxismal atrial
fibrillation) when these are provoked by
increased sympathetic activity.

Question 14

What is the effect of potassium channel blockers?

Answer 14

Prolong AP

Question 15

What is an example of class III AADs? (chemical nature, PK considerations, electrophysiology and PD effects, ADRs) - Amiodarone

Answer 15

Amiodarone

 Chemical nature:
 Contains iodine in its molecule

 PK considerations:
 May be given orally or IV (loading dose)
 Extensively bound to tissue proteins → large Vd and a long t1/2 (10-100
days), therefore slowly established steady state concentration

 Electrophysiological and PD effects
 Blocks K+ outward currents
 Prolongation of the AP and effective RP
 Some beta-adrenoblocking activity

ADRs:
Short term:
- Bradycardia
- AV block
- Hypotension

Long-term:

• Thyroid abnormalities
• pulmonary fibrosis
• corneal deposits and optic neuropathy
• photosensitivity

Therapeutic uses: highly effective in a wide variety of ventricular and
supraventricular arrhythmias

 Despite the significant prolongation of QT, ‘torsade de pointes’ syndrome is relatively seldom seen in clinics.

Question 16

What is sotalol?

Answer 16

Sotalol – combines class III with class II actions and adverse effects.

 It is used in paroxysmal supraventricular
arrhythmias.
 It suppresses ventricular ectopic beats and
short runs of ventricular tachycardia.
 It can cause ‘torsade de pointes’ and is
contraindicated in patients with asthma or
other contraindications to beta-blockade.

Question 17

What is the effect of calcium channel blockers?

Answer 17

Slope of phase 0

Question 18

What are the clinical uses of class IV AADs?

Answer 18

Non-DHP

 Verapamil is the main drug.
 Diltiazem is similar.

 They are used:

 To prevent recurrence of paroxysmal supraventricular
tachycardia

 To reduce ventricular rate in patients with atrial fibrillation
(especially if inadequately controlled with digoxin)

 They are ineffective in ventricular arrhythmias.

Question 19

What are some examples of antiarrhythmic drugs that are unclassified in Vaughan William’s system?

Answer 19

Atropine – Sinus bradycardia

 Digoxin – Atrial fibrillation

 Epinephrine – Cardiac arrest

 Adenosine – Supraventricular tachycardia

 PK: t1/2 10 sec. (it is taken up via a specific nucleoside transporter by red blood
cells and is metabolised by enzymes on the lumenal surface of vascular
endothelium. Consequently, the effects of a bolus dose of adenosine last only 20-
30 s.)

 PD:
 A1 receptor (AV node) – linked to the same cardiac potassium channel
 Hyperpolarises cardiac conducting tissue and slows the rate of rise of the
pacemaker potential
 Inhibition of AV conductance and weaker effect in the SA node

 Clinical use:
 Administered intravenously to terminate SVT

 Unwanted effects:
 Chest pain
 Shortness of breath
 Dizziness
 Nausea