G7iii / 16B21: Classify anti-arrythmic drugs by mechanism of action, giving examples of each (75 marks). Describe the electrophysiological and ECG effects of sotalol (25 marks)

16B21: Exam Report

Classify anti-arrhythmic drugs by mechanism of action, giving examples of each (75% of marks). Describe the electrophysiological and ECG effects of sotalol (25% of marks).

88% of candidates passed this question.

Most answers displayed a good knowledge of the Vaughan Williams classification, classes I to IV and the relevant electrophysiological characteristics of the classes.

Answers should also have included mention of other antiarrhythmics, such as digoxin, magnesium and adenosine. The second part of the question required comment about K ion blockade and its effects. It was helpful to mention prolongation of QT and risk of torsade. Most answers omitted reference to its being a racemic mixture, with different actions of the isomers.

G7iii / 16B21: Compare and contrast the mechanism of action, pharmacokinetics and adverse effects of digoxin and sotalol

  • Arrhythmia = abnormal rate, generation, propagation of an AP
  • Caused by:
  1. Abnormal PM activity
  2. Abnormal impulse propagation

∴ Antiarrhythmic:

  1. ↓ectopic PM activity
  2. Modify conduction

By altering:

  1. Slope Ph 4: β-blockers, adenosine, ↑vagal tone
  2. Threshold AP: Na+ channel blockers, CCB
  3. AP duration: Na+ channel blockers, K+ channel blockers
  4. Maximum diastolic potential: adenosine by hyperpolarisation
PM Action

V – W classify antiarrhythmic in groups based on electrophysiological characteristics → based on micro-electrode studies

Class

I

SODIUM CHANNEL BLOCKERS

Example

IA – PROCAINAMIDE

IB – LIGNOCAINE

IC – FLECAINIDE

Mechanism of Action

Moderate Na+ channel block, ↑refractory period

Weak Na+ channel block, shortens AP

Strong Na+ channel block, no effect refractory period

Class

II

β-BLOCKERS

Non-selective

Selective

Intrinsic sympathomimetic activity

Example

PROPANOLOL

METOPROLOL

LABETALOL

Mechanism of Action

Antagonises effects of catecholamines at β receptors

In heart: – CHRONO, – DROMO, -INOTROPY

↓slope Ph 4 = more time to reach threshold = ↓discharge rate

Class

III

POTASSIUM CHANNEL BLOCKERS

Example

AMIODARONE

SOTALOL

Mechanism of Action

Blocks K+ channels

Prolongs refractory period of all cardiac time

Broad spectrum: blocks Na+ channel, K+ channel, Ca2+ channel & α + β adrenoreceptors

Class

IV

CALCIUM CHANNEL BLOCKERS

Example

DIHYDROPYRIDINES

BENZOTHIAPINES

PHENYLALKYLAMINES

Mechanism of Action

→ NIMODIPINE → Block Ca2+ channel of arteries

→ DILTIAZEM → AV node → inhibits inward Ca2+ current (↓rate conduction AV node)

→ VERAPAMIL → AV node → inhibits inward Ca2+ current (↓rate conduction AV node)

Class

OTHER

Example

Mechanism of Action

DIGOXIN

  1. Activates vagal nuclei = ↑ activity
  2. Inhibits Na/K/ATPase = RMP becomes less negative 2° ↑intrac. K (depol easier); AP shortens 2° ↑K conduction

ADENOSINE

A1 receptor on SA node → stimulates adenosine sensitive K+ channel → ↑K conductance = hyperpolarises – VE DROMOTROPY

MAGNESIUM

  1. Co-factor Na/K/ATPase
  2. L-type Ca2+ channel antagonist ECG prolongs R:R, ↑PR interval
  3. ↑AV conduction time

Sodium Channel Blockers

  • Inhibit Fast Na+ channel of fast AP cells
  • ↓slope of Ph 0
  • ↓amplitude AP
  • ↓conduction velocity (negative dromotrope) so that there is slower transmission of AP

→ Subdivided based on duration of AP (effect on refractory period)

IA – Procainamide

  • Moderate Na channel block
  • ↑refractory period → lengthens AP

IB – Lignocaine

  • Weak Na+ channel block
  • Shortens AP

IC – Flecainide

  • Strong Na+ channel block
  • No effect refractory period

Na+ channel block: IC > IA > IB

Lengthen AP: IA > IC > IB (decreases)

Flecainide

Beta Blockers

  • Competitive antagonists of β1/β2 adrenoreceptors
  • Antagonise effects of catecholamines
  • ↓slope of Ph 4 = more time to reach threshold = ↓discharge rate
  • – VE CHRONO, DROMO, INOTROPY

↓myocardial O2 consumption 

Potassium Channel Blockers

  • Block K+ channels responsible for repolarisation
  • Prolong AP
  • This ↑effective refractory period
  • On ECG → prolongs QT interval
Potassium Channel

Calcium Channel Blockers

  • Class 4 antiarrhythmics
  • Diverse & structurally unrelated
  • All block Ca2+ channels
  • Classified on basis of CHEMICAL STRUCTURE

Dihydropyridines → Nimodipine

  • Block Ca2+ channel of peripheral arteries
  • Via extracellular modulation of Ca2+ channel
  • Prevents Ca2+ entry into smooth m. cell

Benzothiapines → Diltiazem

  • Intermediate between the other 2
  • Predominate effect = AV NODE
  • Inhibits inward Ca2+ current
  • ↓rate conduction of AV Node → ↑PR interval

Phenylalkylamines → Verapamil

  • Predominant AV Node, SA Node
  • Physically occludes Ca2+ channel
  • ↓rate conduction → ↑PR interval

Sotalol: Electrophysiology & ECG Effects

  • Inhibits potassium channels
  • Prolongs repolarisation
  • Lengthens effective refractory period
  • Lengthens QT interval
  • ↓automaticity
  • Slows AV conduction
  • Β-blocking → competitive antagonist of β1 & β2 receptors

 ECG: ↓HR, QT prolongation