G7iii / 19A14: Compare and contrast the MoA, PK and AE of digoxin and sotalol
19A14: Exam Report
Compare and contrast the mechanism of action, pharmacokinetics and adverse effects of digoxin and sotalol.
19% of candidates passed this question.
Good answer listed class and the multiple mechanism of action for both these antiarrhythmics, briefly outlining relevant downstream physiological effects and contrasting effects on inotropy. Clinically relevant adverse effects were frequently omitted (e.g. prolonged QT/Torsades for sotalol, hypokalaemia potentiating toxicity of digoxin).
G7iii / 19A14: Compare and contrast the mechanism of action, pharmacokinetics and adverse effects of digoxin and sotalol
Drugs
Digoxin
Sotalol
Comparison
MoA
Digoxin
Myocardial & Peripheral CVS effects
Myocardial → DIRECT → MECHANICAL
- Inhibits Na/K/ATPase (binds directly)
- ↑intrac. Na+
- ↓activity of Na+/Ca2+ exchanger
- ↑intrac. Ca2+
- Causes further release of Ca2+ from SR = ↑force of contraction
Myocardial → DIRECT → ELECTRICAL
- Inhibits Na/K/ATPase
- Which is essential for maintaining normal RMP/ion concentration
= ↑automaticity
- RMP becomes less negative (depol easier) 2° ↑intrac. K
- AP shortens 2° ↑K conductance
- ↑slope of Ph 4
- ↓slope Ph 0 because less Na gradient (this is the only ∆ that doesn’t ↑automaticity)
Myocardial → INDIRECT → ↑PARASYMP ACTIVITY
- Sensitizes CAROTID SINUS BARORECEPTORS
- Activates vagal nuclei
- Facilitates muscarinic transmission at cardiac cell
→ CHOLINERGIC INNERVATION MORE PRONOUNCED IN ATRIA →
∴ affect atria & AV node movement
- – VE CHRONO / -VE DROMO
Peripheral vascular effects
- Inhibition of Na/K/ATPase of vascular sm m → depolarization → smooth muscle contraction → VC → = ↑PreL & SVR
Sotalol
- Inhibits potassium channels
- Prolongs repolarisation
- Lengthens effective refractory period
- Lengthens QT interval
- ↓automaticity
- Slows AV conduction
- Β-blockade → competitive antagonist of β1 & β2 receptors
Sotalol has direct myocardial effects, whereas Digoxin also affects peripheral SVR
Digoxin blocks the Na/K/ATPase and increases parasympathetic activity whereas sotalol affects K channels has some beta-blocking activity
ECG
Digoxin
Prolonged PR (delayed AV conduction)
Scooped ST (↓slope Ph 3 due to ↑K conductance)
T waves ↓amplitude ST inversion
Shortens QT (↑K conductance, shortens AP)
Sotalol
↓HR, QT prolongation
Comparison
Opposite QT effects
PK
Digoxin
Note; variable drug response
Elderly: ↓skeletal m. = ↓reservoir = ↑plasma levels
Renal failure: ↓dose
Ab development: ↓therapeutic effect
A: 75% OBA, peak plasma 1-2h
D:
PPB 25%
VD 6L/kg
Tissue affinities:
- Heart → 15 – 30x plasma levels
- Skeletal m. → 50% less cardiac levels, principle reservoir
- Fat → minimal accumulation
M: minimal
E:
Excreted by kidneys unchanged
Depends on CrCl
t ½ B = 2 days!
NOT REMOVED BY DIALYSIS
Sotalol
A:
OBA 90%
D: No PPB
M No first pass effect
E:
Kidney, unchanged
T ½ 12hrs
Comparison
Dig has minimal metabolism and Sotalol has none. Both are excreted unchanged in the kidneys
Digoxin has a significant reservoir and dosage requires careful monitoring especially for high risk populations
Dig is not removed by dialysis whereas sotalol is
AE
Digoxin
[Digoxin] myocardium = much more than plasma
Monitor levels
→ 6 – 12hr post dose
→ 0.6 – 2.6nmol/L
But relationship between level & pharmacological effect not always consistent
→ <0.5nmol/L = no dig toxicity
→ >3nmol/L = definitely toxic
TOXIC EFFECTS → Na/K/ATPase inhibition
CVS
- Heart block (AV conduction delayed)
- Arrhythmias (↑slope 4, ↑Ca2+ intrac) → any arrythmia but VF most common cause of death from dig toxicity
CNS
- Insomnia
- Agitation
- Confusion
- Delirium
- Xanthopsia (seeing yellow)
GI: anorexia, N&V (stimulations CTZ)
RISK FACTORS:
- Renal impairment
- Elderly
- ↓K
- ↑Ca2+
- ↓Mg2+
Sotalol
- Bradycardia
- Heart failure
- ↓BP
- TdP (dose related)
- Bronchospasm
- Hypoglycaemia
Comparison
Dig has a much wider side effect profile, but sotalol also confers the unwanted b-blockade effects
- Author: Krisoula Zahariou