Digoxin

Chemical

A cardiac glycoside naturally occurring in many plants

  • Basic structure → steroid nucleus with a glycose & aglycone portion

Glycose → glucose → required to fixate the glycoside to cardiac muscle

Aglycone → influences PD effects

Use

  1. Treatment of heart failure
  2. Slow ventricular response rate

Dose

Load: IV 0.5mg/30mins or 10mcg/kg

Maintenance: 0.125 – 1mg/day

Route

PO/IV

Onset

IV: 15 mins

PO: 1 – 6hrs

DoA

Several days

t ½ 40hrs with normal renal function

MoA

Myocardial

Peripheral vascular effect

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

ECG Effects

ECG ∆

Prolonged PR

Mechanism

Delayed AV conduction

ECG ∆

Scooped out ST

Mechanism

↓slope Ph 3 due to ↑K conductance

ECG ∆

T waves ↓amplitude ST inversion

Mechanism

ECG ∆

Shortened QT

Mechanism

↑K conductance, shortens AP

ECG ∆

NO EFFECT QRS DURATION

Mechanism

Because digoxin doesn’t alter conduction through ventricles or conduction tissues

ECG Effect

PD

CVS

  • ↑myocardial contractility
  • ↓HR
  • ↑SVR

RENAL: ↑renal perfusion & mild diuresis

Response Variability

Elderly: ↓skeletal m. = ↓reservoir = ↑plasma levels

Renal failure: ↓dose

Ab development: ↓therapeutic effect

Drug Interactions

  1. Factors affecting absorption
  2. Factors affecting PPB

ANTIARRHYTHMICS

  • Quinidine → competes for binding sites ∴↑plasma levels
  • Amiodarone → ↓dig excretion & ↑AV block
  • Diuretics → Indirectly by affecting K+ levels
  • CCB → ↓clearance & ↑AV block
  • Β-blockers → precipitate arrhythmias
  • Potassium → & dig inhibit each other binding to Na/K/ATPase
    • ↑K = ↓effect on Na/K/ATPase
    • ↓K = ↑effect on Na/K/ATPase
  • Calcium → overloads Ca2+ stores = ↑automaticity ∴↑risk arrhythmias
  • Magnesium → opposite effect to Ca2+
  • Erythromycin → ↑GI absorption (unpredictable, not all patients)

PK

A

75% OBA

Peak plasma in 1 – 2hr

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

Adverse Effects

[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 (↑slop 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+

Tx:

  1. Stop drug
  2. Tx arrhythmia
  3. Replace electrolytes
  4. Consider DIGOXIN SPECIFIC AB’s

→ Bind dig ∴ less available to inhibit Na/K/ATPase

→ Dig-Ab complex eliminated by kidneys

Digoxin