Indications: Congestive heart failure with reduced ejection fraction (HFrEF) class III and IV and atrial fibrillation/flutter.
Mechanism of Action: Inhibits sodium-potassium ATPase pump causing calcium accumulation in myocytes increasing contractile force. Inhibits AV nodal conduction and prolongation of the effective refractory period.
Onset of Action: 1-4 hours IV, 2-6 hours oral
Bioavailability (F):
Salt (S): Injection; capsules, tablets, and elixir = 1
Molecular Weight: ~ 500 Daltons
Route of Administration: IV, oral
Absorption: Upper intestinal absorption, no first-pass effect. Decreased absorption caused by:
Distribution: Lean body weight, skeletal muscle, does not distribute to fat
Peak Concentrations: Oral ~ 6-8 hours, IV immediate
Protein Binding: 10%
Metabolism: Minimal hepatic metabolism
Excretion: Renally filtered with tubular secretion, renal excretion linearly correlated with creatinine clearance, fecal excretion with enterohepatic cycling, 30-50% nonrenal, 50-70% renal
Numerous equations have been derived to calculate volume of distribution (Jusko, Paulson and Welling, Reuning, Sheiner, Williams). Similar results are obtained with Jusko, Paulson and Reuning's equations. As loading doses are calculated using Vd, Paulson's or Jusko's equation is recommended as they are more conservative with high creatinine clearance values. Vd ranges from ~ 7.3 L/kg of lean body weight to 4.8 L/kg when creatinine clearance is < 10 ml/min. The volume of distribution is decreased with renal dysfunction.
Vd(L) = [3.8 L/kg × Lean Body Weight(kg) + 3.1 × (Creatinine Clearance in ml/min)] × Multiplier
Vd(L) = [226 L/1.73m² + ((298 L/1.73m² × CrCl ml/min/1.73m²) / (29.1 ml/min/1.73m² + CrCl ml/min/1.73m²))] × (Patient Surface Area/1.73) × Multiplier
Vd(L) = (4.5 + 0.028 × CrCl ml/min/1.73m²) × Lean Body Weight (kg) × Multiplier
Digoxin has both a metabolic and renal component to clearance. Several equations have been derived to calculate clearance in patients with and without CHF. The calculated clearance values are lower in Sheiner's equations and they are recommended as the maintenance dose is determined by clearance and a more conservative dose will be calculated.
Clearance (L/hour) = [(0.8 ml/kg/min × Lean Body Weight(kg) + Creatinine Clearance(ml/min)) × 60/1000] × Multiplication Factor
Clearance (L/hour) = [(0.33 ml/kg/min × Lean Body Weight(kg) + 0.9 × Creatinine Clearance(ml/min)) × 60/1000] × Multiplication Factor
Clearance (L/hour) = [(1.303 × CrCl ml/min + 41 ml/min) × 60/1000] × Multiplication Factor
Clearance (L/hour) = [(1.303 × CrCl ml/min + 20 ml/min) × 60/1000] × Multiplication Factor
Hemodialysis: Due to digoxin's very large volume of distribution, little is removed by low and high flux hemodialysis.
K (1/hours): Volume of distribution and clearance dependent (K = Clearance / Vd)
Half-life (hours): Half-life is dependent on volume of distribution and clearance. Normal renal function 2 days, ESRD 4-6 days
Dosage Forms: Injection, tablets, capsules, and elixir
Usual Interval: Adults once daily usually in the morning. Children divided dose twice daily. Divided doses are used if a loading dose is administered (50%, 25%, and 25% of the total dose is administered 6 hours apart). Loading doses may be given IV or orally.
Note: A loading dose is not recommended in CHF but is commonly used in atrial fibrillation/flutter.
| Age | Loading Dose Intravenous (mcg/kg) Divided in 3 doses of 50%, 25%, and 25% of the total dose every 6 hours |
Maintenance Dose Intravenous (mcg/kg/day) |
|---|---|---|
| Premature Neonates less than 4 weeks | 15-25 | 4-6 divided into 2 doses |
| Full Term Neonates | 20-30 | 5-8 divided into 2 doses |
| 1 year < 2 years | 30-50 | 9-15 divided into 2 doses |
| Children 2-5 years | 25-35 | 6-9 divided into 2 doses |
| Children 5-10 years | 15-30 | 4-8 divided into 2 doses |
| Children > 10 years | 8-12 | 2-3 |
| Adults | 10-15 mcg/kg | 62.5-250 per day |
Narrow Therapeutic Window:
Serum Sampling Times: Trough levels are recommended for routine monitoring daily or every other day. Due to the long half-life, steady state achievement is delayed and serum levels will slowly rise without a loading dose.
Post-Dose Levels: Recommended no sooner than 6 hours for an IV dose and 12 hours for an oral dose. In dialysis patients, draw pre-dialysis sample or wait at least 6 hours post-dialysis for re-distribution to be complete.
Note: A wide variation in the minimal time post-dose for sampling may be found in texts; a conservative approach is recommended.
Monitoring: Renal status and serum electrolytes (Potassium, Magnesium, Calcium) should be monitored prior to and periodically during therapy.
Digoxin displays two-compartment model kinetics, with high serum levels during the distribution phase as the central compartment is 1/10 the size of the tissue compartment. The half-life of distribution is ~ 35 minutes. The heart is in the peripheral tissue compartment and the pharmacological effect is seen in a couple of hours. Tissue and central compartment levels are at equilibrium in 4-6 hours.
A linear one-compartment open model is adequate for dosage predictions when levels are drawn after an oral dose when absorption and distribution are complete. Blood levels ≥ 12 hours after a dose are recommended to ensure absorption and distribution are complete.
When levels are at steady state, doses can be adjusted proportionally to the desired concentration. Equations used to calculate Vd and Clearance noted above show a large degree of variation. Conservative dosing is recommended with serum level monitoring to individualize the patient's dose.
Avoid in:
Contraindication: Digoxin is contraindicated in patients with significant sinus or AV block unless permanent pacemaker is in place.
Toxicity Symptoms:
Important: Hypokalemia increases the cardiac effects and risk of digoxin toxicity.
Decreased Clearance: See multiplication factors in Clearance section above
Increased Clearance: See multiplication factors in Clearance section above
Decrease Clearance: CHF, Hypothyroidism
Increase Clearance: Hyperthyroidism
BMI = Actual Body Weight(kg) / (Height in meters)²
IBW(kg) Adult Males (18 years and older) = 50 kg + 2.3 × (Height in inches greater than 60 inches)
IBW(kg) Adult Females (18 years and older) = 45.5 kg + 2.3 × (Height in inches greater than 60 inches)
FFM(kg) Adult Males = [9270 × Actual Body Weight(kg)] / [6680 + (216 × BMI)]
FFM(kg) Adult Females = [9270 × Actual Body Weight(kg)] / [8780 + (244 × BMI)]
BSA (m²) = [(Weight in kg)0.425] × [(Height in centimeters)0.725] × (71.84/10000)
Dosing Weight(kg) = Lean Body Weight
Males: (140 - age(years)) × IBW(kg) / (serum creatinine(mg/dl) × 72)
Females: 0.85 × Creatinine Clearance for males
See Clearance section above
See Volume of Distribution section above
K(1/hours) = Clearance(L/hr) / Vd(L)
Loading Dose(mcg) = [Cpdesired(mcg/L) × Vd(L)] / (Salt × Fraction)
Usually divided into 3 doses of 50%, 25%, and 25% of the total dose given every 6 hours
Maintenance Dose(mcg) = [Cpaverage(mcg/L) × Tau(Hours) × Clearance(L/hr)] / (Fraction × Salt)
Cpssaverage(mcg/L) = [Salt × Fraction × Dose(mcg)] / [Clearance(L/hr) × Tau(hours)]
Cpssmaximum(mcg/L) = [Salt × Fraction × Dose(mcg)] / [Vd(L) × (1 - exp(-K × Tau))]
Cpssminimum(mcg/L) = Cpmaximum(mcg/L) × exp(-K × Tau)
Time(days) = -ln(1 - (level / Cssaverage)) / (K(1/hours) × 24)
Time(days) = -ln(1 - (Fraction of Steady State to Achieve)) / (K(1/hours) × 24)
Time(days) = ln[(1 - (Fraction of Steady State to Achieve)) / (1 - (Current Level / Steady State Level))] / (K × 24)
Cp(mcg/L) = [S × F × Dose(mcg) × (1 - Exp(-K × N × Tau)) × Exp(-K × T)] / [Vd(L) × (1 - Exp(-K × Tau))]
where N equals number of doses given