What are some symptoms associated with digoxin toxicity?
- Confusion
- Nausea, vomiting, poor appetite
- Changes in rate or rhytm of heartbeat (slow or irregular)
What is an antidote for digoxin?
Digibind
What is the mechanism of action for digoxin?
Slowing heart rate:
It inhibits the Na+/K+/ATPase pumps (highly expressed in cardiac and skeletal cells)
These pumps regulate K+ and Na+ transport in these cells
In Na+ influx into cell, Ca2+ is effluxed out by antiporter
If inhibited, Ca2+ starts to build up in cell. In muscle cells this causes contraction, slows heart beat by not relaxing as quickly for another cycle (therefore it is a positive inotrope)
What are some oral absorption PK characteristics for digoxin?
F:
- Tablets (70-80%)
- Pediatric solutions (70-85%)
- Capsule (90-100%)
Food has minimal effect
No significant first-pass effects in 90% of patients
In 10% of patients, GI metabolism by hydrolysis or reduction
What are some drug interactions associated with digoxin?
- Kaolin-pectin (diarrhea treatment) decreases F by 62% (separate dose by 2h)
- Antacids decrease F by 25-35%
- Cholestyramine decreases F by 20-35% (separate doses by 8h)
- High fibre decreases F
- Metoclopramide increases GI motility and decreases F
What compartment model is digoxin most similar to?
two-compartment model
What are the Vd values of digoxin for adults, children, and neonates?
Vd (adults): 7.3L/kg (large due to Na+/K+/ATPase distribution)
Obese: use IBW
Vd (children): 16L/kg
Vd (neonates): 7.5 to 10L/kg
Distribution phase lasts 6 to 8 hours
What are some plasma protein binding characteristics of digoxin?
Binds to albumin
fu(b)=0.7-0.8 in adults
Changes in fu(b) is not clinically significant (changes in Css total, but not Css free)
What are some tissue distribution characteristics of digoxin?
Significant distribution to skeletal and cardiac muscle because high concentration of Na+/K+/ATPase pumps
Vd not influenced by obesity
Review slide 12 for all of the factors that can impact digoxin Vd
What are some hepatic clearance characteristics of digoxin?
1/3 of dose is hepatically cleared
- BIliary excretion by P-gp
- GI breakdown in 10% of patients
What are some renal clearance characteristics of digoxin?
2/3 of dose is renally excreted
Pushed out of the body by glomerular filtration and tubular secretion
What are some types of digoxin toxicities?
- Cardiac (major toxicity): 70-90%
- Sinus bradycardia, AV block, SA block
- Premature ventricular contractions can occur too - GI: 50-70%
- N, V, D, feeding intolerance, abdominal pain - Ocular (classic symptoms of digoxin toxicity)
- Blurred vision (yellow or green halos) - CNS
- Drowsiness, fatigue, lethargy
- Confusion and dizziness - Misc.
- Hyperkalemia with acute toxicity
What are some factors that impact digoxin response?
Mineral status
- Hypokalemia, Hypomagnesaemia and hypercalcemia (enhance digoxin effects and even toxicity)
Age
- Higher dose in young due to higher Cls
- Lower dose in elderly due to increased sensitivity
Thyroid
- HypoT4 (decrease Cls)
- HyperT4 (increase Cls)
Cor Pulmonale
- Increased toxicity due to arterial hypoxia
Nature and Severity of Heart Disease
- Increased sensitivity with CAD
- Decreased sensitivity with tolerance (Afib)
What are some factors that influence digoxin systemic clearance?
Renal dysfunction (decreases Clh and Clr)
Not significantly eliminated by dialysis
Thyroid disease
- HypoT4 (decrease Cls)
- HyperT4 (increase Cls)
Obesity (decreases Clh and Clr)
Congestice Heart Failure (Decreases Clh and Clr)
Review slide 19 for the degree to which certain drugs can influence Cls of digoxin
What are the three types of digoxin analyses?
- Radioimmunoassay
- Enzyme-immunoassay (EMIT)
- Fluorescence polarization immunoassay
An issue with all three is low specificities as they pick up DLIS as digoxin
What are DLIS?
Digoxin-like Immunoreactive Substances (DLIS)
They are endogenous substances that are present at detectable levels in digoxin-free patients
ex. Renal failure, hepatic failure, low renin HTN, pregnant women (3rd trimester), neonates, infants
What are some indications for TDM in digoxin therapy?
- Confirmation of toxicity
- Assessing effect of facttos altering PK
- Therapeutic failure
- Medication compliance
What are some issues with TDM of digoxin therapy?
- Correlation between Cp and response is not great (due to issues in assay specificity)
- Variation in respinse due to alterations in serum electrolytes
- Assay not specific
- Dosage adjustment difficult because of fixed tablet strength (not a lot of choices)
What is the therapeutic range for digoxin?
CHF: 1.0-2.5 nmol/L (0.5-1.0 ng/mL)
- At higher therapeutic dose, 50% of patients exhibit toxicity
Afib: 1.5-2.0 or 2.5ng/mL (rely on patient response)
What are the population PK parameters of digoxin?
Vd: (7.3L/kg)
t1/2: 36 +/- 8 hours
Cls: 1.303 * ClCr + Clnr
F(elixir or capsule) = 0.8-0.85
F(tab)= 0.62 to 0.7
