This presentation gives complete in-depth information about therapeutic drug monitoring of DIGOXIN. Points covered are: 1. Basic pharmacokinetics 2. Target concentration levels 3. Dosage forms available and their bioavailability 4. Procedure to conduct TDM 5. The principle of DIGOXIN estimation 6. Interpretation of TDM results. 7. TDM algorithm

1. DIGOXIN
THERAPEUTIC DRUG MONITORING OF
© PANKHIL GANDHI

2. DOSAGE FORMS
 ORAL SOLUTION (80% BIOAVAILABLE)
 TABLET (50-90% BIOAVAILABLE)
 LIQUID FILLED CAPSULES (APPROX 100% BIOAVAILABLE)
 INTRAVENOUS (100% BIOAVAILABLE)
© PANKHIL GANDHI

3. DOSAGE REGIMEN
LOADING DOSE
750 mcg to 1.5 mg orally in single or
divided doses (6 hours apart) over 24
hours.
MAINTENANCE DOSE
62.5 to 500 mcg daily (higher doses may
be divided).
Intravenous loading dose is not recommended, as the response is no more rapid than following oral
administration.
Doses differ depending on the disease condition
© PANKHIL GANDHI

4.  STEADY STATE – ACHIEVED IN 1 WEEK (WITH NORMAL RENAL FUNCTION)
 THERAPEUTIC RANGE – 1-2 mcg/L
 TOXIC EFFECTS – (NOTED WHEN > 2mcg/L)
 GASTROINTESTINAL: NAUSEA, VOMITING, DIARRHEA OR CONSTIPATION, ABDOMINAL PAIN
 NEUROLOGICAL: HEADACHE, FATIGUE, INSOMNIA, CONFUSION, VERTIGO
 VISUAL DISTURBANCES: BLURRED VISION, COLOR CASTS AND COLORED HALOS ARE CLASSIC SIGNS OF DIGOXIN
DIGOXIN TOXICITY
 CARDIAC: BRADYCARDIA, ATRIOVENTRICULAR BLOCK, VENTRICULAR TACHYCARDIAS AND OTHER ARRHYTHMIAS
ARRHYTHMIAS
 TOXICITY IS RELATED TO DRUG CONCENTRATION BUT IS EXACERBATED BY HYPOKALEMIA (TAKE CARE WHEN
DIURETICS ARE CO-ADMINISTERED)
 AGE AND THE SEVERITY OF HEART DISEASE ARE ALSO INDEPENDENT RISK FACTORS FOR THE DEVELOPMENT OF
TOXICITY
 SEVERE TOXICITY CAN BE TREATED WITH ANTI-DIGOXIN ANTIBODIES (DIGIBIND). USE OF DIGIBIND MAY
INVALIDATE IMMUNOASSAYS
© PANKHIL GANDHI

6. PHARMACOKINETICS
 HALF LIFE – 50 - 100 HOURS
 DISPOSITION – MAINLY EXCRETED THROUGH KIDNEYS IN UNCHANGED FORM. HEPATIC
METABOLISM TO ACTIVE METABOLITES.
 VOLUME OF DISTRIBUTION – 7-8 L/kg
 PROTEIN BINDING – 25%
 PLASMA CONCENTRATION IS INCREASED BY –
 RENAL FAILURE AND HEPATIC DISEASE
 CONCURRENT USE WITH AMIODARONE, DILTIAZEM, VERAPAMIL, QUININE,
CICLOSPORIN AND POSSIBLY ATORVASTATIN
 PLASMA CONCENTRATION IS DECREASED BY –
 ANTACIDS, CHOLESTYRAMINE AND DIETARY FIBER DECREASE ABSORPTION
 ENZYME INDUCERS (EG, PHENYTOIN AND RIFAMPICIN) INCREASE NONRENAL
CLEARANCE
© PANKHIL GANDHI

7. MONITORING THERAPY
 BLOOD SHOULD BE TAKEN AT LEAST 6 H POST-DOSE TO ALLOW
DISTRIBUTION TO OCCUR AND ENSURE PLASMA CONCENTRATIONS
REFLECT TISSUE CONCENTRATION
 PLASMA DIGOXIN AND PLASMA POTASSIUM SHOULD BE MEASURED
 LOWER DIGOXIN CONCENTRATIONS ARE NOW RECOMMENDED IN
HEART FAILURE
 ENDOGENOUS SUBSTANCES MAY CROSS-REACT IN DIGOXIN
IMMUNOASSAYS (DIGOXIN-LIKE IMMUNOREACTIVE SUBSTANCES, DLIS)
AND YIELD SPURIOUSLY HIGH RESULTS. MORE PREVALENT IN THE VERY
YOUNG (PARTICULARLY NEONATES) AND THE ELDERLY. COMMERCIAL
ASSAYS VARY IN THEIR SPECIFICITY FOR DLIS
© PANKHIL GANDHI

8. DIGOXIN TEST –
ESTIMATING DIGOXIN CONCENTRATION IN SAMPLE
REACTION TIME 10 MIN
TEST PRINCIPLE KINETIC INTERACTION OF MICROPARTICLES IN
SOLUTION (KIMS)
CALIBRATION 6 POINT
SAMPLE MATERIAL SERUM, PLASMA (Li HEPARIN PLASMA AND
K2EDTA PLASMA)
SAMPLE VOLUME 5.5 uL
MEASURING RANGE 0.3-5.0 mcg/L
EXPECTED VALUE – THERAPEUTIC
EFFECTS
0.8-2.0 mcg/L
EXPECTED VALUE – ACUTE &
CHRONIC HEART FAILURE
0.6-1.2 mcg/L
© PANKHIL GANDHI

9. © PANKHIL GANDHI

10. SAMPLING
 Sampling time:
 Ideally trough sample taken immediately before next dose.
 Sample must be at least 6 hours after an oral dose and 4 to 6 hours after
an intravenous dose.
© PANKHIL GANDHI

11.  Electrolyte imbalance (decreased K+ and/or Mg2+ or raised Ca2+) can
potentiate toxicity.
 Thyroid dysfunction may alter clinical response.
© PANKHIL GANDHI

12. CONCENTRATION VS EFFECTS
 Clinically beneficial inotropic effects of digoxin are generally achieved at
steady-state serum concentrations of 0.5–1 ng/mL.
 Increasing steady-state serum concentrations to 1.2–1.5 ng/mL may provide
some minor, additional inotropic effect.
 Chronotropic effects usually require higher digoxin steady-state serum
concentrations of 0.8–1.5 ng/mL.
 Additional chronotropic effects may be observed at digoxin steady-state serum
concentrations as high as 2 ng/mL.
 Steady-state digoxin serum concentrations above 2 ng/mL are associated with
an increased incidence of adverse drug reactions.
 At digoxin concentrations of 2.5 ng/mL or above ~50% of all patients will
exhibit some form of digoxin toxicity.
© PANKHIL GANDHI

13. © PANKHIL GANDHI

14. © PANKHIL GANDHI

15. WHAT TO DO IF TARGET PLASMA
CONCENTRATION IS NOT ACHIEVED ?
 Digoxin immune Fab (Digibind) are digoxin antibody molecule segments
that bind and neutralize digoxin which can be used in digoxin overdose
situations.
 The antibody fragments are derived from antidigoxin antibodies formed in
sheep. Improvements in digoxin adverse effects can be seen within 30
minutes of digoxin immune Fab administration.
 Digoxin serum concentrations are not useful after digoxin immune Fab has
been given to a patient because pharmacologically inactive digoxin bound
to the antibody segments will be measured and produce falsely high
results.
© PANKHIL GANDHI

16.  If a patient has a subtherapeutic digoxin serum concentration in an acute
situation, it may be desirable to increase the digoxin concentration as
quickly as possible.
 A rational way to increase the serum concentrations rapidly is to
administer a booster dose of digoxin, a process also known as “reloading”
the patient with digoxin, computed using pharmacokinetic techniques.
 A modified loading dose equation is used to accomplish computation of
the booster dose (BD) which takes into account the current digoxin
concentration present in the patient:
 BD =
[(Cdesired – Cactual)VD]
Fraction of drug bioavailable
© PANKHIL GANDHI

17. TDM ALGORITHM
YES
APPROPRIATE
INDICATIONS
FOR DIGOXIN
TDM ?
YESSTEADY STATE
REACHED ? YESDISTRIBUTION
PHASE
TERMINATED ?
DIGOXIN LEVEL
MONITORING
APPROPRIATE
DIGOXIN LEVEL
MONITORING
NOT
APPROPRIATE
NO
© PANKHIL GANDHI