This document discusses therapeutic drug monitoring (TDM) of drugs used to treat cardiovascular diseases, with a focus on digoxin. It provides details on the indications, pharmacokinetics, and appropriate use of TDM for digoxin including confirming toxicity, assessing factors that alter pharmacokinetics, addressing therapeutic failure, and ensuring medication compliance. The document also discusses dose adjustment and interpreting digoxin concentrations in the context of the clinical situation.

1. TDM OF DRUGS USED
IN CARDIOVASCULAR
DISEASE
DR. RAMESH BHANDARI
ASST. PROFESSOR
DEPARTMENT OF PHARMACY PRACTICE
KLE COLLEGE OF PHARMACY, BELAGAVI

2. Dr.
Ramesh
Bhandari
INTRODUCTION
Cardiovascular drugs are primarily used for the treatment of
cardiovascular diseases like angina, arrhythmias and heart failure.
Digoxin used in congestive cardiac failure is therapeutically
monitored.
Following drugs also can be therapeutically monitored:
Disopyramide
Lidocaine
Flecainide

3. Dr.
Ramesh
Bhandari
TDM OF DIGOXIN
In 1785, Sir William withering published the first account of
digitalis in cardiovascular medicine.
Since that time, digoxin has been used in systolic heart failure or
Heart Failure and controlling ventricular response in atrial fibrillation
and flutter.
Digoxin’s positive inotropic effects were thought to result
primarily from inhibition of the sodium potassium ATPase Pump
and use in atrial fibrillation is due to enhancement of afferent
inhibitory activity and diminishes sympathetic nervous system.

4. Dr.
Ramesh
Bhandari
TDM OF DIGOXIN
It’s been more than 30 years since TDM was introduced
for digoxin and resulted in a marked reduction in the
digoxin toxicity.
Despite a long experience of TDM with this drug, the way
in which TDM is performed is often inappropriate. Hence
these problems most likely relate to a lack of knowledge
about the practice of digoxin TDM.

5. Dr.
Ramesh
Bhandari
General pharmacokinetics of DIGOXIN
Distribution: Highly distributed to lean organ tissues (Heart, muscle,
Kidney and liver)
Elimination: Renal- 50-70%
Non –renal 30-50% (Mainly through biliary and Intestinal
tracts)
Protein binding: 20-30% (Reduced during hypoalbuminemia but not
clinically significant)
Volume of distribution: Adults 6.7±1.4L/kg (varies according to age)
Half life: Adults – 36±8 hours

6. Dr.
Ramesh
Bhandari
INDICATIONS FOR TDM OF DIGOXIN
Confirmation of toxicity
Assessing the effect of factors altering
pharmacokinetic
Therapeutic Failure
Medication Compliance

7. Dr.
Ramesh
Bhandari
CONFIRMATION OF TOXICITY
Need to measure digoxin concentration for confirmation of toxicity is
related to low therapeutic index of digoxin.
Recommended therapeutic range is 0.5-2.0 ng/l.
Toxicity occurs with serum concentration over 2.0 ng/l and is invariable
once the concentration exceeds 3.0 ng/l.
Symptoms include: Nausea, vomiting, abdominal pain, diarrhoea,
confusion, dizziness, agitation, arrhythmias, heat block and various visual
symptoms.
Toxicity is a clinical diagnosis supported by an increase digoxin
concentration but clinical suspicion of toxicity correlates poorly with high
concentration.

8. Dr.
Ramesh
Bhandari
ASSESSING THE EFFECT OF FACTORS
ALTERING PHARMACOKINETICS
Various factors influence the pharmacokinetics of digoxin in an
individual, but renal function is the major contributor.
Maintenance dose estimation based on calculation of the patient’s
creatinine clearance using the Cockcroft and Gault equation will
usually result in appropriate dose in most patients.
However, renal function alone does not explain all the variances
in serum digoxin concentration.
Some of the unpredictable relationship between dose and serum
concentration of digoxin may be explained by genetic
polymorphism of the p-glycoprotein gene.

9. Dr.
Ramesh
Bhandari
ASSESSING THE EFFECT OF FACTORS
ALTERING PHARMACOKINETICS
P-glycoprotein is involved in the transport of digoxin into the
body in the GIT and out of the body in the renal tubules.
Mutation within these genes have been shown to alter the
bioavailability and renal clearance of digoxin.
Drug Interaction also affect serum concentrations of digoxin,
usually through competitive inhibition of p-glycoprotein activity.
Sources of variability other than renal function are less predictable
or measurable, adjusting an individual maintenance dose on the basis
of their creatinine clearance remains the best starting point for dose
individualization.

10. Dr.
Ramesh
Bhandari
DRUG INTERACTIONS FOR DIGOXIN
Drugs that increase digoxin concentration:
•Diuretics: Spironolactone, Amiloride, Triamterene
•Antiarrhythmics: Quinidine, Amiodarone
•Calcium Antagonist: verapamil
•Statins: Atorvastatin
Drugs that decreases digoxin concentration:
•Rifampicin: Induces P-glycoprotein mediated tubular secretion.
•Liquid Antacids: Reduce digoxin absorption

11. Dr.
Ramesh
Bhandari
THERAPEUTIC FAILURE
oWith respect to improving rate control in chronic atrial fibrillation,
few studies suggested weak correlation between digoxin
concentration and ventricular rate.
oThis is may be due to number of other influences on the atrio-
ventricular node such as altered sympathetic drive with other
comorbidities like sepsis, hypoxia etc.
oThus, TDM for individual patients may be useful to detect patients
with a low digoxin concentration and who may benefit from an
increase in digoxin dose.

12. Dr.
Ramesh
Bhandari
THERAPEUTIC FAILURE
oIn Heart failure there is increasing evidence that concentration
lower than the currently recommended limit of the therapeutic range
may be as efficacious as higher concentrations.
oResults from many trials suggests that digoxin concentration
between 0.5 – 1 ng/L is more efficacious than higher
concentrations in patient with heart failure.

13. Dr.
Ramesh
Bhandari
APPROPRIATE SAMPLING TIME
 Digoxin concentrations should be measured at least eight hours following an
oral dose of digoxin and ideally when concentration have reached steady
state.
Digoxin is well absorbed with peak serum concentrations occurring within one
hour.
A large volume of distribution reflects that digoxin concentrates in the tissues
with the active site being within the myocardium.
Redistribution from serum to tissue takes at least 6 – 8 hours.
Steady state of digoxin had to have been reached after 5 half lives after digoxin
was initiated or after digoxin dose adjustment. (with normal renal function)

14. Digoxin
Concentration
(ng/L)
Time in Hours
0 4 8 12 16 20 24
1
2
3
4
Distribution phase
Sampling Time
Elimination Phase
PLASMA DIGOXIN CONCENTRATION PROFILE AFTER AN ORAL DOSE

15. Dr.
Ramesh
Bhandari
DOSE ADJUSTMENT
Digoxin serum concentrations should be interpreted with respect
to the clinical context.
Generally, concentration is above the therapeutic range, the
dose should be reduced even in the absence of obvious toxicity
because the patient is at risk of arrhythmia and there is no any
efficacy associated with high concentration.
Toxicity can occur with concentrations within the therapeutic
range due to several known factors that change tissue sensitivity to
digoxin and alter the therapeutic index.

16. Dr.
Ramesh
Bhandari
DOSE ADJUSTMENT
The period of time that digoxin should be withheld following an
episode of toxicity depends on concentration and half life of
digoxin in that patient.
In normal renal function patient, if concentration is 3.0 ng/L, the
digoxin should be withheld for 1-2 days before restarting at the
appropriately altered dose, as this will allow the concentration to drop
to within the therapeutic range.
In renal impairment with a prolonged digoxin half life doses may
need to be withheld for several days.

17. Dr.
Ramesh
Bhandari
DOSE ADJUSTMENT
When the measured digoxin concentration is low, either stopping
treatment or increasing the dose or making no change.
In atrial fibrillation, if current heart rate is appropriate in the
presence of low digoxin concentrations a trial without digoxin may
be appropriate.
If ventricular rate is not controlled a dose increase is usually
indicated.
Dose adjustment for therapeutic failure should ideally only be
performed following a digoxin concentration measured at steady
state.

18. Dr.
Ramesh
Bhandari
DOSE ADJUSTMENT
A change in dose will normally result in a proportional
change in digoxin concentration. i.e. doubling the dose will
double the digoxin concentration and half the dose will half
the concentration. (Assuming normal Renal function and no
drug interaction)
If change in renal function, the adjustment can be
estimated by calculating the change in creatinine clearance
using the Cockcroft Gault equation.

19. Dr.
Ramesh
Bhandari
DOSE ADJUSTMENT
CrCl Percentage of normal
recommended dose
Interval
>50 ml/min 100 24 hour
10-50 ml/min 25-75 24-36 hour
<10 ml/min 10-25 48 hour

20. THANK YOU