This document summarizes key aspects of the clinical pharmacokinetics of digoxin. Digoxin is absorbed 80% orally and used to treat heart failure and atrial fibrillation. Its absorption is affected by drugs and its distribution follows a two-compartment model with a half-life of 40 hours. It is 25% protein bound and follows first-order kinetics, with 50-70% excreted unchanged in urine. Dosage is determined based on therapeutic and toxic concentrations, age, renal function, and clearance. Toxicity includes gastrointestinal symptoms and arrhythmias. Pharmacists can help optimize digoxin dosing and monitor therapy.

1. CLINICAL
PHARMACOKINETIC
ASPECTS OF :
DIGOXIN
DAVARIYA JAY DINESHBHAI
5TH YEAR PHARM.D
ROLL NO -03
5.3 CLINICAL PHARMACOKINETICS
AND PHARMACOTHERAPEUTIC
DRUG MONITORING SEMINAR
K.B.I.P.E.R GANDHINAGAR DRUG
MONITORING SEMINAR

2. INTRODUCTION:
CLINICAL PHARMACOKINETICS DEFINATION :
• Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution
, metabolism, and excretion.
• According to ASHP clinical pharmacokinetics is the application of pharmacokinetic principles to the
safe and effective therapeutic management of drugs in an individual patient. (1)
APPLICATION OF CLINICAL PHARMACOKINETICS
1 Individualization of drug dosage regimen
2 Therapeutic drug monitoring
3 Design of dosage regimen
4 Conversion of IV infusion to oral dosing
5 Determination of dose
6 Effect of changing dose and dosing interval on Cmax , Cmin .
7 Determination of frequency of drug administration
8 Determination of route of administration

3. 9 Dosing of drugs in infants and children
10 Dosing of drugs in elderly
11 Pharmacokinetic of drug interaction

4. INTRODUCTION OF DIGOXIN
Digoxin is a cardiac glycoside .
CLINICAL INDICATION OF DIGOXIN :
1) Heart failure :
digoxin will increase cardiac output .dose :0.5-1 mcg/L
2) Atrial fibrillation :
digoxin also use in atrial fibrillation . Dose : 0.5-2 mcg /L
STRUCTURE OF DIGOXIN :

5. INTRODUCTION
1) Oral solution :
0.05 mg/mL
2) Injection solution :
0.1 mg/mL
0.25 mg/mL
3) Tablet :
0.0625 mg
0.125 mg
0.1875 mg
0.25 mg
Loading dose of digoxin is 0.008-0.012 mg/kg
Maintenance dose of digoxin is 0.1 -0.4 mg four time in a day (2)

6. INTRODUCTION
• Digoxin is a narrow therapeutic index drug .
• Incorrect dosage of digoxin occur frequently and most cases are over
dosage or under dosage .
• We will understand the clinical pharmacokinetics , this will help us to
improve in a dosage regimen and therapeutic drug monitoring .
Mechanism of digoxin :
Digoxin inhibits Na/k/ATPs pump , resulting in increase in intracellular sodium and calcium
concentration .
Increase in intracellular calcium will promote the activity of contractile protein (actin , myosin )
So increasing calcium will increase myocardial contractility and also increase impulse formation
and conduction

7. OBJECTIVES:
Digoxin concentration in the body is depend on the absorption, distribution , metabolism and
elimination and to the dosage regimen process through a case study .

8. PHARMACOKINETICS OF
DIGOXIN
ABSORPTION :
80 % absorption is occur after oral administration of tablet .
75-80 % absorption is occur after administration of elixir .
80% absorbed IM but not recommended . (3)

9. Factor affecting absorption :
Drugs :
Pantoprazole + digoxin :pantoprazole increase the toxicity of digoxin by increasing gastric PH .
Sulfasalazine + digoxin : sulfasalazine decreases levels of digoxin by inhibition of GI absorption .
Metoclopramide + digoxin : metoclopramide decreases levels of digoxin by inhibition of GI
absorption .
Quinidine + digoxin =quinidine will increase the level of digoxin by P glycoprotein efflux
transporter .(2)

10. Distribution :
Serum digoxin concentration follow two compartment open model .
Time course of action :
Onset of action : 15 – 30 minutes .
Peak of action : 2-5 hours .
Duration of action : 2-6 days .
Half life of digoxin : 40 hours .
Plasma protein binding capacity is 25 % .
Plasma concentration :
Therapeutic concentration : 0.5 – 1.4 ng/ml
Toxic concentration : >2 ng/ml (3)
Two clinical implication :
Loading doses of digoxin need to be administered in divided doses 6 hour apart .
Serum digoxin levels should be check at least 8hr after administration .

12. Metabolism :
Digoxin metabolism is occur in stomach and intestine .
It involves deglycosylation , reduction of lactose ring , oxidation ,epimerization , conjugation to polar
metabolites .
Hepatic metabolism of digoxin will occur at less than 10 % .

15. Elimination :
Digoxin will follow first order kinetics .
50-70 % excreted unchanged in urine by the kidney .
Small proportion of digoxin is cleared by nonrenal routes , biliary excretion and intestinal
clearance.
Vd decrease with decrease in renal function .
In patients with severe renal dysfunction ,18% of digoxin is only bound to protein .
The average volume of distribution for digoxin is 7.3 L/kg
VDigoxin (L) = (3.8 L/kg)(Weight in kg) + (3.1)(ClCr in mL/min) (6)

17. Clearance :
total digoxin clearance in mL/kg/min can be calculated in patients with and without CHF
as follows
Total ClDigoxin (mL/min) (Patients without CHF) = (0.8 mL/kg/min)(Weight in kg) +
ClCr in mL/min
Total ClDigoxin (mL/min) (Patients with CHF) = (0.33 mL/kg/min)(Weight in kg) +
(0.9)(ClCr in mL/min)
Creatinine clearance can be estimated from the patient’s serum creatinine using
Equation .
ClCr for males (mL/min) = (140 - Age)(Weight in kg)/72 *Scr
ClCr for females (mL/min) = (0.85) (140 - Age)(Weight in kg) /72*Scr
Through IBW
Ideal Body Weight for females in kg = 45 + (2.3)(Height in Inches > 60)
Ideal Body Weight for males in kg = 50 + (2.3)(Height in Inches >60) (6)

18. DETERMINATION OF DIGOXIN
DOSAGE REGIMEN
Factors :
Minimum effective concentration : 0.5 ng/mL
Maximum safe concentration : 2 ng/ml (3)
Bioavailability :
Oral tablet of digoxin bioavailability is 0.35
Intravenous administration of digoxin has 0.35 bioavailability (4)
Age :
Increase in age will increase in digoxin toxicity because increase in age will decrease renal
function and also decrease in volume of distribution . (5)

19. Calculation of digoxin dose :
1) Stady state concentration :
Css = (Maint dose x F) /( dig cl x T)
F= bioavailability factor
T= dosing interval
dig cl= digoxin clearance. (7)
2) Loading dose :
LD = Vd x Cp/F
where Vd = Volume of distribution (liters)
Cp = target serum level (mcg/l)
F = bioavailability factor:
IV push = 1
capsules= 0.95
elixir = 0.8
tablets = 0.75 (7)

20. 3) Maintenance dose :
MD = (Cl x Cp x tau) / F
where Cl = Clearance (liters/hour)
Cp = target serum level (mcg/l)
tau = dosing interval (hours)
F = bioavailability factor
4) Estimate steady-state trough level
Cpss = (MD x F) / (Kel x Vd x tau)
where MD = Maintenance dose (mcg)
F = bioavailability factor
Kel = Elimination rate (1/hours)
Vd = Volume of distribution (liters)
tau = dosing interval (hours)

21. TOXICITY OF DIGOXIN :
Acute toxicity :
GI symptoms : nausea , vomiting
Hyperkalemia
CNS (headache ,visual changes ),confusion
Cardiovascular :Arrhythmia
Chronic toxicity
GI symptoms : nausea , vomiting ,anorexia
Hyperkalemia
CNS (headache ,visual changes ),confusion,seizure

22. Diagnosis of digoxin toxicity :
Diagnosis is based on ECG and potassium .
The constellation of gastrointestinal symptoms, along with hyperkalaemia and an
electrocardiogram demonstrating AV blocks, bradycardia, or ventricular dysrhythmias,
along with a digoxin concentration in the upper limit of normal or elevated digoxin
concentration should make the clinician suspect acute digoxin toxicity.
The finding of weakness and malaise, especially in an elderly patient with impaired renal function,
who is on digoxin should make the clinician suspect chronic digoxin toxicity.

23. Specific treatment :
The first priority in treatment is ensuring the patient has an adequate airway and breathing.
Patients who are bradycardia can receive atropine 0.5 mg IV.
Patients should be assessed for the administration of digoxin-specific Fab fragments
(antibodies). Those patients who are hyperkalemia or have life-threatening dysrhythmias should
receive digoxin immune Fab fragments.
It should be noted that digoxin is not removed effectively by extracorporeal elimination
techniques, including hemodialysis.
Drugs and dosage :
The decision to treat a cardiac glycoside-poisoned patient should be based
on the presence of hyperkalemia or life-threatening dysrhythmias .

24. For acute toxicity with an unknown digoxin concentration and unknown
amount ingested, 10 vials can be empirically administered for adults, or 5 vials
for children. For chronic toxicity, these doses will likely over-estimate the
amount of digoxin immune Fab fragment needed. One vial of digoxin immune
fragments binds to 0.5 mg of digoxin.
If the digoxin concentration is known, and the patient has ingested digoxin, the following formula can
be used: Number of vials = (serum digoxin concentration) x (patient weight in kilograms) / 100.
In this equation weight in kilogram and digoxin concentration in ng/ml (9)

25. ROLE OF PHARMACIST
Pharmacist will discuss with the physician about the dosage of digoxin because many cases
healthcare professionals are not aware of the appropriate range of digoxin for each
pathology.(10)
Pharmacist will check the therapeutic and toxicity monitoring of digoxin this way pharmacist
will improve the patients quality of life .

26. REFERENCES :
1) Introduction to Pharmacokinetics and Pharmacodynamics ,lesion 1 ,1-12,https://www.ashp.org/-
/media/store%20files/p2418-sample-chapter-1.pdf
2) Medscape .com
3)Cardiac glycoside and drug for heart failure ,KD TRIPATHI , Essentials of medical pharmacology
,sixth edition , Jaypee brother medical publisher ltd. 2008 , 493-507 .
4)f. marcus ,j.dickerson , s.pipin , Digoxin bioavailability: formulations and rates of infusions available at
site https://pubmed.ncbi.nlm.nih.gov/954346/ .
5)J l Wofford , W H Ettinger , Risk factors and manifestations of digoxin toxicity in the elderly ,
available at site at https://pubmed.ncbi.nlm.nih.gov/1997015
6) Maureen S. Boro and Michael E. Winter ,digoxin , drug monograph ch.3 , pg,198-239
7) Mcauley ,Global Ph the clinical ultimate reference , digoxin dosing site located at
https://globalrph.com/digoxin-dosing/
8) https://clincalc.com/Digoxin/
9)Michael leavine , Digoxin overdose, Cardiac glycoside toxicity, digoxin toxicity, digoxin poisoning
Available at side https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/critical
care-medicine/digoxin-overdose-cardiac-glycoside-toxicity-digoxin-toxicity-digoxin-poisoning/

27. 10)R lopez Sepulveda , E espinola Garcia, PKP-006 Pharmacist’s role in clinical pharmacokinetic
monitoring of digoxin: minimising toxic effects , ejhp-2017 , Published by the BMJ Publishing
Group Limited. Available at site https://ejhp.bmj.com/content/24/Suppl_1/A196.1
11)Chapter 2,3 ,9 ,Brahmandkar .pdf