Clinical pharmacokinetic aspects of digoxin

DOSING OF DIGOXIN WITH CLINICAL PHARMACOKINETIC ASPECT AND ROLE OF PHARMACIST

1. CLINICAL PHARMACOKINETIC ASPECTS OF : DIGOXIN DAVARIYA JAY DINESHBHAI 5 TH 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 .

11. 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 % .

12. Elimination : D igoxin 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)

13. 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)

14. 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)

15. 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)

16. 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)

17. 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

18. 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.

19. 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 .

20. 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)

21. 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 .

22. 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 /

23. 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