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Clinical Pharmacokinetics of Digoxin: Dosage Regimen Optimization

Learn about the pharmacokinetics of Digoxin, dosage determination methods, clinical implications, and case study analysis for optimal dosing. Understand absorption, distribution, metabolism, and elimination of this crucial cardiac drug.

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Clinical Pharmacokinetics of Digoxin: Dosage Regimen Optimization

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  1. Clinical pharmacokinetics: Digoxin

  2. Outlines INTRODUCTION • Part I :Pharmacokinetics of Digoxin • Part II : Determination of Digoxin dose regimen CONCLUSION

  3. Introduction (Digitalis spp.) • Digoxin :naturally occurring drug • Digoxin: primary cardiac glycoside in clinical use • Main Clinical Indications: • Heart Failure • Increases cardiac output by (+) inotropic actions Therapeutic level of 0.5-1 mcg/L • Atrial Fibrillation • Rate control by (-) chronotropic effects Therapeutic level of 0.5-2 mcg/L

  4. Introduction

  5. Introduction • Tablets • 62.5 ; 125 mcg ( yellow,) or 250 mcg ( white,) • Pediatric Injection • 100 mcg per 1 ml (1 ml ampule) • Capsules (Lanoxicaps) • 50 mcg ( red,) , 100 mcg ( yellow,), and 200 mcg ( green,) • Pediatric Elixir • 50 mcg per 1 ml (10% alcohol) • Injection • 250 mcg per 1 ml (1 ml ampule)

  6. Introduction • Most prominent features of the clinical use of digoxin • narrow therapeutic index • An endpoint of therapy which is difficult to define and measure due to great variability in serum digoxin concentrations in patients given the same dose

  7. Introduction • This condition has Led to the development of monograms and equations designed to estimate optimal digoxin dosage. • Equations Based on the most important pharmacokinetic parameters loading dose (LD) F & Vd CL the maintenance dose & rate (t½) time to steady state & the dosing interval

  8. Introduction • Incorrect dosage of digoxin occurs frequently and is due in most cases to relative over- or under dosage • understanding the clinical pharmacokinetics of Digoxin will help us to improve in the dosage regimens design and ‘‘therapeutics drugs monitoring’’.

  9. Objective • To Describethe profile of digoxin concentration in the body which depend of his absorption, distribution, metabolism and elimination and togivea digoxin dose regimen process through a case study.

  10. Part I : Pharmacokinetics of Digoxin

  11. I-Pharmacokinetics of Digoxin Absorption • 80 % absorbed after oral administration of tablets • 75-80 % absorbed after administration of elixir • 75-80 % absorbed from liquid filled capsule • 80 % absorbed IM but not recommended

  12. I-Pharmacokinetics of Digoxin Absorption: factors affecting bioavailability • FOOD: high fiber product • DRUGS: Antacids, cholestyramine, kaolin, sulfasalazine, metoclopramide and neomycin reduce bioavailability • 40 % degraded by intestinal bacteria 1 in 10

  13. I-Pharmacokinetics of Digoxin Distribution DIGOXIN LEVELS after IV Dose serum digoxin concentration–time curve follows a two-compartment model 8-12 hours tissues distribution phase.

  14. I-Pharmacokinetics of Digoxin Distribution DIGOXIN LEVELS after IV Dose During the distribution phase, digoxin in the serum is not in equilibrium with digoxin in the tissues

  15. I-Pharmacokinetics of Digoxin Distribution • Bound tightly to muscles tissues Vd Correlated well with lean body Tissues , very large distribution volume , approximately 475 to 500L Vd = 7.3 L/kg x IBW • 25 % protein bound • Crosses the placenta and enter the breast milk – Pregnancy category C

  16. I-Pharmacokinetics of Digoxin Metabolism • metabolism via stepwise cleavage of the sugar moieties and lactone ring reduction • Less than 10 % undergoes hepatic metabolism • not dependent of the cytochrome P450 system and it is not know to induce or inhibit it

  17. I-Pharmacokinetics of Digoxin Elimination • Digoxin Elimination follows first-order kinetics • 50-70% is excreted almost entirely unchanged by the kidney • Half life 36-48 hours and increase in case of renal impairment • Affected by some drugs interactions & diseases conditions

  18. Part II : Determination of Digoxin dose regimen

  19. Determination of Digoxin dose regimen Factor

  20. Determination of Digoxin dose regimen Digoxin Equation • CLcr = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females) • IBW = 50 (or 45.5) + 2.3 x (inches over 60) • Vd = 7.3 L/kg x IBW w/ renal dysfunction: Vd = (3.12 x CLcr* + 3.84) CT* x IBW • CLdig (L/h)= (0.06 x CHF x CLcr + 0.02) x Factor x IBW

  21. II- Determination of Digoxin dose regimen Digoxin Case WB is a 75-year-old female with PMH including atrial fibrillation, type II diabetes, hypertension, and renal insufficiency. She is 5’4’’tall and weighs 75 kg. Her SCr is 3.4 mg/dL. Calculate a loading and maintenance dose for Lanoxin tablets for Mrs. B. • Target Cpss = 1.0 mcg/L for atrial fibrillation

  22. CALCULATE LOADING DOSE (1/3) 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

  23. CALCULATE LOADING DOSE (2/3) • WB w/ Renal Dysfunction Vd = (3.12 x CLcr + 3.84) CT x IBW • IBW = 45.5 kg + 2.3 (4 in) = 54.7 kg • CLcr = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females) = • ((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min CT = Concurrent Therapy Factors =1 • Vd = (3.8 L/kg x 54.7 kg) + 3.1 (12.35 mL/min) = 246.15 L

  24. CALCULATE LOADING DOSE (3/3) LD = Vd x Cp/F  • WB w/ Atrial fibrillation Target Cpss = 1.0 mcg/L • Dose regimen for Lanoxin tablets F = bioavailability factor = 0.75 • LD = (246.15 L x 1 mcg) / (0.7) = 351.64 mcg • Use 375 mcg tabs once

  25. CALCULATE MAINTENANCE DOSE (1/3) MD = (Cldigx Cp x tau) / F • where Cldig = Digoxin clearance (l/hr) Cp = target serum level (mcg/l) tau = dosing interval (hours) F = bioavailability factor

  26. CALCULATE OF MAINTENANCE DOSE (2/3) Cldig = Digoxin clearance Cldig = (0.8 ml/min/kg x IBW) + CLcr • CLcr = • ((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min = • IBW • 54.7 kg Cldig= • (0.8 mL/min/kg x 54.7 kg) + 12.35 mL/min = 56.11 mL/min Cldig= x • 3.37 L/hr 56.11 mL/min = • 0.06

  27. CALCULATE OF MAINTENANCE DOSE (3/3) Cldig MD = (3.37 L/hx 1 mcg/L x 24h ) / 0.7 =115.54 mcg = • 3.37 L/hr Target Cpss = 1.0 mcg/L tau = 24hours • F tablets = 0.7 • Then Use 125 mcg tabs qday

  28. Conclusion • Digoxin is a very cheap and effective drug and therefore useful clinically in heart failure • equations designed to estimate optimal digoxin dosage are very useful to avoid under or over dosage • NTI : understanding of the clinical pharmacokinetics useful to prevent digoxin toxicity

  29. References • 20th edition top 200 pharmacy drug cards. SFI Medical Publishing. 2004. • Tharp, R. (2006) Digoxin Dosing. : http://www.rxkinetics.com/dig.html • Medicinal Plants. (2006) Digoxin Image. Updated Aug 12, 2005. :http://www.science.siu.edu/plant biology/PLB117/Nickrent.Lecs/Medicine.html • Digoxin Structure. Retrieved March 8, 2006 from world wide web: http://medpharm.chunma.ac.kr/Aldja/CVS/cardiac_glycoside/img/digoxin_structure.GIF

  30. Thank you very much For your attention!!!

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