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Clinical pharmacokinetics: Digoxin

Clinical pharmacokinetics: Digoxin. Outlines. INTRODUCTION Part I : Pharmacokinetics of Digoxin Part II : Determination of Digoxin dose regimen. CONCLUSION. Introduction. (Digitalis spp.). Digoxin :naturally occurring drug.

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Clinical pharmacokinetics: Digoxin

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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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