clinical pharmacokinetics of digoxin
DESCRIPTION
Digoxin : Clinical pharmacokinetics Pharmacokinetics (ADME) and Digoxin case studyTRANSCRIPT
Clinical pharmacokinetics: Digoxin
YOUAN BI BENIET MARIUS
Pharm D, Master student in clinical Pharmacy
University of Nairobi
Outlines
INTRODUCTION
Part I : Pharmacokinetics of Digoxin
Part II : Determination of Digoxin dose regimen
CONCLUSION
Introduction
Digoxin: primary cardiac glycoside in clinical use
Main Clinical Indications:
Atrial Fibrillation
Therapeutic level of 0.5-1 mcg/L
Heart Failure
Increases cardiac output by (+) inotropic actions
Rate control by (-) chronotropic effects Therapeutic level of 0.5-2 mcg/L
Digoxin :naturally occurring drug (Digitalis spp.)
Introduction
Pediatric Injection – 100 mcg per 1 ml (1 ml ampule)
Tablets 62.5 ; 125 mcg ( yellow,) or 250 mcg ( white,)
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)
Introduction
Introduction
narrow therapeutic index
Most prominent features of the clinical use of digoxin
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
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
F & Vd loading dose (LD)
CL the maintenance dose & rate
(t½) time to steady state & the dosing interval
understanding the clinical pharmacokinetics of
Digoxin will help us to improve in the dosage
regimens design and ‘‘therapeutics drugs
monitoring’’.
Introduction
Incorrect dosage of digoxin occurs frequently
and is due in most cases to relative over- or
under dosage
Objective
To Describe the profile of digoxin concentration in
the body which depend of his absorption,
distribution, metabolism and elimination and to
give a digoxin dose regimen process through a
case study.
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
I-Pharmacokinetics of Digoxin
Absorption: factors affecting bioavailability
40 % degraded by intestinal bacteria 1 in 10
FOOD: high fiber product
DRUGS: Antacids, cholestyramine, kaolin, sulfasalazine, metoclopramide and neomycin reduce bioavailability
1. serum digoxin concentration–time curve follows a two-compartment model
2. 8-12 hours tissues distribution phase.
DIGOXIN LEVELS after IV Dose
Distribution
I-Pharmacokinetics of Digoxin
DIGOXIN LEVELS after IV Dose
Distribution
3. During the distribution phase, digoxin in the serum is not in equilibrium with digoxin in the tissues
I-Pharmacokinetics of Digoxin
Distribution
Bound tightly to muscles tissues Vd Correlated well
with lean body Tissues , very large distribution volume
Vd = 7.3 L/kg x IBW , approximately 475 to 500L
25 % protein bound
Crosses the placenta and enter the breast milk –
Pregnancy category C
I-Pharmacokinetics of Digoxin
Less than 10 % undergoes hepatic metabolism
not dependent of the cytochrome P450 system
and it is not know to induce or inhibit it
metabolism via stepwise cleavage of the sugar moieties and lactone ring reduction
Metabolism
I-Pharmacokinetics of Digoxin
Digoxin Elimination follows first-order kinetics
50-70% is excreted almost entirely unchanged by the kidney
Affected by some drugs interactions & diseases conditions
Half life 36-48 hours and increase in case of renal impairment
Elimination
I-Pharmacokinetics of Digoxin
Determination of Digoxin dose regimen
Factors UnitsMinimum effective concentration, 0.5 ng/mL
Maximum safe concentration 2.0 (CHF*) >2.0 (atrial arrhythmias)
ng/mL
Bioavailability 0.7 (tablets) 0.80 (elixir) 0.95 (capsule)
Disease FactorsEuthyroid = 1.0 Hypothyroid = 0.7 Hyperthyroid=1.25
Concurrent Therapy FactorsNone = 1.0 Quinidine = 0.6 Verapamil = 0.6
CHF FactorNone = 1.0 CHF = 0.9 More than one disease or concurrent therapy factor: Use Factor =1.0
Factor
Digoxin Equation
w/ renal dysfunction: Vd = (3.12 x CLcr* + 3.84) CT* x IBW
IBW = 50 (or 45.5) + 2.3 x (inches over 60)
CLdig (L/h)= (0.06 x CHF x CLcr + 0.02) x Factor x IBW
CLcr = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females)
Vd = 7.3 L/kg x IBW
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
II- Determination of Digoxin dose regimen
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
WB w/ Renal Dysfunction
Vd = (3.12 x CLcr + 3.84) CT x IBW
CLcr = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females)
CT = Concurrent Therapy Factors =1
IBW = 45.5 kg + 2.3 (4 in) = 54.7 kg
= ((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min
Vd = (3.8 L/kg x 54.7 kg) + 3.1 (12.35 mL/min) = 246.15 L
CALCULATE LOADING DOSE (2/3)
WB w/ Atrial fibrillation
Target Cpss = 1.0 mcg/L
Lanoxin tablets Dose regimen for
F = bioavailability factor = 0.75
LD = Vd x Cp/F
LD = (246.15 L x 1 mcg) / (0.7) = 351.64 mcg
CALCULATE LOADING DOSE (3/3)
Use 375 mcg tabs once
CALCULATE MAINTENANCE DOSE (1/3)
MD = (Cldig x Cp x tau) / F
where Cldig = Digoxin clearance (l/hr)
Cp = target serum level (mcg/l)
tau = dosing interval (hours)
F = bioavailability factor
CALCULATE OF MAINTENANCE DOSE (2/3)
Cldig = Digoxin clearance
((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min CLcr =
IBW = 54.7 kg
3.37 L/hr
Cldig=
Cldig = (0.8 ml/min/kg x IBW) + CLcr
(0.8 mL/min/kg x 54.7 kg) + 12.35 mL/min = 56.11 mL/min
Cldig= 56.11 mL/min x 0.06 =
Cldig 3.37 L/hr
Target Cpss = 1.0 mcg/L
tau = 24hours
F tablets = 0.7
=
MD = (3.37 L/h x 1 mcg/L x 24h ) / 0.7 =115.54 mcg
Then Use 125 mcg tabs qday
CALCULATE OF MAINTENANCE DOSE (3/3)
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
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
Thank you very much
For your attention!!!