anticonvulsant pharmacokinetics
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Anticonvulsant Pharmacokinetics. Dennis Mungall, Pharm.D. Director, Virtual Education, NTPD Associate Professor Pharmacy Practice Ohio State University College of Pharmacy. Absorption of Phenytoin. Phenytoin sodium is 92% phenytoin - PowerPoint PPT PresentationTRANSCRIPT
Anticonvulsant Anticonvulsant PharmacokineticsPharmacokinetics
Dennis Mungall, Pharm.D.
Director, Virtual Education, NTPD
Associate Professor Pharmacy Practice
Ohio State University
College of Pharmacy
Absorption of PhenytoinAbsorption of Phenytoin
Phenytoin sodium is 92% phenytoinThe time to peak is 3-12 hours after single
dose of a capsule or tabletDilantin Kapseals are the only formulation
that has absorption characteristics necessary for once daily dosing
Oral absorption fo Dilantin approaches 100%
Oral preparations of PhenytoinOral preparations of Phenytoin
Time to Peak CpTime to Peak Cp
Dose (mg) 400 800 1600
Peak Time ( hrs) 8.4 13.2 31.5
Parenteral Administration of Parenteral Administration of PhenytoinPhenytoin
Gugler R et al . Clin Pharmac.Ther 1976; 135-42
Distribution of PhenytoinDistribution of Phenytoin
Following IV phenytoin distribution to tissues occurs in 30-60 minutes
Distribution to the brain is very rapid The mean volume of distribution is comparable to
total body water: 0.6-0.7 Liters/kg. Phenytoin binds primarily to albumin, with
approximately 10 percent of the drug normally unbound.
Conditions that lead to decreased Conditions that lead to decreased protein binding of Phenytoinprotein binding of Phenytoin
Decreased In serum Albumin
Burns Hepatic cirrhosis Nephrotic syndrome Pregnancy Cystic Fibrosis
Decreased in affinity of binding to albumin
Renal Failure Jaundice Other medications
Adjustment of Total Phenytoin Adjustment of Total Phenytoin concentration for Albumin concentration for Albumin
Cnormal = Cobserved/(0.2*alb+0.1)
MetabolismMetabolism
Elimination of phenytoin occurs primarily by biotransformation to inactive hydroxylated metabolites.
The process of phenytoin elimination is saturable
Thus , increases in dose lead to disproportionate increases in phenytoin concentration
Variation in Phenytoin Variation in Phenytoin Dose/cpDose/cp
Lund L. Bilogical Effects of Drugs. University Park Press1972;227-39
Demonstration of Dose/CP Demonstration of Dose/CP nonlinearity for Phenytoinnonlinearity for Phenytoin
Richens A., Dunlop A. Lancet 1975;2:247-48
Steady State ConcentrationSteady State Concentration
Vmax= maximum rate of phenytoin metabolism in mg/day
Km: the concentration at which the rate
of metabolism is half maximal ( mg/liter
Css= Km-Dose(day)/Vmax-Dose(day)
Saturation Pathway for Saturation Pathway for PhenytoinPhenytoin
Time to steady state based on Time to steady state based on dosing ratedosing rate
Time to 90% of SS as a Time to 90% of SS as a function of Vmax and Kmfunction of Vmax and Km
Equation for Time to 90% SSEquation for Time to 90% SS
T90% =(Km*Vd)/(Vm-Dose) *
(2.3*Vm –0.9*Dose)
Conditions Affection PhenytoinConditions Affection PhenytoinCondition or Disease
Example
Vmax increased Enzyme induction Concurrent phenobarb/Carbazepine
Vmax decreased Cirrhosis Decreased enzyme activity
Km increased Competitive Inhibition
Cimetidine or Chloramphenicol
Km decreased Decrease ProteinBinding
Dec. albumin or displacers:Valproic acid
Clinical Response and Side Clinical Response and Side EffectsEffects
Kutt H et al. Arch Neurol 1964; 11:642-48
Estimating the Loading Dose Estimating the Loading Dose of Phenytoinof Phenytoin
LD= Vd (C desired – C observed)/S*F Where:
Vd = volume of distribution ( 0.65L/kg)
S=salt factor ( 0.92)
F= fraction absorbed ( 1 )
Cdesired=10 to 20 mg/L
Cobserved: if the patient is on phenytoin
already and has a level prior to therapy
Estimating Maintenance DoseEstimating Maintenance Dose
Mean Km for adults: 5.8 mg/L ( 0.1-27) and
5.3 mg/l for children
Mean Vmax for adults:8mg/kg/day, children 12 mg/kg/day
Dose/day= Vmax*Css/Km+Css
Estimating Maintenance Dose Estimating Maintenance Dose Based on one SS Phenytoin CPBased on one SS Phenytoin CP
Vozeh S et al . J Pharmacokinet Biopharm 1981;9:131-46
Estimation of Dose based on two SS Estimation of Dose based on two SS Phenytoin CP:Mullen MethodPhenytoin CP:Mullen Method
Mullen RW. Clin Pharm Ther 1978;23:228-32
Estimation of Dose based on two SS Estimation of Dose based on two SS Phenytoin CP:Ludden MethodPhenytoin CP:Ludden Method
Ludden TM et al . Clin Pharm Ther 1977;21:287-93
Case Study #1Case Study #1
Mr SG is a 58 y/o, 72 inch, 70 kg male, seen recently with symptoms of a lower Respiratory infection. At this time he had a lesion noted on hisChest X-ray. A lung biopsy revealed a carcinoma with metastasis to The head , demonstrated via a CT scan. His albumin was 4 gm/l and serum creatinine 1.0 .Phenytoin therapy was initiated prohylactically at a dosage of 400 mg daily. Two weeksLater the patient had a grand mal seizure and the phenytoin Cp was5 mg/l. The dosage was increased to 500 mg qd and 3 weeks laterThe phenytoin concentration was 7 mg/l.
Case # 1: QuestionsCase # 1: Questions
Using the Ludden method graph and estimate the Vmax and Km for this patient.
Using this information , estimate a dose necessary to achieve a phenytoin concentration of 15 mg/l
Given the Vmax and Km estimate the timeto 90% of steady state
Estimate a Loading dose to achieve 15mg/l
now.
Case 1: Using DrugCalcCase 1: Using DrugCalc
Using drugcalc, input the patient history , dosing history, and phenytoin history and model this
See how Vmax and Km compare with the Ludden method.
Case 1 : Answers to Ludden Case 1 : Answers to Ludden MethodMethod
Dose Cp Dose/CP
Ludden ExampleLudden Example
Y intercept=1225mg/day= VmaxSlope=11.6mg/l= KmDose/day=Vmax xCp/Km+cpDose/day=1225x15/11.6+15Dose/day= 690mg phenytoin acidDose/day=750 mg phenytoin sodium
Case 1 : Using DrugcalcCase 1 : Using Drugcalc
Input the patient dosage/cp history and estimate Vmax and Km
Using the Dosage calculator, estimate
the dose to achieve a phenytoin concentration of 15 mg/L
Screen # 1 : Input the Screen # 1 : Input the name/agename/age
After inputing the name and age click on accept
Choose phenytoin Choose phenytoin
Select Edit DemographicsSelect Edit Demographics
Enter in the height , weight, Enter in the height , weight, serum albumin and serum serum albumin and serum
creatininecreatinine
When completed , click on accept
Select inpatient dosingSelect inpatient dosing
Insert Dose/Cp historyInsert Dose/Cp history
Using the shortcut for multiple doses, 14s indicating 2 weeks , 21 s Indicating 3 weeks. D is for data ( concentration) . ( s for sustained release) Click on add after entering each line. When complete click on accept
Choose Predict to Model : Choose Predict to Model : Select ParametersSelect Parameters
Review the Vmax, Km, VdReview the Vmax, Km, Vd
Click on done when finished
Predicting SS dosePredicting SS dose
Using the new vmax and Km and the equation for dose, reestimate, by hand the dose of phenytoin necessary to achieve a ss concentration of 15 mg/l