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tdm of phenobarbital

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tdm of phenobarbital

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    1. TDM of Phenobarbital Theerachai Ruangbandit B.Sc. in Pharm, Pharm.D. (Pharm care)

    2. Introduction Phenobarbital is barbiturate. Effective in the management of generalized tonic-clonic and partial seizures.

    3. Mechanism of action Elevation of seizure threshold by interaction with ?-aminobutyric acid (GABA) postsynaptic receptors. This interaction potentiates synaptic inhibition

    4. Absorption 90-100 % of Phenobarbital administered orally is absorbed Phenobarbital is frequently orally admin as Sodium salt which ~ 91 % phenobarbital acid (S=0.91)

    5. Distribution Vd is about 0.5-1 l/kg Volume are largest at birth through infancy

    6. Metabolism First order kinetics Half-life about 5 day in adult Non-first past, non-dose dependent biotransformation Phenobarbital is potent inducer of CYP3A4, CYP1A2, CYP2C and CYP2D6

    7. Clearance Renal excreation of unchanged drug is urine flow and pH dependent ++ with alkaline urine Combined diuresis and alkalosis can increase renal clearance up to 4 fold.

    8. Drug interation -- absorption: activated charcoal, cholestyramine ++ metabolism: rifampicin -- metabolism: chloramphenicol, Valproic acid

    9. Suggest sampling time Since the peak to trough fluctuation is minimal during dosing interval Actual sampling times are not usually important. Steady-state will be obtained 3-4 wk after initiation of therapy, dose change, or discontinuation or introduction of enz inducer and inhibitors

    10. Suggest sampling time Concentration should be determined immediately for patient: Seizure control is lost Toxicity is evident

    11. Phenobarbital concentration-related toxicity > 5 mg/l Sedation > 19 mg/l Impaired cognition > 35-80 mg/l Sedation, slowness ataxia > 65 mg/l potential coma

    12. Monitoring concentration-related efficacy Efficacy is usually determined by seizure frequency. Noncompliance must always be considered with patients receiving anticonvulsant 25-75 % of patient receiving phenobarbital therapy have been reported to be noncompliant

    13. Dosage form availability Oral tablet: 30, 60 Oral elixir: 20 mg/5 ml

    14. Therapeutic Regimen Design Adult (19-65 yr) Loading dose 10-20 mg/kg Maintenance dose 1.5-2 mg/kg/day /* Once-daily dosing at bedtime is preferred to minimized daytime sedation and increase compliance */

    15. Key PK parameter Tx plasma conc 10-40 mg/l F 1.0 S oral 0.91 IV, IM 1 Vd 0.65 l/kg Cl 0.1 l/kg/d

    16. Initial dosage determination Css = SFD/t Cl Cl = Vd x Ke

    17. Ex: Calculate an oral maintenance dose for Patient 70 kg which will maintain a phenobarbital concentration of 20 mg/l. How should the dose be administered? CL = 0.1 l/kg/day x Weight in kg = 0.1 x 70 = 7.0 l/day Maintenance dose = CL x Css x t / SxF = 7 x 20 x 1 / 0.91 x 1 = 153 mg ********************************************************** t1/2 = 0.693 x Vd /CL = 0.693 x 45.5 / 7 = 4.5 day MD = 153/70 = 2.1 mg/kg **********************************************************

    18. Ex: Calculate an oral maintenance dose for Patient 70 kg which will maintain a phenobarbital concentration of 20 mg/ml. How should the dose be administered? CL = 0.1 l/kg/day x Weight in kg = 0.1 x 70 = 7.0 l/day Maintenance dose = CL x Css x t / SxF = 7 x 20 x 1 / 0.91 x 1 = 153 mg ********************************************************** t1/2 = 0.693 x Vd /CL = 0.693 x 45.5 / 7 = 4.5 day MD = 153/70 = 2.1 mg/kg **********************************************************

    19. Use of serum concentration of Phenobarbital to alter doses C1 = Dose1 C2 = Dose2

    20. Ex: ?????????????? ???? 45 ?? ??????? 60 kg ???????? Phenobarbital 120 mg ??????? ????????????????? 1 ????? ?????????????????????????????? ???????????????????????????????? ????????????????????????????????????????????????????? ?????????????????????????? 12 mg/l ????????????????????????????????? 18 mg/l ???????????????????????????????

    21. Ex: ?????????????? ???? 45 ?? ??????? 60 kg ???????? Phenobarbital 120 mg ??????? ????????????????? 1 ????? ?????????????????????????????? ???????????????????????????????? ????????????????????????????????????????????????????? ?????????????????????????? 12 mg/l ????????????????????????????????? 18 mg/l ??????????????????????????????? C1/C2 = Dose1/Dose2 12/18 = 120/Dose2 Dose2 = 180 mg/d ********************************************************** C = SFD/T CL CL = SFD/T C CL = 0.91x1x120/12 = 9.1 l/day 18 = 0.91x1xD/1 9.1 D = 180 mg/d

    22. http://www.pha.nu.ac.th/theerach/tdm_phenobarb.ppt

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