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Clinical Pharmacokinetic of thenophylline

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Clinical Pharmacokinetic of thenophylline

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Clinical Pharmacokinetic of thenophylline

  1. 1. Clinical pharmacokinetic of theophylline Lecturer Nin Prapongsena Huachiew Chalermprakiet University
  2. 2. Objective • Student could apply clinical pharmacokinetic of theophylline in ambulatory care and acute care. – Predicted theophylline plasma concentration – Evaluated toxicities of theophylline and solved problems – Adjusted theophylline dose – Prepared theophylline injection and co-operated with nurse
  3. 3. Introduction Theophylline
  4. 4. Mechanism of Action 1. Bronchodilator Therapeutic range 11 – 20 mg/L
  5. 5. 2. Anti-inflammation Mechanism of Action Therapeutic range 5 – 10 mg/L
  6. 6. Toxicities of theophylline Plasma theophylline concentration (mg/L) ADR Severity > 10 or IV infusion rate > 20 mg/min - Nausea - Insomnia - Nervousness - Headache Minor
  7. 7. Plasma theophylline concentration (mg/L) ADR Severity > 20 - Nausea/vomiting - Insomnia - Diarrhea - Irritability - Headache - Tremor - Tachycardia Serious > 35 - Hyper K+ - Hyperglycemia - Hypotension - Hyperthermia - Arrythmia - Respiratory arrest - Cerebral hypoxia - Brain injury - Seizure Life threatening
  8. 8. การเจาะเลือดเพื่อวัดระดับยา 1.Peak concentration level (Cpeak) concern distribution phase 2.Trough concentration level (Ctrough) just before next dose 8
  9. 9. Slow release Sampling time Rapid release Sampling ≥ 2h post doseSampling ≥ 4h post dose
  10. 10. Absorption Distribution Metabolism Excretion
  11. 11. Absorption Salt factor Anhydrous theophylline content Aminophylline anhydrous 85-86% Aminophylline hydrous 79-80% Theophylline monohydrate 91% Choline theophyllinate 64-65% Dosage form Bioavailability (F) IV 1.0 Tablets & capsules (immediated release) 1.0 Tablets & capsules (extended release) 0.9-1.0
  12. 12. Distribution •Distributed in to fat-free tissues and body fluid (Vd = 0.5 L/kg) •Freely across: Breast milk, cerebrospinal fluid, placenta, saliva, •Protein binding 40-60% (especially albumin) Note: Protein binding decrease in - lower pH 0.1 = decrease binding 4% - rises body temperature
  13. 13. Vd(L) = 0.5 x IBW* + 0.4 (TBW* - IBW) Adjusted Body Weight = IBW + [CF x (TBW - IBW)] . . . where CF = correction factor (usually 20 to 40%) . . . where WT = patient's total weight Use when IBW < 30% of actual body weight 1) Vd Calculation Vd(L) = 0.5 x actual body weight If obese
  14. 14. Metabolism • CYP 1A2 (53%) • CYP 2E1 or CYP3A4 (40%) • CYP 2C9 or CYP 2D6 (7%) Please !!! Concerned drug interaction
  15. 15. Excretion • Influencing factors of theophylline clearance – Age – Smoking – Hepatic disease – CHF – Obesity – COPD – Cystic fibrosis – Infection
  16. 16. Clearance of theophylline Age Half life (h) Vd (L/kg) CL (L/h/kg) Children (1-9y) 3.5 0.5 L/kg 0.102 Adult (16-65) 8 (6-12) 0.039 Eldery (>65 y) 12 0.025 CLpop = CL* [ABW or IBW(obesity)] * Disease factors
  17. 17. CLpop = CL* [ABW or IBW(obesity)] * Disease factors Clearance of theophylline
  18. 18. Adjusment factor for CLtheophylline = 0.75 Drug interaction
  19. 19. 2) CLpop calculation • ผู้ป่วยชาย อายุ 19 ปี น้าหนักตัว 100 kg สูง 165 cm ป่วยเป็น โรค cirrhosis และ COPD class A ปัจจุบันผู้ป่วยยังคงสูบบุหรี่ 14 มวน/วัน ซึ่งขณะนี้ผู้ป่วยกาลังได้รับยา theophylline อยู่ Question? จงหา CL ของยา theophylline ในผู้ป่วยรายนี้ CLpop(L/h) = 0.039*IBW*0.5*1.6
  20. 20. 3) Chiou method for CL calculation ***โดยเงื่อนไขพิเศษของ Chiou method คือ 1. ระดับ theophylline ในกระแสเลือดที่วัด ณ 2 จุดเวลา ควรห่างกันไม่เกิน 4-6 ชั่วโมง ในขณะที่ให้ IV infusion 2. วิธีการบริหารยาดังกล่าวจะให้แก่ผู้ป่วยได้ก็ต่อเมื่อผู้ป่วยได้รับ theophylline แล้วไม่น้อยกว่า 12- 16 ชั่วโมง*** ใช้เพื่อปรับขนาดยาก่อนถึง steady state
  21. 21. 4) Loading dose (LD) calculation Initial: Loading dose (LD) = Css ∙ Vd LD = (Cp(target)-Cp(current)) ∙ Vd Incremental Loading Dose
  22. 22. 5) Maintenance dose (MD) calculation R0 = K0 = Rate for infusion
  23. 23. 6) Cmax & Cmin calculation (steady state) IV bolus model ในกรณีที่ยาเข้า steady state แล้ว แต่เราทราบแต่ Cmin เราจะหา Cmax ได้อย่างไร Answer: Method of requiring single concentration (Ctrough,ss)
  24. 24. Method of requiring single concentration (Ctrough,ss) Conc.(mg/L) Time (h) Cmin,ss (measure) Cmax,ss (calculate) tin Ƭ Ƭ-tin 24
  25. 25. Method of requiring single concentration (Ctrough,ss) Conc.(mg/L) Time (h) tin Ƭ-tin Ƭ Cmax,ss = (SFD/Vd)+Cmin,ss Cmax,ss = (SFD/Cltin)[(1/(1-e-Kt in)]+Cmin,ss
  26. 26. Theophylline dosing flow chart
  27. 27. Theophylline dosing flow chart (continue)
  28. 28. References • John E. Murphy. Clinical pharmacokinetics. Bethesda, Maryland : American Society of Health-System Pharmacists, c2008. • John E. Murphy. Clinical pharmacokinetics : pocket reference. Bethesda, Md: American Society of Health-System Pharmacists, c2001. • Soraya Dhillon, and Andrzej Kostrzewski. Clinical pharmacokinetics. London : Pharmaceutical Press, c2006. • Elliott P, et al. Clinical pharmacokinetics: A Simplified Approach, Part 2. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 78, NO. 9,1986. • สุเพ็ญพร อักษรวงศ์ และคณะ. การใช้ theophylline dosage program ทานายและ ปรับขนาดยาให้ผู้ป่วยที่มีโรคแทรกซ้อน | นิพนธ์ต้นฉบับ : การบริบาลทางเภสัชกรรม. Group of Thai Aseptic Dispenasry and Pharmaceutical care Pharmacists Association of Hospital Pharmacy Community of Practice. 2006
  29. 29. Homework 1 A 42-year-old non-smoker man with a total body weight of 78 kg (180 cm)was admitted to Hospital complaining of shortness of breath. The diagnosis was asthma. The physician wanted to start the treatment with theophylline as soon as possible hence sought your advice. The patient has not been taking theophylline before. You recommended a 450 mg loading dose of aminophylline to be injected slowly over 30 minutes followed by a maintenance dose of 40 mg/h of aminophylline. You also asked for two blood samples 1 and 5 h after the start of the maintenance dose. The lab results indicated serum theophylline concentrations of 6.5 and 7.2 for samples taken 1 and 5 post-dose h, respectively. 1. Comment on the appropriateness of the recommended dose. 2. Estimate the upcoming theophylline steady-state concentration. 3. Recommend an appropriate dose if a target concentration of 12 ug/mL is desired.

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