2015/1/27報告臨床案例討論：phenytoin過量之處理 2015/1/27 a case report about phenytoin overdose, presented to our pharmacy.

1. 2015/01/27
簡百秀

3. • 61 y/o female, BH 156 cm, BW 39.4 kg.
• CC: malaise, poor appetite, sleepy for 1 wk
• Admission date: 2014/11/11
• Past hx: hyperthyroidism; HIVD at L4/5, L5/S1; R’t knee
osteoarthritis; Major depression.
• Liver function, renal function: WNL
• Impression: Urosepsis with septic encephalopathy 
Suspect JEV(11/18), due to facial convulsion 11/17~

4. 11/17 11/18~11/19 11/20~2
3
11/24 11/25~2
8
11/29~1
2/11
Aleviatin IV 750 mg ST+
100 mg Q8H
500 mg ST
Anxicam IV 2 mg ST PRN
Dilantin PO 300 mg
HS
100 mg
QOD
100 mg
TID
Facial
convulsion
Morning: level 24 mcg/mL(37.5 mcg/mL).
Afternoon: Transferred to A15.
E3V2M4  E2V1M3
Suggest: hold for 2 days then recheck then
250 mg/day.
Sudden onset of con’s disturbance with
poor respiratory pattern, suspect seizure
attack. Level: 11.9 mcg/mL(18 mcg/mL,
alb 2.8 g/dL).
EEG: Diffuse cortical dysfunction
Suggest: recheck level on 11/20.
11/29 Level: 1.3
mcg/mL(1.97 mcg/mL)
E2V1M3  E4V2M5

6. • Oral absorption: slow but complete.
• Distribution(Vd): neonate 0.8-0.9 L/kg; adult 0.6-0.7 L/kg.
• Protein binding: 90-95%
• Metabolism: via CYP2C9 and CYP2C19. Dose-
dependent capacity-limited (Michaelis-Menten)  non-
linear!
𝐷𝑜𝑠𝑒 =
𝑉𝑚𝑎𝑥×𝐶𝑝
𝐾𝑚+𝐶𝑝 ×𝑆×𝐹
Vmax(最大代謝容量): 7 mg/kg/day (if child, < 7)
Km(Michaelis-Menten 常數): 4 mg/L
S = 0.92(for injection and capsule)
• Half-life: 7-42 hrs, and ↑ when concentration ↑.
• Dosing weight(if obese) =(IBW)+1.33∗(TBW-IBW)

7. Food interactions
Ethanol ↓ serum level
Food
Tube feeding ↓ absorption, ∵ phenytoin-
calcium, phenytoin-protein
↓absorption of vit. D, folic acid, calcium
Drugs interactions
↓ serum
level
Folic acid, Dexamethasone, Phenobarbital, Diazepam,
Rifampin, Methadone, Nitrofurantoin, Estrogens
↑ serum
level
Valproic acid, Carbamazepine, Warfarin, Isoniazid,
Cimetidine, Ranitidine, Omeprazole, Ibuprofen,
Metronidazole, Chloramphenicol, Fluconazole,
Fluoxetine, Risperidone, Amiodarone, Allopurinol

8. • Total form 10-20 mcg/mL.
• Free form 1-2.5 mcg/mL.
• Adjustment when hypoalbuminemia:
• Ccr > 10 mL/min: new concentration =
𝐿𝑒𝑣𝑒𝑙
0.2×𝑎𝑙𝑏+0.1
• Ccr ≦ 10 mL/min: new concentration =
𝐿𝑒𝑣𝑒𝑙
0.1×𝑎𝑙𝑏+0.1
• Because protein binding ↓ when renal failure.

9. • Not concentration-related: folic acid deficiency, gingival
hypertrophy(齒齦增生), hypertrichosis(多毛症),
osteomalacia(骨軟化), peripheral neuropathy, systemic
lupus erythematosus, vitamin D deficiency.
• Concentration-related: Ataxia, blurred vision, diplopia,
coma, drowsiness, hyperglycemia, N+V, nystagmus(眼球
震顫)
> 20 mcg/mL Nystagmus
> 30 mcg/mL Ataxia, slurred speech,
confusion
> 40 mcg/mL Mental status changes
> 50 mcg/mL Seizure
>100 Death

10. • Hold if toxic symptoms observed.
• If emergent, give activated charcoal.
• How many days to hold?
• 算出病人此時的Vmax (用 𝐷𝑜𝑠𝑒 =
𝑉𝑚𝑎𝑥×𝐶𝑝
𝐾𝑚+𝐶𝑝 ×𝑆×𝐹
公式)
• Km是常數4，Vd用體重*0.65算出
• Then…
• 𝑇(𝑑𝑎𝑦) =
𝑉𝑑
𝑉𝑚
[𝐾𝑚 × ln(
𝐶𝑝1
𝐶𝑝2
) + (𝐶𝑝1 − 𝐶𝑝2)]
• 意思是從Cp1降到Cp2要花幾天時間？
• Windows 小算盤可以算得出來！

12. • BW 39.4 kg, Cp 37.5 mcg/mL under PO 300 mg/day.
Hold until level reaches 20 mcg/mL.
•  𝐷𝑜𝑠𝑒 =
𝑉𝑚𝑎𝑥×𝐶𝑝
𝐾𝑚+𝐶𝑝 ×𝑆×𝐹
 Vmax = 332 mg/day
• 𝑇 =
𝑉𝑑
𝑉𝑚
𝐾𝑚 × ln
𝐶𝑝1
𝐶𝑝2
+ 𝐶𝑝1 − 𝐶𝑝2 = 1.54 days
• New maintenance dose = 277 mg/day.
• Finally: hold 2 days, then start with 250 mg/day.

13. BW 65 Overdose
Vd(L) 42.25 Dose 400
Vmax( mg/day) 455 C(over) 50
Km(mg/L) 4 New Vmax 432
Desire C 20
Days to hold 3.29
Desired C 22 New MD 360.00
LD (mg) 1010.33
MD(mg/day) 418.48

14. • Mark Su.(2014). Phenytoin poisoning. Retrieved
2015/1/22, from UpToDate®
• Phenytoin_Drug Information. Retrived 2015/1/22, from
UpToDate ®
• Pharmacotherapy: a Pathophysiologic approach, 9th ed.
• Basic Pharmacokinetics.
• 臨床藥物動力學概論
• TDM作業標準書
• Abernethy DR, Greenblatt DJ. Phenytoin disposition in
obesity. Determination of loading dose. Arch Neurol.
1985;42(5):468-71. PMID 3994563