Case Report-Phenytoin Overdose2015/01/27簡百秀

Case Report

Patient Profile• 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~

AEDs for Seizure11/17 11/18~11/19 11/20

~2311/24 11/25

~2811/29~12/11

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 E2V1M3Suggest: 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 dysfunctionSuggest: recheck level on 11/20.

11/29 Level: 1.3 mcg/mL(1.97 mcg/mL) E2V1M3 E4V2M5

Phenytoin Overdose

Phenytoin Pharmacokinetics• 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!

Vmax(最大代謝容量 ): 7 mg/kg/day (if child, < 7)Km(Michaelis-Menten 常數 ): 4 mg/LS = 0.92(for injection and capsule)

• Half-life: 7-42 hrs, and ↑ when concentration ↑. • Dosing weight(if obese) =(IBW)+1.33∗(TBW-IBW)

Drugs and Foods InteractionsFood interactions

Ethanol ↓ serum level

Food

Tube feeding ↓ absorption, ∵ phenytoin-calcium, phenytoin-protein

↓absorption of vit. D, folic acid, calciumDrugs 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

Reference Range

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

Phenytoin Toxicology• 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 mcg/mL

Death

Overdose Management• Hold if toxic symptoms observed.• If emergent, give activated charcoal.• How many days to hold?• 算出病人此時的 Vmax (用公式 )• Km是常數 4， Vd用體重 *0.65算出• Then…

• 意思是從 Cp1降到 Cp2要花幾天時間？• Windows 小算盤可以算得出來！

Return to Case

Suggestion• BW 39.4 kg, Cp 37.5 mcg/mL under PO 300

mg/day. Hold until level reaches 20 mcg/mL.• Vmax = 332 mg/day

• = 1.54 days• New maintenance dose = 277 mg/day.

• Finally: hold 2 days, then start with 250 mg/day.

Let’s use EXCEL

BW 65 OverdoseVd(L) 42.25 Dose 400Vmax( mg/day) 455 C(over) 50Km(mg/L) 4 New Vmax 432

Desire C 20Days to hold 3.29

Desired C 22 New MD 360.00LD (mg) 1010.33MD(mg/day) 418.48

References• 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