Phenytoin

Question 1

what is phenytoin?
plasma protein binding?
how is its pharmacokinetics?
target level?

Answer 1

• it is an anticonvulsant with antiarrhythmic properties
• highly bound to plasma proteins (90% bound to albumin)
• capacity - limited metabolism –> non linear pharmacokinetics
• 10 - 20 mcg / ml

Question 2

what are the side effects of phenytoin?

Answer 2

• concentration dependent side effects:
  1. gingial hyperplasia
  2. folate deficiency
  3. peripheral neuropathy
• propylene glycol in IV formulation: CV effects (arrhythmia, hypotension)
• hypocalcemia, osteoporosis, anemia, hepatotoxicity, hirsutism, acne, dermatological reactions
• if > 20 mcg/mL chronic phenytoin level: CNS damage, neuropathy, nystagmus, diplopia, dysarthria, permanent tremor.

Question 3

absorption of phenytoin:
- solubility
- metabolite or..?
- F ?
- time to achieve peak concentration is ?
- when is IV loading dose preferred?

Answer 3

• poorly soluble acid
• fosphenytoin (prodrug): more soluble ester of phenytoin
• 1 (except in rapid GI transit times, nasogastric feedings, neonates, concomitant administration of antacids)
• both product and time dependent
• when rapid achievement of therapeutic concentration is required

Question 4

volume of distribution?
for obese patients, volume of distribution?
protein binding is?
interaction (drug)?

Answer 4

Vd = 0.65 L/kg (in neonates and infants < 1 year: 1 L/kg)
- 0.65 (IBW + 1.3 (TBW - IBW))
- fu = 1 (10% of phenytoin in the plasma is free to equilibrate with the tissues where the pharmacological effects and metabolism occur)
- valproic acid displaces phenytoin from plasma albumin.

Question 5

what alters protein binding?
in renal failure patients?
available as?
dosages available?

Answer 5

• hypoalbuminemia (elderly, alcoholics, malnourished)
• uremia, hypoalbuminemia, changes in configuration of albumin –> increased free phenytoin level
• chewable tablets and suspension, capsules, IV, IM (fosphenytoin)
• 100, 200, 300 mg

Question 6

what is the sheiner - tozer equation?
for which drug do we use it?

Answer 6

corrected phenytoin level (in case of no remal impairment) = measured level / 0.2 (albumin) + 0.1
for renal impairment (if CrCl < 15 ml/min):
corrected phenytoin level = measured level / 0.1 (albumin) + 0.1

Question 7

• how is phenytoin eliminated
• what happens when the maintenance dose is increased
• t1/2?
• is half life cst?

Answer 7

• CYP2C9 and CYP2C19
• disproportionate rise in the plasma levels
• 22 hours
• not cst

Question 8

drug interactions of phenytoin:
drugs that inc phenytoin serum level?
drugs that dec phenytoin serum level?

Answer 8

• fluconazole, fluoxetine, isoniazid, amiodarone, cimetidine
• carbamazepine, rifampin, phenobarbital
• phenytoin is also a potent enzyme inducer (decreases levels of theophylline, warfarin, oral contraceptives)

Question 9

time & frequency of sampling?
time to reach SS in oral?

Answer 9

IV : > 2 hours after end of infusion
IM (fosphenytoin): > 4 hours after injection

Oral: time to reach steady state is variable 3
50 days) usually first sample should be drawn within 3 4 days then decreasing frequency (can check every 6 months in stable patients)

Question 10

what is the loading dose in adults?
pediatrics?

Answer 10

10 - 15 mg/kg (max infusion rate of 50 mg/min)
15 - 20 mg/kg (max IV infusion rate of 1 - 3 mg/kg/min)

Question 11

maintenance dose:
- divided every?
- for adults
- for peds

Answer 11

• 6 - 8 hours
• 4 - 7 mg/kg/day
• 4 - 10 mg/kg/day

Question 12

V ?
what does each one represent

Answer 12

• V = Vm x Css / Km + Css
• V: metabolic rate
• Vm: max rate of metab
• Km; conc at which V will be 1/2 Vm
• Css: substrate conc

Question 13

LD eqn
daily dose eqn

Answer 13

• Css x Vd / F
• Vm x Css / Km + Css