Phenytoin

Question 1

Indication of Phenytoin (Dilantin)

Answer 1

-tonic clonic seizures
-complex partial seizures
-prevention of seizures after head trauma

Question 2

Dosage forms of Phenytoin

Answer 2

Salts (sodium): 92% phenytoin
-IV
-capsule
-XR

Acids: 100% Phenytoin
-suspension
-chewable tablets

Question 3

What is the therapeutic plasma concentration of Phenytoin?

Answer 3

10-20 mg/L

GOAL free concentration concentration of phenytoin: 1-2 mg/L

Question 4

What is the maximum IV infusion rate?

Answer 4

50 mg/min
-the excipient propylene glycol may cause hypotension when infused to rapidly

slow to 20g/min when ADR
1-3 mg/kg/min for children

-0.22 micron needle filter should be used for IV administration

Question 5

What is the function of Propylene glycol in Phenytoin?

Answer 5

-to make Phenytoin more water-soluble
Phenytoin is lipophilic

Question 6

What to look out for in the Phenytoin formulation?

Answer 6

-it may precipitate out -> use a 0.22 micron needle filter
bc Phenytoin is not very water-soluble

Question 7

Rate to infuse for patients with CV disease

Answer 7

20 mg/min

Question 8

Rate of infusion for children

Answer 8

1-3 mg/kg/h

Question 9

What happens if Phenytoin IV is administered too rapidly?

Answer 9

-Hypotension
-cardiac arrhythmias

Question 10

What would be the loading dose in a patient with status ellipticus (actively seizing)?

Answer 10

15-20 mg/kg

when given orally: administer in divided doses bc there is a rate-limited GI absorption
-> max 400 mg per dose
-> f.e for a loading dose of 1200 mg: 400mg every 2h x3 doses

Question 11

What is the maintenance dose for Phenytoin?

Answer 11

5-6 mg/kg/day or 300 mg per day (adults)
OR

-300mg in 3 divided doses

-1-2 doses if extended-released

Question 12

Adverse effects of Phenytoin

Answer 12

-GI: N/V (especially with high doses)
-CNS: dizziness, confusion, drowsiness, ataxia (loss of coordination) -> at high doses, with frequent use

-often given at bedtime, so the patient sleeps, and they are not affected by the side effects

-anti-epileptic hypersensitivity syndrome (AES): rash within the first 5 weeks as a symptom triad

Question 13

Which side effects are referred to as the symptom triad when taking Phenytoin

Answer 13

rash, pruritus (itching), and fever

-it may progress to life-threatening Steven-Johnsons-syndrome (SJS) or toxic epidermal necrolysis

Question 14

Other side effects

Answer 14

Hirsutism: hair growth in unusual areas
Osteomalacia: soft, weak bones
Teratogenicity: defects in the fetus
Megaloblastic anemia
Arrhythmia
Inhibits insulin release
Lymphadenopathy (swelling of the lymph nodes)

Gum hypertrophy (gingival hyperplasia)
Ataxia (loss of coordination, at high doses)
Nystagmus (repetitive uncontrolled eye movements)
Diplopia (double vision)
K: Vitamin K deficiency

remember: Hotmail G and K

Question 15

Other side effects II

Answer 15

ADR: hepatoxicity, hyperglycemia, thickening of facial features, peripheral neuropathy (numbness and pain of hands and feet)Sig

Question 16

Signs of acute toxicity (Phenytoin)

Answer 16

-Intention tremor
>20 mg/L: nystagmus and diplopia
>30 mg/L: ataxia and GI
>40 mg/l: lethargy, confusion, combative, slurred speech
<50 mg/L: choreoathetois (involuntary twitching)

Question 17

Signs of chronic toxicity (Phenytoin)

Answer 17

-Confusion (delirium)
-Cerebellar dysfunction (dysarthria (difficulty speaking, ataxia, muscular hypotonia)
-peripheral neuropathy

Question 18

What type of enzyme kinetics applies to Phenytoin?

Answer 18

Michaelis Menten kinetics

-when changing from one formulation to the other (salt (92%) to acid (100%)) -> small changes in bioavailability can have a significant effect

Question 19

What is the Volume of distribution of Phenytoin?

Answer 19

adults and children: 0.6 - 0.7 L/kg
infants and neonates: 1.2 L/kg

obese: adjusted Vd for obese patients (higher than the normal)
0.65 L/kg * [IBW + 1.33 (TBW - IBW)]

Question 20

What is the percentage of free concentration of phenytoin?

Answer 20

-10% free concentration

-90% bound to albumin

Question 21

Which portion of phenytoin is reported on lab reports?

Answer 21

Bound + Unbound = total phenytoin

the free fraction of phenytoin is 0.1

in patients with normal albumin and achieved goal of 10-20 mg/L
-> the free concentration (active drug) is 1-2 mg/L

Question 22

What affects the free concentration of phenytoin?

Answer 22

-diseases and meds affecting albumin levels
-diseases and meds affecting phenytoins binding affinity (Ka) to albumin

-hypoalbuminemia -> the total phenytoin appears normal, but the free concentration is higher bc less albumin to bind to

-end-stage-renal disease (ESRD): accumulation of toxic substances affecting the affinity of phenytoin to albumin

Question 23

A patient with hypoalbuminemia has a total concentration of 17 mg/L and a free concentration of 3.5 mg/L

Is the patient therapeutic?
What is the unbound fraction?

Answer 23

No, possible toxicity bc his free concentration is over the recommended free concentration of 1-2 mg/L
-could be due to low albumin or meds affecting the affinity of phenytoin

unbound fraction: 20.58%

Question 24

How to account for low albumin

Answer 24

Equation for Albumin Correction to phenytoin

Corrected Phenytoin = Phenytoin observed / (Albumin x 0.2) + 0.1

Question 25

What is the normal albumin level range?

Answer 25

3.5 - 5 g/dl

Question 26

Diseases affecting the binding affinity of phenytoin to albumin II

Answer 26

-hyperalbuminemia
-Jaundice: bilirubin competes with phenytoin to bind to albumin
-ESDR
-renal insufficiency
-renal failure with CrCl < 25 ml/min (fu increase 2-3 fold in uremia (build up in waste products))

Question 27

What is the equation to correct for phenytoin in ESRD?

Answer 27

Corrected Phenytoin = Phenytoin observed / (Albumin x 0.2) + 0.1

Question 28

Which phenytoin drug formulation is often used to load patients?

Answer 28

suspension and IV
-bc they are associated with the most rapid increase in serum concentration

Question 29

Loading dose equation for Phenytoin

Answer 29

derived from IV push equation dose = C * V

Loading dose = target C * V * TBW / F * S

S… salt factor: 0.92
F… Bioavailability = 100% = 1

Question 30

What are the CYP enzymes interacting with Phenytoin?

Answer 30

inducer of:
CYP2C9 (primarily)
CYP2C19
CYP3A4

CYP2B6
CYP2C8

CYP inhibitor will increase phenytoin levels -> TOXICITY

Question 31

How does Phenytoin affect/ is affected by Azoles?

Answer 31

Azoles are CYP2C9 inhibitors
-> increase Phenytoin level

Question 32

How does Phenytoin affect/ is affected by Apixaban/Rivaroxaban?

Answer 32

-reduces Apixaban/Rivaroxaban bc it is metabolized by CYP3A4
-Phenytoin is inducing CYP3A4

Question 33

How does Phenytoin affect/ is affected by Warfarin?

Answer 33

-Warfarin could go any way
-Risk of Phenytoin toxicity
-> close INR monitoring or avoid it if possible

Question 34

How does Phenytoin affect/ is affected by oral contraceptives?

Answer 34

lowers the concentration of oral contraceptives

Question 35

How does Phenytoin affect/ is affected by Calcium channel blockers?

Answer 35

-CCB (especially diltiazem and verapamil) are CYP450 inhibitors
-increases Phenytoin concentration

Question 36

What is the difference between Fosphenytoin and Phenytoin?

Answer 36

-more water-soluble version PRODRUG (it has a phosphate group attached, making it more water-soluble)

-decreases the risk of cardiac side effects (hypotension, arrhythmias)
-decreases risk of injection-site-related side effects due to its sodium hydroxide, propylene glycol, and alcohol

Question 37

Equivalence between Fosphenytoin and Phenytoin

Answer 37

-Fosphenytoin (Cerebyx) is heavier due to the attached phosphate group

-1.5 fosphenytoin to 1 phenytoin

-150 mg Fosphenytoin = 100 mg PE

Question 38

What is the max infusion rate of fosphenytoin?

Answer 38

100 - 150 mg PE/min

-more quickly because it is water-soluble and the risk of side effects is lower