Pharmacology of Epilepsy and
Migraines
Rachel W. Flurie,
PharmD, BCPS
VCU School of
Pharmacy
Which ASD Am I?

I am a first generation ASD and am very effective for focal
seizures. I induce many CYP450 enzymes. If I reach toxic serum
levels the first warning sign may be nystagmus.




A. Lacosamide
B. Phenytoin
C. Carbamazepine
D. Valproic acid
PHENYTOIN
 Pharmacokinetics


Saturable absorption
 Divide doses greater than 400 mg into at least two doses
Steady state achieved in 7-10 days (half-life 9-42 hours)



Loading doses may be used
Saturable metabolism




Metabolized by CYP2C9 and CYP2C19
A small change in dose may result in a very large disproportionate increase in blood level
The dose where saturation occurs cannot be predicted
Saturation occurs at lower doses in the elderly
Highly protein bound (~90%) and affected by
 Low albumin
 Age
Renal failure
Other drugs
PHENYTOIN PHARMACOKINETICS
CORRECTED PHENYTOIN CONCENTRATION
Patient’s Serum Albumin (gm/dL)
3.5
Measured
Total Phenytoin
Concentration
(mcg/mL)
3.0
2.5
2.0
Adjusted Total Phenytoin Concentration
(mcg/mL)
5
6
7
8
10
10
13
14
17
20
15
19
21
25
30
*Adjusted concentration = measured total phenytoin concentration
(0.2 x albumin) + 0.1
 Note: Can draw free phenytoin levels to avoid albumin
interference
 Therapeutic drug range:
 Total: 10-20 mcg/mL
 Free: 1-2 mcg/mL
Which ASD Am I?

I am a CYP450 enzyme inducer. Similar versions of me have been
created since my inception. I commonly cause low serum sodium
levels but can also cause a bad rash.




A. Zonisamide
B. Lamotrigine
C. Carbamazepine
D. Topiramate
CARBAMAZEPINE
 Pharmacokinetics
 Auto-induction (induces its own metabolism)



Begins after 3 to 5 days, but takes 21 to 28 days to complete
Half-life becomes shorter with continued dosing (25-65 hrs vs 12-17 hrs)
Occurs with each dosage increase
 Metabolized to 10,11-diepoxide which is active
 Suspension is absorbed more quickly than immediate release tablets
 Variable absorption with generic formulations
 Therapeutic drug range: 4-12 mcg/mL
OXCARBAZEPINE (TRILEPTAL®)
 Pharmacokinetics
 Pro-drug; rapidly converted to the monohydrate derivative (MHD) which is
active
 There is no auto-induction
 MHD excreted unchanged and metabolized by glucuronidation
 Faster clearance in children
 Slower clearance in elderly
ESLICARBAZEPINE (APTIOM®)
 Pharmacokinetics





Prodrug with the same active metabolite as oxcarbazepine
No auto-induction
Active drug undergoes glucuronidation
Once daily dosing due to longer half-life
66% excreted renally (renal dose adjust)
Which ASD Am I?

I am a CYP450 inhibitor. I can also be used for migraines. Better
monitor liver enzymes because I can cause hepatoxicity. Avoid me
in women who are pregnant.




A. Topiramate
B. Lacosamide
C. Levetiracetam
D. Valproic acid
VALPROIC ACID
 Pharmacokinetics
 Absorption is dependent of formulation
 Syrup and capsule are rapidly absorbed – 3-4 x / day
 “Sprinkle,” delayed release (Depakote DR) and sustained release (Depakote ER) are
slowly absorbed
 Sprinkle – 2-3 x / day
 Depakote DR – 2-3 x/ day
 Depakote ER – once daily
Cannot be
crushed
VALPROIC ACID
 Pharmacokinetics
 Highly protein bound (90-95%) which saturates in the
therapeutic range
 Nonlinear PK
 As dose or concentration increases, clearance rate increases
 Therapeutic drug range:
 Total: 50-100 mcg/mL
 Free: 5-25 mcg/mL
 Multiple metabolites (10+)
 4-ene-VPA metabolite may cause hepatotoxicity
VALPROIC ACID
Practice Question

Patient MH comes to your office with a new diagnosis of migraines.
She’s tried acetaminophen OTC without relief and is experiencing the
beginnings of a migraine today that she says is mild.

PMH: 20 weeks pregnant, asthma
 Medications: prenatal MVI, albuterol HFA as needed

What is the most appropriate agent to recommend for abortive therapy?

A. Acetaminophen-aspirin-caffeine
 B. Ibuprofen
 C. Ergotamine tartrate
 D. Topiramate
Practice Question

A patient with new onset focal seizures was started on levetiracetam in
the hospital. Today they are complaining of mood swings and
experienced a breakthrough seizure 1 week ago.

PMH: Depression, obesity
 Meds: sertraline

Which of the following is the most appropriate therapy to switch the
patient to?

A. Carbamazepine
 B. Brivaracetam
 C. Valproic acid
 D. Eslicarbazepine