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Selection of Antiepileptic
Medications in Adults
Michele Y. Splinter, Pharm.D., M.S., BCPS
Associate Professor
College of Pharmacy
University of Oklahoma HSC
Objectives
Discuss selection of AEDs for
partial seizures in adults
 Assess drug-related problems
associated with AEDs

– Common
– Chronic
– Idiopathic

Identify treatment options for S.E.
Epidemiology
Seizure in a lifetime: 8% of
population
 New diagnosis of epilepsy:

– 50/100,000 people per year
– 125,000 new cases /year

Prevalence: 2 million people in
U.S.
Causes of Seizures

Mechanical-trauma, tumor, vascular
– Hemorrhagic Stroke

10.6% in 9 months
– Ischemic Stroke

8.6% in 9 months
– Subdural hematoma
– Epidural hematoma
– Vasculitis
Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.
Leppik IE, Birnbaum AK. Ann NY Acad Sci 2010;1184:208-224.
Causes of Seizures

Metabolic
– Hyponatremia
– Hypomagnesemia
– Hypoglycemia
– Hyperglycemia
– Hypocalcemia
Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.
Causes of Seizures

Toxic
– Sudden withdrawal of CNS meds
– Cocaine
– Anticholinergics

Fever, infection
– Meningitis
– Encephalitis
– Brain abscess
.
Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64
AED Selection
Efficacy for type of seizure
 Tolerability
 Co-Morbidities
 Drug Interactions

S.Z.
SZ is a 72 year-old-female with a history of stroke 5
months ago, hypertension diagnosed (2001), and
osteoporosis (2008).
Medications: Aspirin 81 mg, lisinopril 10 mg daily,
alendronate 70 mg weekly.
History obtained from husband: Yesterday evening, she
got up from the couch and moved objects from one side of
the table to the other side. She did not respond to him
when he spoke to her. This went on for about 3 minutes
and then she finally responded, but she was very lethargic
for the next 15 minutes.
Which of the following medications
would be most appropriate for S.Z.?
A. Gabapentin
 B. Levetiracetam
 C. Oxcarbazepine
 D. Phenytoin

Efficacy and Tolerability

Retrospective study (n=417) over 5
years
– ≥ 55 years and older
– Outpatients
– Outcomes


12-month retention
12 month seizure freedom
– Newly started AED treatment (n=247)
Arif H, et al. Arch Neurol 2010; 67:408-413.
Drug Selection in
Adult Partial Seizures

12-month retention
–
–
–
–
–
–
–
–
Lamotrigine 78.6% (n=126)
Levetiracetam 72.5% (n=102)
Valproic acid 69.6% (n=23)
Zonisamide 68.2%, (n=22)
Phenytoin 59.3% (n=27)
Gabapentin 59% (n=39)
Topiramate 55.6% (n=18)
Oxcarbazepine 23.5% (n=34)
Arif H, et al. Arch Neurol 2010; 67:408-413.
Drug Selection in
Adult Partial Seizures

12-month seizure freedom
– lamotrigine 54.1% (n=85)
–
–
–
–
–
levetiracetam 42.6% (n=68)
valproic acid 27.8% (n=18)
carbamazepine 27.6% (n-29)
topiramate 20% (n=15)
gabapentin 18.5% (n=27)
– oxcarbazepine 9.4% (n=32)
Arif H, et al. Arch Neurol 2010; 67:408-413.
Osteomalacia/Osteoporosis
• Decreased Vitamin D levels (phenobarbital,
primidone, phenytoin, and carbamazepine)
– Secondary hyperparathyroidism
– Increased bone turnover
– Osteomalacia

Antifolate properties (phenobarbital,
primidone, phenytoin, carbamazepine,
oxcarbazepine, lamotrigine)
– Increase homocysteine levels
– Reduction of bone mineral density
Stephen LK, Brodie MJ. Neurol Clin. 2009; 27:967-992.
Treatment failure
Inappropriate drug selection
 Inappropriate dose
 Poor adherence
 Negative lifestyle-alcohol/drug
abuse
 Refractory patient

470 de novo epilepsy patients
Variable
N
%
Seizure-free on 1st monotherapy
222
47
Seizure-free on 2nd monotherapy
61
13
Seizure-free on 3rd monotherapy
6
1
12
3
301
64
Seizure-free on 2 drugs
Total Seizure-free
Initial therapy: CBZ 45%, Na Valproate 22%, LMT 17%
Brodie MJ, Kwan P. Neurology 2002; 58 (Suppl 5):S2-S8.
Polypharmacy



Titrate initial drug to maximal
therapeutic levels
Titrate second drug to therapeutic
levels before withdrawal of first agent
Hard to control patients often have
underlying cerebral pathology &
higher # (>20) of seizures prior to
treatment
Adverse Drug Effects (ADE)
Concentration Dependent
 Chronic Side Effects
 Idiosyncratic

Concentration Dependent

Most AEDs
– GI


Nausea
Vomiting
– CNS




Dizziness
Drowsiness
Unsteadiness/ataxia
Nystagmus/diplopia/blurry vision
Concentration Dependent ADE
AED
ADE
Carbamazepine
Hyponatremia
Ethosuximide
Hiccoughs
Levetiracetam
Behavior disturbances
Phenobarbital
Hyperactivity*
Tiagabine
Weakness
Topiramate
Word finding difficulties, Psychomotor slowing,
difficulties concentrating
Valproic Acid
Tremor, thrombocytopenia
Zonisamide
Cognitive Impairment
* children
Levetiracetam
Behavioral Symptoms

Incidence
– Adults 13% vs. 6.2% placebo
– Children 37.6% vs. 18.6% placebo

Symptoms
–
–
–
–
–
Agitation
Aggression
Anger
Anxiety
Apathy
-Depression
-Emotional lability
-Hostility
-Irritability
Chronic ADE
AED
ADE
Carbamazepine Hyponatremia, metabolic bone disease
Ethosuximide
Behavior changes, headache
Phenobarbital
Behavior changes, connective tissue disorders,
intellectual blunting, metabolic bone disease, mood
change, sedation
Phenytoin
Behavior changes, connective tissue changes, skin
thickening, folate deficiency, gingival hyperplasia,
hirsutism, coarsening of facial features, acne, cognitive
impairment, metabolic bone disease, sedation
Valproic Acid
Polycystic ovarian disease, weight gain,
hyperammonemia, menstrual cycle irregularities
Gum Hyperplasia
Chronic ADE
AED
ADE
Gabapentin
Weight gain
Oxcarbazepine
Hyponatremia (7% >65 yrs)
Pregabalin
Weight gain
Topiramate
Weight loss, kidney stones (1.5%,weak carbonic
anhydrase inhibitor)
Vigabatrin
Visual field defects (30-50%), weight gain
Zonisamide
Weight loss, kidney stones (4%),
aggression, depression, mood swings
Idiosyncratic ADE
AED
ADE
Carbamazepine
Blood dyscrasias, rash
Ethosuximide
Blood dyscrasias, rash
Phenobarbital
Blood dyscrasias, rash, hepatotoxicity
Phenytoin
Blood dyscrasias, rash, lupus-like syndrome
Primidone
Blood dyscrasias, rash
Valproic Acid
Acute hepatic failure, acute pancreatitis,
alopecia
Valproic Acid

Liver Toxicity
– Risk factors





<2 years of age
Intellectually disabled
Inborn errors of metabolism
Multiple AEDs
Difficult to control seizures
– Monitor for



Nausea
Fatigue
Loss of seizure control
Idiosyncratic ADEs
AED
ADE
Felbamate
Aplastic anemia, acute hepatic failure
Gabapentin
Peripheral edema (2-8%)
Lacosamide
Hepatic dysfunction, 1st degree AV block, rash
Lamotrigine
Rash (non-serious) 7%, Rash (SJS /TEN) children <16 years
0.8%, Adults adjunctive therapy 0.3%, Adults epilepsy
monotherapy 0.13%, hepatic and renal failure, DIC, arthritis
Oxcarbazepine
Rash
Pregabalin
Peripheral edema, creatine kinase elevation, decreased
platelets
Tiagabine
Stupor
Topiramate
Metabolic acidosis, open angle glaucoma, hypohidrosis*
Vigabatrin
Psychosis
Zonisamide
Rash, hypohidrosis*
* children
Severe Cutaneous Adverse
Reactions (SCARs)
Implicated drugs
 Recognition

– Causative Agent?
– Differential



Infectious- mononucleosis, toxic shock
syndrome or bacterial septic shock
Inflammatory - SLE
Neoplastic - lymphoma
Classification

SJS/TEN
– Stevens-Johnson Syndrome
– Toxic epidermal necrolysis
– SJS-TEN overlap syndrome

Anticonvulsant hypersensitivity
syndrome
Anticonvulsant
Hypersensitivity Syndrome
Incidence: 1/1000 – 1/10,000
 Triad of fever, skin rash and
internal organ involvement
 Onset

– Initial: 2-8 weeks
– Challenge: rapid
Comparison
AHS
SJS/TEN
2-8 weeks
1-3 weeks
Fine,red rash
confluence, blisters
All types primarily
morbiliform
Fever
+++
+++
Facial edema
+++
---
Hepatitis
+++
++
+/-
+++
Normal
decreased
Time to eruptions
Typical Lesion
Mucosal involvement
Neutrophils
Mechanism

Association with excess of reactive
metabolites
– Oxidative metabolism of parent compounds
by CY P450 and other enzyme systems to
toxic arene oxide metabolites
– Detoxification by epoxide hydroxylase

Susceptibility to AHS
– Lack of enzyme or mutated enzyme

Cross reactivity between phenytoin,
carbamazepine and phenobarbital
Bohan KH, et al. Pharmacotherapy 2007;27:1425-1439.
Management



Discontinue causative agent
Symptomatic and supportive therapy
New AED Concerns
–
–
–
–
–
Wait till SCAR wanes
Cross reactivity
Hepatotoxicity
Incidence of rash
Long induction times
Bohan KH, et al. Pharmacotherapy 2007;27:1425-1439.
Management of SCARs
Burn unit or specialized center
 Biological, biosynthetic, silver or
antibiotic impregnated dressing
 NO systemic corticosteroids
 NO prophylactic antibiotics

Endorf FW, et al. J Burn Care Res 2008;29:706-712.
Status-Epilepticus

S.E. is a 25 yo, 60 kg male, recently
diagnosed with idiopathic epilepsy. He
has been treated with CBZ 600 mg/day
for GTCS with a serum concentration of
10 mcg/ml. He had 2 tonic-clonic
seizures while visiting friends, each
lasting 3-4 minutes. He was
transported to a hospital within 15
minutes and seized again at the ER.
Status Epilepticus
BP 197/104
 Pulse 124 beats/min
 Respirations 23/min
 Rectal temp 37.5 C
 Does he meet criteria for S.E.?
 What are the risks associated with
S.E.?

S.E. Criteria

More than 5 minutes of
– continuous seizure activity or
– 2 or more sequential seizures
without full recovery of
consciousness in between
Risks of S.E.






Hyperthermia
Cardiorespiratory collapse
Myoglobinuria
Renal failure
Neurologic damage
– excessive electrical activity
– increased demand for glucose and oxygen
– decreased blood flow and accumulation of
lactate and necrosis
Peripheral lactate accumulation, alterations in
glucose, electrolytes
Status Epilepticus
Mortality - 30%
 Long-term neurologic
consequences

– Cognitive impairment
– Memory loss
– Worsening of seizure disorder
Treatment of S.E.

Ensure ventilation
– airway established
– if not, prevent aspiration




IV Line with NS
Glucose, electrolytes, AED
concentration, toxicology screens
Adults: Thiamine 100 mg (prevent
Wernicke’s)
Followed by 25 gm glucose
(hypoglycemia)
Status Epilepticus
1st line

Lorazepam 0.1 mg/kg at 2 mg/min IV
push (usual 2-4 mg)
– dilute with NS or H2O to prevent venous
irritation
– Repeat every 5-10 minutes as needed
(maximum dose of 12 mg)
– Monitor for hypotension, respiratory
depression
– Effective up to 72 hours
Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.
Status Epilepticus
1st line

Diazepam
– Alternative to lorazepam
– 0.2 mg/kg at 5 mg/min IV until seizure activity is
stopped or maximum dose of 20 mg
– Redistribution occurs quickly

Must give long acting AED (i.e., fosphenytoin) to prevent
recurrent seizures
– Cannot be given IM
– Unpredictable respiratory collapse or sudden
hypotension
Kinirons P, Doherty CP. Eur J Emerg Med 2007;15:187-195.
Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.
Phenytoin/Fosphenytoin
2nd line

Phenytoin
– Can be given IV, NOT IM
– Loading dose 20 mg/kg





Rate ≤50 mg/min
Dilute in 100-500 ml 0.45%-0.9% NaCl
Use 0.45 to 0.22 micron filter
Monitor BP, ECG, burning pain
Fosphenytoin
– Give IV in status epilepticus
– 500 mg P.E./10 ml
– Can be given IM for maintenance

Therapeutic levels within 60 minutes
– ≤150 mg P.E./minute
Status Epilepticus
2nd line

Valproic Acid
– Rapid IV infusion over 5-10 minutes
diluted in 50-100 ml D5W/NS/LR
– 20-45 mg/kg up to 6 mg/kg/min
– Usual 20-30 mg at 3 mg/kg/min
– Efficacy


First line: 66% vs. 42% phenytoin
Second Line: 79% vs. 25% phenytoin
– Caution


Hyperammonemia
Mitochondrial disorders
Kinirons P, Doherty CP. Eur J Emerg Med 2007;15:187-195.
Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.
Misa UK, et al. Neurology 2006;67:340-342.
Status Epilepticus
2nd line

Levetiracetam
– Up to 20 mg/kg in 100 ml NS/LR/ or D5W
– Usually 1500 to 2500 mg over 5-15 minutes
Fattouch J, et al. ACTA Neurol Scand 2010;121:418-421.
Berning S, et al. J Neurol 2009;256:1534-1642.
Refractory
Status Epilepticus
Phenobarbital
 General anesthesia

– Midazolam
– Propofol
– Pentobarbital
Diazepam Rectal Gel

0.2-0.5 mg/kg depending on age
– 2 - 5 yrs: 0.5 mg/kg
– 6-11 yrs: 0.3 mg/kg
– >=12 yrs: 0.2 mg/kg




Calculate recommended dose by
rounding upward
Elderly: adjust dose downward to
decrease ataxia or oversedation
2nd dose may be given 4 to 12 hr after
first dose
Availability: 2.5, 5, 10, 15, 20 mg
Questions?