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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

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selection of antiepileptic medications in adults

Selection of Antiepileptic Medications in Adults

Michele Y. Splinter, Pharm.D., M.S., BCPS

Associate Professor

College of Pharmacy

University of Oklahoma HSC

objectives
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
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
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 AcadSci2010;1184:208-224.

causes of seizures1
Causes of Seizures
  • Metabolic
    • Hyponatremia
    • Hypomagnesemia
    • Hypoglycemia
    • Hyperglycemia
    • Hypocalcemia

Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.

causes of seizures2
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
AED Selection
  • Efficacy for type of seizure
  • Tolerability
  • Co-Morbidities
  • Drug Interactions
slide8
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
Which of the following medications would be most appropriate for S.Z.?
  • A. Gabapentin
  • B. Levetiracetam
  • C. Oxcarbazepine
  • D. Phenytoin
efficacy and tolerability
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
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 seizures1
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
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
Treatment failure
  • Inappropriate drug selection
  • Inappropriate dose
  • Poor adherence
  • Negative lifestyle-alcohol/drug abuse
  • Refractory patient
470 de novo epilepsy patients
470 de novo epilepsy patients

Initial therapy: CBZ 45%, Na Valproate 22%, LMT 17%

Brodie MJ, Kwan P. Neurology 2002; 58 (Suppl 5):S2-S8.

polypharmacy
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
Adverse Drug Effects (ADE)
  • Concentration Dependent
  • Chronic Side Effects
  • Idiosyncratic
concentration dependent
Concentration Dependent
  • Most AEDs
    • GI
      • Nausea
      • Vomiting
    • CNS
      • Dizziness
      • Drowsiness
      • Unsteadiness/ataxia
      • Nystagmus/diplopia/blurry vision
levetiracetam behavioral symptoms
LevetiracetamBehavioral Symptoms
  • Incidence
    • Adults 13% vs. 6.2% placebo
    • Children 37.6% vs. 18.6% placebo
  • Symptoms
    • Agitation -Depression
    • Aggression -Emotional lability
    • Anger -Hostility
    • Anxiety -Irritability
    • Apathy
valproic acid
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
severe cutaneous adverse reactions scars
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
Classification
  • SJS/TEN
    • Stevens-Johnson Syndrome
    • Toxic epidermal necrolysis
    • SJS-TEN overlap syndrome
  • Anticonvulsant hypersensitivity 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
mechanism
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
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
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
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 epilepticus1
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
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
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 epilepticus2
Status Epilepticus
  • Mortality - 30%
  • Long-term neurologic consequences
    • Cognitive impairment
    • Memory loss
    • Worsening of seizure disorder
treatment of s e
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 1 st line
Status Epilepticus1st 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 1 st line1
Status Epilepticus1st 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 2 nd line
Phenytoin/Fosphenytoin2nd 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 2 nd line
Status Epilepticus2nd 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 2 nd line1
Status Epilepticus2nd 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
Refractory Status Epilepticus
  • Phenobarbital
  • General anesthesia
    • Midazolam
    • Propofol
    • Pentobarbital
diazepam rectal gel
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 given4 to 12 hr after first dose
  • Availability: 2.5, 5, 10, 15, 20 mg