Topic discussion regarding first generation antiepileptics made and presented by pharmacy student Shayne McKee

1. Shayne McKee
Seizure Disorders
Importance
Seizures come in a largevariety of forms, lengths, and intensities.There areseveral types of seizures and seizuredisorders –and much of the time we don’t know the true causeof a
seizure. Seizures are thought to be a resultof genetic (inherited or not) and environmental abnormalities thatcan either function separately or synergistically to produce a seizure.
Definitions
(any definitions pertinent to today’s topic. Examples: what is the definition of the diagnosispresented/how do you define an ischemic stroke; stroke scales may be discussed here;
etc.)
 Seizure – a sudden, excessive,highly synchronous dischargeof neuronal activity that results in changes in perception, sensation,and behavior.
 Epilepsy – A brain disorder thatresults in the patient experiencing recurrent seizures. Seizures may or may not resultin loss of consciousness,abnormal movements,
behavior,impairment. 2 or more seizures,at least24 hours apart, provoked by systemic or neurological insults.
 Status epilepticus –a prolonged seizure; a continuous state of seizureactivity.Can be defined as lastinglonger than 5 minutes.
 Syndrome – a group of signs and symptoms that characterizea disease/disorder
Background/Epidemiology
 The annual incidence of seizuresare about80 in100,000 (epilepsyisseenin45in 100,000). In the US, the prevalence of epilepsyisincreasing.Floridahasthe
3rd
highestprevalence,afterCaliforniaandTexas.
 Epilepsyisthe mostcommonneurologicaldisorderinchildren,withaprevalence of 1 in100 inthe US. Childrenyoungerthan3 yearsold have the highest
incidence.The mostcommontype of seizure inchildrenyoungerthan5 are febrile seizures.
Risk Factors
 Age
 Familyhistory
 Genetics
 Headinjuriesortraumas
 Dementia
 Infections
 Environment
Causes/Etiology/Pathophysiology
 Seizures can be caused or triggered by many things,including:
o Electrolyte deficiencies (hyponatremia,hypocalcemia,hypomagnesemia,hypogl ycemia)
o Alcohol/sedativewithdrawal
o TBI

2. o Strokes
o Brain tumors
o Stress/sleep deprivation
o Drug overdoses or interactions,drugs that lower seizurethreshold
o But…. most commonly, the etiology is UNKNOWN!
 Duringa seizure,neurons become synchronized to produce a paroxysmal depolarizingshift (PDS).A PSD becomes pathological when too many cells undergo a PDS
simultaneously,which may end up producinga seizure. How this happens is still notentirely clear,but could be the resultof dysfunctional feedback inhibition of GABA-ergic
neurons (a failureof surround inhibition). When GABA interneurons fail to neutralizeexcitation from other surrounding neurons,such as glutaminergic neurons,this
excitation can spread in a multisynaptic fashion throughoutthe entire brain and resultin a seizure– whereas with a functional GABA system, for example, this neuronal
transmission would normally bemonosynaptic.Many drugs work by increasingor enhancingsurround inhibition to prevent recurrent excitation (iemany AED drugs enhance
GABA transmission).Another common drug mechanismis by reducingexcitation,usually by interactingwith sodiumchannels.
Signs/Symptoms
 Staring
 Stiffeningorincreasedmuscle tone
 Jerkingmovementsof the armsor legs
 Loss of consciousness
 Loss of bowel orbladdercontrol
Types, Diagnosis and Assessment
 The 2017 ILAE Classification of Epilepsies
o Levels of Diagnosis
 Seizure type
 1. Focal
o Results from a specific region in the brain
 Many subtypes
 Simple partial
o Motor
o Sensory
o Autonomic
o Psychic
 Complex partial
o Non-evolving
o Evolving (aka secondarily generalized seizures)
 2. Generalized
o Can begin likea focal seizure,but the focal pointmay be in the thalamus.This causes a generalized seizurethat affects both hemispheres.A
focal seizurecan develop into a generalized seizureif it recruits the thalamus (a secondarily generalized seizure or evolvingcomplex partial
seizure)

3. o Can be convulsiveor nonconvulsive
 Convulsiveseizures can be tonic,clonic,myoclonic,or atonic in nature
 Tonic: muscletone increased,sudden stiffeningmovements
 Clonic:Rhythmic jerking
 Atonic: loss of muscletone
 Myoclonic:brief shock-likejerks of a muscleor group of muscles
 Tonic-clonic:presents as a tonic seizure,followed by a clonic seizure.“Grand-mal”
 Nonconvulsiveseizures can be described as simpleabsence,complex absence, or atypical absence
 Simple absence: Start and stop abruptly.Awareness is impaired,and patients may not realizethey had a seizure. “Petit-mal”
 Complex absence: Same as a simpleabsence seizurebut involves changes in muscleactivity,such as eyeblinking,finger
twitching, etc.
 Atypical absence: Longer than the others, and patient is usually awarea seizuretook place.
 3. Unknown
 Epilepsy type
 Focal
 Generalized
 Combined Focal & Generalized
 Unknown
 Epilepsy Syndrome
 Brings together EEGs, imaging,and other seizure characteristics thattend to occur together. Also takes into accountpatient characteristics likeage,
seizuretriggers, onset, remission,etc.
 Types:
o Febrileseizures
o Childhood Absence Seizures
o Juvenile Myoclonic
o LGS
o West syndrome
 Autoimmune Encephalitis
o Antibodies produced againstNMDA-recepetors, GABA-B receptors, GABA-A receptors, and LGI1 proteins can causeseizure.
o Anti-NMDAR is diagnosed by confirmingantibody presence in the CSF againstthe GluN1 subunitof the NMDA receptor. The Dopamine-2 receptor may also beinvolved.
 Diagnosis& Assessment
o An EEG is used to diagnoseand assess a seizure.The EEG reports synchrony of neurons in terms of frequency and amplitude. When the brain is actively engaged in
activity,there is a high frequency and low amplitude. When the brain is less active,the EEG will showa lowfrequency and higher amplitudewhile the brain is atrest. The
electrodes are measuring neuronal activity and as a result,when all neurons arefiringtogether, synchrony will bedisplayed as lowfrequency and high amplitude. During
a seizure, neurons appear to be more synchronized.

4. 
Treatment/Management
(be sureto be familiar with each medication and the clinical pearlsof each)
1st
Generation AEDs
Drug
Molecular Target/
Mechanism
PK/PD Drug Interactions
Adverse Reactions
(separate by dose dependent,
chronic, idiosyncratic)
Monitoring
(levels, labs)
Clinical Pearls
Phenytoin  Sodium blockade
 Suspensionformulation
absorptionis highly
variable
 Highlyproteinbound
 Hepatic metabolism;
2C9
 Half-life ~20 hours
 Decreased
metabolism with
2C9 *2/3 alleles,
most commonly
seenin Caucasians.
 Valproic acid,
warfarin, aspirin,
Bactrim, and
ceftriaxone all
compete for
bindingwith
albumin. This will
increase phenytoin
free concentration.
 Dose-dependent
o >20mg: Blurred vision
o >40mg: cognitive
impairment
o >100mg:death
o N/V
o Hyperglycemia
o Fever
 Idiosyncratic
o Hypertrichosis
o Gingival hyperplasia
o Rash(SJS/TENS)
o Bradycardia, hypotxn
o Phlebitis;purple
glove syndrome
o Osteomalacia
 LFTs
 BMD
 Cardiac (BPduring IV
administration)
 HLA-B haplotype
 Behavior
 TDM:
o Metabolismis
saturable and
non-linear,
thus a narrow
therapeutic
index drug
 Binds to enteraltube
feeds, holdfeeds 1 hour
before & after
administration
 In Asian patients, must
test for HLA-B*1502. If
positive, contraindicated.
 Associated withDRESS
syndrome
 Steadystate cantake up
to a week
Fosphenytoin  ^  ^  ^
 Lower risk for cardiac
arrythmias
 ^
 Injectable only;can
be administered IM
where phenytoin
cannot.
 A prodrug of
phenytoin
 No phlebitis
 Can administer at a
faster rate
(150mg/minvs
50mg/min).
However, the onset
will not be anyfaster
since it is a prodrug

5. and must be
converted first.
 First-line inneonatal
seizures
Valproic Acid
 Enhance, mimic,
or increase GABA
availability
 Highlyproteinbounds
 Hepatic metabolism
(conjugation)
 Half-life about 15 hours
 Phenytoin, warfarin,
aspirin, Bactrim, and
ceftriaxone all compete
for bindingwith
albumin. This will
increase phenytoinfree
concentration.
 Phenytoin,
warfarin, aspirin,
Bactrim, and
ceftriaxone all
compete for
bindingwith
albumin. This will
increase VPA free
concentration.
 Alopecia, rash
 Insulinresistance + weight gain
 N/V/D/Abdominal pain
 Tremor
 Increasedammonia
levels/encephalopathy
 CBC/platelets
 LFTs (Q6mo)
 Drug concentrations
(therapeutic range 50-
100mg/L)
 Ammonia levels –
especiallyif lethargic of
alteredmental status
 Behavior
 Contraindicatedina
historyof urea cycle
disorder
 Associated withDRESS
syndrome
Phenobarbital
 Barbiturate with
high therapeutic
index. Inhibits
spreadof seizure
activity, increases
threshold.
Promote GABA
bindingand
increase lengthof
time that chloride
channels are
open.
 Acidosis canincrease
BBB penetration
(leaves phenobarbital
unionized)
 The longest acting of all
barbiturates(t1/2 96h)
 2C9 metabolism, may
induce clearance of
other drugs
 Opiates
 Anesthetics
 H1 antagonists
 TCAs/MAOIs
 1st Gen
antipsychotics
 EtOH
 HIV drugs
 There is poor separation
betweenanticonvulsant effects
and sedative side-effects
 Aganulocytosis
 Anemia
 Anxiety
 Respiratorydepression at conc.
>50mcg/mL
 CBC
 LFTs
 Serum Cr/BUN
 TDM:15-40 mcg/mL
 Avoid use inpatients with
acute painas
phenobarbital can
exacerbate pain.
 Paradoxical reactions
(agitation, hyperactivity,
acute pain)
 Oral administration
contraindicatedin
patients withpulmonary
disease with dyspnea or
obstruction.
 Not usedoften, but are
first-line drugs inneonatal
seizures
Primidone
 Both parent drug
and metabolite
are active
(phenobarbital).
Increases the
seiure threshold
and inhibits
spreadof a focal
seizure. Toxic
(but also active)
metabolite is
PEMA.
 Metabolizedinliver to
produce phenobarbital
and PEMA.
 Minimal plasma
proteinbinding
 Half-life 10 hours
 PEMA half-life 30+
hours and
phenobarbital half-life
several days ->
accumulation
 Renal excretion
 Primidone andits
metabolites
increase clearance
of other drugs
metabolized by
CYP2C, 3A, and
1A2.
 Accumulate in
patients withrenal
impairment
 Increasedsuicide risk/mood
changes
 Sexual dysfunction
 Inc. riskof fallsingeriatrics
(drowsiness/dizziness)
 VitaminB andD deficiencies
 CBC
 LFTs
 Toxic concentrations:
>15mcg/mL
 Neonates andinfants
minimallyconvert
primidone to
phenobarbital.
Carbamazepine
 Unknown;
thought to block
sodium
 Absorptionimproved
with highfat meals
 Half-life 36hr with
single dose, but
significantlydecreases
with multiple doses
 Similar structure to
TCAs, avoidif
hypersensitive to
TCAs or using
concurrent MAOI.
 Hyponatremia (SIADH)
 GI – nausea, vomiting, diarrhea,
abdominal pain
 CNS – dizziness/drowsiness
 RASH
 Blurredvision, cataracts,
increasedIOP
 CBC/platelets for
anemia/agranulocytosis
 Sodium for
hyponatremia
 LFTs
 Eye exam
 HLA-B*1502 allele
 Cross-reactive
dermatologic reaction
with phenytoin.
 Auto-inductioncanoccur
within 3-5 days

6.  Hepatic metabolism
with anactive
metabolite.
 Auto-induces its own
metabolism
 Mostlyexcretedin
urine withsome inthe
feces
 BOXED WARNING: aplastic
anemia/agranulocytosis.
 BOXED WARNING: severe
dermatologic reactions inHLA-
B*1502 allele
 Behavior/cognitive fxn  Maysee Tegretol XR
formulation/casing in
stool
 Oxcarbazepine doesnot
have anyautoinduction
but has more
hyponatremia
Lorazepam
 Allosteric GABA
enhancement.
Increases affinity
for GABA to
GABA-receptor,
increases
frequencyof
chloride channel
openings.
 Different from
barbituratesin
that theyrequire
GABA to work.
Also different by
increasing
frequency of
GABA channel
openings vs.
barbiturates
increasing
duration of time
 Crosses BBB
 Highlyproteinbound
 Conjugatedin liver
 Doesn’t accumulate
 T1/2 13hrs
 Opiates
 Anesthetics
 H1 antagonists
 TCAs/MAOIs
 1st Gen
antipsychotics
 EtOH
 Sedation
 Allergic reactions in asthmatics
 Respiratorydepression
 Hypotension
 Lab monitoring is not
necessary
 Must taper off slowly, esp.
shorter acting agents.
Abstinence syndrome:
panic, muscle twitches,
convulsions
 ADEs decrease over
repeatedtreatment
Clonazepam  ^
 Has noactive
metabolite
^ ^
 CBC
 LFTs ^
Diazepam  ^
 Verylong half-life
up to 100hrs
 Metabolizedby
2C19 and 3A4
^ ^
 CBC
 LFTs
 ^
References
 March 1, 2018
N Engl J Med 2018;378:840-851
DOI: 10.1056/NEJMra1708712
 Clinical Pharmacology (for druginformation)
 Class notes (for drug information)