Hemostasis Physiology and Clinical correlations by Dr Faiza.pdf
First Generation Anti-Epileptic Drugs (AEDs) - Shayne McKee Pharmacy
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)