PHARMACOLOGY ANTISEIZURE Flashcards
a severe form of epilepsy, usually beginning @ childhood and is characterized by cognitive impairment; can suffer from multiple types of seizures
Lennox-Gastaut Syndrome
characterized by an
abnormal interictal high-amplitude slow waves, and EEG
will yield multifocal asynchronous spikes
Infantile Spasms s/ hypsarrhythmia:
continuous seizures; goal is to rapidly
terminate the behavioral and electrical seizure activity
because the longer episode untreated → more difficult to
control → higher risk for permanent brain damage (vessels constricted during seizures → brain hypoxia)
Status Epilepticus
(effective for newly diagnosed absence epilepsy, but not yet approved for said indication
Lamotrigine
CONVENTIONAL ANTISEIZURE
Focal Aware
Carbamazepine
Phenytoin
CONVENTIONAL ANTISEIZURE
Focal Aware w/ Impaired Awareness
Valproate
CONVENTIONAL ANTISEIZURE
Focal to Bilateral Tonic-Clonic
Carbamazepine
Phenytoin
Valproate
Phenobarbital
Primidone
RECENTLY DEVELOPED ANTISEIZURES
Focal Aware
Focal w/ Impaired
Awareness
Focal to Bilateral Tonic-Clonic
Brivaracetam
Eslicarbazepine
Ezogabine
Gapantin
Lacosamide
Lamotrigine
Levetiracetam
Perampanel
Rufinamide
Tiagabine
Topiramate
Zonisamide
CONVENTIONAL ANTISEIZURE
Generalized
Absence
Ethosuximide
Valproate
Clonazepam
CONVENTIONAL ANTISEIZURE
Generalized
Myoclonic
Valproate
Clonazepam
CONVENTIONAL ANTISEIZURE
Generalized
Tonic-Clonic
Carbamazepine
Phenobarbital
Phenytoin
Primidone (not first line drug)
Valproate
RECENTLY DEVELOPED ANTISEIZURES
Generalized
Absence
Lamotrigine
RECENTLY DEVELOPED ANTISEIZURES
Generalized
Myoclonic
Levetiracetam
RECENTLY DEVELOPED ANTISEIZURES
Generalized
Tonic-Clonic
Lamotrigine
Levetiracetam
Topiramate
CONVENTIONAL ANTISEIZURE
Infantile spasms w/
hypsarrhythmia
Vigabatrin
CONVENTIONAL ANTISEIZURE
Lennox-Gastaut
Syndrome
ASDs + Lamotrigine
CONVENTIONAL ANTISEIZURE
Status Epilepticus
and Other
Convulsive
Emergencies
IV Diazepam (rapidly
absorbed) followed by
Phenytoin
Lorazepam
Phenobarbital; and
Phenytoin
RECENTLY DEVELOPED ANTISEIZURES
Lennox-Gastaut
Syndrome
Felbamate
Adjunct: Topiramate
Clobazam
RECENTLY DEVELOPED ANTISEIZURES
Status Epilepticus
and Other
Convulsive
Emergencies
IM Midazolam
considered equally effective for generalized absence
Ethosuximide & Valproate:
D.O.C. for generalized tonic-clonic and for
myoclonic seizures, particularly in the syndrome of
Juvenile Myoclonic Epilepsy
Valproate
also demonstrated to be efficacious AS
AN ADJUNCT (additional only) for refractory (not
responsive to initial treatment) Generalized Myoclonic
Levetiracetam
Enhancement of GABA neurotransmission through actions on
GABAA receptors
Modulation of GABA metabolism
Inhibition of GABA reuptake into the synaptic
terminal
actions on the synaptic vesicle protein SV2A or Ca 2+ channels containing the α2δ subunit
Modulation of synaptic release
This period is also thought to be the refractory period, where neuronal cell may be rendered
unresponsive to any form of stimulation for a short time
Depolarization
Molecular Target
& Activity
Enhance fast inactivation (shortens recovery period from
inactivation)
Phenytoin (PHT)
Carbamazepine
(CBZ)
Lamotrigine (LTG)
Felbamate (FBM)
Topiramate (TPM)
Oxcarbazepine
(OxCBZ)
Valproate (VPA)
Eslicarbazepine
(ESL)
Rufinamide (RUF)
Molecular Target
& ActivityMolecular Target & Activity
Enhance slow
inactivation (prolongs
inactivated state)
Lacosamide (LCM)
Consequence of Action
Lacosamide (LCM)
↑ Spike frequency adaptation (not really important_
↓ AP bursts, focal firing,
and seizure spread
Stabilize neuronal
membrane
Molecular Target &
Activity
GABAA receptor
allosteric modulators
Benzodiazepines
(BZDs)
Phenobarbital (PB)
Felbamate (FBM)
Primidone (PRM)
Carbamazepine
(PRM))
Oxcarbazepine
(PRM)
Topiramate (TPM)
Clobazam (CLB)
Stiripentol (STP)
Consequences of Action
Benzodiazepines
(BZDs)
Phenobarbital (PB)
Felbamate (FBM)
Primidone (PRM)
Carbamazepine
(PRM))
Oxcarbazepine
(PRM)
Topiramate (TPM)
Clobazam (CLB)
Stiripentol (STP)
↑ Membrane
hyperpolarization and seizure threshold (anything that increases GABA activity also increases membrane
hyperpolarization)
↓ Focal firing
(BZDs—attenuate
spike-wave discharges;
PB, CBZ, OxCBZ—aggravate spike-wave
discharges)
Molecular Target &
Activity
GABA uptake inhibitor/
GABA transaminase inhibitor
Tiagabine (TGB)
Vigabatrin (VGB)
Consequences of Action
Tiagabine (TGB)
Vigabatrin (VGB)
↑ Extrasynaptic GABA levels & membrane hyperpolarization
↓ Focal firing
Aggravate spike-wave
discharges
Inhibition of α2δ subunit on Ca 2+ channel → promote GABA release
Gabapentin
Pregabalin
Inhibition of SV2A → inhibits Glutamate release
Levetiracetam
Molecular Target & Activity
α2δ Ligands
Gabapentin (GBP)
Pregabalin (PGB)
Consequences of Action
Gabapentin (GBP)
Pregabalin (PGB)
Modulate neurotransmitter release discharges
Molecular Target
& Activity
SV2A protein ligand
Levetiracetam (LEV)
Brivaracetam (BRV)
Consequences of Action
Levetiracetam (LEV)
Brivaracetam (BRV)
- Unknown; may decrease NTA release
predominantly expressed in neurons & are important determinants of cellular activity
KCNQ 2-5 channels
increases number of KCNQ channels that are open at rest and also prime the cell to respond with a larger, more rapid, and more prolonged response to membrane depolarization
Ezogabine (a.k.a. Retigabine)
KCNQ 2-5 channels
Seem to act like a brake to prevent the high levels of neuronal AP burst firing
epileptiform activity
levels increase with epileptic
condition
Carbonic Anhydrase
highly (>90%) bound to plasma proteins
can be displaced → temporary increased free fraction → transient toxicity but easily corrected
Phenytoin
Tiagabine
Valproate
Diazepam
Perampane
do not affect microsomal enzymes
Levetiracetam
Gabapentin
Pregabalin
Absorption
○ Almost complete (100%), slower with food (do not give it with food)
○ Peak levels: 6-8 hours
CARBAMAZEPINE
Distribution
○ slow, Vd = 1L/kg
○ 70% protein bound (no displacement observed)
CARBAMAZEPINE
Elimination
○ low systemic clearance = 1L/kg/day
○ microsomal enzyme inducer (biphasic elimination)
○ T ½ = 36 hours, 8-12
hours
CARBAMAZEPINE
Preparation
○ Oral form; extended release formulations
CARBAMAZEPINE
Dose
○ Higher dosage is achieved if given at multiple divided doses daily
○ If you give the extended release form, this may permit twice daily dosing
○ Pediatric: 15-25 mg/kg/day
○ Adults: maintenance dose is 800-1200 mg/d
○ maximum recommended dose is 1600 mg/d (Giving maximum dose is avoided because it
increases risk of adverse effects)
CARBAMAZEPINE
Therapeutic plasma level:
4-8 mcg/ml
CARBAMAZEPINE
○Focal seizure
○ Focal-to-bilateral tonic-clonic seizure
○ Trigeminal and glossopharyngeal neuralgia
○ Mania in Bipolar Disorder
○ There’s anecdotal evidence that it may be
effective in treatment of generalized tonic clonic
(idiopathic generalized epilepsies)
○ Use it with caution because it can exacerbate absence and myoclonic seizures
CARBAMAZEPINE
CARBAMAZEPINE
increase the rate of the metabolism (Inducer -
decrease the plasma concentration)
Primidone, Phenytoin, Ethosuximide,
Valproic acid, Clonazepam, Warfarin, Oral contraceptives, Doxycycline, Haloperidol
CARBAMAZEPINE
inhibit carbamazepine clearance (Inhibitor -
increase the plasma concentration)
Propoxyphene, Troleandomycin, Valproic
Acid, lithium
■ e.g. Valproic Acid (inhibitor) +
Carbamazepine = increase plasma
concentration of Carbamazepine
increase carbamazepine
Cimetidine, Erythromycin, Isoniazid
■ e.g. Cimetidine (potent microsomal enzyme
inhibitor) + Carbamazepine = incr
decrease carbamazepine steady-state
Phenytoin, Phenobarbital
common, dose-related (the higher the dose, the greater the toxic effects)
■ ataxia, diplopia (if drug is above 7mcg/mL)
CARBAMAZEPINE
mild GI upsets, unsteadiness, drowsiness
■ hyponatremia, water intoxication
CARBAMAZEPINE
idiosyncratic (particular individuals)
■ erythematous skin rash
■ aplastic anemia, agranulocytosis
■ hepatic dysfunction
CARBAMAZEPINE
Remedy for Carbamazepine a/e
initiate at a lower dose then slowly increase
until you reach the therapeutic dose
10-keto analog of Carbamazepine
same moa as Carbamazepine
OXCARBAZEPINE
half life of OXCARBAZEPINE
1-2 hours
antiseizure activity resides almost exclusively in the active 10-hydroxy metabolites, S (+), and R (-) licarbazepine (also referred to as monohydroxy derivatives or MHDs)
OXCARBAZEPINE
● less potent than Carbamazepine (clinical dose may need to be 50% higher from that of carbamazepine to
obtain equivalent seizure control)
OXCARBAZEPINE
prodrug of S(+) - licarbazepine
ESLICARBAZEPINE ACETATE
effective half-life of S(+)-licarbazepine (oral
administration): 20-24 hours (long)
ESLICARBAZEPINE ACETATE
dosage: 400-1600 mg/d; titration typically required
for higher doses
ESLICARBAZEPINE ACETATE
eliminated primarily by renal excretion (Adjust dose if patient has renal impairment)
ESLICARBAZEPINE ACETATE
MOA: binds selectively to the fast inactivated state of sodium channels but the binding is much slower
LACOSAMIDE
Dose: administered BID with 50mg doses and
increasing by 100-mg increments weekly:
○ effective at 200 mg/d
○ greater and roughly similar overall efficacy at 400 and 600 mg/d
LACOSAMIDE
Clinical use: focal-to-bilateral tonic-clonic
(secondarily generalized seizures)
LACOSAMIDE
Adverse effects:
○ dizziness, headache, nausea, diplopia
LACOSAMIDE
Contraindication: phenylketonuria (PKU) - Avoid in patients because aspartame is source of
phenylalanine which is harmful for patients with PKU
LACOSAMIDE
Pharmacokinetics
○ rapidly and completely absorbed, with no food
effect
○ bioavailability nearly 100%
○ plasma concentrations are proportional to oral
dosage up to 800 mg
○ peak concentrations = 1 to 4 hours after oral
dosing
○ elimination half-life = 13 hours
LACOSAMIDE
Absorption:
● oral: salt form almost complete
● IM: unpredictable, precipitation occurs (unlike fosphenytoin)
PHENYTOIN
Distribution:
● peak plasma concentration: 3 to 12 hours
● steady state reached 5-7 d (low levels), 4-6 w (high
levels)
PHENYTOIN
highly protein bound
○ with uremia or hypoalbuminemia - total plasma
level
○ hyperbilirubinemia (bilirubin is also protein
bound)
○ liver disease or nephrotic syndrome (proteins
are excreted)
PHENYTOIN
CSF is proportionate to free plasma concentration
● volume of distribution: 0.6-0.7 L/kg in adults
(low Vd because highly protein bound)
● accumulates in the brain, liver, muscle, fat
PHENYTOIN
Elimination
● metabolized by CYP2C9 and CYP2C19 to inactive
metabolites
● dose-dependent
● Low blood levels - first order kinetics
● blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize the drug
is approached (saturation kinetics)
○ give at high doses, high blood levels, tendency
for phenytoin to accumulate
● T ½ (low to mid therapeutic range) = 24 hrs (12-36
hrs)
○ as half life increases markedly or prolonged,
steady state is not achieved because plasma
levels continue to rise
PHENYTOIN
therapeutic plasma level = 10/20 mcg/ml
when oral therapy is started, it is common to begin
adults at 300 mg/d, regardless of body weight
in adults, dosage should be increased in increments
of no more than 25-30 mg/d
PHENYTOIN
in children, dosage of 5 mg/kg should be followed by
readjustment after steady-state plasma levels are
obtained
predominant form is the sodium salt in an
extended-release pill (OD or BID)
free acid available in immediate-release suspension
and chewable tablets
Fosphenytoin sodium available for IV or IM use and
usually replaces IV phenytoin sodium
PHENYTOIN
Phenytoin displaced from protein binding (increase free form → increase transiently the toxicity)
Phenylbutazone, Sulfonamides, Valproate,
Warfarin
Phenytoin microsomal enzyme inducer
reduce its steady state: Carbamazepine,
Chloramphenicol, Corticosteroids, Haloperidol,
Quinidine, Theophylline, Oral Contraceptives,
Warfarin
reduce plasma levels of Valproic Acid, Tiagabine,
Ethosuximide, Lamotrigine, Topiramate,
Oxcarbazepine and MHDs, Zonisamide,
Felbamate, many Benzodiazepines, Perampane
Phenytoin
inhibit Phenytoin metabolism
INH, Cimetidine, Disulfiram, Doxycycline,
Phenylbutazone, Sulfas, Warfarin,
Chloramphenicol, Valproate
Adverse effects- dose-related
● Short-term
○ diplopia, ataxia, nystagmus, sedation, gingival
hyperplasia, hirsutism
PHENYTOIN
Adverse effects- dose-related
Long-term
○ coarsening of facial features, mild peripheral
neuropathy, osteomalacia (problem in Vit D
metabolism), megaloblastic anemia (folate
levels may be decreased)
PHENYTOIN
Adverse effects- dose-related
Others - Idiosyncratic reactions
○ lymphadenopathy, agranulocytosis, relatively
rare hypersensitivity (rash), fever, exfoliative
skin lesion
PHENYTOIN
MOA: inhibitor of GABA uptake (GAT-1 GABA
transporter
TIAGABINE
Structure: active moiety - nipecotic acid and a
lipophilic anchor (can pass through BBB)
TIAGABINE
Pharmacokinetics
○ bioavailability - 90 to 100%
○ linear kinetics
○ highly protein-bound
○ metabolism - hepatic oxidation by CYP3A
○ T ½ = 5 to 8 hrs
○ elimination: feces (60-65%), urine (25%)
TIAGABINE
○ second line treatment for focal seizures
TIAGABINE
initial dose - 4 mg/d with
○ weekly increments = 4-8 mg/d - to total doses =
16-56 mg/d (4 divided doses)
TIAGABINE
Adverse effects (dose-related)
○ Nervousness, dizziness, tremor, difficulty in
concentrating, depression
○ Requires discontinuation: excessive confusion,
somnolence, ataxia
○ rare: psychosis
○ uncommon: rash (idiosyncratic)
TIAGABINE
Precaution: hepatic impairment
● Contraindication: generalized onset epilepsies
TIAGABINE
MOA: an allosteric opener of KCNQ2-5
(Kv7.2-Kv7.5) voltage-gated potassium channels in
axons and nerve terminals → inhibits release of
various neurotransmitters (e.g. glutamate)
RETIGABINE (EZOGABINE)
Clinical Use: focal seizures (3rd line)
RETIGABINE (EZOGABINE)
Pharmacokinetics
○ Absorption
■ linear kinetics
■ not affected by food
○ major metabolic pathways: N-glucuronidation
and N-acetylation
RETIGABINE (EZOGABINE)
Adverse effects - does not inhibit or induce CYP450
enzymes
○ dose-related: dizziness, somnolence, blurred vision, confusion, and dysarthria
○ urinary symptoms: retention, hesitation, and dysuria (KCNQ channels found in detrusor muscles promoting detrusor smooth muscle elaxation)
○ blue pigmentation (skin, lips, palate, sclera, and conjunctiva
○ ophthalmologic (3rd line because of this)
■ retinal pigment abnormalities
■ macular abnormalities (vitelliform lesions) -
macular degeneration type
■ decreased visual acuity
RETIGABINE (EZOGABINE)
MOA: Na-channel blockade
LAMOTRIGINE
Pharmacokinetics
○ No active metabolite
○ Nearly complete absorption (90%)
○ Vd = 1-1.4L/kg
○ Protein binding = 55%
○ Metabolism
■ Linear kinetics
■ Glucuronidation
■ t1/2 = 24hrs; 13-14hrs (w/ enzyme
inducers)
LAMOTRIGINE
Dose = 100-300mg/d
○ Initial dose = 25 mg/d → increasing to 50 mg/d after 2 wks → titration by 50 mg every 1-2 wks → usual maintenance dose of 225-375 mg/d (in
2 divided doses)
LAMOTRIGINE
Enzyme inducers?
- plasma conc of lamotrigine is
decreased (metab is enhanced)
Carbamazepine,
Oxcarbazepine, Phenytoin, Phenobarbital,
Primidone
(inhibitor of Lamotrigine metabolism) → 2 fold inc. t1/2 (prolonged) → plasma conc of
lamotrigine is increased
Start at a lower dose: Reduce dose to
12.5-25 mg every other day, with increases
of 25-50 mg/d every 2 weeks as needed to a
usual maintenance dose of 100-200 mg/d
(lower)
Valproate
Adverse Effects
○ Dizziness, headache, diplopia
○ Nausea
○ Insomnia
○ Somnolence
○ Skin rash, hypersensitivity
■ Can be life-threatening bc it might progress
to hypersensitivity among pedia pt (1-2%)
■ Serious rash can occur in 0.3-0.8% of
children bet 2-17 y/o
■ In adults: 0.08-0.3%
LAMOTRIGINE
MOA: Binds selectively to a synaptic vesicular
protein SV2A → reduces the release of excitatory
NTA glutamate
SV2A: an integral part of vesicle membrane protein w/c
promotesthe release of NTAs via exocytosis
LEVETIRACETAM
Dose = 500-1000 mg/d BID
○ Increased every 2-4 wks by 1000 mg to a max
dose of 3000 mg/d
○ From Doc: Usually 2000 mg/d
LEVETIRACETAM
Pharmacokinetics
○ Absorption
■ Nearly complete, rapid, unaffected by food
Peak plasma concentration = 1.3 hrs
Distribution: <10% protein binding
Elimination
■ Linear
■ t1/2 = 6-8 hrs
■ 2/3 excreted unchanged in urine
■ Metabolized in the bld
LEVETIRACETAM
Available Preparations
○ Oral formulations extended-release tablets
○ IV prep
LEVETIRACETAM
Drug Interactions: Minimal
○ Neither does it inhibit or induce microsomal
enzymes
LEVETIRACETAM
Adverse effects:
○ Somnolence
○ Asthenia
○ Ataxia
○ Infection (colds)
○ Dizziness
○ Idiosyncratic reactions
○ Less common more serious: Behavioral and
mood changes - irritability, aggression, agitation,
anger, anxiety, apathy, depression, and
emotional lability
LEVETIRACETAM
4-n-propyl analog of Leviracetam w/ high-affinity to SVA2A ligand
BRIVARACETAM
Approved clinical use: Focal (partial) onset seizures
BRIVARACETAM
Pharmacokinetics
○ Rapidly and completely absorbed after oral
administration
○ Low plasma protein-binding (<20%)
○ Linear over a wide dose range (10-600 mg, single
oral dose); twice daily dosing
○ Elimination half-life = 7-8hrs
BRIVARACETAM
Drug Interactions
○ With Carbamazepine → carbamazepine epoxide
(active metab of carba) → INC a/e of carba
○ With Phenytoin → INC phenytoin lvl
BRIVARACETAM
MOA: Potent non-competitive antagonist of the AMPA receptor
Binds to an allosteric site of the extracellular
side of the channel, acting as a wedge to prevent
channel opening
■ AMPA receptor → critical to generation of
local seizure activity in an epileptic foci
■ Responsible for synchronization of
impulses
● From Doc: If you give Perampanel w/ CYP3A4 inducing agents,
you may have to give it at a higher dose
PERAMPANEL
Clinical Use
○ Focal and focal-to-bilateral tonic-clonic seizures
○ Generalized tonic-clonic seizures
○ Maintenance dose (12 y/o and older) = 4, 6, or 8 mg/d
PERAMPANEL
Adverse Effects (dose-dependent)
○ Dizziness, somnolence, and headache
○ Behavioral (aggression, hostility, irritability. and
anger)
■ From Doc: Pag AMPA – pagka Glutamate receptor inhibition, usually s/e is behavioral
■ Common din in YOUNG ppl and those w/ learning
disabilities or dementia
PERAMPANEL
Pharmacokinetics
○ From Doc: Food SLOWS down its absorption
○ Absorption is rapid and drug is fully bioavailable
○ Half-life = 70-110 hrs (prolonged in moderate
hepatic failure)
○ Steady state is not achieved for 2-3 wks
○ Kinetics are linear in the dose range of 2-12
mg/d
○ 95% bound to plasma proteins
○ Metabolism: Oxidation by CYP3A4 and glucuronidation
PERAMPANEL
Drug Interactions
○ From Doc: Behavioral effects are more common in younger
pt
○ CYP3A4-inducing anti-seizures
(Carbamazepine, Oxcarbazepine, and
Phenytoin) - INC clearance by 50-70%
○ Alcohol - exacerbate anger level
○ Levonorgestrel-containing hormonal
contraceptives - decreased effectiveness
PERAMPANEL
MOA: Enhancement of inhibition at
neurotransmission synapses mediated by
GABA-acting at GABA receptors by increasing mean open duration of Cl- channel w/o altering
conductance or opening frequency
○ Depress voltage → activated calcium currents
○ Blockage of AMPA receptors
○ From Doc:
■ They are positive allosteric modulators at a LOW concentration. If the phenobarbsis at a HIGH concentration → directly activation of GABA-A receptor
■ Di na sya 1st choice cosit has a lot of a/e (kaya dun ka sa first choice ka beh)
■ This drug must be discontinued overseveral wksto
avoid recurrence ofsevere seizures/status
epilepticus(i-tapersis)
. PHENOBARBITAL
Clinical Uses
○ Focal seizures
○ Generalized tonic-clonic seizures
○ Juvenile myoclonic epilepsy
● From Doc: DO NOT USE IN ABSENCE OR INFANTILE SPASMS
→ WORSENS
. PHENOBARBITAL
Dose = 6-200 mg, BID or TID
○ Minimally effective dose = 60 mg/d
○ Median effective dose = 100-150 mg/d
○ Accepted serum concentration = 15-40 mcg/mL (may tolerate chronic lvl if >40 mcg/mL)
. PHENOBARBITAL
Pharmacokinetics
○ Absorption: Rapid and complete
○ Distribution: Onset of action 10-60 mins
■ Crosses placenta
■ Undergo redistribution
. BARBITURATES
Biotransformation
■ Major pathway: Oxidation at C5 → alcohol, ketones, phenols, & carboxylic acid
■ N-glycosylation (Phenobarbital)
■ N-deakylation (Mephobarbitalto
Phenobarbital)
■ From Doc: Its metabolic elimination is more rapid in younger people, BUT slower in elderly and infants
■ If your pt is PREGNANT and is given this drug, its t1/2 tendsto PROLONG d/t expanded V.D. for
preggo
■ Chronic liver dse → prolonged t1/2
■ Repeated administration → shortenst1/2 bec
phenobarb will induce ITS OWN metabolism
(common for long-acting agents)
BARBITURATES
Excretion: Urine
BARBITURATES
Adverse Effects
○ After-effects
■ Residual CNS depression
■ Subtle distortion of mood (irritability,
temper)
■ Impairment of judgment and fine motor
skills
■ Other residual effects: Vertigo, vomiting,
nausea, or diarrhea
■ Awaken slightly intoxicated, euphoric, and
energetic
BARBITURATES
Adverse Effects
Paradoxical Excitement (geriatric/debilitated
individuals) – common in Phenobarbital and Methylphenobarbital (methylbarbital sabi ni doc tho)
Restless, excited, delirium, worsens pain
perception
Hypersensitivity
Respiratory depression
Tolerance and dependence
BARBITURATES
Drug Interactions
○ Enhances CNS depression
■ Ethanol, antihistamines, isoniazid,
methylphenidate, monoamine oxidase
○ Absorption of calcium is inhibited
○ CCl4 (carbon tetrachloride) → HIGH risk of hepatotoxicity
○ Competitively enhances metabolism of the ff since barbs is an enzyme INDUCER:
■ Steroid hormones, cholesterol, bile salts, vit K and D, dicumarol, phenytoin, digitalis
compound, griseofulvin,
oral contraceptives
■ Effect? Low plasma conc of these drugs
BARBITURATES
MOA: Acts more like the sodium-channel blocking anti-seizure drugs than phenobarbital
PRIMIDONE (2-DEOXY PHENOBARBITAL)
Clinical Use
○ Focal seizures (complex partial seizure daw to w/ impaired awareness)
○ Generalized tonic-clonic seizures
● From Doc: Carbamazepine and Phenytoin are more superior to
Primidone
PRIMIDONE (2-DEOXY PHENOBARBITAL)
Pharmacokinetics
○ Peak concentration = 3hrs (oral)
○ VD = 0.6L/kg
○ 70% unbound
○ Metabolized by oxidation → conjugation
■ Metabolites: Phenobarbital and PEMA (active metabolite)
■ PEMA: Minimal contribution to its efficacy
○ t1/2 = 6-8hrs; PEMA = 8-12hrs
○ Clearance = 2K/kg/day
○ From Doc: Slowly metabolized sa newborns and elderly
PRIMIDONE (2-DEOXY PHENOBARBITAL)
Therapeutic Levels
○ Parent drug steady-state = 30-40 hrs
○ Active metabolites
■ Phenobarbital = 20 days
■ PEMA = 3-4 days
○ Plasma Level
■ Primidone: 8-12 mcg/ml
■ Phenobarbital: 15-30 mcg/ml
○ To increase the dose, it is done days to weeks
PRIMIDONE (2-DEOXY PHENOBARBITAL)
MOA
○ use-dependent block of N-methyl-d–aspartate (NMDA) receptors, with selectivity for those
containing the GluN2B (NR2B) subunit
○ Barbiturate-like potentiation of GABA-A
receptor responses (allosteric modulator)
FELBAMATE
Clinical Use:
○ Refractory seizures
■ For cases that are not responsive to conventional tx
○ Focal seizures
○ Lennox-Gastaut syndrome
FELBAMATE
Pharmacokinetics
○ Preparation: oral form (well absorbed, >90%)
○ Metabolism: hydroxylation, conjugation
(CYP3A4 and CYP2E1)
○ T1/2 = 20 hrs;
■ 13-14 hrs when taken with phenytoin or
carbamazepine (inducers)
○ Excretion: 30-50% is excreted unchanged in the urine
FELBAMATE
● Drug dosage: 400 mg TID (max 3600 mg/d)
FELBAMATE
Therapeutic plasma level: 30-100 mcg/ml
FELBAMATE
Adverse effects
○ Aplastic anemia
○ Severe hepatitis
○ Only a third line drug because of AE
FELBAMATE
Drug interactions
○ Shorten T1/2
: phenytoin, carbamazepine
○ Plasma levels increased: phenytoin
○ Plasma levels decreased: carbamazepine
FELBAMATE
MOA:
○ Blockade of NMDA receptor-mediated
excitation
○ Facilitate glutamic acid decarboxylase (GAD)
○ Inhibit GABA transporter GAT-1
○ Inhibit GABA transaminase (GABA-T)
VALPROATE & DIVALPROEX SODIUM
Pharmacokinetics:
○ Bioavailability: 80%
○ Peak plasma blood levels achieved in 2 hrs
○ 90% plasma protein-bound
○ Highly ionized
○ Vd = 0.15 L/kg
○ T1/2 = 9-18 hrs
VALPROATE & DIVALPROEX SODIUM
Therapeutic levels and dosage
○ Dose: 25-30 mg/kg/d (max 60 mg/kg/d)
○ Therapeutic levels= 50-100 mcg/ml
VALPROATE & DIVALPROEX SODIUM
Clinical use
○ DOC for
■ Absence with generalized tonic-clonic
seizures
■ Myoclonic seizures (juvenile myoclonic
epilepsy)
○ Partial seizures
○ Atonic attacks (Lennox-Gastaut syndrome)
○ Bipolar disorders
○ Migraine prophylaxis (not first line)
VALPROATE & DIVALPROEX SODIUM
an enzyme inhibitor
○ Decrease levels from increase metabolism with carbamazepine (enzyme inducer)
○ Increase levels with antacid (increase
absorption)
○ Displaces phenytoin from protein-binding →
phenytoin free-form will increase
○ Displaced from protein-binding sites by
salicylates
Inhibits metabolism of phenobarbital,
ethosuximide, lamotrigine
○ When used with clonazepam may precipitate
absence status
VALPROATE & DIVALPROEX SODIUM
Adverse effects
○ Most common, dose-related
■ GI complaints: nausea, vomiting, abdominal
pain, heartburn
■ Start with lower dose to avoid
○ Fine tremor (high doses)
○ Uncommon reversible adverse effects
■ Weight gain, increased appetite, hair loss
○ Idiosyncratic:
■ Hepatotoxicity
■ Thrombocytopenia
○ Teratogenic:
■ Spina bifida
■ Other congenital abnormalities:
Cardiovascular, orofacial, digital
■ If given in the 1st 14 weeks
■ Decreases folic acid
VALPROATE & DIVALPROEX SODIUM
MOA:
○ Blocks voltage-gated Na
+ channels
○ Potentiates effects of GABA
○ Depresses excitatory action of kainate or AMPA
receptors
○ Weak inhibitor of carbonic anhydrase
isoenzymes 2 and 4
■ This doesn’t account for antiseizure activity
■ But may cause metabolic acidosis
TOPIRAMATE
Pharmacokinetics
○ Rapidly absorbed
○ Food doesn’t affect absorption
○ Bioavailability: 80%
○ Protein-binding: 15%
○ Metabolism: 20-50%
○ T1/2
: 20-30 hrs
■ If given with enzyme inducers, T1/2 will
shorten to 12-15 hrs
○ Primary route of excretion: renal
TOPIRAMATE
● Dose
○ Initial dose= 100 mg/d
○ 200-600 mg/d
TOPIRAMATE
Clinical Use
○ Focal seizures
○ Primary generalized tonic-clonic seizures
○ Lennox-Gastaut syndrome
○ Juvenile myoclonic epilepsy, infantile spasms
○ Dravet’s syndrome (severe myoclonic epilepsy in
infancy)
○ Childhood absence seizures
○ Migraine headaches
TOPIRAMATE
Drug interactions
○ OCPs (oral contraceptives): reduced
contraceptive effect
TOPIRAMATE
Adverse effects
○ Dose-related, 1st 4 weeks
○ Somnolence, fatigue, dizziness, cognitive
slowing, paresthesias, nervousness, confusion
○ Requires discontinuation if px experience:
■ Acute myopia
■ Glaucoma
○ Urolithiasis
○ Fatigue, anorexia, or nausea and vomiting
■ Carbonic anhydrase inhibition → dec serum
HCO3 → metabolic acidosis
○ Long-term therapy: weight loss peaks at 12-18 months after initiation of therapy
○ Teratogenic in animals → hypospadias
■ Oral cleft in newborns
TOPIRAMATE
Sulfonamide derivative
ZONISAMIDE
Pharmacokinetics:
○ Good bioavailability
○ Low protein-binding (>50-60%)
○ Linear kinetics
○ T1/2 = 1-3 days
○ Metabolism:
■ Acetylation (N-acetyl-zonisamide)
■ CYP3A4
(2 sulfamoylacetylphenol)
○ Renal excretion
ZONISAMIDE
Dose
○ Maintenance doses are 200-400 mg/d in adults (max 600 mg/d)
○ 4-8 mg/kg/d in children (max 12 mg/kg/d)
ZONISAMIDE
Adverse effects
○ Drowsiness
○ Cognitive impairment
○ Skin rash
○ Renal stone
ZONISAMIDE
Drug interactions
○ Carbamazepine, phenytoin and phenobarbital -
increase clearance
ZONISAMIDE
MOA: block voltage-gated Na
+ channels
ZONISAMIDE
Clinical use: Myoclonic epilepsies and in infantile
spasms
ZONISAMIDE
Drug of choice for generalized absence seizure
ETHOSUXIMIDE
Main action: inhibition of low-voltage-activated
T-type calcium channels in thalamocortical
neurons
■ Thalamocortical neurons: where impulses
fire for absence seizures
■ T-type calcium channels provide pacemaker
current in these neurons and would
generate rhythmic cortical discharge of an
absence attack
■ If calcium channels are inhibition, it will
reduce synchronization and propagation of
impulses
○ Other actions:
■ Inhibit voltage-gated sodium channels
■ Inhibit inward rectifier potassium channels
ETHOSUXIMIDE
Pharmacokinetics
○ Oral absorption: complete
○ Peak concentration: 3-7 hrs
○ Not protein-bound
○ Metabolism: hydroxylation (CYP3A4)
○ Clearance: 0.25 L/kg/d
○ T1/2 = 40 hrs (18-72 hgrs)
ETHOSUXIMIDE
Therapeutic levels and Dosage
○ Therapeutic range: 60-100 mcg/ml
○ Dose: 750-1500 mg/d (single or 2-3 divided
doses)
■ Single dose because of long T1/2
, but can be
divided to minimize GI AE
○ Children:
■ Initial dose: 10-15 mg/kg/d
■ Maintenance dose: 15-40 mg/kg/d
○ Older children and adults:
■ Initial dose: 250-500 mg/d
■ Increasing in 250-mg increments, maximum
of 1500 mg/d
○ Therapeutic serum concentration: 40-100
mcg/mL
○ Linear relationship between dose and
steady-state concentration
○ Narrow spectrum
ETHOSUXIMIDE
Drug interactions
○ Valproic acid (inhibitor) - decrease its clearance, increase plasma concentration
ETHOSUXIMIDE
Adverse Effects
○ Dose-related: Gastric distress, transient
lethargy or fatigue, headache, dizziness, hiccup, euphoria
○ Non-dose related/Idiosyncratic: Skin rash, Stevcens-Johnson syndrome, SLE
ETHOSUXIMIDE
Oxazolidinedione
TRIMETHADIONE
Clinical use: Generalized absence seizures (old DOC)
TRIMETHADIONE
Major metabolites: paramethadione & dimethadione
TRIMETHADIONE
Adverse effects:
○ Dose-related and idiosyncratic: Hemeralopia
(day blindness)
TRIMETHADIONE
DRUGS EFFECTIVE FOR MYOCLONIC SEIZURES
(SYNDROME OF JUVENILE MYOCLONIC EPILEPSY)
DOC: Valproate
DRUGS EFFECTIVE FOR MYOCLONIC SEIZURES
(SYNDROME OF JUVENILE MYOCLONIC EPILEPSY)
Alternatives: Levetiracetam, Zonisamide,
Topiramate, Lamotrigine
DRUGS EFFECTIVE FOR ATONIC SEIZURES SUCH
AS IN THE LENNOX-GASTAUT SYNDROME
Valproate in combination with lamotrigine and a
BZD
● Topiramate
● Felbamate
● Lamotrigine
● Use with caution: Phenobarbital and Vigabatrin
1, 5-benzodiazepine
CLOBAZAM
MOA: positive allosteric modulator of GABA-A
receptors
CLOBAZAM
Clinical use: only for Lennox-Gastaut syndrome (2
years of age or older)
CLOBAZAM
Pharmacokinetics
○ T1/2
: 18 hours
○ Metabolism: CYP and non-CYP transformations
(14 metabolites)
○ Major metabolite: Desmethylclobazam
(norclobazam)
■ T1/2
: 8-20 times higher
CLOBAZAM
Adverse effects: dose-dependent
○ Somnolence and sedation, dysarthria, drooling,
behavioral changes (aggression)
○ Withdrawal symptoms with abrupt
discontinuation
CLOBAZAM
Drug interaction
○ Moderate inhibitor of CYP2D6 → increase
plasma levels of phenytoin and carbamazepine
CLOBAZAM
MOA: blocker of voltage-gated Na
+ channels
RUFINAMIDE
Clinical Use:
○ Children
■ 10 mg/kg/d in two equally divided doses
(initial dose) and gradually increased to 45
mg/kg/g
■ Maximum dose: 3200 mg/d
○ Adults
■ 400-800 mg/d in two equally divided doses
(initial dose)
■ Maximum dose: 3200 mg/d
○ Given with food
RUFINAMIDE
Pharmacokinetics
○ Well-absorbed
○ Peak plasma concentrations: 4-6 hrs
○ T1/2
: 6-10 hrs
○ Minimal plasma protein binding
○ Extensive non-cytochrome metabolism
○ Excreted in the urine
RUFINAMIDE
Drug interactions: clearance decreased by valproate
RUFINAMIDE
Adverse effects: somnolence, vomiting
RUFINAMIDE
Still a new drug
RUFINAMIDE
Severe myoclonic epilepsy of infancy
○ Rare genetic epileptic encephalopathy
○ Characterized by diverse generalized and focal seizure types
Child may present with myoclonic, tonic-clonic,
absence, atonic, and one-sided hemiconvulsive
and focal seizures
○ Due to mutations in SCN1A gene encoding
NAV.1 voltage-gated dependent Na
+ channels
and cause 79% of Dravet’s Syndrome
○ If there is a mutation in the SCN1A gene, Na
+ channel blocking antiseizure drugs are
contraindicated because this worsens seizures
Dravet’s Syndrome
Aromatic allylic alcohol
STIRIPENTOL
Used in conjunction with clobazam or valproate
STIRIPENTOL
Pharmacokinetics: Nonlinear
○ Clearance decreases as dose increases
STIRIPENTOL
Dosage: started at 10 mg/kg/d and is increased
gradually as tolerated
STIRIPENTOL
Drug interaction
○ Potentinhibitor of CYP3A4, CYP1A2,
CYP2C19
○ Increases levels of clobazam and norclobazam
STIRIPENTOL
Adverse effects
○ Sedation/drowsiness, reduced appetite, slowing
of mental function, ataxia, diplopia, nausea,
abdominal pain
STIRIPENTOL
DRUGS EFFECTIVE FOR INFANTILE SPASMS
(WEST’S SYNDROME)
ACTH IM injection or Oral Corticosteroids
(prednisone or hydrocortisone)
○ associated with substantial morbidity
● Vigabatrin - can cause loss of vision
● Valproate
● Topiramate
● Zonisamide
● BZD (Clonazepam or Nitrazepam)
S(+) enantiomer is active and the R(-) enantiomer
appears to be inactive
VIGABATRIN
Pharmacodynamic activity of this drug is more
prolonged and not well-correlated with its half-life
because recovery from the drug requires synthesis
and replacement of GABA-T (because inhibition is
irreversible
VIGABATRIN
MOA
○ Irreversibly inhibits GABA Transaminase
(GABA-T) → inhibits metabolism of GABA
○ Inhibition of synaptic GABA-A receptor
responses
○ Prolongs the activation of extrasynaptic
GABA-A receptors
○ Produces a sustained increase in the
extracellular concentration of GABA in the brain
VIGABATRIN
Duration of action not correlated with half-life
VIGABATRIN
Clinical Use
○ Focal seizures (but not generalized seizures)
○ Treatment of infantile spasms associated with
tuberous sclerosis
VIGABATRIN
Dose
○ Infants: 50-150 mg/kg/d
Adults: initial oral dosage of 500 mg BID, total of
2-3 g/d
VIGABATRIN
Pharmacokinetics
○ Complete absorption
○ Peak plasma concentration: 1hr
○ Nor protein bound
○ T1/2
: 6-8 hrs
○ Not metabolized
○ Excretion: urine (unchanged)
VIGABATRIN
Adverse Effects
○ Irreversible retinal dysfunction
○ Permanent bilateral concentric visual field
constriction
■ Often asymptomatic but can be disabling
■ Onset of vision loss can occur within weeks
of starting the treatment or after months or
years
○ Somnolence, Headache, Dizziness, Weight gain
○ Less common: agitation, confusion and psychosis
VIGABATRIN
Relative Contraindication: Mental illness (Psychotic
disorders)
VIGABATRIN
MECHANISM OF ACTION
Bind to specific GABAA
receptor subunits at central nervous
system (CNS) neuronal synapses facilitating GABAmediated chloride ion channel opening FREQUENCY
● Positive allosteric modulators but do not activate the
GABA receptor directly
● Difference from Barbiturates
○ PROLONG the open state of the chloride
channels
○ Low concentration: positive allosteric
modulator
○ high concentration: can directly activate the
GABA receptor
Enhance membrane hyperpolarization
BENZODIAZEPINES
ACTIONS: CNS (Review. Doc skipped slides cos same lang
● Sedation
● Hypnosis
○ Decreased anxiety
○ Muscle relaxation
■ Inhibit polysynaptic reflexes and
internuncial transmission
■ Inhibit transmission at skeletal neuromuscular junction
○ Anterograde amnesia
○ Anticonvulsant activity (Clonazepam,
Nitrazepam, Lorazepam, Diazepam)
○ Anesthesia (Diazepam, Midazolam)
BENZODIAZEPINES
Ethanol - increase rate of absorption
● Cimetidine } inhibit N-dealkylation &
3-hydroxylation
● Oral contraceptives } - inhibits metabolism
● Erythromycin, Clarithromycin, Ritonavir,
Itraconazole, Ketoconazole, Grapefruitjuice (inhibit
CYP3A4)
○ Inhibit BZ metabolism
● Ethanol, Opioid analgesics, Anticonvulsants,
Phenothiazines, Antihistamines, TCA
○ Additive effect on CNS depression
BENZODIAZEPINES
Seizure disorder
○ Status epilepticus
FIRST LINE TREATMENT
DIAZEPAM
Seizure disorder
○ Status epilepticus
ALTERNATIVE
LORAZEPAM
Seizure disorder
○ Status epilepticus
PREERRED IN THE OUT-OF-HOSPITAL (IM IF YOU CAN’T GIVE IV LINE)
MIDAZOLAM
- absence, atonic, and myoclonic
seizure
CLONAZEPAM
- infantile spasms and myoclonic
seizures
NITRAZEPAM
BENZODIAZEPENE FOR FOCAL SEIZURE
Clorazepate dipotassium
BENZODIAZEPENE FOR ATONIC SEIZURE
CLOBAZAM
MECHANISM OF ACTION
Note: Bicarbonate efflux thru GABA receptors that can exert a
depolarizing/excitatory influence especially relevant during
intense GABA receptor activation which occurs during seizure. This happens when there is diminution of the
hyperpolarizing chloride gradient. As entry of chloride decreases (after GABA activation), bicarbonate enters.
● Inhibitors of carbonic anhydrase, particularly the cytosolic forms CA II and CA VII —> prevents
replenishment of intracellular bicarbonate —>
depresses depolarizing action of bicarbonate
○ So even if the chloride efflux is decreasing already in amount, you don’t expect intense receptor activation due to bicarbonate because it islost after inhibiting carbonic anhydrase
`CARBONIC ANHYDRASE INHIBITORS
Prototype: Sulfonamide acetazolamide
CARBONIC ANHYDRASE INHIBITORS
CLINICAL USE:
● Focal and generalized tonic-clonic seizures and especially generalized absence seizures
● Intermittent treatment of menstrual seizure
exacerbations
CARBONIC ANHYDRASE INHIBITORS
ADVERSE EFFECT:
● Tolerance
CARBONIC ANHYDRASE INHIBITORS
DOSE: 10 mg/kg/day to a maximum of 1,000 mg/day
***Topiramate and Zonisamide - sulfonamide derivatives - they have weak carbonic anhydrase activity
CARBONIC ANHYDRASE INHIBITORS
When to initiate treatment in patients who had a
seizure (conditions where risk of recurrence may be high)
Pre-existing neurological disorder or
developmental delay
○ With family history of seizure
○ With abnormal neurologic exam
○ An abnormal EEG
○ Abnormal MRI that carries risk for recurrence
■ Tumor in cortico-thalamic area
○ Complicated febrile seizure and epilepsy for
children (i.e., the febrile seizure lasted >15 mins,
was one sided, or was followed by a second
seizure in the same day)
■ Diazepam for children at the time of fever
● Rectally - to avoid side effects of the drug when given chronically
Goal of initiating treatment:
To reduce recurrence
Choice for drug treatment (antiseizure)
Still the best - lesser adverse effects
(overlapping adverse effects - ataxia, GI
adverse effects)
Monotheraphy
Dose initiated at reduced amount and adjusted at
appropriate intervals
Titration takes 1-2 weeks
Duration of therapy
At least 2 years seizure-free
○ Tapering and discontinuation - to avoid rebound
seizures or status epilepticus
Degree of success varies as a function of:
Seizure type
○ Cause - may be due to electrolyte imbalance
(correct it first)
○ Other factors
Measurement of drug concentrations in plasma
facilitates optimizing antiseizure medication,
especially when:
Therapy is initiated
○ After dosage adjustments
○ In the event of therapeutic failure
○ When toxic effects appear
○ Multiple-drug therapy is instituted - especially
Valproate (can inhibit metabolism)
■ Give lower dose with the 2nd agent - to
monitor if the 2nd agent isreally reaching the
therapeutic plasma level
(very teratogenic esp during 1st trimester -spina bifida)
Valproate
Cleft lip and cleft palate
Topiramate
Major congenital cardiac defect
Phenobarbital
Low risk antiseizure drugs for pregnant women
carbamazepine, phenytoin, and levetiracetam
What are the Effects on Vitamin K metabolism in pregnant women
ASDs that induce CYPs have been associated
with Vitamin K deficiency in the newborn —>
coagulopathy and intracerebral hemorrhage
Treatment for vit k. deficiency due to antiseizure drugs
Treatment: Vitamin K1, 10 mg/day during the
last month of gestation for prophylaxis
drugs that can penetrate into
breast milk in relatively high concentration
Primidone, Levetiracetam, Gabapentin,
Lamotrigine, and Topiramate:
drugs that do not penetrate into breastmilk
Valproate, Phenobarbital, Phenytoin, and
Carbamazepine
suicidality
Lamotrigine, Levetiracetam, and Topiramate
Typically, ___% of recurrence will occur within __ months of
discontinuing the therapy for these types of seizures
80% and 4 months
