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Antiepileptic Drugs (DRUGS USED FOR FOCAL (PARTIAL ONSET) SEIZURES…
Antiepileptic Drugs
DRUGS USED FOR FOCAL (PARTIAL ONSET) SEIZURES
CARBAMAZEPINE
Induces microsomal Es
Has an active metabolite
Toxicity:
Similar to phenytoin except concern over blood dyscrasias
(aplastic anemia & agranulocytosis)
OXCARBAZEPINE
ESLICARBAZEPINE ACETATE
LACOSAMIDE
PHENYTOIN
[prescribed for prevention of
focal seizures & generalized tonic-clonic seizures
] and for acute treatment of status epilepticus
pharmacokinetics
oral
Metabolites
clinically
inactive
[
Elimination dose-dependent
]
[At
low [ ]s: proportionate to rate at which drug presented to liver
(1st order kinetics)]
[As blood levels rise
toward upper therapeutic levels max metabolism
reached (Shift to zero order elimination kinetics)]
[At moderate to high doses]
[Further incr in dose may give large changes in free-drug [ ]s and result in markedly incr half-life, steady-state not reached, toxicity develops]
Half-life (12 - 36 hours (mean = 24 hours))
Plasma therapeutic range (10 -20 ug/mL)
Must change dosage very carefully
Two types available differing in bioavailability
Drug interactions related to pr binding or to metabolism
Dose-related
adverse effects
similar to other AED’s
Nystagmus
Loss of smooth extraocular pursuit movements
Diplopia and ataxia most common-lower dose
Gingival hyperplasia and hirsutism
other phenytoins:
MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE
TIAGABINE
RETIGABINE (EZOGABINE)
GABAPENTIN
& PREGABALIN
Effective as an adjunct against partial seizures & generalized tonic-clonic seizures
Adverse effects:
Somnolence, Dizziness, Ataxia, Headache, Tremor
Pharmacokinetics
not metabolized & doesn't induce hepatic Es
Absorption non linear (Dose-dependent at very high doses)
Elimination
kinetics
linear
not bound to plasma prs
Elimination renal
; Excreted
unchanged
Half-life
short
(5 to 8 h); Administered 2 or 3 times per day
DRUGS EFFECTIVE FOR FOCAL SEIZURES & CERTAIN GENERALIZED ONSET SEIZURE TYPES
PERAMPANEL
LAMOTRIGINE
add-on therapy or as monotherapy for partial seizures & Active against absence and myoclonic seizures in children
Adverse effects:
Dizziness, Headache, Diplopia, Nausea, Skin rash
Pharmacokinetics
Almost completely absorbed
Volume of distribution (1-1.4 L/kg )
Pr binding 55%
Linear kinetics
Metabolized by glucuronidation to 2-N-glucuronide (excreted in urine )
Half-life 24 h (decr to 13-15 h in pxs taking E inducing drugs )
Valproate causes a twofold incr in drug half-life
In px receiving Valproate, initial dosage of Lamotrigine must be reduced to 25 mg every other day
Usual dose between 100 and 300 mg/d
LEVETIRACETAM
Piracetam analog
Effective against partial seizures
Begin with 500 mg orally twice daily
Some patients require up to 3000 mg/d
Side effects:
Somnolence, Asthenia, Dizziness
Pharmacokinetics
Oral absorption nearly complete (rapid and unaffected by food)
Peak plasma concentrations in 1.3 h
Kinetics are linear
Pr binding <10%
Half-life 6-8 h
Excreted unchanged in urine (Two-thirds)
Drug interactions minimal
Not metabolized by Cytochrome P 450
BRIVARACETAM
PHENOBARBITAL
Partial & Generalized Tonic-Clonic
Seizures
1st AED (Not All Barbiturates Have AED Activity)
Limitation
Sedation
Induces P-450
PRIMIDONE
Converted to phenobarbital
Mechanism similar to phenytoin
Toxicity: Dose-related and similar to those of phenobarbital
FELBAMATE
Effective in some w/ partial seizures, and seizure that occur in Lennox-Gastaut syndrome
Third-line drug for refractory cases
Adults ( 2000 - 4000 mg/d )
Effective plasma levels range from 30 µg/ml to 100 µg/ml
Side effect (high rates):
Aplastic anemia, Severe hepatitis
Pharmacokinetics
Half-life 20 h (Shorter with Phenytoin or Carbamazepine)
Increases plasma Phenytoin and Valproic acid levels
Decr levels of Carbamazepine
Metabolized by hydroxylation and conjugation
Excreted unchanged in urine
PHARMACOKINETICS
[Good
absorption (80-100%)
;
Not
highly bound to plasma pr
(except
phenytoin
&
valproic acid
--> displace other highly bound drugs] OR displaced by them-->
transient toxicity
)
Drugs cleared
[Chiefly
hepatic
]
[Plasma clearance relatively slow--> many
medium to long-acting
]
[Some (
primidone & benzodiazepines) converted to active metabolites cleared by liver
]
[Some
induce microsomal E activity (phenobarbital & carbamazepine)
]
[Liver metabolism of AEDs generally low and independent of concentration (except phenytoin)]
Distributed to total body water
DRUGS EFFECTIVE FOR GENERALIZED ONSET SEIZURES
TOPIRAMATE
A
substitued monosaccharide structurally different from all other antiseizure drugs
Partial and generalized tonic-clonic seizure; Lennox-Gestaut syndrome; Absence seizure
Typically ranged from 200 to 600 mg/d
Most clinicians begin slowly ( 50 mg/d ) and incr slowly to avoid adverse effect
Side effects:
Somnolence, Fatigue, Dizziness, Cognitive slowing, Paresthesias, Nervousness, Confusion, Urolithiasis, Teratogenic (in animal models)
Pharmacokinetics
Plasma pr binding minimal (15%); Metabolism moderate (20-50 % ); No active metabolites
Excreted unchanged in urine; Half-life about 20-30 h; Kinetics linear
Rapidly absorbed
(about 2 h);
80% bioavailable
;
No food effect on absorption
ZONISAMIDE
Sulfonamide derivative; Effective against partial and generalized tonic-clonic seizures; Useful against infantile spasms and certain myoclonias
Dosage: Adults (100 – 600 mg/d ) Children (4 – 12 mg/d )
Adverse effects: Drowsiness, Cognitive impairment
Pharmacokinetics: Bioavailability good, Linear kinetics, Low pr-binding, Renal excretion, Half-life 1-3 days
VALPROATE AND DIVALPROEX SODIUM
Effective in absence; some myoclonic; some partial seizures
Valproic acid fully ionized at body pH
Active
form:
valproate
ion
Highly ionized; highly pr-bound, distribution confined to EC water
Drug interactions
Inhibits own metabolism
, decr intrinsic clearance of drug
Displaces phenytoin from prs
Inhibits metabolism of Phenobarbital, phenytoin & carbamazepine
Toxicity
Most common
dose-related
effect:
GI
problems (nausea, vomiting, abdominal pain & heartburn)
Idiosyncratic hepatotoxicity
which may be severe:
Risk greatest <2 yrs
old;--> monitor liver function carefully
drug during pregnancy--> birth defects: Spina bifida and cardiovascular, orofacial and digital abnormalities
ADDITIONAL TOPICS
Withdrawal
of drug: can-->
incr seizure freq & severity
Overdose: Most
dangerous
:
Respiratory depression
which may be
potentiated
by other agents ex
alcohol
Tetratogenicity: -->
folic acid as supplemental therapy
in women of child bearing age to prevent birth defects (e.g. spina bifida)
DRUGS EFFECTIVE FOR GENERALIZED ABSENCE SEIZURES
ETHOSUXIMIDE
linear relationship betw dose and steady state plasma levels
Valproic acid decr ethosuximide clearance
--> higher steady state [ ]s
Toxicity
Dose-related gastric distress
(pain, nausea, vomiting)
Avoid by Starting at low dose and gradually incr until reach therapeutic range
Other side effects mild;
relatively safe drug
TRIMETHADIONE
DRUGS EFFECTIVE FOR ATONIC SEIZURES SUCH AS IN THE LENNOX-GASTAUT SYNDROME
CLOBAZAM
RUFINAMIDE
OTHER DRUGS USED IN MANAGEMENT OF SEIZURES AND EPILEPSY
BENZODIAZEPINES
route
IV; status epilepticus: Diazepam, Lorazepam
Oral; long acting; absence seizures: Clonazepam
Oral; complex partial seizures in adults: Clorazepate dipotassium
Common side effects
Drowsiness
Lethargy
CARBONIC ANHYDRASE INHIBITORS
MECHANISMS OF ACTION
Molecular Target
Synaptic release machinery
Ionotropic glutamate receptors
GABA inhibition
GABAa receptors [chloride ion channel]
Benzodiazepines
[Barbiturates]
:
also reduction of glutamate-mediated excitation
GAT-1 GABA transporter
gabapentin
: Not to act on GABA receptors; It
may, alter GABA metabolism, its nonsynaptic release, or its reuptake by GABA transporters
GABA transaminase
[Valproic Acid (high levels)]
Vigabatrin
:
Irreversible
inhibitor of GABA aminotransferase ( GABA-T ); Potentiate GABA
by inhibiting GABA transporter
Mixed/unknown
[
Valproic
acid causes neuronal membrane
hyperpolarization
Involve K+ enhancing potassium ion permeability];
Broad spectrum in nature due to having more than one molecular mechanism; In some cases involves sodium currents; some changes in GABA levels in brain, may also involve potassium channels
[
Phenobarbital
also blocks
glutamate-mediated (excititory) responses by activation of AMPA receptor
; Thought to selectively suppress abnormal neurons, inhibiting the spread of impulses and suppressing firing from the loci; Also see enhancement of GABA-mediated inhibition & reduction of glutamate-mediated excitation at therapeutic levels; Has some similar action to phenytoin
Topiramate
: Blocks voltage-dependent Na channels; Potentiate inhibitory effect of GABA; Acting at a site different from benzodiazepine or barbiturate sites; Depress exitatory action of kainate on AMPA Rs
Levtiracetam
Voltage-gated ion channels
calcium
(T-type)
Ethosuximide
:
Inhibits low-threshold Ca2+ currents
Acts in
thalamic
neurons which act as
pacemakers
for
generation of rhythmic cortical discharge
valproate, dimethadione
potassium (Kv7)
sodium
(Nav)
Carbamazepine (Tegretol)
[Action probably independent of GABAergic system]
Phenobarbital (Luminal)
Phenytoin (Dilantin)
[Alters Na, K and Ca conductance], Alters membrane potentials
[Alters [ ]s of aas & NTs, norepi, ACh and GABA]
Valproic acid (Depakote)
Lamotrigine
:
dependent inactivation of Na channels (explains it’s efficacy in focal epilepsy)
Actions on voltage-activated Ca2+ channels
Zonisamide
: It’s primary site of action appears to be on Na channel; It may also act on voltage-dependent calcium channels
DRUGS EFFECTIVE FOR MYOCLONIC SEIZURES SUCH AS IN THE SYNDROME OF JUVENILE MYOCLONIC EPILEPSY
Valproate is the drug of first choice for the treatment of myoclonic seizures. Other drugs effective in the treatment of this seizure type are levetiracetam, zonisamide, topiramate, and lamotrigine
DRUGS EFFECTIVE FOR DRAVET’S SYNDROME
STIRIPENTOL
DRUGS EFFECTIVE FOR INFANTILE SPASMS (WEST’S SYNDROME)
VIGABATRIN
Partial seizures &
Infantile spasms
(refractory to other treatments).
Toxicity
Drowsiness, Dizziness & Weight gain
Adverse reactions
Agitation, Confusion &
Psychosis
Visual field defects in long-term therapy
(1/3 of pxs)
Contraindication
(relative):
Preexisting mental illness
Pharmacokinetics
Absorption rapid
; Peak levels (1-3 h ); Bioavailability excess of 60%; Volume of distribution (0.8 L/kg )
Half-life ( 6-8 h);
Linear
kinetics;
No active metabolites; Binds minimally to plasma prs; Elimination by kidneys (predominantly)
Dosage: In adults: 500 mg twice daily( should be started); Total of 2-3 g daily for full effectiveness