3. Chemical properties
• Levetiracetam is a white powder ,wholly
soluble in water.
• racemically pure S-enantiomer .
• The R-enantiomer devoid of anticonvulsant
properties in animals
4. Preclinical data
• levetiracetam is not active against acute
seizures, namely the maximal electroshock
(MES) and pentylenetetrazol (PTZ) seizure
tests
• Levetiracetam also appears to lack
anticonvulsant activity in other acute seizure
tests utilizing chemoconvulsant agents,
5. • levetiracetam does possess activity chronic
epilepsy, such as kindled and genetic animals
• reduces seizure severity, duration of motor
seizures as well as after discharge duration in
fully amygdala-kindled rats
• effective in genetic animal models of
epilepsy, such as the genetic absence epilepsy
rat from Strasbourg (GAERS) (resembling
human spike-wave conditions)
6. • Wide safety margin between the effective
dose (ED50; dose protecting 50% of animals
from seizures) and the dose impairing rotarod
performance(TD50; dose causing 50% of
animals to lose equilibrium on the rotarod).
7. mechanism of action
• inhibits a specific high-voltage activated calcium
channel, the N-type
• inhibit the release of calcium from intracellular
stores .
• oppose the inhibitory action of zinc and beta-
carbolines on GABAA- and glycine-gated currents
• inhibits burst firing without affecting normal
neuronal excitability
• inhibit hypersynchronization of epileptiform
activity, which distinguishes levetiracetam from
other AEDs
• stereoselective, saturable and reversible binding
site specific for levetiracetam in the CNS,SV2A
8. Pharmacokinetics
• water-soluble compound, which is rapidly and
almost completely absorbed after oral
administration
• Administration with food does not reduce the
extent, but may slow the rate of absorption .
• Bioavailability approaches 100% .
• Peak plasma concentrations are reached in 1-2 h.
• The pharmacokinetics are linear,
• Levetiracetam is <10% protein bound.
9. • Sixty-six per cent of the dose is excreted
unchanged in the urine.
• Twentyseven per cent of the dose is metabolized
by an enzymatic hydrolysis of the acetamide
group, mainly to L057
• This process occurs diffusely in the body, and is
not hepatically mediated.
• no inhibition of drug-metabolizing enzymes
including
CYP3A4, CYP1A2, CYP2C19, CYP2C9, CYP2E1, CYP
2D6, epoxide hydrolase and various uridine
glucuronyltransferases
10. • The metabolites of levetiracetam are renally excreted.
• Because there is no hepatic metabolism,
• and because levetiracetam does not induce or inhibit
hepatic enzymes,
• it does not interfere with the metabolism of other
AEDs,
• nor do other AEDs interact with its metabolism or
elimination.
• Probenecid increases plasma levels of the
levetiracetam metabolite L057 2.5-fold, by a reduction
in renal clearance
11. children
• The half-life of levetiracetam in children, as for
most drugs, is shorter than adults.
• After a single oral dose of 20mg/kg, values for
Cmax and AUC equated for a 1-mg/kg dose
were -30-40% lower than adults, whereas
renal clearance was higher.
• The half-life was ~6h
12. elders
Elderly individuals may have altered drug metabolism,
• gastric mucosal atrophy
• decreased gastric motility leading to altered absorption,
• change in hepatic and renal function,
• altered albumin levels.
• Studies demonstrated a prolonged half-life, which could be
explained entirely by reduced creatinine clearance
• The elimination half-life is approximately 10-llh, compared
to 7.7h in younger normal subjects
• Adjustments in dosage should be made based on
estimated creatinine clearance, taking body mass into
account.
13. Liver failure
• Mild to moderate (Child-Pugh class A or B)
hepatic impairment do not alter the clearance of
levetiracetam, and no dosage adjustments are
required.
• However, in severe hepatic failure (Child-Pugh
class C) there is a reduced clearance, most likely
due to concomitant renal insufficiency .
• Adjustments in dose should therefore be made
based on renal rather than hepatic function.
14. Renal failure
patients with renal failure on dialysis, a dose of 500-1000 mg once
daily is recommended, with a supplemental dose of 250-500 mg
after dialysis treatment
17. • The efficacy of levetiracetam in treatment of primary generalized
epilepsy including tonic-clonic, absence and myoclonic epilepsy
was reported in a recent small case series.
• effective in juvenile myoclonic epilepsy (JME). Among 30 patients
with resistant JME who received levetiracetam, 62% became seizure
free
• reports suggest that levetiracetam is potentially efficacious in
photosensitive epilepsy
• patients with progressive myoclonic epilepsy have experienced
dramatic improvements with the addition of levetiracetam to their
regimen
• useful in the treatment of other epilepsies including atypical
absence and atonic seizures
18. indications
Adjunctive to
• Partial onset seizures in adults,children >4 yrs
• Myoclonus in adults,children>12 yrs ,JME
• Primary GTCS in adults,children>6 yrs
19. Side-effects
• Somnolence ,20.4% of patients on lOOOmg of levetiracetam vs. 18.8% on
3000 mg, as compared to 13.7% of placebo patients
• asthenia. 14.7% vs. 9.1 % of placebo
• nausea,
• dizziness and headache.
• Infections including upper respiratory tract (rhinitis and pharyngitis) and
urinary tract infections
• agitation, hostility, anxiety, apathy, emotional lability, depersonalization
and depression,13.3% of levetiracetam patients compared to 6.2% in
placebo
• suicidal behaviour was reported in 0.5% vs. none for placebo group
• In a pooled analysis, >25% worsening of seizures occurred during add-on
trials in the placebo group (26%) than in the levetiracetam-treated group
(14%)
• Anemia,leukopenia
20.
21. • Idiosyncratic adverse effects
• Teratogenicity
• Adverse effects of levetiracetam in paediatric
patients
• Overdosage
• Tolerance
22. 50- Bourgeois B etal. 57- Wannag E, Eriksson A, Brockmeier, 59- Faircloth VC
.
etal 60- Strunc M, Levisohn P .
23. Clinical therapeutics
• highly water soluble,
• Levetiracetam is not metabolized by the liver.
• It is free of non-linear metabolic kinetics, autoinduction
and drug-drug interactions
• it lacks protein binding (<10%), which avoids the problem
of displacement of highly protein-bound drugs.
• potentially broadspectrum effects
• low rate of side-effects
• The starting dose of levetiracetam is typically 500 mg BID,
• The dose can be titrated by 500-1000 mg every 1-2 weeks
until maximum benefit
• children aged 6-12 years used mean doses of 40mg/kg/day
24. FORMS
• TABLETS OF 250 mg, 500 mg, 1000mg,
• Solution form
• Parenteral form(phase iv trails )
