Levetiracetam is a white powder that is wholly soluble in water. It is the S-enantiomer form which has anticonvulsant properties, while the R-enantiomer does not. It inhibits calcium channels and prevents the release of calcium from intracellular stores. It is rapidly absorbed after oral administration, has a high bioavailability, and is excreted unchanged in the urine. Common side effects include somnolence, asthenia, and nausea. It is indicated as an adjunctive treatment for partial onset seizures, myoclonus, and primary generalized tonic-clonic seizures in adults and children.
Levera (Levetiracetam Tablets) is used for adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy.
Levera (Levetiracetam Tablets) is used for adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy.
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Charles Locock commented in the Lancet on his use of potassium bromide in 15 cases of "hysterical" epilepsy in young women. The next development was the serendipitous discovery of the anticonvulsant properties of phenobarbital by Alfred Hauptmann in 1912. This predated by more than 20 years the screening of potential therapeutic agents against "electrical seizures" in cats by Houston Merritt and Tracy Putnam. The result was the launching of phenytoin in 1938. Next came primidone, ethosuximide, carbamazepine and valproic acid, all of which can be regarded as first generation antiepileptic drugs (AEDs). Shortly after their synthesis, the benzodiazepines were rapidly recognised as having anticonvulsant activity. The modern era focused on the systematic screening of many thousands of compounds against rodent seizure models under the Anticonvulsant Drug Development Program in the US. This resulted in the global licensing, in chronological order, of vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin and lacosamide.
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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 )