Levetiracetam

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  • 1. LEVETIRACETAM
  • 2. (S)-alfa-ethyl-2-oxo-l-pyrrolidine- acetamide is a pyrrolidine derivative
  • 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
  • 15. 31 -Betts T, Waegemans T, Crawford 32 Cereghino JJ etal. 33 . Shorvon SD etal 41 -Ben-Menachem E, Falter U .
  • 16. • 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
  • 17. 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
  • 18. 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
  • 19. • Idiosyncratic adverse effects • Teratogenicity • Adverse effects of levetiracetam in paediatric patients • Overdosage • Tolerance
  • 20. 50- Bourgeois B etal. 57- Wannag E, Eriksson A, Brockmeier, 59- Faircloth VC . etal 60- Strunc M, Levisohn P .
  • 21. 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
  • 22. FORMS • TABLETS OF 250 mg, 500 mg, 1000mg, • Solution form • Parenteral form(phase iv trails )