New anti epileptic drugs
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NEWER ANTI-EPILEPTIC DRUGSIMRAN RIZVI
ModeratorDr.H.S.Malhotra, DMAssociate Professor, NeurologyKGMU
IntroductionPrior to 1993, the choice of an anticonvulsant medication was limited to the traditional anticonvulsants [Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate.]Since 1993, Several new medications have been approved by the US Food and Drug Administration (FDA).These newer antiepileptic drugs offer the potential advantages of fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity.
LaRoche SM et al. JAMA, February 4, 2004Vol 291, No. 5
ANTIEPILEPTIC DRUG DEVELOPMENT18401860188019001920194019601980200005101520BromidePhenobarbitalPhenytoinPrimidoneEthosuximideSodium ValproateBenzodiazepinesCarbamazepineZonisamideFelbamate
GabapentinTopiramateFosphenytoinOxcarbazepineTiagabineLevetiracetamRufinamideLacosamideBrivaracetamPregabalinRetigabine?Calendar YearNumber of Licensed Antiepileptic DrugsLamotrigine
Antiepileptic DrugYear approvedFelbamate1993Gabapentin1993Lamotrigine1994Topiramate1996Tiagabine1997Levetiracetam1999Oxcarbazepine2000Zonisamide2000Pregabalin2005Rufinamide2008Lacosamide2009
Advantages of new AEDsCompared with older agents, many new drugs exhibit simpler pharmacokinetics. (Renal excretion, Lack of interactions.)Unlike most of the older agents newer AEDs are devoid of significant enzyme inducing or inhibiting properties. Newer AEDs have a favorable side effect profile when compared to older agents.
Mechanism of action of new AEDs
Drug MechanismLevetiracetamModifies Synaptic Vesicle Protein (SV2A)Lamotrigine Blocks excitatory sodium channels in a voltage dependent manner.Lacosamide Modifies sodium channels.Oxcarbazabine Blocks sodium channels, N/P and R type Calcium channels.TopiramateModulatory effect on sodium channels, GABA, AMPA/Kainate receptors.GabapentinReduction of Glutamate release at cortical synapses, reduction of activity dependent release via interaction with P/Q type calcium channels.
Mechanism of action of new AEDs
Drug MechanismVigabatrin Selective irreversible inhibitor of GABA transaminaseTiagabinePotent, specific GABA uptake inhibitorRufinamideLimitation of sodium dependent action potential firing.ZonisamideSodium channel and T-type calcium channel blocker.
Adverse events associated with the new AEDs
Adverse events associated with the new AEDs
LevetiracetamLevetiracetam is a highly effective, broad-spectrum, newer class of AED with a unique mechanism of action.It was licensed in 1999.It can be used to treat all focal or generalized, idiopathic or symptomatic epileptic syndromes in all age groups.
Authorized indicationsMonotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy.Adjunctive therapy In the treatment of partial onset seizures with or without secondary generalization in adults, children and infants from 1 month of age with epilepsy.In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with JME.In the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with IGE.
Advantages It is broad spectrum, which is of practical significance, particularly for clinicians who may not have special expertise in differentiating between focal and generalized epileptic seizures.
It has a relatively good safety profile and does not cause significant idiosyncratic reactions or other serious ADRs.
It does not need slow titration, the starting dose is often therapeutic for all forms of seizures and epilepsies.It is easier to use if polytherapy is necessitated, as it does not cause clinically significant drugdrug interactions
Advantages It does not interact with hormonal contraception and is a pregnancy category C drugIt does not interfere with liver function (a major problem with most other AEDs that are metabolized in the liver).
Dosage and titration (Adults)Start treatment with 1000 mg/day (twice-daily dosing), which may be sufficient for seizure control.If needed, Levetiracetam can be titrated in steps of 500 mg/week to a maximum of 3000 mg/day.
Dosage and titration (children)Start with 510 mg/kg/day, which may be sufficient for seizure control.If needed, Levetiracetam can be titrated in steps of 510 mg/kg/week to a usual maintenance dose of 2040 mg/kg/day given in two divided doses.
Main ADRsLevetiracetam is probably the AED that is most free from ADRs.The most common ADRs are somnolence, asthenia and dizziness, which are dose dependent and reversible.Others include headache, common cold or upper respiratory infections, anorexia and behavioral disturbances.Levetiracetam interferes with rapid motor learning in humans due to suppression of excitatory activity in the motor cortex.
In an uncontrolled study, add-on Levetiracetam was associated with a paradoxical increase in seizure frequency, particularly in mentally retarded patients and those with difficult-to-treat focal-onset seizures treated with high doses of Levetiracetam.All patients who are currently taking or starting on Levetiracetam for any indication should be monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression
Considerations in womenPregnancy: category CIn the UK Epilepsy and Pregnancy Register of 117 pregnancies exposed to Levetiracetam only three infants (all in the polytherapy group) had a Major Congenital Malformation.
Hunt S et al. Neurology 2006;67:18769.
Considerations in womenBreastfeeding: There is an extensive transfer of Levetiracetam from mother to fetus and into breast milk.However, breast-fed infants have very-low Levetiracetam plasma concentrations, suggesting a rapid elimination of Levetiracetam.Interaction with hormonal contraception: none.
Mechanisms of actionIt has a novel mechanism of action that is distinct from that of other AEDs.It acts by targeting a synaptic vesicle protein in presynaptic terminals.Its antiepileptic activity does not involve a direct interaction with any of the three main mechanisms of the other AEDs.
Mechanism contd.Recent experiments have shown that the synaptic vesicle protein 2A (SV2A) is the binding site of Levetiracetam.Studies in mice lacking SV2A indicate that this protein has a crucial role in the regulation of vesicle formation and fusion.Mice lacking SV2A develop severe seizures by 1-2 weeks of age.Thus Levetiracetams interaction with SV2A provides a significant contribution to its anti-epileptic activity.Lynch BA et al. Proc Natl Acad Sci USA 2004;101:98616.
Pharmacokinetics Levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED.it has a high oral bioavailability, which is unaffected by food. (100%)it is not significantly bound to plasma proteins.it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes.
Pharmacokinetics contd.It has linear kinetics.It is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs.Perucca E et al. Epileptic Disord 2003;5 Suppl 1:S1726.
Drug interactions Unlike the majority of other AEDs, Levetiracetam has no clinically meaningful drugdrug interactions.Other AEDs: Levetiracetam does not influence the plasma concentration of existing AEDs.Enzyme inducers may decrease Levetiracetam plasma levels by 2030%.Other non-AEDs: Levetiracetam has no known interactions with other drugs such as oral contraceptives, warfarin and digoxin.
Contin M et al. Ther Drug Monit 2004;26:3759.
Main disadvantagesThere are some reports of increased behavioral and psychiatric abnormalities, particularly in children or patients that may be prone to such problems.
White JR et al. Neurology 2003;61:121821.Mula M et al. Seizure 2004;13:557.
LacosamideLacosamide is a functionalized amino acid (R)-2- acetamido-N-benzyl-3-methoxypropionamide.It is one of the latest AEDs to be licensed (at the end of 2008)Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
Authorized indicationsTablets are indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older.Injection for intravenous use is indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible.Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
Dosage and titrationStart with 50 mg twice daily (100 mg/day).Increase at weekly intervals by 100 mg/day to 200400 mg/day.The maximum recommended dose of Lacosamide is 400 mg/day because higher doses may be associated with CNS and gastrointestinal ADRs.A maximum dose of 300 mg/day is recommended by the FDA for patients with mild or moderate hepatic impairment.
Dosage for I.V LacosamideLacosamide injection (without further dilution or mixed in compatible diluents) should be administered intravenously over 1560 minutes.When switching from oral Lacosamide, the initial total daily intravenous dosage should be equivalent to the total daily dosage and frequency of oral Lacosamide.
Main ADRsFrequent : Dizziness, headache, diplopia, nausea, vomiting and blurred vision.Serious: A small, asymptomatic, dose-related increase in the PR interval measured on ECG has been observed in