New Antiepileptic Drugs in Childhood Epilepsy

Sajun Chung

doi:10.5124/jkma.2009.52.6.611

J Korean Med Assoc > Volume 52(6); 2009 > Article

Chung: New Antiepileptic Drugs in Childhood Epilepsy

Pharmacotherapeutics

Journal of the Korean Medical Association

Journal of the Korean Medical Association 2009; 52(6): 611-626.

Published online: June 30, 2009

DOI: http://dx.doi.org/10.5124/jkma.2009.52.6.611

New Antiepileptic Drugs in Childhood Epilepsy

Sajun Chung, MD

Department of Pediatrics, Kyunghee University College of Medicine, Korea. sajchung@khmc.or.kr

Abstract

Many new antiepileptic drugs (AEDs) have been developed in the last two decades, contributing to the optimal treatment for childhood epilepsy. The goal of the treatment is to achieve seizure-free without any side effects, that deteriorates the quality of life by causing negative consequences. The new AEDs have not shown better efficacy, but generally seem to be better tolerated, having fewer systemic reactions and better pharmacokinetics than the established AEDs. The new AEDs have a broad spectrum of activities, which offer new opportunities to patients who have not shown any favorable responses to the established ones. There are more choices when trying to select AEDs for epileptic seizures and syndromes. Majority of the new AEDs have more than one action mechanism. AEDs acting selectively through the GABAergic system are tiagabine and vigabatrin; acting by inhibition of voltage-dependent Na⁺ and Ca²⁺ channels are lamotirigine, oxcabarbazepine and topiramate; and acting by inhibition of glutamate-mediated excitation are felbamate, topiramate. The pharmacokinetic parameters of the new AEDs compared to the established AEDs, new AEDs have improved in terms of longer half-lives, permitting less frequent daily dosing, reduced potential for drug interactions. Considerations in selecting an AEDs are not only dependent on seizure types or syndromes, side effect profile, action mechanism, drug interaction, pharmacokinetic profile, facility of drug initiation, but also on age and sex of patients. Patients with worsened seizure frequency or development of new types of seizure after the introduction of AEDs, should be questioned on the previously diagnosed seizure types or syndromes.

New antiepileptic drugs; Action of mechanism; Pharmacokinetics/pharmacodynamics; Side effects; Seizure aggravation

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Figure 1

An excitatory synapse. the putative major sites of action of various AEds.

MDA: N-methyl-D-asparate, AMPA: a-amino-3-hydroxy-4-isoxazo-lepropionic acid (2).

Figure 2

An inhibitory synapse. the putative major sites of action of various AEds.

GABA: γ-aminobutyric acid, GABA-T, GABA transaminase, GAD: glutamic acid decarboxylase (2).

Figure 3

Plasma concentration of a drug following repeated oral drug administration (4) as a function of interval of administration measured as multiples of elimination half-life.

Figure 4

Relationship between serum drug concentration (ordinate) and drug dose (abscissa) for a drug observing (B) first-order kinetics (linear) and (A, C) zero-order kinetics (4) A, PHT, ZNS; B, FBM, ESM, PB, TPM, VPA,OXC, LEV, ZNS; C, LTG, VPA.

Table 1

List of the established and newer antiepileptic drugs

Table 2

Correlation between animal models and proposed mechanisms of action of antiepileptic drugs

scPTZ, subcutaneous pentylenetetrazole.

Table 3

Summary of the principal molecular actions of newer antiepileptic drugs

R, receptor; Tr, transaminase; KA, kainate; CAH,carbonic anhydrase; +++, well documented action, major part of AEDs effect; ++, effect probably of clinical significance; +, effect only tentatively.

Table 4

Pharmarcokinetic parameters of newer and established antiepileptic drugs

F: bioavailability, Tmax, time interval ingestion and maximal serum concentration; Vd, volume of distribution, T_½, elimination of half-life; Tse, steady-state time.

Table 5

Pharnacokunetic interactions between new AEDs and established drugs

^* CBZ-epoxide elevated only, CBZ may be decreased. ↔, no significant pharmacokinetic interaction expected; ↓ [↔] or ↑ [↔], (marked) decrease or increase in serum concentrations expected.

Table 6

The changes of concentration by the interaction between new AEDs and other drugs

↔, no interaction, F-1, decrease in progestin; F-2, increase in wafarin; G-1and G-2, decrease in GBP L-1, decrease in LTG; L-2, increase in LTG; O-1, decrease in cyclosporine; O-2, decrease in ethinyl estradiol; T-1, decrease in digoxin; T-2, decrease in ethinyl estradiol; T-3, increase in haloperidol.

Table 7

Risks and adverse effects of antiepileptic drug dherapy

Table 8

Commandments in the pharmacological treatment of epilepsy (7)

Table 9

Choice of antiepileptic drugs in children according to seizure type

Table 10

Summary of Pediatric epilepsy syndromes and treatments^*

^* based on less than class I and class II evidence (5).

BECTS, benign epilepsy of childhood with centrotemporal spikes; CJAE, childhood and juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; GTC, generalized tonic-clonic seizures.

Table 11

Efficacy of newer antiepileptic drugs for a particular seizure syndromes (1)

GTC: genralized tonic-clonic, +, effective, not approved; a: Indication approved by either the US Food and Drug Administration (FDA) or European Medicines Agency (EMEA)

Table 12

Comparison of recommendations for treatment of pediatric epilepsy (10)

BECT, BECTS, benign epilepsy of childhood with centrotemporal spikes.

^* Pediatric Expert Consensus survey. Drugs rated as treatment of choice listed

^† International League Against Epilepsy, Recommendations listed according to levels of evidence supporting the efficacy options. Level A, B, C (French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drug I: treatment of new onset epilepsy. Neurology 2004; 62: 1252 -1260)

^‡ SIGN: scottish intercollegiate guideline network. Diagnosis and manegement of epilepsies in children and young people; A national clinical guideline Edinburgh, SIGN: MArch 2005. (Copies available at: http://www.sign.ac.uk/pdf/sign81.pdf)

^§ National Institute for Clincal Excellence, Technology Appraisal Guidance 79. Newer drugs for epilepsy in children (www.nice.org/uk/TA079 guidance) and Clinical guidance 20. The epilepsies: The diagnosis and mangement of the epilepsies in adults and children in primary and secondary care, October 2004 (www.nice.org/uk/CG020NICE guideline).

^∥ FDA approval for each selzures type or epilepsy syndrome.

Table 13

Reasons for pseudoresistance to antiepileptic drugs drug therapy

Table 14

Combinations of drug reported to be useful in refractory epilepsy

Table 15

Combination therapy according to action mechanisms of antiepileptic drugs

Table 16

Idiosyncratic reactions and long term side effects of the new antiepileptic drugs

Table 17

Suggested mechanisms for an antiepileptic drug-induced seizure aggravation (11)

Table 18

AED-induced aggravation of seizures or epileptic syndromes (11)

+, limited; ++, moderate; +++. significant.

JME, juvenile myoclonic epilepsy; LGS, Lennox-Gastaut syndrome; MAE, myoclonic astatic epilepsy; BECTS, benign epilepsy of childhood with centrotemporal spikes; SMEI, severe myoclonic epilepsy of infancy; LKS, Landau-Kleffner syndrome; ESES, electrical status epilepticus of sleep.