DROGAS ANTICONVULSIVANTES DE SEGUNDA GERAÇÃO

SECOND GENERATION ANTI SEIZURE DRUGS
Chandra Mohan Kumar Postgraduate Department of Pediatrics, Narayana Medical College, Nellore, India. Address for Correspondence: Dr Chandra Mohan Kumar, Assistant Professor, PG Dept of Pediatrics, Narayana Medical College, Nellore, India- 524002. Email: cmkumar1@rediffmail.com
Abstract
The Second Generation Anti Seizure Drugs (SGASD) have been traditionally known as "Newer Antiepileptic Drugs" since 1993. Now after 16 years of use in clinical practice the term "Second Generation Anti Seizure Drugs" should replace this term. Felbamate, the first of the SGASDs is approved for monotherapy and adjunctive treatment of partial seizures with or without generalization in patients 14 years and older, and in Lennox-Gastaut syndrome in children 2 to 14 years of age. Lamotrigine and Topiramate are broad spectrum Anti seizure drugs (ASD) for monotherapy in partial epilepsy and add-on for partial and generalized seizures associated with Lennox-Gastaut syndrome and typical absences. In children with Autism, ADHD and mental retardation, Lamotrigine is useful. Tiagabine, Gabapentin and Zonasamide are approved partial seizures in adults and adolescents. Vigabatrin is used in patients with refractory partial epilepsy when other appropriate drugs have failed, and in children with infantile spasms. Levetiracetam, a very exciting drug is unique among ASDs because it is effective starting with the initial dose. It is effective against refractory partial seizures. Oxcarbazepine, better tolerated derivative of carbamazepine is as effective as its parent drug. Fosphenytoin is better suited than Phenytoin in control of seizure in status epilepticus. Retigabine, a potassium channel opener and Lacosamide are under development. While choosing an add-on drug, co-morbid conditions, safety and it's mechanism of action should be taken into consideration as well, for the best results. If the initial drug is working on sodium channel the second one should be working through GABA (Gamma aminobutyric acid) and vice versa. Key words- Seizures, Anti seizure drugs, Refractory Epilepsy, Adjunctive therapy, Levetiracetam, Lamotrigine, Retigabine
Introduction
The Second Generation Anti Seizure Drugs (SGASDs) have been traditionally known as "Newer Antiepileptic Drugs". "Newer Antiepileptic Drugs" has been used in the literature for Felbamate, Lamotrigine, Vigabatrin and Gabapentin. Now some more drugs have been added to this group but the name "Newer Antiepileptics" is still used even after 16 years of use in clinical practice. However not all the seizure episodes are epilepsy and not all the anti seizure drugs (ASD) are used as anti epileptics (AED) (for e.g. Fosphenytoin is available only as IV formulation, hence this anti seizure drug cannot be termed as anti-epileptic.) Hence, now the term "Second Generation Anti seizure Drugs" can and should replace this term. The first-line anticonvulsants came into existence after discovery of Phenytoin in 1930s and continued till 1978 when last of this series and the most versatile one, the Sodium Valproate was marketed. Then there was a lull in the development of new drugs for seizure control. In US the 1990s were declared as "Decade of Brain" by President George Bush (Sr.) by Presidential Proclamation 6158, signed on July 17th 1990, hence in 1990s the emphasis again shifted towards discovery of newer molecules for seizure control. Eventually in 1993, after a hiatus of 15 years Felbamate was marketed, marking the beginning of the "Second Generation Anti Seizure Drugs" and which was followed by a flurry of new discoveries which is still continuing. Availability of a plethora of choices makes a physician's choice more challenging too. This review article aims to evaluate the Second Generation Anti Seizure drugs on the basis of their pharmacological properties, uses and their efficacy in management of Pediatric Seizure Disorders. Most of the new ASDs are approved only as adjunctive therapy for partial seizures, however now a huge amount of data is available supporting their efficacy as initial monotherapy also. Thus, indications for these drugs are gradually broadening for e.g. oxcarbazepine, lamotrigine, topiramate and levetiracetam are now considered appropriate for monotherapy in partial seizures and topiramate for treatment of primary generalized seizures. The choice of the most suitable ASD should take into account its spectrum of efficacy and special pharmacological properties as well as patient's co-morbid conditions and special needs, although the first consideration should be effectiveness of the drug against a particular seizure type. Equivalence in efficacy with better tolerability and lesser adverse effects may be considered as superiority. (1)
Second Generation Anti Seizure Drugs: The drugs are depicted in Table 1.
Table 1: Second generation anti-seizure drugs:FelbamateGabapentinLamotrigineVigabatrinTopiramateTiagabineLevetiracetamZonisamide
New Derivatives or formulations of First line ASDs
Oxcarbazepine, Fosphenytoin and IV Valproate Sodium Felbamate: It was first of the SGASDs approved by US FDA in 1993. It has a broad spectrum of activity in both partial and generalized seizures. It inhibits NMDA (N-Methyl D-Aspartate) and potentiates GABA (Gamma aminobutyric acid) and this dual action results in broad spectrum of action. It is approved in various countries worldwide for monotherapy and adjunctive treatment of partial seizures with or without generalization in patients 14 years and older, and as adjunctive therapy for partial and generalized seizures associated with Lennox-Gastaut syndrome in children 2 to 14 years of age (2). After its approval by the Food and Drug Administration in the United States, cases of aplastic anemia and hepatic failure were reported in significant numbers (3) hence its use is now restricted to patients with refractory epilepsy for whom benefits of treatment outweigh its risks. Interestingly aplastic anemia has not been observed in children below 13 years of age but hepatotoxicity remains a concern (4). Gabapentin: It is an AED formed by the incorporating a cyclohexyl group to GABA, which allows this form of GABA to cross the blood-brain barrier (2). Gabapentin is characterized by excellent tolerability. It is not protein bound, has no appreciable hepatic metabolism and is excreted by the kidneys. Thus, Gabapentin is appropriate for use in patients who have multiple drug intolerances and who require relatively quick titration. It is approved for adjunctive use for treatment of partial seizures with or without secondary generalization in patients older than 12 years. Two randomized studies evaluated Gabapentin as adjunctive therapy in a pediatric population, the first in patients aged 3 to 12 years, where it was effective, and the second in patients aged 1 to 36 months, where only a trend was demonstrated (2,5). Thus beyond 3 years it may be used as an effective adjunctive drug. Adverse effects are somnolence, ataxia and dizziness. Lamotrigine: It has a broad spectrum of activity against multiple seizure types. It partly blocks the release of the excitatory neurotransmitter glutamate from nerve endings, and reduces the influx of sodium in the recipient neurons. Lamotrigine is found to be equally effective and better tolerated than Carbamazepine. It is completely absorbed after oral administration and metabolized primarily by glucuronidation. Its half life is about 36 hours on monotherapy but it is reduced to 15 hours if used in combination with Phenytoin or Carbamazepine. If used in combination, Valproate increases its concentration where as lamotrigine decreases Valproate levels by 25%. It has the best cognitive profile amongst all AEDs. Sedation is seen very rarely with this drug in monotherapy and it even has an "alerting" response in some patients. In children with Autism, ADHD and mental retardation and other behavior problems, where sedatives should be avoided, lamotrigine being a non sedative provides a good option. Another advantage of this drug is that, it doesn't reduce bone density with long term use (6,7). One idiosyncratic side effect of lamotrigine, which is similar to effects of older antiepileptic drugs is a rash. Infrequently (in less than 1 percent of cases), the rash can be serious and may progress to Stevens-Johnson syndrome, which can be life-threatening. Rashes are more common in children when lamotrigine is taken in association with Valproate Sodium and with rapid titration. Blurring of vision and ataxia are other adverse effects encountered with lamotrigine. Lamotrigine is approved for adjunctive therapy in partial epilepsy, as well as for partial and generalized seizures associated with Lennox-Gastaut syndrome in children. It is also found to be efficacious in pharmacoresistant partial epilepsy as well as typical absence (8,9). Topiramate: It also has a broad spectrum of activity. It acts by promoting the inactivated state of voltage gated sodium channels. It appears to help balance electrical activity in the brain while blocking other substances that increase activity. Weight loss has been noted, which can be a desirable lateral side effect. It also inhibits enzyme carbonic anhydrase, which is believed to be the mechanism of developing some other side effects like paresthesia and nephrolithiasis. Topiramate is approved for adjunctive therapy for partial and generalized seizures in adult and pediatric patients older than 2 years of age. It has been found to be effective as adjunctive therapy for Lennox-Gastaut syndrome and infantile spasms (10,11). Tiagabine: It is a GABA Transporter GAT1 inhibitor that reduces uptake of GABA and thus acts as anti seizure drug. It is rapidly absorbed, extensively bound to protein and metabolized in liver. Efficacy and tolerability in children have been encouraging. Tiagabine has no significant systemic or serious idiosyncratic adverse side effects, but it does have a relatively narrow spectrum of activity and must be titrated slowly. It is approved as adjunctive therapy for partial seizures in adults and adolescents. It has been found to be efficacious in refractory partial epilepsy. It should be used with caution in patients with generalized seizures, as they may be exacerbated (13,14). Note: One limitation of Lamotrigine, Topiramate and Tiagabine, is that they need to be initiated at a low dosage and slowly increased in dosage over several weeks. Vigabatrin: It is another second generation ASD working on GABA inhibitory neurons. It is an irreversible inhibitor of GABA transaminase which leads to increased levels of GABA. It is used as add-on treatment of patients with refractory partial epilepsy. Vigabatrin has been approved in many countries but not the United States. It is rapidly absorbed following oral administration and peak plasma concentrations are reached within 2 hours. It is only slightly metabolized and majority of the drug is eliminated unchanged through kidneys. In some studies it has been attributed to cause irreversible visual field defects, hence it should be used with caution particularly in children having renal impairment (14). Its use has been limited to patients with refractory partial epilepsy when other appropriate drugs have failed, and to patients with infantile spasms. Many regard vigabatrin as the drug of choice for infantile spasms. Vigabatrin may exacerbate absence and myoclonic seizures (15). Levetiracetam: It is another very exciting drug. It is unique among the SGASDs because it is effective starting with the initial dose and thus it has a role in treating ongoing seizure activities including status epilepticus. Its mechanism of action is not known. Neither inactivation of voltage gated sodium channel nor GABA activation is observed. Like Gabapentin, its tolerability and pharmacokinetics profiles are very attractive. Levetiracetam is not metabolized by the liver (about 65% is excreted by the kidneys unchanged), and less than 10 percent is protein bound. It is neither an inducer nor inhibitor of hepatic microsomal enzyme systems. As a result, drug interactions are minimal. Levetiracetam is approved for adjunctive treatment of partial seizures with or without generalization in adults and children. Various clinical trials has showed effective conversion to monotherapy in patients with refractory partial seizures (16-18). Zonisamide: It was recently approved in US for adjunctive treatment of partial seizures although it has been used in Japan for more than a decade now. Chemically it is a sulphonamide. It inhibits a particular voltage activated calcium channel known as T current. It also inhibits sodium channel. It is well absorbed and metabolized by acetylation and glucuronidation. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. Zonisamide is easy to titrate and has a short latency of onset, thereby making it an attractive therapeutic alternative. It is excreted through kidneys.Its important adverse effect is development of renal calculi (19). But various studies in Japan have confirmed its efficacy and safety (20). It has been found efficacious in refractory partial epilepsy (21).
Table 2: Clinical Uses of Second Generation Anti-seizure drugs in Pediatric Practice
Drug
Acts on
Indications
Dose
Felbamate
NMDA & GABA
Adjunctive therapy for partial seizures with or without generalization. Adjunctive therapy for partial and generalized seizures associated with Lennox-Gastaut syndrome
Start with 15mg/mg/day and increase up to 45mg/kg/day or seizure control is achieved
Gabapentin
GABA
Adjunctive treatment of partial seizures with or without generalization in patients older than 12 years
25-40 mg/kg/day and given in divided doses (three times a day).
Lamotrigine
Sodium Channel
Partial epilepsy, Add-on treatment of generalized seizures in Lennox-Gastaut syndrome, Childhood and Juvenile absence, Juvenile myoclonic epilepsy
Start with 0.3mg/kg/day. Increase 0.3 mg/kg weekly to up to 4.5-7 mg/kg/day or seizure control is achieved
Topiramate
Sodium Channel
Adjunctive therapy for partial and generalized seizures in adult and pediatric patients older than 2 years of age. Adjunctive therapy for Lennox-Gastaut syndrome and infantile spasms, Juvenile myoclonic epilepsy
Start with 1-3 mg/kg/day and increase 1-3 mg/kg weekly up to 5-9 mg/kg/day in two divided doses or seizure control is achieved
Tiagabine
GAT1/GABA
Refractory partial epilepsy in children above 12 years of age
Start with 4 mg daily and increase 4 mg weekly to reach a maximum dose of 32 mg daily or seizure control is achieved
Levetiracetam
Not Known
Partial seizures with or without generalization. Adjunctive therapy for Juvenile myoclonic epilepsy
Start with 20 mg/kg in two divided doses and increase 20 mg/kg every 2 weekly up to 60 mg/kg/day or seizure control is achieved
Vigabatrin
GABA
Refractory partial seizures, Infantile spasms
40 mg/kg/day, increasing to 80 to 100 mg/kg/day or seizure control is achieved
Zonisamide
Ca2+ (T Current)
Adjunctive treatment of partial seizures in patients older than 16 years
Start with 100 mg/day and increase 100 mg every 2 weeks up to 400 mg/day or seizure control is achieved
New Derivatives or formulations of First line ASDs: In addition to the newer drugs, several chemical reformulations have been made to the old antiepileptic drugs that have resulted in more favorable pharmacological profile. Oxcarbazepine, Fosphenytion and IV Valproate Sodium come under this category. Oxcarbazepine: It is a newer and better-tolerated derivative formulation of carbamazepine. It has several advantages over carbamazepine which includes weaker and more selective liver enzyme induction and absence of auto-induction. Thus it has lesser interaction with erythromycin and other drugs that cause carbamazepine accumulation and oral contraceptive pills. Oxcarbazepine has been approved for monotherapy as well as adjunctive therapy in children aged 4 years or older and adjunctive therapy for children over 2 years of age, with partial seizures with or without secondary generalization. Its mechanism of action and efficacy profile is similar to the parent drug i.e. carbamazepine, but its adverse effects are less. Dizziness, diplopia and ataxia are the commonly encountered side effects. Fosphenytoin: It is a prodrug that is converted to its active metabolite phenytoin with a conversion half-life of 8 to 15 minutes. Recently Fosphenytoin has emerged as a preferred treatment option for of status epilepticus. The major advantage of fosphenytoin over phenytoin is that it does not contain propylene glycol and has a pH of 8.6-9.0 as opposed to 11-12 for phenytoin. This allows fosphenytoin to be administered in dextrose containing IV solutions at a more rapid rate (3mg/kg/min Vs 1mg/kg/min). As the pH is more physiological there is less risk of soft tissue injury with extravasations at the IV site. The elimination of propylene glycol from the vehicle is also beneficial as it reduces the incidence of hypotension. Its dose is calculated on basis of Phenytion Equivalent (PE). 1.5 mg of fosphenytoin is equal to1 mg of phenytoin.
Table 3: Pharmacokinetic and Pharmacodynamic properties of Second Generation ASDs
Drug
Action on CYP
Action on UGT
Metabolized by CYP
Metabolized by UGT
Important Adverse Effects
Felbamate
No
No
Yes
Yes
Aplastic anemia, hepatitis
Gabapentin
No
No
No
No
Weight gain
Levetiracetam
No
No
No
No

Lamotrigine
No
Induces
No
Yes
Rash
Tiagabin
No
No
Yes
No

Topiramate
Inhibits
No
-
-
Nephrolithiasis, paresthesias, weight loss
Zonisamide
No
No
Yes
No
Nephrolithiasis, weight loss
Oxcarbazepine
Iinduces3A4/5 Inhibits 2C19
weakly
No
Yes
HyponatremiaCYP-Cytochrome P 450, UGT-UDP Glucuronosyl Transferase
Anti-Seizure Drugs in Development
Retigabine: It is a new anti-seizure molecule under development, has exhibited a broad spectrum of antiepileptic activity in animal models, which is believed to be due to its ability to enhance potassium currents mediated by human KCNQ2 and KCNQ3 potassium channels as well as augment GABA-medicated currents. The phase three trials of this drug Retigabine Efficacy and Safety Trial for Partial-Onset Epilepsy (RESTORE 1and 2) have demonstrated a linear dose effect in seizure reduction from 600 to 1200mg doses (22). Adverse events were most common at the 900 and 1200 mg doses, and tended to affect the central nervous system. At the 1200-mg dose, somnolence was the most common adverse event (22.6%), followed by dizziness (19.8%), confusion (17.9%), and speech disorder (16%). Treatment discontinuations were most common at the highest dose. Retigabine has the promise to open a new channel for seizure control by acting on potassium channel. Lacosamide: It is another new antiepileptic drug in development. Recently it has been launched in UK as a new adjunctive therapy (dose 200-400mg/day) in the treatment of partial-onset seizures with or without secondary generalization in patients with seizure disorder aged 16 years and older. Its efficacy has been demonstrated in three randomized, double-blind, multicenter, placebo-controlled trials over 12 weeks maintenance period. Both the 200 mg/day dose and the 400 mg/day dose had a statistically significant median percentage seizure reduction compared with placebo (23). Lacosamide had no significant effect on laboratory values, body weight, or vital signs. The most common adverse events leading to withdrawal were diplopia and vomiting which were observed with higher (400 mg/day) dose. Conclusion: In the present scenario, oxcarbazepine and topiramate are approved for initial monotherapy for partial seizures but lamotrigine, levetiracetam and gabapentin have also been found eligible to make to that grade. Others are also effective but at present they are at best the add-on drugs. While choosing an add-on drug, co-morbid conditions, safety and it's mechanism of action should be taken into consideration as well, for the best results. If the initial drug is working on sodium channel the second one should be working through GABA and vice versa.
References

1.

French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004; 62: 1252-1260

2.

Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the Fifth Eilat Conference (EILAT V). Epilepsy Res. 2001; 43: 11-58

3.

Arroyo S, de la Morena A. Life-threatening adverse events of antiepileptic drugs. Epilepsy Res. 2001; 47: 155-174

4.

Azar NJ, Abou-Khalil BW. Considerations in the choice of an antiepileptic drug in the treatment of epilepsy. Semin Neurol. 2008; 28: 305-316

5.

Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, Garofalo E. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Gabapentin Paediatric Study Group. Epilepsia. 1999; 40: 1147-1154

6.

Gilliam F, Vazquez B, Sackellares JC, Chang GY, Messenheimer J, Nyberg J.et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology. 1998; 51: 1018-1025

7.

Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007; 369: 1000-1015

8.

Ramaratnam S, Marson AG, Baker GA. Lamotrigine add-on for drug-resistant partial epilepsy [Cochrane Review on CD-ROM]. Oxford, England: Update Software; 2002

9.

Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, Chen C, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia. 1999; 40: 973-979

10.

Glauser TA, Clark PO, McGee K.. Long-term response to topiramate in patients with West syndrome. Epilepsia. 2000; 41 Suppl 1: S91-94

11.

Glauser TA, Levisohn PM, Ritter F, Sachdeo RC. Topiramate in Lennox-Gastaut syndrome: open-label treatment of patients completing a randomized controlled trial. Topiramate YL Study Group. Epilepsia. 2000; 41 Suppl 1: S86-90

12.

Lassen LC, Sommerville K, Mengel HB, Edwards D, Nielsen B, Shu V. Summary of five controlled trials with tiagabine as adjunctive treatment of patients with partial seizures. Epilepsia. 1995; 36: S148

13.

Pellock JM. Tiagabine (gabitril) experience in children. Epilepsia. 2001; 42 Suppl 3: 49-51

14.

Tassinari CA, Michelucci R, Ambrosetto G, Salvi F. Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy. Arch Neurol. 1987; 44: 907-910

15.

Tartara A, Manni R, Galimberti CA, Hardenberg J, Orwin J, Perucca E. Vigabatrin in the treatment of epilepsy: a double-blind, placebo-controlled study. Epilepsia. 1986; 27: 717-723

16.

Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I.. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000; 55: 236-242

17.

Shorvon SD, Lwenthal A, Janz D, Bielen E, Loiseau P. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia. 2000; 41: 1179-1186

18.

Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia. 2000; 41: 1276-1283

19.

Leppik IE, Willmore LJ, Homan RW, Fromm G, Oommen KJ, Penry JK, et al.. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res. 1993; 14: 165-173

20.

Schmidt D, Jacob R, Loiseau P, Deisenhammer E, Klinger D, Despland A, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993; 15: 67-73

21.

Faught E, Ayala R, Montouris GG, Leppik IE; Zonisamide 922 Trial Group., et al. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology. 2001; 57: 1774-1779

22.

Porter R, Partiot A, Sachdeo R, Nohria V, Alves WM; 205 Study Group. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology. 2007; 68: 1197-1204

23.

Ben-Menachem E. Lacosamide: an investigational drug for adjunctive treatment of partial-onset seizures. Drugs Today (Barc). 2008; 44: 35-40

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Last updated on 1st September 2009. Vol 6 Issue 9 Art # 47
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