NEWER ANTIEPILEPTIC

DRUGSModerator: Dr. Afroz AbidiPresenter: Fariha Fatima

Epilepsy is a chronic disorder characterized by recurrent seizures, which

may vary from a brief lapse of attention or muscle jerks, to severe and

prolonged convulsions.

INTRODUCTION

With optimal drug therapy, epilepsy is controlled completely in about 75% of

patients, but about 10% continue to have seizures at intervals of 1 month or

less, which severely disrupts their life and work.

There is therefore a need to improve the efficacy of therapy.

Patients with epilepsy usually need to take drugs continuously for many years,

so avoidance of side effects is particularly important.

Nevertheless, some drugs that have considerable adverse effects are still quite

widely used even though they are not drugs of choice for newly diagnosed

patients.

Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than

to correct the underlying cause. Three main mechanisms of action appear to be

important :

Enhancement of GABA action.

Inhibition of sodium channel function.

Inhibition of calcium channel function.

NEWER ANTIEPILEPTIC DRUGS:VIGABATRIN:

Vigabatrin, the first 'designer drug' in the epilepsy field, is a vinyl-substituted

analogue of GABA that was designed as an inhibitor of the GABA-

metabolising enzyme GABA transaminase.

Vigabatrin is extremely specific for this enzyme and works by forming an

irreversible covalent bond.

In humans, vigabatrin increases the content of GABA in the cerebrospinal fluid.

P/K: Although its plasma half-life is short, it produces a long-lasting effect

because the enzyme is blocked irreversibly, and the drug can be given by mouth

once daily.

Vigabatrin has been reported to be effective in a substantial proportion of

patients resistant to the established drugs.

S/E: development of peripheral visual field defect in a proportion of patients

on long-term therapy.

Therefore the benefit of using this drug in refractory epilepsy must be weighed

against the potential risk of developing visual problems.

Vigabatrin may cause depression, and occasionally psychotic disturbances and

hallucinations, in a minority of patients.

LAMOTRIGINE

S/E: nausea, dizziness and ataxia, and hypersensitivity reactions (mainly mild

rashes, but occasionally more severe).

P/K: Its plasma half-life is about 24 h, with no particular pharmacokinetic

anomalies, and it is taken orally.

Indications: lamotrigine has a broader therapeutic profile than the earlier drugs,

with significant efficacy against absence seizures (it is also used to treat

unrelated psychiatric disorders).

Felbamate is an analogue of an obsolete anxiolytic drug, meprobamate.

S/E: mild, mainly nausea, irritability and insomnia, but it occasionally causes

severe reactions resulting in aplastic anaemia or hepatitis.

P/K: Its plasma half-life is about 24 h, and it can enhance the plasma

concentration of other antiepileptic drugs given concomitantly.

Carisbamate, a new drug currently in clinical trials, was designed with the

intention of producing a drug similar to felbamate that does not cause aplastic

anaemia.

FELBAMATE

Its spectrum of action resembles that of phenytoin, and it is claimed to produce

less severe side effects, as well as being devoid of the pharmacokinetic

properties that cause trouble with phenytoin.

Its main drawback is that it is teratogenic in animals, so it should not be used in

women of child-bearing age .

Currently, it is mainly used as add-on therapy in refractory cases of epilepsy.

TOPIRAMATE

GABAPENTIN AND PREGABALIN Gabapentin is effective against partial seizures.

P/K: The absorption of gabapentin from the intestine depends on the l-amino

acid carrier system and shows the property of saturability, which means that

increasing the dose does not proportionately increase the amount absorbed.

This makes gabapentin relatively safe and free of side effects associated with

overdosing.

Its plasma half-life is about 6 h, requiring dosing two to three times daily.

It is free of interactions with other drugs.

As these drugs are excreted unchanged in the urine they must be used with care

in patients whose renal function is impaired.

Tiagabine is an analogue of GABA that is able to penetrate the blood-brain

barrier.

It is an equipotent inhibitor of both neuronal and glial GABA transporter

GAT1, thus inhibiting the removal of GABA from the synapse.

It enhances the extracellular GABA concentration, as measured in

microdialysis experiments, and also potentiates and prolongs GABA-mediated

synaptic responses in the brain

S/E: drowsiness and confusion.

Tiagabine is mainly used as an add-on therapy for partial seizures.

TIAGABINE

Levetiracetam was developed as an analogue of piracetam, a drug used to

improve cognitive function, and discovered by accident to have antiepileptic

activity in animal models.

Unusually, it lacks activity in conventional models such as electroshock and

PTZ tests, but is effective in the audiogenic and kindling models.

LEVETIRACETAM

Zonisamide is a sulfonamide compound originally intended as an antibacterial

drug and found accidentally to have antiepileptic properties.

MOA: It is believed to act by blocking sodium channels and T-type calcium

channels but may well have other effects such as enhancing GABA function.

S/E: It is free of major unwanted effects, although it causes drowsiness, and of

serious interaction with other drugs. It tends to suppress appetite and cause

weight loss, and is sometimes used for this purpose.

ZONISAMIDE

P/K: Zonisamide has a long plasma half-life of 60-80 h, and is partly excreted

unchanged and partly converted to a glucuronide metabolite.

It is licensed for use as an adjunct treatment of partial and generalised seizures

but may be effective as a monotherapy.

Stiripentol has some efficacy as an adjunctive therapy in

children.

It enhances GABA release and prolongs GABA-mediated

synaptic events in a manner similar to phenobarbital.

STIRIPENTOL

Third-generation AEDs introduced in the last 5 years include:

Lacosamide, (LCM),

Rufinamide (RFN),

Ezogabine (EZG),

Eslicarbazepine(ESL), and

Perampanel (PER).

It is approved for focal epilepsy, and studies to establish its safety and

efficacy in idiopathic generalized epilepsy are on the way.

Mechanism of action: slow inactivation of voltage gated Na+ channels

limits sustained repetitive firing.

LACOSAMIDE

In a multicenter, double-blind, placebo-controlled, randomized trial, LCM

was found to be effective at doses of 200 and 400 mg/day as add-on therapy for

focal epilepsy.

In another double-blind, multicenter, randomized study, a 600 mg/day dose

was found to be more effective, than a 400 mg/day dose in reducing secondarily

generalized seizures.

However, the 400 mg/day dose was associated with fewer adverse effects.

LCM recently received monotherapy approval by the U.S. Food and Drug

Administration (FDA) in 2014 for focal epilepsy.

RFN is a structurally unique triazole derivative that prolongs the inactive state

of sodium channels and slows sodium channel recovery.

Indications:

efficacious in focal epilepsy,

it is used primarily in the treatment of drop attacks in Lennox Gastaut

Syndrome (LGS).

RUFINAMIDE

P/K: It is metabolized in the liver and, consequently, its clearance is increased

in the presence of enzyme-inducing AEDs (e.g. carbamazepine, phenobarbital,

phenytoin, and primidone), limiting its efficacy, while valproate inhibits its

metabolism, yielding an increase in its serum concentrations.

S/E: dizziness, fatigue, nausea, somnolence, diplopia, confusion, ataxia, and

impaired concentration.

EZG is a novel AED that is used as add-on treatment for treatment-resistant

focal epilepsy.

It has a novel mechanism of action mediated by activating voltage-gated

potassium channels, causing hyperpolarization of the membrane potential and

stabilizing the resting membrane potential.

S/E:dizziness, somnolence, fatigue, speech disorder and confusion,

The FDA issued a warning indicating that EZG can cause a blue discoloration

in the skin and retina.

EZOGABINE

ESL acetate is a VGSC blocker that is chemically related to carbamazepine and oxcarbazepine.

Class I evidence demonstrates the efficacy of this AED as adjunctive therapy in treatment-resistant focal epilepsy at 800 and 1200 mg/day doses given once/day

S/E: dizziness,

headache,

diplopia,

somnolence,

nausea,

emesis, and

poor coordination.

Patients should be monitored for serious rash and hyponatremia.

ESLICARBAZEPINE:

PER is an AED that acts as an antagonist of the a-amino- 3-hydroxy-5-methyl-

4-isoxazole propionic acid (AMPA) receptor of glutamate, which is the primary

excitatory neurotransmitter.

PER was approved as an add-on therapy for drug-resistant focal epilepsy.

Its long half-life allows once-a-day dosing, facilitating compliance.

PERAMPANEL

S/E: It has a boxed warning for serious psychiatric and behavioral reactions,

such as aggression, hostility, irritability, anger, and homicidal ideation, and

threats from patients randomly assigned to PER have been reported.

NEW DRUGS IN PIPELINE:

a competitive AMPA/kainate receptor

antagonist

a GABA transaminase inhibitor((vigabatrin

derived)

structurally resembling endogenous neurosteroids ,is a positive allosteric

modulator of GABAA receptors containing δ subunits

BGG492 (Novartis)

Brivaracetam (UCB)

Ganaxolone

Tonabersat a neuronal gap junction inhibitor.

ICA-105665 (Pfizer)

highly selective opener of neuronal potassium channels

T2000 (Taro) a non-sedating barbiturate

Imepitoina low-affinitypartial agonist at the benzodiazepine site of the GABA-A receptor

Sadly, while new AEDs with novel mechanisms of action and new molecular

targets have been added to our pharmacologic armamentarium, their impact on

treatment-resistant epilepsy has been very limited.

Hopefully, future advances in research will change this landscape.

CONCLUSION