Date post: | 15-Apr-2017 |
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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