Current Therapeutic Approaches to Epilepsy
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Review Article [Rahman et al., 4(1): Jan., 2014] CODEN (USA): IJPLCP ISSN: 0976-7126 INTERNATIONAL JOURNAL OF PHARMACY & LIFE SCIENCES Current therapeutic approaches to epilepsy Azizur Rahman*, Fareedullah Md, Ansari Javed Akhtar and Sayyed Abdul Mateen Department of Pharmacology, MESCO College of Pharmacy, Hyderabad, (A.P.) - India Abstract Epilepsy is one of the most common ailments of man with a prevalence of approximately 1%. It is estimated that 50 millions person’s worldwide may have this disorder. Although many are well controlled with available therapies, perhaps one quarter of the total continue to have seizures. Anticonvulsant drugs are the mainstay of epilepsy management and may have to be taken for life. In more than 20% of those affected, chronic in aractable (refraction) epilepsy develops. This necessitates the use of combination therapy. But the use of these drugs in combination is plagued by cognitive impairment and drug interactions with the results that only about 10% of the patients with refractory epilepsy seem to benefit substantially from polypharmacy. The last past two decades has brought many advances to the treatment of epilepsy, including many new pharmacological agents. So substantial data has been collected both chemically as well as pharmacological point of view. Hopefully this will be helpful for Primary care physicians and as well as those involved in epilepsy patients care. Therefore they should be familiar with the new options available. Key-Words: Epilepsy, Seizures, Anticonvulsant drugs, Polypharmacy Introduction The term “epilepsy” refers to a disorder of brain The particular symptoms produced depend on the function characterized by the periodic and function of the region of the brain that is affected. Thus unpredictable occurrence of seizures. The term involvement of the hypothalamus causes peripheral “seizure” refers to a transient alteration of behaviour autonomic discharges and involvement of the reticular due to abnormal excessive, hyper synchronous formation in the upper brain stem that leads to loss of discharges from an aggregate of CNS neurons. consciousness 1. Seizure can be of following types: Aetiology a) Non epileptic - when evoked in a normal brain by Usually there is no recognizable cause (idiopathic), the treatment such as electric shock or chemical although it may be develop as a consequence of various convulsants. kinds of brain damage, such as trauma, infection or b) Epileptic - when occur without evident provocation. tumour growths 2. The epilepsies are common and frequently devastating disorder, affecting approximately 0.5 to 1% of the population. More than 40 distinct forms of epilepsy have been identified. The incidence increases again, epilepsy begins before the age of 18 in over 75% population. Seizure, the characteristic event in epilepsy is associated with the episodic high frequency discharges of impulses by a group of neurons in the brain. What starts as local abnormal discharges may then spread to other areas of the brain. The site of primary discharge and extent of its spread determines the symptoms that are produced, which range from a brief lapse of attention to a full blown convulsive fit lasting for several minutes. * Corresponding Author E.mail: [email protected], Classification of Epileptic Seizures [email protected] Epilepsy is classified in several ways: Mob.: +91 9010412319 1. Clinical events (usually seizure type). Int. J. of Pharm. & Life Sci. (IJPLS), Vol. 4, Issue 1: January: 2013, 2282-2287 2282 Review Article [Rahman et al., 4(1): Jan., 2014] CODEN (USA): IJPLCP ISSN: 0976-7126 2. Electro encephalographic changes (EEG). I II 3. Aetiology 4. Pathophsiology 5. Anatomy 6. Age The widely adopted method is the classification of seizures type in which only EEG data is taken into account. This scheme was introduced in 1969 by international league against epilepsy (ILAE) and was revised in 1981 1-3. I. Generalized II. Partial seizures 2 III. seizures 2 Unclassified epileptic III IV seizures A. Tonic– A. Simple partial clonic seizures seizures (grand mal) i) With motor B. Tonic signs seizures ii) With C. Clonic somatosensory or seizures special D. Absence sensory Fig. 1: Types of epileptic seizures. I. Normal; II. seizure hallucination Generalized tonic-clonic seizures; III. Absence (petitmal) iii) With automatic seizure; IV. Partial seizure. E. Myoclonic symptoms and seizure signs The bursting is caused by a relatively long lasting F. Atonic iv) With Psychic depolarization of the neuronal membrane due to influx seizures symptoms of extracellular calcium (Ca 2+ ), which leads to the (astatic) B. Complex partial pening of voltage dependent sodium (Na 2+ ) channel: Seizures influx of sodium and generation of repetitive action i) Simple partial potentials. This is followed by a hyperpolarizing after onset followed by potential mediated by GABA receptors of potassium impairement of channel depending on the cell type. conciousness. The synchronized bursts from a sufficient number of ii) With impaired neuro result in a so called spike discharge on the EEG. conciousness on Repetitive discharges of neurons lead to the following onset An increase in extracellular K +, C. Partial seizures which blunts the activity of hyperpolarization evolving to and depolarizes neighbouring neurons. secondary Accumulation of Ca 2+ in presynaptic generalized terminals, leading to enhance neurotransmitter seizures. release. Basic mechanisms of seizures initiation and Depolarization induced activation of propagation the NMDA subtype of the excitatory amino Partial seizure activity can begin in a very discrete acid receptor, which causes more Ca 2+ influx region of cortex and then spread to neighbouring and neuronal activation. regions i.e., there is a seizure initiation phase and a The recruitment of a sufficient number of neurons seizure propagation phase. Studies of experimental leads to a loss of the surrounding inhibition and models of these phases suggest that the initiation phase propagation of seizure activity into contiguous areas is characterized by two concurrent events in aggregate via local cortical connection and to more distant areas neurons. via long commissural pathways such as the corpus 1. High frequency burst of action potential and callosum. 2. Hypersynchronization Int. J. of Pharm. & Life Sci. (IJPLS), Vol. 4, Issue 1: January: 2013, 2282-2287 2283 Review Article [Rahman et al., 4(1): Jan., 2014] CODEN (USA): IJPLCP ISSN: 0976-7126 Epileptogenesis 4. OXAZOLIDINEDIONES clonic Seizures Epileptogenesis refers to the transformation of normal • Trimethadione Generalised Tonic- neurons network into one that is chronically • Paramethadion clonic Seizures hyperexcitable. For example, there is often a delay of e month to year between an initial injury such as trauma, 5. SUCCINIMIDES Generalised Tonic- stroke or infection and the first seizure. The injury • Ethosuximide clonic Seizures appears to initiate a process that gradually lowers the • Phensuximide Generalised Tonic- seizure threshold in the effected region until a 6. ALIPHATIC CARBOXYLIC clonic Seizures spontaneous seizure occurs. Pathologic studies of the ACID hippocampus from patients with temporal lobe epilepsy • Valproic Acid Generalised Tonic- (MTLE) are related to structural change in neuronal • Divalproex clonic Seizures networks. For example many patients with MTLE 7. BENZODIAZEPINES Generalised Tonic- syndrome have a highly selective loss of neurons clonic Seizures • Clonazepam within the dentate gyrus. In response, to the loss of • Diazepam neurons, there is recognition or “spouting” of surviving Absence Seizures • Lorazepam neurons in a way that affects the excitability of the Absence Seizures 8. NEWER DRUGS network. Thus an initial injury such as head injury may • lead to a very focal, confined region of structural Lamotrigine Partial and • change that causes local hyperexcitability. Gabapentin generalised tonic • The local hyperexcitability leads to further structure Levetiracetam clonic, absence change that evolves over time unit the focal lesion • Tiagabine seizure produces clinically evident seizures. • Felbamate Absence seizure Genetic cause of epilepsy • Topiramate The genetic causes of a few epilepsy syndromes have • Zonisamide Absence Seizures recently been discovered. They are: • Viagabatrin Status Epilepticus Myoclonic epilepsy with ragged red Absence fibres (MERRF) syndrome is associated with seizures,Myocloni a mutation of mitochondrial lysine. c Seizures Mutation in the cystation B give may cause another form of progressive myoclonus epilepsy. adjuvant in partial Mutation with gene encoding the B4 and secondarily subunit of the acetyl choline receptor appears generalised responsible for a frontal lobe epilepsy seizures syndrome. adjuvant in partial Treatment of epilepsy and secondarily Antiepileptics are agents used medically to control the generalised epilepsy; these are the mainstay of epilepsy seizures management. Refractory Partial Classification 3,6,7,8 Epilepsy Drugs Types of seizures Partial and Used Generalised Tonic 1. BARBITURATES Clonic Seizure • Phenobarbital Generalised tonic- Lennox Gastaut • Mephobarbital clonic seizures Syndrome • Primidone Generalised tonic- Refractory Partial 2. HYDANTOINS clonic seizures Epilepsy, Lennox • Phenytoin Generalised tonic- Gastaut Syndrome • Mephytoin clonic seizure Refractory Partial • Ethotoin Epilepsy 3. IMINOSTILBENES Complex partial Partial Epilepsy seizure • Carbamazepine Generalised Tonic- • Oxcarbazepine Int. J.