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Anti Epileptic Drugs | Epilepsy | Drugs

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Anti epileptic drugs Anti epileptic drugs The characteristic event in epilepsy is seizure. Seizure: episodic high frequency discharge of impulses by a group of neurons. The local abnormal discharge then spreads to other areas of brain. Site of primary discharge and extent of its discharge determine the symptoms (ranging from loss of consciousness to convulsions; particular features depend on functions of area of brain affected). Involvement of motor area causes convulsions, of hypothalamus cause
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  Anti epileptic drugs 1 Anti epileptic drugsThe characteristic event in epilepsy is seizure.Seizure: episodic high frequency discharge of impulses by a group of neurons. The local abnormal discharge then spreads to other areas of brain. Site of primarydischarge and extent of its discharge determine the symptoms (ranging from loss of consciousness to convulsions; particular features depend on functions of area of brainaffected). Involvement of motor area causes convulsions, of hypothalamus causesautonomic discharge and of reticular formation causes loss of consciousness. Biochemical changes: Imbalance between. ã Excitatory amino acid transmission NMDA/AMPA and Inhibitory transmission(GABA). ã Alteration of membrane function affecting Na+/K+ channels.Repeated seizure activity leads to neurodegeneration due to excitotoxicity Type of seizuresDrug of choiceAlternativedrugs1. Partial seizures:Simple partial seizures : manifestations depend onthe area involved; motor or sensory, consciousnessmaintained. Seizure lasts 20-60 sec.CarbamazepinePhenytoinPhenobarbitoneValproateLamotrigineVigabatrinGabapentinFelbamateTopiramateTiagabine Complex partial seizure: impaired consciousness,lasting 30 sec to 2 minutes associated with purposeless movements such as lip smacking, handwringing.CarbamazepinePhenytoinPhenobarbitoneValproateLamotrigineVigabatrinGabapentinFelbamateTopiramateTiagabine Partial with secondarily generalized tonic-clonicseizures : simple or complex partial seizure evolvesinto a tonic clonic seizure with loss of consciousness and sustained contractions (tonic ) of muscles throughout the body followed by periods of muscle contraction alternately with periods of relaxation (clonic),typically taking 1-2 minCarbamazepinePhenytoinPhenobarbitoneValproateLamotrigineVigabatrinGabapentinFelbamateTopiramateTiagabine 2. Generalized seizures:Absence seizures (petit mal): Abrupt onset of impaired consciousness associatedwith staring and cessation of ongoing activitieslasting less than30 seconds. In EEG spike and wave discharges at afrequency of 3 per seconds . ClonazepamEthosuximideValproateClonazepamLamotrigine Atonic (loss of muscle tone/strength) ValproatePhenobarbitoneLamotriginePhenytoinClonazepam Myoclonic seizures- a brief perhaps for a secondshock like contractions of muscles (localized or generalized)ValproateClonazepamPhenobarbitoneLamotrigineTopiramateClonazepamEthosuximide  Anti epileptic drugs 2 Generalised tonic clonic seizures (grand mal),tonic, clonic. Loss of consciousness with sustainedcontractions (tonic) of muscles throughout the bodyfollowed by period of muscles contractionalternating with periods of relaxation (clonic),typically lasting 1-2 minutes.CarbamazepinePhenobarbitonePhenytoinPrimidoneValproateLamotrigineVigabatrinClobazamGabapentinFelbamateTopiramateTiagabine Mechanisms of action of anticonvulsant drugs 1. Enhancement of GABA function: raises the seizure threshold. Examples: – Phenobarbitone, benzodiazepines and topiramate –GABA-A mediatedopening of chloride channels. – Vigabatrin –irreversible inhibition of GABA transaminase, whichinactivates GABA) –increases GABA content of the brain. – Gabapentin- increases release of GABA. – Tiagabine- inhibits GABA uptake – Valproate 2.Inhibition of sodium channel function: – Phenytoin – Carbamazepine – Valproate – Lamotrigine ã Block high frequency discharge occurring in epileptic fit. ã Does not interfere with low frequency firing of neurons in normalstate. ã Depolarization, of neurons seen in PDS, increases the proportion of the sodium channels in the inactivated state. ã These drugs bind preferentially to channels in this inactivated state, prevent them from returning to the resting state and thus reducingthe number of functional channels available to generate APs. 3.Inhibition of calcium channels : – Ethosuximide: type T channels- activation of which causes rhythmicdischarge seen in absence seizures. – Gabapentin may act on L type of channels – Valproate – Zonisamide 4.Inhibition of excitatory transmitter NMDA or AMPA: ã Felbamate. ã Barbiturates, topiramate act by antagonizing AMPA (α amino-3 hydroxy-5methyl 4- isoxazolepropionate) receptors. Antiepileptic drugs: I.Long established antiepileptic drugs : phenytoin, carbamazepine, valproate,ethosuximide, phenobarbitone and various Bzs- diazepam, clonazepam, clobazam. IIThe newer drugs: vigabatrin, gabapentin, lamotrigine, felbamate, tiagabine,topiramate.  Anti epileptic drugs 3 I.Long established drugs 1. Phenytoin (diphenylhydantoin). ã  Non sedative, effective against partial and generalized seizures,.but not againstabsence seizures- may even get worst. Mechanism of action: ã Blockade of sodium channels (use dependent) and inhibition of generation of high frequency repetitive action potentials . ã At high conc: reduction in calcium influx- responsible for inhibition of secretory processes: release of hormones (ADH, insulin) and neurotransmitters (NE,5HT). promotes uptake of dopamine and inhibits MAO activity. ã Alters sodium, potassium, calcium conductance, membrane potentials andconcentrations of aminoacids and neurotransmitters. ã Drug interacts with membrane lipids and this promotes stabilization of membrane. PharmacokineticsAbsorption : affected by formulation of dosage form. Bioavailability problem (particlesize and additives).Absorption from GIT is good.On IM injection-absorption poor- gets precipitated.Fosphenytoin (more soluble prodrug phosphate ester) is used for parenteral injection (IM,IV) Distribution : 90% bound to plasma proteins mainly albumin. Widely distributed. CSFconcentrations- similar to free fraction. Free fraction affects efficacy and toxicity and theconcentration of free fraction is increased in uremia, hypoalbuminemia, so measurementof free phenytoin is important to adjust dosage. Metabolism and excretion: Metabolised in liver by SER to parahydroxyphenylderivative- excreted as glucuronide in bile and urine. – Metabolism is capacity limited; changes from first order to zero order over the therapeutic range-small increments in dose produce disproportionatelyhigh plasma concentrations. – The half-life 12-36 (24) hours with mild therapy and steady state isreached in 5-6 days but with higher levels, it may take 4-6 weeks with half life reaching to 60 hour. – Monitoring plasma concentration is necessary. – Phenytoin causes enzyme induction , increases the metabolism of other drugs like oral contraceptives, oral anticoagulants. Adverse effects:Dose dependentI.Acute effects: ã  Nystagmus ã Diplopia- reduce dose ã Ataxia ã Lethargy, sedation at higher concentration.Therapeutic range: 10-12 microgram/ml 2.Chronic therapy:  Anti epileptic drugs 4 ã GIT disturbances- nausea, vomiting, epigastric pain, anorexia. ã Gingival hyperplasia ã Coarsened facial features - involve altered collagen metabolism. ã Hirsutism , acne. ã Megaloblastic anemia (also produced by primidone and phenobarbitone)- due toaltered folate metabolism- responds to folic acid. ã Hemorrhagic disease of new born: hypoprothrombinemia and hemorrhage innew borns of mothers due to altered vitamin K metabolism - use vitamin K  ã Use during pregnancy- teratogenic : may produce fetal hydantoin syndrome (hypoplastic phalanges, cleft palate, hare lip, microcephaly), which is probablycaused by its epoxide metabolite. ã Peripheral neuropathy- depressed tendon reflexes. Endocrine effects: ã Osteomalacia with hypocalcemia due to altered vitamin D and K metabolism. ã Inhibition of release of ADH secretion ã Inhibition of insulin secretion. II.Hypersensitivity or idiosyncratic effects ã Skin rashes, fever, and rarely Stevens-Johnson syndrome, exfoliative lesion, SLEand fatal hepatic necrosis. ã Hematological reactions: neutropenia and leukopenia, thrombocytopenia andrarely red cell aplasia, agranulocytosis. ã Lymphadenopathy resembling Hodgkin's disease Uses ã Partial seizures. ã Generalized tonic-clonic seizures. ã Status epilepticus- slow IV injection. ã Trigeminal neuralgia- 2 nd choice drug. ã Cardiac arrhythmias- especially digitalis induced.. 2.Carbamazepine ã Pharmacological actions and mechanism: similar to phenytoin. Blocks Na + channels, inhibits high frequency repetitive firing of neurons. ã Acts presynaptically to decrease synaptic transmission. ã Inhibits uptake and release of NE, potentiate postsynaptic GABA action.The differences from phenytoin are: ã It is more effective in treating complex partial seizures (psychomotor epilepsy). ã Has active metabolite. ã Is effective in mood disorders. ã Enhances ADH action on renal tubules. ADME ã Slowly but completely absorbed orally (poor water solubility). Available only for oral administration. ã 75% bound to plasma proteins.
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