Saddam AnsariAchiever’s AcademyIntroduction and Drugsused to Treat Epilepsy
Epilepsy? Second most common neurologicaldisorder. Family of different recurrent seizuresdisorders that have in common thesudden, excessive and synchronousdischarge of cerebral neurons. Abnormal movements or perceptionsthat are of short duration but tend to
Types of EpilepsyPrimary or Idiopathic Epilepsy: No specific anatomic cause for the seizure Inherited abnormality Treated often for lifetime with antiepilepticdrugs
Continued…Secondary Epilepsy: Reversible disturbances such as tumors, headinjury , hypoglycemia , meningeal infection orwithdrawal Antiepileptic are given until primary cause iscorrected Seizures secondary to stroke or trauma maycause irreversible CNS damage.
Classification of SeizuresPartial Seizure Simple partial Complex partial
Mechanism of action ofantiepileptic drugs Block the initiation of the electric dischargefrom the focal area Prevent the spread of the abnormal electricaldischarge to adjacent brain areas Blockade of voltage gated channels Enhancement of GABAergic impulses Interference with glutamate transmission
Phenytoin Formerly called as diphenylhydantoin Effective in suppressing tonic-clonic andpartial seizures Choice for initial therapy , particularly inadults
Continued…Mechanism of action: Blocks voltage – gated sodium channels Selectively binds to the channels ininactive state and recovery rate slowsdown At higher concentration – block voltagedependent calcium channels andinterfere with the release ofmonoaminergic neurotransmitters
Continued…Actions: Reduces the propagation of abnormalimpulses in the brain Is not a generalized CNS depressantlike the barbiturates But produces some degree ofdrowsiness and lethargy withoutprogression to hypnosis
Continued…Therapeutic uses: Highly effective for all partial seizures ,tonic – clonic seizures and in the statusepilepticus caused by recurrent tonic-clonic seizures Not effective in absence seizures , mayworsen if treated with this drug
Continued…Absorption and fate: Oral absorption is slow but distribution israpid and brain concentration are high Chronic administration of phenytoin isalways oral Largely bound to plasma albumin Metabolized by hepatic cytochrome P450system to an inactive metabolite
Continued…Absorption and fate: At low doses, half life is 24 hours Hydroxylation system becomessaturated as dose increases Increase in plasma concentration resultsin drug induced toxicity In status epilepticus – IV in form offosphenytoin
Continued…Adverse effects: Depression of CNS particularly incerebellum and vestibular system –nystagmus and ataxia GIT problems – nausea and vomiting Gingival hyperplasia particularly inchildren Coarsening of facial features occurs inchildren
Continued…Adverse effects: Megaloblastic anemia – B12 reactions Confusion, hallucination and drowsiness Inhibition of antidiuretic hormone Insulin secretion Should not be stopped abruptly
Continued…Teratogenic effects: “Fetal Hydantoin Syndrome” includescleft lip, cleft palate and congenital heartdisease Stunted growth Mental deficiency Congenital birth defects in untreatedmothers Drugs are given at the lowest possibledose in pregnant women
Continued…Drug InteractionsDrugs that affect phenytoin metabolism:Chloramphenicol, dicumarol , cimetidine,sulfonamides and isoniazidMicrosomal metabolism is inhibited by thesedrugs in the liverPhenytoin metabolism is enhanced bycarbamzepine
Continued…Drug InteractionsIncreased metabolism of other drugscaused by phenytoin:Induces the cytochrome P450 systemResults in increased metabolism of otherantiepileptics, anticoagulants, oralcontraceptives, quinidine, doxycycline,cyclosporine, mexiletine, methadone, andlevodopa.
CarbamazepineActions: Reduces the propagation of abnormalimpulses in the brain by blocking sodiumchannels Inhibits the generation of repetitiveaction potentials in the epileptic focusand preventing their spread
Continued…Therapeutic uses: Highly effective for all partial seizures ,first choice drug Effective in tonic-clonic seizures Used in treatment of trigeminal neuralgia Used in manic-depressive patients toameliorate the symptoms
Continued…Absorption and Fate: Absorbed slowly through oral administration Highly lipid solubility Half life – 5 to 7 days Half life decreases with chronic administration Induces cytochrome P450 system,cytochrome P450 isozyme, CYP3A4
Continued…Adverse effects: Chronic administration can cause stupor,coma and respiratory depression along withdrowsiness, vertigo, ataxia, blurred vision andrash. GIT – nausea and vomiting Liver toxicity Blood dyscrasias ( 10,11- epoxide metaboliteof drug) Leukopenia and aplastic anemia Hyponatremia in elderly people
Continued…Drug interaction:Hepatic metabolism of carbamazepine isinhibited byCimetidineDiltiazemErythromycinIsoniazidPropoxypheneToxic symptoms may arise if dose is notadjusted
Oxcarbazepine 10-keto derivative of carbamazepine Reduces to 10-monohydroxy metaboliteand blocks sodium channels preventingthe spread of the abnormal discharge Anticonvulsant spectrum and toxicitiesare similar to that of carbamazepine Less potent inducer of drug-metabolizing enzyme Reduced effectiveness of oralcontraceptives
PhenobarbitalActions: Limiting the spread of seizuredischarges in the brain and elevating theseizures threshold Exact mechanism is unknown Believed that potentiation of GABAneurons
Continued…Therapeutic uses: 50% favorable response rate for simplepartial seizures Not very effective for complex partialseizures First choice of drug for recurrentseizures in children including febrileseizure ,diazepam is also effective
Continued…Actions: Used to treat recurrent tonic-clonicseizures (if diazepam and phenytoin isnonresponsive) Mild sedative to relieve anxiety , nervoustension, insomnia but benzodiazepinesare superior
Continued…Absorption and Fate: Well absorbed orally Freely penetrates the brain Approximately 75 % drug is inactivatedby the hepatic microsomal system Remaining drug is excreted unchangedby the kidney Potent inducer of cytochrome P450system
Continued…Adverse effects: Nausea and vomiting with morbilliformrash Agitation and confusion at high doses Rebound seizures can occur ondiscontinuance of phenobarbital
Primidone Related to phenobarbital Alternate choice in partial and tonic-clonic seizures Often used with carbamazepine andphenytoin Ineffective in absence seizures Well absorbed orally but poor proteinbinding Adverse effects is same asphenobarbital
Valproic Acid Blocks sodium channel Enhancement of GABAergictransmission Broad-spectrum anticonvulsant Most effective in myoclonic seizures
Continued… Its second choice of drug due itshepatotoxicity Reduces the incidence and severity oftonic-clonic seizures Effective orally and rapidly absorbed About 90% bound to plasma proteins
Continued… 3% excreted unchanged Metabolized by CYP
Continued…Adverse effects Nausea and vomiting Sedation, ataxia and tremor arecommon Rare hepatic toxicity Rash and alopecia Thrombocytopenia Inhibits the metabolism of otherantiepileptic drugs
Ethosuximide Introduced in 1960 in the USA. Ethosuximide has very little activity againstmaximal electroshock Considerable efficacy againstpentylenetetrazol seizures; it was introducedas a "pure petit mal" drug.
Continued…Mechanism of Action Ethosuximide has an important effect on Ca2+currents, reducing the low-threshold (T-type)current. This effect is seen at therapeutically relevantconcentrations in thalamic neurons. The T-type calcium currents are thought toprovide a pacemaker current in thalamic neuronsresponsible for absence seizures. (INHIBITION ofthalamic neurons)
Continued…Therapeutic uses: Particularly effective against absence seizures Very narrow spectrum of clinical activity Documentation of its effectiveness in humanabsence seizures was achieved with long-termelectroencephalographic recording techniques
Continued…Pharmacokinetics Absorption is complete following administration ofthe oral dosage forms. Peak levels are observed 3–7 hours after oraladministration Ethosuximide is not protein-bound. Ethosuximide is completely metabolized,principally by hydroxylation, to inactivemetabolites.
Continued… The drug has a very low total body clearance(0.25 L/kg/d) This corresponds to a half-life of approximately40 hours, although values from 18 to 72 hourshave been reported.
Continued…Therapeutic Levels & Dosage Therapeutic levels of 60–100 mcg/mL can beachieved in adults with dosages of 750–1500mg/d Although lower or higher dosages and bloodlevels (up to 125 mcg/mL) may be necessary andtolerated in some patients.
Continued…Drug Interactions Administration of ethosuximide with valproic acidresults in a decrease in ethosuximide clearanceand higher steady-state concentrations. No other important drug interactions have beenreported for the succinimides.
Continued…Adverse effects and Toxicity Gastric distress, including pain, nausea, andvomiting. When an adverse effect occur, temporary dosagereductions may allow adaptation. Other dose-related adverse effects are transientlethargy or fatigue and much less commonly,headache, dizziness, hiccup, and euphoria. Behavioral changes are usually in the direction ofimprovement.
Continued…Phensuximide & Methsuximide Phensuximide and Methsuximide arePhenylsuccinimides that were developed andmarketed before Ethosuximide They are used primarily as anti-absence drugs Methsuximide is generally considered more toxic,and Phensuximide less effective, thanEthosuximide
continued… Unlike Ethosuximide, these two compoundshave some activity against maximalelectroshock seizures Methsuximide has been used for partialseizures by some investigators
Benzodiazepines Diazepam Potentiates GABAA responses Well absorbed orally , rectal administrationgives peak concentration in ~1 h with 90%bioavailability IV for status epilepticus , highly protein-bound, extensively metabolized to several activemetabolites ,t1/2 ~2 d Status epilepticus, seizure clusters
Continued… Clonazepam Action : As for diazepam >80% bioavailability extensively metabolizedbut no active metabolites , t1/2 20–50 h Therapeutic uses: Absence seizures,myoclonic seizures, infantile spasms Toxicity: Similar to diazepam
Felbamate Blocking voltage-dependent sodium channels Competing with the glycine-coagonist bindingsite on the N-methyl-D-aspartate (NMDA)glutamate receptor Blocking calcium channels
Continued… Potentiating the action of GABA. It is aninhibitor of drugs metabolized by CYP2C19and â-oxidation, and induces drugsmetabolized by CYP3A4. It is reserved for use in refractory epilepsies(particularly Lennox-Gastaut syndrome)because of the risk of aplastic anemia (about1:4000) Hepatic failure.
Gabapentin Decreases excitatory transmission by actingon Voltage-Gated Ca2+ channelspresynaptically Bioavailability 50%, decreasing withincreasing doses not bound to plasma proteins Not metabolized , excreted through kidney
Levetiracetam Action on synaptic protein SV2A Well absorbed orally Not bound to plasma proteins , t1/2 6–11 h Generalized tonic-clonic seizures, partialseizures, generalized seizures Adverse effects: Nervousness, dizziness,depression, seizures Interactions: Phenobarbital, phenytoin,carbamazepine, primidone
Tiagabine Blocks GABA reuptake in forebrain byselective blockade of GAT-1 Well absorbed highly bound to plasmaproteins Metabolism is mainly completed by theCYP3A family of enzymes t1/2 4–8 h Partial seizures Adverse effects: Nervousness, dizziness,depression, seizures
Topiramate Broad spectrum antiseizure activity. Blocks voltage-dependent sodium channels Increase the frequency of chloride channelopening by binding to the GABAA receptor High-voltage calcium currents (L type) arereduced
Continued… It is a carbonic anhydrase inhibitor and mayact at glutamate (NMDA) sites Effective and approved for use in partial andprimary generalized epilepsy It is also approved for treatment of migraine Topiramate is eliminated renally t1/2 20 h
Continued… It inhibits CYP2C19 and is induced byphenytoin and carbamazepine Lamotrigine is reported to cause an increasein topiramate concentration Coadministration of topiramate reducesethinyl estradiol
Continued… Adverse effects include somnolence, weight loss,and paresthesias Renal stones are reported to occur at a higherincidence than in a non-treated population Glaucoma, oligohidrosis, and hyperthermia havealso been reported
Zonisamide sulfonamide derivative that has a broad spectrumof action. The compound has multiple effects onneuronal systems thought to be involved inseizure generation. These include blockade of both voltage-gatedsodium channels T-type calcium currents Its use should be monitored in patients withreported allergies.
Continued… Approved for use in patients with partialepilepsy It is metabolized by the CYP3A4 isozyme andmay, to a lesser extent, be affected byCYP3A5 and CYP2C19 t1/2 50–70 h In addition to typical CNS adverse effects, itmay cause kidney stones Oligohidrosis has been reported