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  1. 1. Modern treatment of seizures started in 1850 with the introduction of bromides, on the basis of the theory that epilepsy was caused by an excessive sex drive. In 1910, phenobarbital, which then was used to induce sleep, was found to have antiseizure activity and became the drug of choice for many years. A number of medications similar to phenobarbital were developed, including primidone. Houston Merrit and Tracy Putnam introduced animal models for screening multiple compounds for antiepileptic activity, published in Journal of the American Medical Association in 1938. In 1940, phenytoin (PHT) was found to be an effective drug for the treatment of epilepsy, and since then it has become a major first- line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures. In 1968, carbamazepine (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures. Ethosuximide has been used since 1958 as a first- choice drug for the treatment of absence seizures without generalized tonic-clonic seizures. Valproate was licensed in Europe in 1960 and in the United States in 1978, and now is widely available throughout the world. It became the drug of choice in primary generalized epilepsies and in the mid 1990s was approved for treatment of partial seizures. These anticonvulsants were the mainstays of seizure treatment until the 1990s, when newer AEDs with good efficacy, fewer toxic effects, better tolerability, and no need for blood level monitoring were developed. The new AEDs have been approved in the United States as add-on therapy only, with the exception of lamotrigine, which is approved for conversion to monotherapy. The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma- aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action.
  2. 2. Carbamazepine The main mode of action Block sodium channels during rapid, repetitive, sustained neuronal firing and to prevent posttetanic potentiation. Formulations that are available include suspension, syrup, tablets (100 mg, 200 mg, 400 mg). Antiepileptic effect and clinical use Highly effective for partial onset seizures, including cryptogenic and symptomatic partial seizures. Treatment of generalized tonic-clonic seizures. Side effects and toxicity Dose-related adverse effects, which include dizziness, diplopia, nausea, ataxia, and blurred vision. Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens-Johnson syndrome. Asymptomatic elevation of liver enzymes in 5-10% of patients. Rarely, severe hepatotoxic effects can occur. Drug interactions Several drugs, such as macrolide antibiotics (erythromycin and clarithromycin), isoniazid, chloramphenicol, calcium channel blockers, cimetidine, and propoxyphene, inhibit the hepatic enzyme cytochrome P-4503A4 (CYP3A4), which is responsible for the metabolic breakdown of CBZ, thereby raising its levels. CBZ induces the metabolism of tricyclic antidepressants, oral contraceptives, cyclosporin A, and warfarin by inducing the hepatic enzyme CYP3A4.
  3. 3. Phenytoin The main mode of action It blocks movements of ions through the sodium channels during propagation of the action potential, and therefore blocks and prevents posttetanic potentiation, and reduces the spread of seizures. It also demonstrates an inhibiting effect on calcium channels and the sequestration of calcium ions in nerve terminals, thereby inhibiting voltage-dependent neurotransmission at the level of the synapse. Antiepileptic effect and clinical use PHT is one of the most commonly used first-line or adjunctive treatments for: partial and generalized seizures Lennox-Gastaut syndrome status epilepticus childhood epileptic syndromes. It is not indicated for myoclonus and absence seizures. Adverse effects and toxicity One disadvantage of this drug is that it causes CNS and systemic adverse effects. The long-term use is associated with osteoporosis. CNS effects occur particularly in the cerebellum and the vestibular system, causing ataxia and nystagmus. Some degree of drowsiness and lethargy is present. Nausea and vomiting, rash, blood dyscrasias, headaches, vitamin K and folate deficiencies, loss of libido, hormonal dysfunction, and bone marrow hypoplasia are among the most common adverse effects. When given during pregnancy, PHT, like other AEDs, can cause cleft palate, cleft lip, congenital heart disease, slowed growth rate, and mental deficiency in the offspring.
  4. 4. Fosphenytoin Fosphenytoin sodium injection is a prodrug intended for parenteral administration. Its active metabolite is PHT. It is safer and better tolerated than PHT and can be infused 3 times faster than intravenous (IV) PHT. Antiepileptic effect and clinical use The antiepileptic effect of fosphenytoin is attributable to PHT. Fosphenytoin is indicated for treatment of status epilepticus. Adverse effects and toxicity Cardiovascular depression and hypotension may occur but less than with PHT. Severe burning, itching, and/or paresthesia, mainly in the groin area, have been associated with rapid infusion. The discomfort may be improved by lowering the infusion rate . Oxcarbazepine The main mode of action Like CBZ, OXC blocks the neuronal sodium channel during sustained rapid repetitive firing. Antiepileptic effects and clinical use OXC is approved for monotherapy or adjunctive therapy in partial and secondary generalized seizures. OXC is better tolerated and has fewer drug interactions than CBZ. In adults, the dose is 600 mg/d up to a maximum of 2400 mg/d. Adverse effects and toxicity Somnolence, headache, dizziness, rash, hyponatremia, weight gain, GI disturbances, and alopecia are the most commonly reported adverse effects. Dose-related adverse effects include fatigue, headache, dizziness, and ataxia. Hyponatremia is mild and can be
  5. 5. corrected by fluid restriction. Idiosyncratic reactions appear to be less common than with CBZ. Lamotrigine The main mode of action Inhibit depolarization of the glutaminergic presynaptic membrane, thus inhibiting release of glutamate. Antiepileptic effect and clinical use It is effective in: partial seizures secondarily generalized tonic-clonic seizures primary generalized seizures atypical absence seizures tonic/atonic seizures Lennox-Gastaut syndrome myoclonic seizures, but can worsen "in some patients" juvenile myoclonic epilepsy or myoclonic epilepsy of infancy. In children on valproate, the starting dose of LTG is 0.15 mg/kg, with increments every 1-2 weeks up to a maximum of 1-5 mg/kg. Adverse effects and toxicity LTG produces few CNS side effects. Rash is the main concern associated with this drug. Severe rash (more common in children taking valproate) may develop and lead to Stevens-Johnson syndrome, which may be fatal, but this is rare (0.1%). Other adverse reactions are headache, blood dyscrasias, ataxia, diplopia, GI disturbance, psychosis, tremor, hypersensitivity reactions, somnolence, and insomnia. Zonisamide The main mode of action Reduction of neuronal repetitive firing by blocking sodium channels and preventing neurotransmitter release.
  6. 6. Antiepileptic effect and clinical use Adjunctive therapy for patients with partial seizures who are 12 years or older. Treatment of myoclonus, esp., in juvenile myoclonic epilepsy. Adverse effects and toxicity Dizziness, anorexia, headache, ataxia, confusion, speech abnormalities, mental slowing, irritability, tremor, and weight gain. Somnolence and fatigue have been reported frequently. ZNS is associated with renal stones in 1.5% of patients. Idiosyncratic skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Clobazam The main mode of action In addition to its agonist action at the GABA-A receptor, clobazam may affect voltage-sensitive conductance of calcium ions and the function of sodium channels. Antiepileptic effect and clinical use Clobazam is a potent anticonvulsant for partial epilepsy. Adverse effects and toxicity The most common effect is sedation. Others include dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle fatigue, and weakness. Idiosyncratic reactions are very rare. Clonazepam The main mode of action Clonazepam has higher affinity for the GABA-A receptor site . Antiepileptic effect and clinical use The drug of choice for myoclonic seizures and subcortical myoclonus.
  7. 7. Effective in generalized convulsions and, to a lesser extent, in partial epilepsies. Very effective in the emergency treatment of status epilepticus, like diazepam, and can be given IV or rectally. Withdrawal from clonazepam may induce status epilepticus or exacerbation of seizures. Psychiatric withdrawal also may occur, manifested as insomnia, anxiety, psychosis, and tremor. Adverse effects and toxicity The major adverse effect is sedation, even at low doses. Clonazepam has the typical adverse effects of benzodiazepines (eg, ataxia, hyperactivity, restlessness, irritability, depression, cardiovascular or respiratory depression). Children and infants may have hypersalivation. Occasionally. Phenobarbital The main mode of action 1) It has a direct action on GABA-A receptors prolonging the duration of chloride channel opening. 2) It also reduces sodium and potassium conductance and calcium influx and depresses glutamate excitability. Antiepileptic effect and clinical use As effective as PHT and CBZ in the treatment of partial and secondarily generalized seizures. It is a second-line drug because of its adverse effects such as sedation and cognitive slowing. Physical dependence and withdrawal seizures occur with long-term use. Adverse effects and toxicity The most important adverse effects are cognitive and behavior alterations. Sedation is prominent. Psychomotor slowing, poor concentration, depression, irritability, ataxia, and decreased libido
  8. 8. are other effects. Coarsening of facial features, osteomalacia, and Dupuytren contractures. Folate deficiency, megaloblastic anemia, and idiosyncratic skin reaction are rare. Primidone The main mode of action This drug is metabolized to PHB and phenylethylmalonamide (PEMA). The main action is through the derived PHB. Antiepileptic effect and clinical use Primidone has the same indications as PHB. Adverse effects and toxicity The major adverse effects are intense sedation, dizziness, and nausea. Other effects are the same as those of PHB. Tiagabine The main mode of action Inhibition of the GABA transporter-1 (GAT-1). Antiepileptic effect and clinical use Add-on therapy in patients with partial or secondarily generalized seizures refractory to treatment. Adverse effects and toxicity The adverse effects include dizziness, asthenia, nervousness, tremor, depressed mood, and emotional lability. Others included somnolence, headaches, abnormal thinking, abdominal pain, pharyngitis, ataxia, confusion, psychosis, and skin rash. A few clinical trials have reported the occurrence of convulsive and nonconvulsive status epilepticus with TGB. TGB therapy should be used cautiously in patients with a history of status epilepticus. TGB is contraindicated in severe hepatic impairment, pregnancy, and lactation.
  9. 9. Vigabatrin The main mode of action It is a close structural analog of GABA, binding irreversibly to the active site of GABA-T. Antiepileptic effect and clinical use Very effective in the treatment of infantile spasms; therefore, it is the drug of choice for this indication in many countries. The usual starting dose for adults is 500 mg twice daily, to a maximum dose of 4000 mg/d. Adverse effects and toxicity The most common adverse effect is drowsiness. Others include neuropsychiatric symptoms, such as depression (5%), agitation (7%), confusion and, rarely, psychosis. Recent studies showed visual field changes, characterized by concentric constriction, with preservation of central vision. Gabapentin The main mode of action Gabapentin (GBP) was developed to have a structure similar to that of GABA. Antiepileptic effect and clinical use Useful in the treatment of partial and secondarily generalized tonic- clonic seizures but is ineffective in myoclonus and in most generalized seizure disorders. Adverse effects and toxicity GBP is relatively well tolerated. No significant serious idiosyncratic or systemic adverse effects have been reported.
  10. 10. Valproate The main mode of action The mechanism of action is uncertain. VPA enhances GABA function, but this effect is observed only at high concentrations. It may increase the synthesis of GABA by stimulating GAD. Antiepileptic effect and clinical use It is the drug of choice in: • Idiopathic generalized epilepsy • Juvenile myoclonic epilepsy and can be used in other types of myoclonus a first-line drug in photosensitive epilepsy and Lennox-Gastaut syndrome. a second choice in the treatment of infantile spasms. In focal epilepsy, VPA is effective as other first-line agents. Adverse effects and toxicity Dose-related adverse effects include nausea, vomiting, tremor, sedation, confusion or irritability, and weight gain. Metabolic effects from interference in mitochondrial metabolism include hypocarnitinemia, hyperglycinemia, and hyperammonemia. Severe sedation or even coma may result from hyperammonemia, typically with normal liver function tests. Hair loss or curling of hair may occur. VPA has adverse endocrine effects, including insulin resistance and change in sex hormone levels causing anovulatory cycles, amenorrhea, and polycystic ovary syndrome. Bone marrow suppression with neutropenia and allergic rashes are rare. Acute pancreatitis is rare but potentially fatal and usually reverses after withdrawal of VPA. The most serious idiosyncratic adverse effect is hepatotoxicity.
  11. 11. Felbamate The main mode of action Blocks the NMDA receptors and voltage-gated calcium channels and also modulates sodium-channel conductance, but has no effect on GABA receptors. Antiepileptic effect and clinical use Felbamate is restricted to patients with severe partial epilepsy or Lennox-Gastaut syndrome who do not respond to other medications. This limited usage is because of the small but definitive risk of aplastic anemia and hepatic failure. Adverse effects and toxicity Common adverse effects include insomnia, weight loss, nausea, decreased appetite, dizziness, fatigue, ataxia, and lethargy. Topiramate The main mode of action Exerts an inhibitory effect on sodium conductance. Enhances GABA by unknown mechanisms. Inhibits the AMPA subtype glutamate receptor. Weak inhibitor of carbonic anhydrase. Antiepileptic effect and clinical use It also has been effective in drug-resistant generalized epilepsies as adjunctive therapy, including: Juvenile myoclonic epilepsy, Absence seizures Generalized tonic-clonic seizures Lennox-Gastaut syndrome. Adverse effects and toxicity 1) The most common adverse effects of topiramate include ataxia, impairment of concentration, confusion, dizziness, fatigue,
  12. 12. paresthesia in the extremities, somnolence, disturbance of memory, depression, agitation, and slowness of speech. 2) The most common adverse effects in children are somnolence, anorexia, fatigue, and nervousness. 3) The drug causes weight loss in many patients, sometimes more than 10 kg, an effect that may lead to discontinuation. The weight loss appears to be related to appetite suppression. 4) No idiosyncratic severe reactions or allergic rashes have been reported. No hepatotoxicity, hematologic toxicity, serious GI toxicity, or cardiotoxicity have been documented. 5) Recently, acute myopia with angle-closure glaucoma has been reported as a rare adverse event associated with topiramate. Levetiracetam The main mode of action Levetiracetam (LEV) is a piracetam derivative. The mechanism of action is unknown. However, LEV inhibits Ca2+ release from the IP3-sensitive stores which could explain some of LEV's antiepileptic properties. Antiepileptic effect and clinical use The results suggest that LEV might have a significant effect in generalized epilepsies. In March, 2007 it was approved by the FDA for primary generalized tonic-clonic seizures in adults and children aged 6 years and older. Adverse effects and toxicity The most significant adverse effects are somnolence, asthenia, and dizziness. LEV has no strong tendency to exacerbate seizures, unlike this paradoxical effect recorded in some patients treated with other AEDs.