Primidone Related to phenobarbital Alternate choice in partial

Primidone �Related to phenobarbital �Alternate choice in partial and tonic- clonic seizures �Often used with carbamazepine and phenytoin �Ineffective in absence seizures �Well absorbed orally but poor protein binding �Adverse effects is same as phenobarbital

Valproic Acid �Blocks sodium channel �Enhancement of GABAergic transmission �Broad-spectrum anticonvulsant �Most effective in myoclonic seizures

Continued… �Its second choice of drug due its hepatotoxicity �Reduces the incidence and severity of tonic-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 are common �Rare hepatic toxicity �Rash and alopecia �Thrombocytopenia �Inhibits the metabolism of other antiepileptic drugs

Ethosuximide �Introduced in 1960 in the USA. �Ethosuximide has very little activity against maximal electroshock �Considerable efficacy against pentylenetetrazol seizures; it was introduced as a "pure petit mal" drug.

Continued… Mechanism of Action �Ethosuximide has an important effect on Ca 2+ currents, reducing the low-threshold (T-type) current. �This effect is seen at therapeutically relevant concentrations in thalamic neurons. �The T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for absence seizures. (INHIBITION of thalamic neurons)

Continued… Therapeutic uses: �Particularly effective against absence seizures �Very narrow spectrum of clinical activity �Documentation of its effectiveness in human absence seizures was achieved with long-term electroencephalographic recording techniques

Continued… Pharmacokinetics �Absorption is complete following administration of the oral dosage forms. �Peak levels are observed 3– 7 hours after oral administration �Ethosuximide is not protein-bound. �Ethosuximide is completely metabolized, principally by hydroxylation, to inactive metabolites.

Continued… �The drug has a very low total body clearance (0. 25 L/kg/d) �This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.

Continued… Therapeutic Levels & Dosage �Therapeutic levels of 60– 100 mcg/m. L can be achieved in adults with dosages of 750– 1500 mg/d �Although lower or higher dosages and blood levels (up to 125 mcg/m. L) may be necessary and tolerated in some patients.

Continued… Drug Interactions �Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations. �No other important drug interactions have been reported for the succinimides.

Continued… Adverse effects and Toxicity �Gastric distress, including pain, nausea, and vomiting. �When an adverse effect occur, temporary dosage reductions may allow adaptation. �Other dose-related adverse effects are transient lethargy or fatigue and much less commonly, headache, dizziness, hiccup, and euphoria. �Behavioral changes are usually in the direction of improvement.

Continued… Phensuximide & Methsuximide �Phensuximide and Methsuximide are Phenylsuccinimides that were developed and marketed before Ethosuximide �They are used primarily as anti-absence drugs �Methsuximide is generally considered more toxic, and Phensuximide less effective, than Ethosuximide

continued… �Unlike Ethosuximide, these two compounds have some activity against maximal electroshock seizures �Methsuximide has been used for partial seizures by some investigators

Benzodiazepines �Diazepam Potentiates GABAA responses �Well absorbed orally , rectal administration gives peak concentration in ~1 h with 90% bioavailability �IV for status epilepticus , highly protein-bound , extensively metabolized to several active metabolites , t 1/2 ~2 d � Status epilepticus, seizure clusters

Continued… �Clonazepam Action : As for diazepam �>80% bioavailability extensively metabolized but no active metabolites , t 1/2 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 binding site on the N-methyl-D-aspartate (NMDA) glutamate receptor �Blocking calcium channels

Continued… �Potentiating the action of GABA. It is an inhibitor of drugs metabolized by CYP 2 C 19 and â-oxidation, and induces drugs metabolized by CYP 3 A 4. �It is reserved for use in refractory epilepsies (particularly Lennox-Gastaut syndrome) because of the risk of aplastic anemia (about 1: 4000) �Hepatic failure.

Gabapentin �Decreases excitatory transmission by acting on Voltage-Gated Ca 2+ channels presynaptically �Bioavailability 50%, decreasing with increasing doses �not bound to plasma proteins �Not metabolized , excreted through kidney

Continued… t 1/2 6– 8 h �Generalized tonic-clonic seizures, partial seizures, �Adverse effects: Somnolence, dizziness, ataxia

Lamotrigine �Prolongs inactivation of VG-Na+ channels �Acts presynaptically on VG-Ca 2+ channels �Decreases glutamate release �Well absorbed orally �No significant protein binding

Continued… �Metabolized primarily to the N-2 glucuronide through the UGT pathway t 1/2 25– 35 h �Generalized tonic-clonic seizures, generalized seizures, partial seizures, generalized seizures, absence seizures �Adverse effects: Dizziness, headache, diplopia, rash �Interactions: Valproate, carbamazepine, oxcarbazepine

Levetiracetam �Action on synaptic protein SV 2 A �Well absorbed orally �Not bound to plasma proteins , t 1/2 6– 11 h �Generalized tonic-clonic seizures, partial seizures, generalized seizures �Adverse effects: Nervousness, dizziness, depression, seizures �Interactions: Phenobarbital, phenytoin, carbamazepine, primidone

Tiagabine �Blocks GABA reuptake in forebrain by selective blockade of GAT-1 �Well absorbed highly bound to plasma proteins �Metabolism is mainly completed by the CYP 3 A family of enzymes t 1/2 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 channel opening by binding to the GABAA receptor �High-voltage calcium currents (L type) are reduced

Continued… �It is a carbonic anhydrase inhibitor and may act at glutamate (NMDA) sites �Effective and approved for use in partial and primary generalized epilepsy �It is also approved for treatment of migraine �Topiramate is eliminated renally t 1/2 20 h

Continued… �It inhibits CYP 2 C 19 and is induced by phenytoin and carbamazepine �Lamotrigine is reported to cause an increase in topiramate concentration �Coadministration of topiramate reduces ethinyl estradiol

Continued… �Adverse effects include somnolence, weight loss, and paresthesias �Renal stones are reported to occur at a higher incidence than in a non-treated population �Glaucoma, oligohidrosis, and hyperthermia have also been reported

Zonisamide �sulfonamide derivative that has a broad spectrum of action. The compound has multiple effects on neuronal systems thought to be involved in seizure generation. �These include blockade of both voltage-gated sodium channels � T-type calcium currents �Its use should be monitored in patients with reported allergies.

Continued… �Approved for use in patients with partial epilepsy �It is metabolized by the CYP 3 A 4 isozyme and may, to a lesser extent, be affected by CYP 3 A 5 and CYP 2 C 19 t 1/2 50– 70 h �In addition to typical CNS adverse effects, it may cause kidney stones �Oligohidrosis has been reported