Continued...

New Derivatives or formulations of First line ASDs

New Derivatives or formulations of First line ASDs: In addition to the newer drugs, several chemical reformulations have been made to the old antiepileptic drugs that have resulted in more favorable pharmacological profile. Oxcarbazepine, Fosphenytion and IV Valproate Sodium come under this category.

Oxcarbazepine: It is a newer and better-tolerated derivative formulation of carbamazepine. It has several advantages over carbamazepine which includes weaker and more selective liver enzyme induction and absence of auto-induction. Thus, it has lesser interaction with erythromycin and other drugs that cause carbamazepine accumulation and oral contraceptive pills. Oxcarbazepine has been approved for monotherapy as well as adjunctive therapy in children aged 4 years or older and adjunctive therapy for children over 2 years of age, with partial seizures with or without secondary generalization. Its mechanism of action and efficacy profile is similar to the parent drug i.e. carbamazepine, but its adverse effects are less. Dizziness, diplopia and ataxia are the commonly encountered side effects.

Fosphenytoin: It is a prodrug that is converted to its active metabolite phenytoin with a conversion half-life of 8 to 15 minutes. Recently Fosphenytoin has emerged as a preferred treatment option for of status epilepticus. The major advantage of fosphenytoin over phenytoin is that it does not contain propylene glycol and has a pH of 8.6-9.0 as opposed to 11-12 for phenytoin. This allows fosphenytoin to be administered in dextrose containing IV solutions at a more rapid rate (3mg/kg/min Vs 1mg/kg/min). As the pH is more physiological, there is less risk of soft tissue injury with extravasations at the IV site. The elimination of propylene glycol from the vehicle is also beneficial as it reduces the incidence of hypotension. Its dose is calculated on basis of Phenytoin Equivalent (PE). 1.5 mg of fosphenytoin is equal to1 mg of phenytoin.

Table 3: Pharmacokinetic and Pharmacodynamic properties of Second Generation ASDs

Drug	Action on CYP	Action on UGT	Metabolized by CYP	Metabolized by UGT	Important Adverse Effects
Felbamate	No	No	Yes	Yes	Aplastic anemia, hepatitis
Gabapentin	No	No	No	No	Weight gain
Levetiracetam	No	No	No	No
Lamotrigine	No	Induces	No	Yes	Rash
Tiagabin	No	No	Yes	No
Topiramate	Inhibits	No	-	-	Nephrolithiasis, paresthesias, weight loss
Zonisamide	No	No	Yes	No	Nephrolithiasis, weight loss
Oxcarbazepine	Iinduces3A4 /5 Inhibits 2C19	weakly	No	Yes	Hyponatremia

CYP-Cytochrome P 450, UGT-UDP Glucuronosyl Transferase