Medication Summary
The goals of pharmacotherapy are to reduce seizure frequency, severity, and morbidity and prevent complications with the least side effects. The agents used for tonic-clonic seizures include anticonvulsants such as valproate, lamotrigine, levetiracetam, felbamate, topiramate, zonisamide, clobazam, and perampanel.
Anticonvulsant Agents
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Valproate (Depakote, Depakote ER, Depakene, Depacon, Stavzor)
Considered the drug of first choice for primary generalized epilepsy, valproate has a very wide spectrum and is effective in most seizure types, including myoclonic seizures. It has multiple mechanisms of anticonvulsant effects, including increasing gamma-aminobutyric acid (GABA) levels in brain as well as T-type calcium channel activity, which is important for absence seizures. The extended-release (ER) formulation allows for once-a-day administration.
Ethotoin (Peganone)
Ethotoin may act in the motor cortex, where it may stabilize the seizure threshold and inhibit the spread of seizure activity. The activity of the brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited.
Phenytoin (Dilantin, Phenytek)
Phenytoin is effective in the treatment of tonic-clonic seizures and is often used because it can be administered once a day if the extended release formulation is administered (there is also an IV formulation). Acute adverse effects include rash and a remote risk of SJS. Long-term use may cause osteopenia and cerebellar ataxia, which has caused practitioners to prescribe it less often. It is one of the most difficult AEDs to use due to its zero-order kinetics and narrow therapeutic index. Recent studies have reported different serum levels when patients use the brand and generic phenytek. In addition, it can have significant drug interactions. The need to monitor liver function, CBC, and drug levels (including free fraction in those with altered protein) add to the cost of using this AED.
Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro, Carnexiv)
This AED is used as a second-choice agent along with phenytoin. It has active metabolite 10-11 epoxide. Like phenytoin, carbamazepine has been associated with rash and osteopenia. The rash can progress to SJS and has an HLA-B1502 marker, which needs to be tested on Asian patients. An IV formulation that is to be used for 7 days or less, when oral administration is temporarily not feasible, has been recently approved and has received orphan designation. The manufacturer plans to make it available in 2017.
Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)
Lamotrigine is a newer antiepileptic drug with a very broad spectrum of activity, like valproate. It is FDA approved for both primary generalized and partial-onset epilepsy.
Lamotrigine has several mechanisms of action that may account for its effectiveness. A major disadvantage is that the dose has to be increased very slowly over several weeks to minimize the chance of rash, especially if the patient is on valproic acid.
Zonisamide (Zonegran)
One of newer antiepileptics recently introduced in the US market, zonisamide has been studied extensively in Japan and Korea and seems to have broad-spectrum properties. It blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.
Felbamate (Felbatol)
Felbamate is approved by the FDA for medically refractory partial seizures and Lennox-Gastaut syndrome. This agent has multiple mechanisms of action, including (1) inhibition of NMDA-associated sodium channels, (2) potentiation of GABA-ergic activity, and (3) inhibition of voltage-sensitive sodium channels. It is used only as drug of last resort in medically refractory cases because of the risk of aplastic anemia and hepatic toxicity, which necessitates regular blood tests.
Topiramate (Topamax, Quedexy, Trokendi XR, Topamax Sprinkle)
An AED with a broad spectrum of antiepileptic activity, topiramate is approved for generalized tonic-clonic seizures. It has multiple mechanisms of action, including state-dependent sodium channel blocking action; it also potentiates inhibitory activity of the neurotransmitter GABA. It may block glutamate activity and is a carbonic anhydrase inhibitor.
Levetiracetam (Keppra, Keppra XR, Roweepra, Spritam)
Levetiracetam is indicated for primary generalized tonic-clonic seizures in adults and children aged 6 years or older, as well as for use in juvenile myoclonic epilepsy and for partial seizures.
Rufinamide (Banzel)
An AED that is structurally unrelated to current antiepileptics, rufinamide modulates sodium channel activity, particularly prolongation of the channel's inactive state. It significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Rufinamide is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.
Primidone (Mysoline)
Primidone decreases neuron excitability and increases the seizure threshold.
Perampanel (Fycompa)
Perampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor. It is indicated as adjunctive treatment for primary generalized tonic-clonic seizures and for partial-onset seizures (with or without secondary generalized seizures) in adults and children aged 12 years or older.
Clobazam (ONFI)
Clobazam is a 1,5-benzodiazepine that possesses potent anticonvulsant properties. May enhance the inhibitory effect of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions. Has been approved as adjunct treatment for refractory epilepsy, specifically LGS, in pediatric and adult patients.
