Anticonvulsant drugs
Anticonvulsants drugs can be classified according to their molecular mechanism of action. In general, the most useful mechanisms exploited therapeutically are those that enhance gamma-aminobutyric acid (GABA) action and inhibit sodium channel activity. Other mechanisms include inhibition of calcium channels and glutamate receptors.
AMPA receptor antagonists: Perampanel (the first and only FDA-approved non-competitive AMPA receptor antagonist) is used as an adjunctive therapy in the treatment of focal seizures with or without secondary generalised seizures.
Barbiturate anticonvulsants: Barbiturates act as positive allosteric modulators of GABAA receptors (or GABA receptor agonists at high doses) and block the excitatory AMPA and kainite glutamate receptors. These drugs bind to receptor site discinct from the GABA and benzodiazepine binding sites. Barbiturate action elevates seizure threshold and reduces the spread of seizure activity from a seizure focus. Primidone is indicated for the treatment of all forms of epilepsy except typical absence (petit mal) seizures and essential tremor. Phenobarbital is indicated for the treatment of all forms of epilepsy except typical absence seizures and status epilepticus.
Benzodiazepine anticonvulsants: Diazepam can be used to control muscle spasms of varied aetiology, status epilepticus, febrile convulsions, convulsions due to poisoning, and acute drug-induced dystonic reactions. Clonazepam can be used to treat all forms of epilepsy and myoclonus. Lorazepam can be used alongside other medications to treat seizures, for example slow intravenous injection is used in the control of status epilepticus, febrile convulsions and poison-induced convulsions.
Carbamate anticonvulsants: Felbamate (not available in the UK) appears to exhibit some inhibitory effect at N-methyl-D-aspartate (NMDA) receptor and to modestly potentiate GABA activity. It has broad spectrum anti-epileptic activity but due to its propensity to cause severe side-effects (e.g. aplastic anemia, hepatitis and liver failure) it is generally only used in patients who are unresponsive to other anticonvulsant drugs.
Carbonic anhydrase inhibitor anticonvulsants inhibit the enzyme carbonic anhydrase. Carbonic anhydrase inhibitors have several clinical uses, including treatment of epilepsy, glaucoma, mountain sickness, and as diuretics. Topiramate appears to enhance GABA action via effects on kainate and AMPA receptors to bring about inhibition of the excitatory neurotransmission underlying seizure generation. Topiramate can be used as monotherapy or adjunctively to treat generalised tonic-clonic seizures or focal seizures with or without secondary generalisation and as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome.
Dibenzazepine anticonvulsants: Oxcarbazepine is approved for use as monotherapy or adjunctive treatment for focal seizures with or without secondary generalised tonic-clonic seizures and treatment of primary generalised tonic-clonic seizures. Eslicarbazepine acetate can be used as an adjunctive treatment in adults with focal seizures with or without secondary generalisation.
Fatty acid derivative anticonvulsants appear to increase the availability of the inhibitory neurotransmitter GABA. They have several mechanisms of action. They have inhibitory action against GABA transaminase, which breaks down GABA. This leads to increased concentration of GABA in the synapses. Other proposed mechanisms of action that account for their anticonvulsant properties is they either enhance the action of GABA or mimic its action at postsynaptic receptor sites. They also block voltage gated sodium channels and T-type calcium channels, and cause inhibitory activity in the brain. Fatty acid derivatives are broad-spectrum anticonvulsant drugs, which are effective against most types of seizures, including absence seizures, tonic-clonic seizures, juvenile myoclonic epilepsy and complex partial seizures. Valproic acid and sodium valproate (1:1 dose-equivalency) are used to treat generalised, partial or other forms of epilepsy.
Gamma-aminobutyric acid analogs generally act as GABA receptor agonists and cause inhibitory action just like endogenous GABA, although gabapentin’s ability to bind GABA receptors is debated. Gabapentin can be used as monotherapy or adjunctive treatment for focal seizures with or without secondary generalisation. Pregabalin can be used as adjunctive therapy for focal seizures with or without secondary generalisation. Vigabatrin can be used as an adjunctive treatment for focal seizures with or without secondary generalisation not satisfactorily controlled with other anti-epileptics (under expert supervision).
Gamma-aminobutyric acid reuptake inhibitors are analogues of GABA that bind to GABA transporters and inhibit GABA reuptake. This increases extracellular levels of GABA and enhances GABA mediated synaptic activity in the brain. Tiagabine may be used as adjunctive treatment for focal seizures with or without secondary generalisation that are not satisfactorily controlled by other anti-epileptics, with or without enzyme-inducing drugs.
Hydantoin anticonvulsants are structurally related to barbiturates. They have an allantoin heterocyclic base. They act to slow synaptic transmission by blocking sodium channels from recovering from the inactivated state, and inhibit neuronal firing. This inhibits the repeated excitation of cells that results in seizures. Hydantoin anticonvulsants are used to treat a wide range of seizures types. Phenytoin can be used to manage tonic-clonic seizures, focal seizures and for acute symptomatic therapy, prevention and treatment of seizures during or following neurosurgery or severe head injury, and for status epilepticus. Preparations containing phenytoin sodium are not bioequivalent to those containing phenytoin base (100 mg of phenytoin sodium is approximately equivalent in therapeutic effect to 92 mg phenytoin base). Fosphenytoin sodium is used in the management of status epilepticus, as prophylaxis or treatment of seizures associated with neurosurgery or head injury (dose-equivalence: 1.5mg fosphenytoin sodium ≡ 1mg phenytoin sodium). Ethotoin (not available in the UK) is used to treat generalized tonic-clonic or complex-partial seizures.
Miscellaneous anticonvulsants: Magnesium sulfate may be used in the prevention of seizures in pre-eclampsia and treatment of seizures and prevention of seizure recurrence in eclampsia. Lacosamide is used as adjunctive therapy of focal seizures with or without secondary generalisation. Rufinamide (a triazole derivative sodium channel inactivator) can be used as an adjunctive treatment for seizures in Lennox-Gastaut syndrome with valproate.
Neuronal potassium channel openers: The only such drug, retigabine (a.k.a. ezogabine), binds the KCNQ (Kv7.2-7.5) voltage-gated potassium channels, which stabilises the channels in the open formation and enhances the M-current. This action controls neuronal excitability such that epileptiform activity is suppressed. Retigabine may also augment GABA-mediated currents. Retigabine is used as adjunctive treatment of drug-resistant focal seizures with or without secondary generalisation when other appropriate drug combinations have proved inadequate or have not been tolerated.
Oxazolidinedione anticonvulsants are used to treat absence seizures. The exact mechanism of action of oxazolidinedione anticonvulsants is unknown. An example is trimethadione (not available in the UK) which is used to treat absence seizures in adults and children where other anti-epileptics have been unsuccessful.
Pyrrolidine anticonvulsants are used as anti-epileptics, although the exact mechanism of action is not fully defined. They appear to depress nerve transmission. Levetiracetam is used as monotherapy or adjunctive therapy for focal seizures with or without secondary generalisation and as adjunctive therapy of myoclonic seizures and tonic-clonic seizures.
Succinimide anticonvulsants are thought to increase the seizure threshold, inhibit T-type calcium channels and inhibit the three-cycle per second thalamic 'spike and wave' discharge in absence seizures. They also appear to depress nerve transmission in the motor cortex. Ethosuximide is used to treat absence seizures, atypical absence seizures (adjunct) and myoclonic seizures. Methsuximide (not available in the UK) is used to control of absence seizures that are refractory to other drugs.
Triazine anticonvulsants act on presynaptic sodium channels which subsequently inhibits release of the excitatory neurotransmitters, glutamate and aspartate. Lamotrigine can be used as monotherapy of focal seizures, primary and secondary generalised tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome and as adjunctive therapy of these three indications with valproate.