Epilepsy is a chronic brain disease of diverse etiology; it is characterized by recurrent paroxysmal episodes of uncontrolled excitation of brain neurons.
Involving larger or smaller parts of the brain, the electrical discharge is evident in the electroencephalogram (EEG) as synchronized rhythmic activity and manifests itself in motor, sensory, psychic, and vegetative (visceral) phenomena.
Because both the affected brain region and the cause of abnormal excitability may differ, epileptic seizures can take many forms. From a pharmacotherapeutic viewpoint, these may be classified as:
- general vs. focal seizures
- seizures with or without loss of consciousness
- seizures with or without specific modes of precipitation
The brief duration of a single epileptic fit makes acute drug treatment unfeasible. Instead, antiepileptics are used to prevent seizures and therefore need to be given chronically.
Only in the case of status epilepticus (a succession of several tonic-clonic seizures) is acute anticonvulsant therapy indicated — usually with benzodiazepines given i.v. or, if needed, rectally.
The initiation of an epileptic attack involves “pacemaker” cells; these differ from other nerve cells in their unstable resting membrane potential, i.e., a depolarizing membrane current persists after the action potential terminates.
Therapeutic interventions aim to stabilize neuronal resting potential and, hence, to lower excitability. In specific forms of epilepsy, initially a single drug is tried to achieve control of seizures, valproate usually being the drug of first choice in generalized seizures, and carbamazepine being preferred for partial (focal), especially partial complex, seizures.
Dosage is increased until seizures are no longer present or adverse effects become unacceptable. Only when monotherapy with different agents proves inadequate can changeover to a second-line drug or combined use (“add on”) be recommended, provided that the possible risk of pharmacokinetic interactions is taken into account.
Mechanism of Action of Antiepileptics
The precise mode of action of antiepileptic drugs remains unknown. Some agents appear to lower neuronal excitability by several mechanisms of action.
In principle, responsivity can be decreased by inhibiting excitatory or activating inhibitory neurons. Most excitatory nerve cells utilize glutamate and most inhibitory neurons utilize γ-aminobutyric acid (GABA) as their transmitter.
Various drugs can lower seizure threshold, notably certain neuroleptics, the tuberculostatic isoniazid, and β-lactam antibiotics in high doses; they are, therefore, contraindicated in seizure disorders.
Glutamate receptors comprise three subtypes, of which the NMDA subtype has the greatest therapeutic importance. (N-methyl-D-aspartate is a synthetic selective agonist.) This receptor is a ligand-gated ion channel that, upon stimulation with glutamate, permits entry of both Na+ and Ca2+ ions into the cell.
The antiepileptics lamotrigine, phenytoin, and phenobarbital inhibit, among other things, the release of glutamate. Felbamate is a glutamate antagonist.
Mechanism of Action of Benzodiazepines and Phenobarbital
Benzodiazepines and phenobarbital augment activation of the GABAA receptor by physiologically released amounts of GABA. Chloride influx is increased, counteracting depolarization. Progabide is a direct GABA-mimetic. Tiagabin blocks removal of GABA from the synaptic cleft by decreasing its re-uptake. Vigabatrin inhibits GABA catabolism. Gabapentin may augment the availability of glutamate as a precursor in GABA synthesis and can also act as a K+-channel opener.
Mechanism of Action of Carbamazepine, valproate, and phenytoin
Carbamazepine, valproate, and phenytoin enhance inactivation of voltage- gated sodium and calcium channels and limit the spread of electrical excitation by inhibiting sustained high-frequency firing of neurons.
Mechanism of Action of Ethosuximide
Ethosuximide blocks a neuronal Ttype Ca2+ channel and represents a special class because it is effective only in absence seizures.
Side Effects of Antiepileptics
All antiepileptics are likely, albeit to different degrees, to produce adverse effects. Sedation, difficulty in concentrating, and slowing of psychomotor drive encumber practically all antiepileptic therapy.
Moreover, cutaneous, hematological, and hepatic changes may necessitate a change in medication.
- Phenobarbital, primidone, and phenytoin may lead to osteomalacia (vitamin D prophylaxis) or megaloblastic anemia (folate prophylaxis).
- During treatment with phenytoin, gingival hyperplasia may develop in ca. 20% of patients.
- Valproic acid (VPA) is gaining increasing acceptance as a first-line drug; it is less sedating than other anticonvulsants. Tremor, gastrointestinal upset, and weight gain are frequently observed; reversible hair loss is a rarer occurrence. Hepatotoxicity may be due to a toxic catabolite (4-en VPA).
- Adverse reactions to carbamazepine include: nystagmus, ataxia, diplopia, particularly if the dosage is raised too fast. Gastrointestinal problems and skin rashes are frequent. It exerts an antidiuretic effect (sensitization of collecting ducts to vasopressin water intoxication). Carbamazepine is also used to treat trigeminal neuralgia and neuropathic pain.
- Valproate, carbamazepine, and other anticonvulsants pose teratogenic risks. Despite this, treatment should continue during pregnancy, as the potential threat to the fetus by a seizure is greater. However, it is mandatory to administer the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may prevent neural tube developmental defects.
- Carbamazepine, phenytoin, phenobarbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticonvulsants or with other drugs may result in clinically important interactions (plasma level monitoring!).