Mechanism of action of antiepileptic and antimyoclonic drugs.
Most drugs used to treat myoclonus are also antiepileptic. The main drugs are the benzodiazepines, valproate, and barbituates. Advances in the understanding of antiepileptic drug mechanisms of action have revealed two main patterns: increasing inhibition either through GABA or glycine, or decreasing excitation due to glutamate. Anticonvulsants such as the benzodiazepines, barbiturates, vigabatrin, tiagabine, or progabide act through GABA. New prototype anticonvulsants such as dizocilpine and remacemide target glutamate receptors or associated ion channels. For some antimyoclonic drugs such as piracetam, many effects are reported but no mechanism of action has been established. Many newer anticonvulsants have not been tested in human myoclonic disorders but efficacy against PTZ-induced seizures suggests antimyoclonic activity. Our ability to improve the treatment of myoclonus requires greater knowledge of the molecular mechanisms of myoclonus and more exact delineation of its relation to epilepsy. Better drugs also will result from refinements from prototype drugs and new concepts about brain function. Most of the discussion has been focused on the use of drugs as symptomatic treatment, but drugs such as glutamate blockers are already having a role in the treatment of degenerative neurological disorders, an important cause of some myoclonic disorders. It also may be possible to improve treatment by focusing on selective regional effects of drugs or drug delivery. The CNS penetration of drugs is often no uniform. For many antimyoclonic and antiepileptic drugs, regional studies have not been performed, especially in humans. Lack of efficacy could therefore be due to lack of drug delivery to myoclonic generators or suppression structures. It is conceivable that drug effects in different brain regions also may be opposing, such as in forebrain and hindbrain structures. Stimulation of the same receptor subtype may have different implications for myoclonus if the sites are pre- or postsynaptically located (as in 5-HTIA sites), or predominantly cerebellar versus hippocampal (as in BDZ I vs II sites). Molecular genetic abnormalities in neurological disease may affect neurotransmission and the action of drug either directly at the receptor site or in other ways such as transduction, translation, or expression. Further insights into these abnormalities may provide new targets for pharmacotherapy. Most antiepileptic and antimyoclonic drugs developed to date have aimed at broad-spectrum treatment of the symptoms, rather than treatment of regional problems such as in the forebrain or the hindbrain. Because of this, the currently available drugs have broad side effects such as cognitive impairment, tremors, teratogenicity, etc. To develop more region-specific and more efficacious drugs, we need to develop a better understanding of local central nervous system problems in myoclonus and epilepsy. The development and application of molecular biological techniques have increased our knowledge of receptors and transporters immensely. It is conceivable that in the near future we will be able to determine whether small mutations affect the structure and function of these molecules. In addition, the glimpses into the process of cell death and sprouting by remaining neurons in the epileptic brain, and perhaps the myoclonic brain, raise the possibility of designing regionally oriented drugs with greater efficacy and fewer side effects. The current developments in the understanding of the central neurons should allow for the development of exciting new pharmacotherapies in the future.
Pranzatelli
M R
MR
Department of Pediatrics, George Washington University, Washington, DC 20010, USA.
Nadi
N S
NS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001463:Barbiturates / Q000494:pharmacology; D004831:Epilepsies, Myoclonic / Q000188:drug therapy*; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000927:Anticonvulsants; D001463:Barbiturates; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid