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Pathway Description
Topiramate Action Pathway (New)
Homo sapiens
Drug Action Pathway
Created: 2022-02-16
Last Updated: 2023-10-25
Topiramate is an anticonvulsant drug used in the control of epilepsy and in the prophylaxis and treatment of migraines.
Topiramate is indicated for the following conditions: 1)Monotherapy for partial onset or primary generalized tonic-clonic seizures for patients 2 years of age and above 2)Adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures for both adult and pediatric patients above 2 years old 3)Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients above 2 years of age 4)Prophylaxis of migraine in children 12 years of age and older and adults.
Topiramate is also used off-label as an adjunct therapy for weight management21 and for mood disorders.
A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions.
Topiramate inhibits excitatory neurotransmitter activity by antagonizing AMPA and kainate glutamate receptors on the post synaptic membrane. These receptors are ligand gated ion channels, once bound to glutamate, the allow the influx of sodium ions into the post-synaptic neuron leading to depolarization and neuronal excitation. By antagonizing these glutamate receptors, topiramate prevents depolarization of the post-synaptic receptors. Topiramate may also prevent glutamate release from pre-synaptic neurons. This occurs by topiramate inhibiting voltage gated sodium channels in the presynaptic neuron, these sodium channels are responsible for allow sodium ion influx into the presynaptic neuron and depolarization. Depolarization leads to the opening of L-type voltage gated calcium channels at the neuronal terminal. This leads to the influx of calcium ions which stimulate the release of glutmate via exocytosis. By inhibiting the voltage gates sodium channels, depolarization in the presynaptic neurons is prevented, thus preventing calcium channel activation, calcium influx and glutamate release. Topiramate may also enhance the activity of GABA-A receptors on post synaptic neurons. GABA-A receptors, when activated, lead to the influx of negative chloride ions causing hyperpolarization and neuronal inhibition.
Topiramate is a weak inhibitor of carbonic anhydrase; acidosis in the brain has partial protection against seizures by downregulating NMDA receptor activity. NMDA receptor are excitatory since they are ion channels that cause the influx of calcium ions into the neuron. By downregulating NMDA receptors, excitatory activity is reduced.
Overall, topiramate functions are to reduce excitatory activity in neurons and enhance inhibitory activity.
Most common adverse effects in epilepsy trials included the involvement of the central nervous system (paresthesia, fatigue, cognitive problems, dizziness, somnolence, psychomotor slowing, memory/concentration difficulties, nervousness, confusion), endocrine/metabolism (weight loss, anorexia), respiratory (infection), miscellaneous (fever, flushing).
References
Topiramate Pathway (New) References
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