| Indication |
Used for the treatment and control of partial seizures and severe
tonic-clonic (grand mal) seizures and also for the prevention of
migraine headaches. In children it is also used for treatment of
Lennox-Gastaut syndrome. |
| Pharmacodynamics |
Topiramate is an anticonvulsant indicated in the treatment of
epilepsy and migraine. Topiramate enhances GABA-activated chloride
channels. In addition, topiramate inhibits excitatory neurotransmission,
through actions on kainate and AMPA receptors. There is evidence that
topiramate has a specific effect on GluR5 kainate receptors. It is also
an inhibitor of carbonic anhydrase, particular subtypes II and IV, but
this action is weak and unlikely to be related to its anticonvulsant
actions, but may account for the bad taste and the development of renal
stones seen during treatment. Its possible effect as a mood stabilizer
seems to occur before anticonvulsant qualities at lower dosages.
Topiramate inhibits maximal electroshock and pentylenetetrazol-induced
seizures as well as partial and secundarily generalized tonic-clonic
seizures in the kindling model, findings predective of a broad spectrum
of antiseizure activities clinically. |
| Mechanism of action |
The precise mechanism of action of topiramate is not known.
However, studies have shown that topiramate blocks the action potentials
elicited repetitively by a sustained depolarization of the neurons in a
time-dependent manner, suggesting a state-dependent sodium channel
blocking action. Topiramate also augments the activity of the
neurotransmitter gamma-aminobutyrate (GABA) at some subtypes of the GABAA
receptor (controls an integral chloride channel), indicating a possible
mechanism through potentiation of the activity of GABA. Topiramate also
demonstrates antagonism of the AMPA/kainate subtype of the glutamate
excitatory amino acid receptor. It also inhibits carbonic anhydrase
(particularly isozymes II and IV), but this action is weak and unlikely
to be related to its anticonvulsant actions. |
| Absorption |
Rapid with pleak plasma concentrations occurring after 2 hours and a bioavailability of 80%. |
| Volume of distribution |
Not Available |
| Protein binding |
15-41% (over the blood concentration range of 0.5 - 250 mg/mL). |
| Metabolism |
Not extensively metabolized, 70% of the dose is eliminated
unchanged in the urine. The other 30% is metabolized hepatically to six
metabolites (formed by hydroxylation, hydrolysis, and glucuronidation),
none of which constitute more than 5% of an administered dose. |
| Route of elimination |
Topiramate is not extensively metabolized and is primarily
eliminated unchanged in the urine (approximately 70% of an administered
dose). |
| Half life |
19 to 23 hours |
| Clearance |
- Oral plasma cl=20 – 30 mL/min [in humans following oral administration]
|
| Toxicity |
Symptoms of overdose include abdominal pain, agitation, blurred
vision, convulsions, depression, dizziness, double vision, drowsiness,
impaired coordination, impaired mental activity, low blood pressure,
reduced consciousness, severe diarrhea, sluggishness, and speech
problems. |
