Topiramate

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Topiramate
Topiramate structure.svg
Topiramate 3D.png
Clinical data
Trade names Topamax, Trokendi XR, Qudexy XR, others
Other namesTopiramic acid
AHFS/Drugs.com Monograph
MedlinePlus a697012
License data
Pregnancy
category
  • AU:D
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80%
Protein binding 13–17%; 15–41%
Metabolism Liver (20–30%)
Elimination half-life 19–25 hours
Excretion Urine (70–80%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.129.713 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H21NO8S
Molar mass 339.36 g·mol−1
3D model (JSmol)
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Topiramate, sold under the brand name Topamax among others, is a carbonic anhydrase inhibitor medication used to treat epilepsy and prevent migraines. [1] It has also been used in alcohol dependence. [1] For epilepsy this includes treatment for generalized or focal seizures. [2] It is taken by mouth. [1]

Contents

Common side effects include tingling, loss of appetite, feeling tired, abdominal pain, hair loss, and trouble concentrating. [1] [2] Serious side effects may include suicide, increased ammonia levels resulting in encephalopathy, and kidney stones. [1] Use in pregnancy may result in harm to the baby and use during breastfeeding is not recommended. [3] How it works is unclear. [1]

Topiramate was approved for medical use in the United States in 1996. [1] It is available as a generic medication. [2] In 2018, it was the 89th most commonly prescribed medication in the United States, with more than 8 million prescriptions. [4] [5]

Medical uses

A package of topiramate 25mg from Norway Topimax 25mg.jpg
A package of topiramate 25mg from Norway

Topiramate is used to treat epilepsy in children and adults, and it was originally used as an anticonvulsant. [6] In children, it is indicated for the treatment of Lennox-Gastaut syndrome, a disorder that causes seizures and developmental delay. It is most frequently prescribed for the prevention of migraines [6] as it decreases the frequency of attacks. [7] [8] Topirimate is used to treat medication overuse headache and is recommended by the European Federation of Neurological Societies as one of the few medications showing effectiveness for this indication. [9]

Pain

A 2018 review found topiramate of no use in chronic low back pain. [10] Topiramate has not been shown to work as a pain medicine in diabetic neuropathy, the only neuropathic condition in which it has been adequately tested. [11]

Other

One common off-label use for topiramate is in the treatment of bipolar disorder. [12] [13] [14] A review published in 2010 suggested a benefit of topiramate in the treatment of symptoms of borderline personality disorder, however the authors noted that this was based only on one randomized controlled trial and requires replication. [15]

Topiramate has been used as a treatment for alcoholism. [16] The VA/DoD 2015 guideline on substance use disorders lists topiramate as a "strong for" in its recommendations for alcohol use disorder. [17]

Other uses include treatment of obesity [18] [19] and antipsychotic-induced weight gain. [20] [21] It is being studied to treat post traumatic stress disorder. [22] In 2012, the combination phentermine/topiramate was approved in the United States for weight loss.

Adverse effects

People taking topiramate should be aware of the following risks:

Frequency

Adverse effects by incidence: [26] [27] [28] [29]

Very common (>10% incidence) adverse effects include:

Uncommon (1-10% incidence) adverse effects include:

Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance. [30]

The U.S. Food and Drug Administration (FDA) has notified prescribers that topiramate can cause acute myopia and secondary angle closure glaucoma in a small subset of people who take topiramate regularly. [31] The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. Discontinuation of topiramate may halt the progression of the ocular damage and may reverse the visual impairment.

Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations. [32] This might be particularly important for women who take topiramate to prevent migraine attacks. In March 2011, the FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy and placed it in Pregnancy Category D. [25]

Topiramate has been associated with a statistically significant increase in suicidality, [33] and "suicidal thoughts or actions" is now listed as one of the possible side effects of the drug "in a very small number of people, about 1 in 500." [23] [34]

Overdose

Symptoms of acute and acute on chronic exposure to topiramate range from asymptomatic to status epilepticus, including in patients with no seizure history. [35] [36] In children, overdose may also result in hallucinations. [36] Topiramate has been deemed the primary substance that led to fatal overdoses in cases that were complicated by polydrug exposure. [37] The most common signs of overdose are dilated pupils, somnolence, dizziness, psychomotor agitation, and abnormal, uncoordinated body movements. [35] [36] [37]

Symptoms of overdose may include but are not limited to:[ citation needed ]

A specific antidote is not available. Treatment is entirely supportive.

Interactions

Topiramate has many drug-drug interactions. Some of the most common are listed below:

Pharmacology

Chemically, topiramate is a sulfamate modified fructose diacetonide - a rather unusual chemical structure for a pharmaceutical.

Topiramate is quickly absorbed after oral use. Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized by hydroxylation, hydrolysis, and glucuronidation. Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose.

Several cellular targets have been proposed to be relevant to the therapeutic activity of topiramate. [40] These include (1) voltage-gated sodium channels; (2) high-voltage-activated calcium channels; (3) GABA-A receptors; (4) AMPA/kainate receptors; and (5) carbonic anhydrase isoenzymes. There is evidence that topiramate may alter the activity of its targets by modifying their phosphorylation state instead of by a direct action. [41] The effect on sodium channels could be of particular relevance for seizure protection. Although topiramate does inhibit high-voltage-activated calcium channels, the relevance to clinical activity is uncertain. Effects on specific GABA-A receptor isoforms could also contribute to the antiseizure activity of the drug. Topiramate selectively inhibits cytosolic (type II) and membrane associated (type IV) forms of carbonic anhydrase. The action on carbonic anhydrase isoenzymes may contribute to the drug's side-effects, including its propensity to cause metabolic acidosis and calcium phosphate kidney stones.

Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of activities clinically. Its action on mitochondrial permeability transition pores has been proposed as a mechanism. [42]

While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is one of the very few anticonvulsants [see: levetiracetam, carbamazepine, lamotrigine] that do not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect. [43]

Detection in body fluids

Blood, serum, or plasma topiramate concentrations may be measured using immunoassay or chromatographic methods to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, or to assist in a medicolegal death investigation. Plasma levels are usually less than 10 mg/L during therapeutic administration, but can range from 10–150 mg/L in overdose victims. [44] [45] [46]

History

Topiramate was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceuticals. [47] [48] The commercial usage of Topiramate began in 1996. [49] Mylan Pharmaceuticals was granted final approval by the FDA for the sale of generic topiramate in the United States and the generic version was made available in September 2006. [50] The last patent for topiramate in the U.S. was for use in children and expired on February 28, 2009. [51]

Related Research Articles

Carbamazepine Anticonvulsant medication

Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures. It is not effective for absence or myoclonic seizures.

Valproate Medication used for epilepsy, bipolar disorder and migraine

Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.

Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.

Lamotrigine

Lamotrigine, sold as the brand name Lamictal among others, is an anticonvulsant medication used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome. In bipolar disorder, lamotrigine has not been shown to reliably treat acute depression; but for patients with bipolar disorder who are not currently symptomatic, it appears to be effective in reducing the risk of future episodes of depression.

Levetiracetam Medication

Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.

Clonazepam Benzodiazepine sedative

Clonazepam, sold under the brand Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class. It is taken by mouth. Effects begin within one hour and last between six and twelve hours.

Tiagabine

Tiagabine is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder.

Primidone

Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures, as well as essential tremors. It is taken by mouth.

Vigabatrin

Vigabatrin, brand name Sabril, is a medication used to treat epilepsy. It became available as a generic medication in 2019.

Pregabalin Anticonvulsant drug

Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, and generalized anxiety disorder. Its use in epilepsy is as an add-on therapy for partial seizures. When used before surgery, it reduces pain but results in greater sedation and visual disturbances. It is taken by mouth.

Zonisamide

Zonisamide, sold under the brand name Zonegran, is a medication used to treat the symptoms of epilepsy and Parkinson's disease. Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy in adults with Parkinson's disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure. Despite this it is also sometimes used as a monotherapy for partial-onset seizures.

Stiripentol

Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of epilepsy.

Felbamate

Felbamate is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drug's usage to severe refractory epilepsy.

Carbonic anhydrase inhibitor

Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, idiopathic intracranial hypertension, neurological disorders, or osteoporosis.

Lacosamide

Lacosamide, sold under the brand name Vimpat among others, is a medication used in the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain. It is used by mouth or intravenously.

Safinamide

Safinamide is a drug used as an add-on treatment for Parkinson's disease during "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B.

Retigabine

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production has been discontinued in June 2017.

Phentermine/topiramate

Phentermine/topiramate, sold under the brand name Qsymia, is a combination of phentermine and topiramate used to treat obesity. It is used together with dietary changes and exercise. If less than 3% weight loss is seen after 3 months it is recommended the medication be stopped. The weight loss is modest. Effects on heart related health problems or death is unclear.

JNJ-26990990

JNJ-26990990 is a broad-spectrum anticonvulsant drug currently under development by Janssen Pharmaceutica as a second-generation follow-up to the marketed drug topiramate. It was designed to have the same anticonvulsant effects as topiramate, but without the side effects associated with topiramate's carbonic anhydrase inhibition. It also has potential use in the treatment of inflammatory pain, neuropathic pain, and depression.

JNJ-26489112

JNJ-26489112 is an anticonvulsant drug being developed by Johnson & Johnson for the treatment of epilepsy. JNJ-26489112 was designed as a successor to topiramate. It is expected to have fewer side effects than topiramate because it lacks activity against carbonic anhydrase.

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