Chemistry:Tiagabine

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Tiagabine, sold under the brand name Gabitril, is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy.[1][2] It is also used off-label in the treatment of anxiety disorders including panic disorder[3] and to treat insomnia.[4][5][6] The drug is taken orally.[1][2]

Medical uses

Epilepsy

Tiagabine is approved by the United States Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in epilepsy in individuals of age 12 and up. It is effective as monotherapy and combination therapy with other anticonvulsant drugs in the treatment of partial seizure.[7]

Other uses

Anxiety disorders

It may also be prescribed off-label by physicians to treat anxiety disorders, such as panic disorder and social anxiety disorder.[8][9][10] Tiagabine may be used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), or benzodiazepines for anxiety.[8]

Neuropathic pain

Tiagabine can be used in the treatment of neuropathic pain.[11][12][8] It can be used alongside antidepressants, gabapentin, other anticonvulsants, or opioids for neuropathic pain.[8]

Insomnia

Tiagabine has been used in the treatment of insomnia and has been found to enhance slow wave sleep (SWS) in this context.[4][5][6] However, the American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to limited effectiveness and very low quality of evidence.[5]

Side effects

Side effects of tiagabine are dose-related.[7] The most common side effect of tiagabine is dizziness.[13] Other side effects that have been observed with a rate of statistical significance relative to placebo include asthenia, somnolence, nervousness, memory impairment, tremor, headache, diarrhea, and depression.[2][13][14] Adverse effects such as confusion, aphasia, stuttering, and paresthesia (a tingling sensation in the body's extremities, particularly the hands and fingers) may occur at higher dosages of the drug (e.g., over 8 mg/day).[13] Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold.[8] There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive.[15][16] Tiagabine can also reportedly interfere with visual color perception.[15]

Overdose

Tiagabine overdose can produce neurological symptoms such as lethargy, single or multiple seizures, status epilepticus, coma, confusion, agitation, tremors, dizziness, dystonias, abnormal posturing, and hallucinations, as well as respiratory depression, tachycardia, and hypertension or hypotension.[17] Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness.[17]

Pharmacology

Pharmacodynamics

Tiagabine increases the level of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, by blocking the GABA transporter 1 (GAT-1), and hence is classified as a GABA reuptake inhibitor (GRI).[18][19]

Tiagabine is primarily used as an anticonvulsant in the treatment of epilepsy as a supplement. Although the exact mechanism by which tiagabine exerts its antiseizure effect is unknown, it is thought to be related to its ability to increase the activity of γ-aminobutyric acid (GABA), the central nervous system's major inhibitory neurotransmitter. Tiagabine is thought to block GABA reuptake into presynaptic neurons through inhibition of GAT-1 and, as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells.[20][21] In rat studies, tiagabine prolonged GABA-mediated inhibitory post-synaptic potentials in the hippocampus, as well as increased GABA concentration in the extracellular space of the globus pallidus, ventral palladum and substantia nigra.[22] However, tiagabine does not decrease neuronal GABA levels and induces compensatory GABA synthesis from glucose or glial glutamine precursors.[23]

Being a nipecotic acid derivative, introduction of 4,4-diphenylbut-3-enyl and 4,4-bis(3-methylthiophene-1-yl)but-3-enyl sidechain increased lipophilicity compared to the parent compound, allowing blood-brain barrier crossing and GAT-1 selectivity.[21]

Tiagabine also increases benzodiazepine-type anticonvulstants' affinity to cortical and limbic GABAA receptors and influences EEG measurements by increasing frontal activity and reducing posterior activity in the brain.[24][25]

Tiagabine does not affect key cardiac ion channels.[26]

With regard to pharmacophore, the most stable binding mode of tiagabine in the GAT-1 transporter is that where the nipecotic acid fragment is located in the main ligand binding site, and aromatic thiophene rings are arranged within the allosteric site, which yields GAT-1 in an outward-open state. This interaction is mediated through GAT-1's sodium ion mimicry, hydrogen bonding and hydrophobic interactions.[27]

Pharmacokinetics

Absorption

Tiagabine is nearly completely absorbed (>95%) and has an oral bioavailability of 90%.[22][2] The time to peak levels is approximately 1 hour.[2] Peak levels occur after 45 minutes in a fasted state and after 2.5 hours when taken with a high fat meal.[22][2] A high fat meal decreases peak levels by 40% but does not affect area-under-the-curve levels.[22][2] Tiagabine was administered with food in clinical trials and it is recommended that it be taken with food.[22][2] The pharmacokinetics of tiagabine are linear over a dose range of 2 to 24 mg.[22][2] Steady-state levels are achieved after 2 days of continuous dosing.[22]

Distribution

Tiagabine is widely distributed through the body.[2] Its volume of distribution is approximately 1 L/kg.[2] The drug readily crosses the blood–brain barrier.[2] The plasma protein binding of tiagabine is 96%, mainly to albumin and α1-acid glycoprotein.[22]

Metabolism

The metabolism of tiagabine has not been fully characterized.[22] In any case, it is metabolized by at least two known pathways.[22] One is thiophene ring oxidation resulting in 5-oxotiagabine and the other is glucuronidation.[22] 5-Oxotiagabine is said not to contribute to the pharmacodynamics of tiagabine.[22] In-vitro studies suggest that tiagabine is metabolized primarily by the cytochrome P450 enzyme CYP3A4, although involvement of other enzymes like CYP1A2, CYP2D6, or CYP2C19 has not been excluded.[22] Two other metabolites of tiagabine have yet to be identified.[2]

Elimination

Tiagabine is excreted about 2% unchanged.[22][2] About 25% is excreted in urine and 63% is excreted in feces.[22][2] The elimination half-life of tiagabine is 4.5 to 9.0 hours.[22][2] The half-life of tiagabine was found to be decreased by 50 to 65% to 3.8 to 4.9 hours (range 2–5 hours) in patients whose hepatic enzymes had been induced with other anticonvulsants including carbamazepine, phenytoin, primidone, and phenobarbital.[22][2][28] In addition, the half-life of tiagabine is extended to 11.7 to 15.9 hours in hepatic dysfunction.[2][28] These settings as such may require dose adjustment.[22][2][28]

Chemistry

Tiagabine is a GABA analogue and a derivative of nipecotic acid.[2]

History

Tiagabine was discovered at Novo Nordisk in Denmark in 1988 by a team of medicinal chemists and pharmacologists under the general direction of Claus Bræstrup.[29] The drug was co-developed with Abbott Laboratories, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company. It was approved for treatment of epilepsy in the United States in September 1997.[28]

US patents on tiagabine listed in the Orange Book expired in April 2016.[30]

Tiagabine was previously subject to Risk Evaluation and Mitigation Strategies (REMS) in the United States, which was instituted in 2010.[31][32] However, this requirement was eliminated in 2012.[33]

Research

Other conditions

In addition to epilepsy, tiagabine was under formal development for the treatment of anxiety disorders, insomnia, and neuropathic pain.[31] However, development for all of these indications was discontinued.[31]

Bipolar disorder

There have been case reports and case series of tiagabine for treatment of bipolar disorder.[34] However, no clinical trials have been conducted.[34]

Effects on brain activity

Tiagabine (15 mg) enhances MEG delta power in healthy volunteers.

Tiagabine enhances the power of cortical delta (< 4 Hz) oscillations up to 1,000% relative to placebo, which may result in an EEG or MEG signature resembling non-rapid eye movement sleep even while the person who has taken tiagabine is awake and conscious.[35] This demonstrates that cortical delta activity and wakeful consciousness are not mutually exclusive, i.e., high amplitude delta oscillations are not always a reliable indicator of unconsciousness.

See also

References

  1. ↑ 1.0 1.1 "Tiagabine". Lancet 351 (9097): 203–207. January 1998. doi:10.1016/S0140-6736(97)05035-6. PMID 9449883. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 "Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy". Drugs 55 (3): 437–460. March 1998. doi:10.2165/00003495-199855030-00013. PMID 9530548. 
  3. ↑ "Tiagabine in anxiety disorders". Expert Opin Pharmacother 7 (14): 1977–1987. October 2006. doi:10.1517/14656566.7.14.1977. PMID 17020423. 
  4. ↑ 4.0 4.1 "Enhancement of slow wave sleep: implications for insomnia". J Clin Sleep Med 5 (2 Suppl): S27–S32. April 2009. PMID 19998872. 
  5. ↑ 5.0 5.1 5.2 "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". Journal of Clinical Sleep Medicine 13 (2): 307–349. February 2017. doi:10.5664/jcsm.6470. PMID 27998379. 
  6. ↑ 6.0 6.1 "Insomnia in Elderly Patients: Recommendations for Pharmacological Management". Drugs Aging 35 (9): 791–817. September 2018. doi:10.1007/s40266-018-0569-8. PMID 30058034. 
  7. ↑ 7.0 7.1 "Tiagabine", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases), 2012, PMID 31643697, https://www.ncbi.nlm.nih.gov/books/NBK548376/, retrieved 2021-12-24 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Stahl's essential psychopharmacology: the prescriber's guide; antipsychotics and mood stabilizers (3rd ed.). New York, NY: Cambridge University Press. 2009. pp. 523–526. ISBN 978-0-521-75900-7. 
  9. ↑ "New frontiers in the pharmacological treatment of social anxiety disorder in adults: an up-to-date comprehensive overview". Expert Opin Pharmacother 24 (2): 207–219. February 2023. doi:10.1080/14656566.2022.2159373. PMID 36519357. 
  10. ↑ "Tiagabine for social anxiety disorder". Hum Psychopharmacol 22 (4): 241–244. June 2007. doi:10.1002/hup.846. PMID 17476705. 
  11. ↑ "Newer anticonvulsant drugs in neuropathic pain and bipolar disorder". J Pain Palliat Care Pharmacother 16 (4): 19–37. 2002. doi:10.1080/j354v16n04_03. PMID 14635823. 
  12. ↑ "Use of anticonvulsants for treatment of neuropathic pain". Neurology 59 (5 Suppl 2): S14–S17. September 2002. doi:10.1212/wnl.59.5_suppl_2.s14. PMID 12221151. 
  13. ↑ 13.0 13.1 13.2 "Tiagabine: the safety landscape". Epilepsia 36 (Suppl 6): S10–S13. 1995. doi:10.1111/j.1528-1157.1995.tb06009.x. PMID 8595787. 
  14. ↑ Antiepileptic Drugs: Pharmacology and Therapeutics. Springer Science & Business Media. 6 December 2012. pp. 459–. ISBN 978-3-642-60072-2. https://books.google.com/books?id=8iv6CAAAQBAJ&pg=PA459. 
  15. ↑ 15.0 15.1 Cite error: Invalid <ref> tag; no text was provided for refs named Leduc_2012
  16. ↑ "Antihistamines". Meyler's Side Effects of Psychiatric Drugs. Elsevier. 2009. pp. 652–. ISBN 978-0-444-53266-4. https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA652. 
  17. ↑ 17.0 17.1 "Retrospective evaluation of tiagabine overdose". Clinical Toxicology 43 (7): 855–859. 2009. doi:10.1080/15563650500357529. PMID 16440513. 
  18. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Brodie_1995
  19. ↑ "The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study". The Journal of Clinical Psychiatry 66 (11): 1401–1408. November 2005. doi:10.4088/JCP.v66n1109. PMID 16420077. 
  20. ↑ "Gabitril (tiagabine) dosing, indications, interactions, adverse effects, and more". https://reference.medscape.com/drug/gabitril-tiagabine-343022#91. 
  21. ↑ 21.0 21.1 "Rational approaches for the design of various GABA modulators and their clinical progression". Molecular Diversity 25 (1): 551–601. February 2021. doi:10.1007/s11030-020-10068-4. PMID 32170466. 
  22. ↑ 22.00 22.01 22.02 22.03 22.04 22.05 22.06 22.07 22.08 22.09 22.10 22.11 22.12 22.13 22.14 22.15 22.16 22.17 "Gabitril (tiagabine hydrochloride) prescribing information". U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020646s016lbl.pdf. 
  23. ↑ "Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo". Journal of Neuroscience Research 93 (7): 1101–1108. July 2015. doi:10.1002/jnr.23548. PMID 25663257. 
  24. ↑ "[11Cflumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels"]. PLOS ONE 7 (2). 2012. doi:10.1371/journal.pone.0032443. PMID 22384252. Bibcode: 2012PLoSO...732443F. 
  25. ↑ "Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions". European Neuropsychopharmacology 50: 34–45. September 2021. doi:10.1016/j.euroneuro.2021.04.005. PMID 33957336. 
  26. ↑ "Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2". Molecules 26 (12): 3522. June 2021. doi:10.3390/molecules26123522. PMID 34207748. 
  27. ↑ "Analysis of Different Binding Modes for Tiagabine within the GAT-1 Transporter". Biomolecules 12 (11): 1663. November 2022. doi:10.3390/biom12111663. PMID 36359013. 
  28. ↑ 28.0 28.1 28.2 28.3 "Tiagabine: a novel antiepileptic drug". Ann Pharmacother 32 (11): 1173–1180. November 1998. doi:10.1345/aph.18053. PMID 9825084. 
  29. ↑ "The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate". Journal of Medicinal Chemistry 36 (12): 1716–1725. June 1993. doi:10.1021/jm00064a005. PMID 8510100. 
  30. ↑ "Search Results for Tiagabine". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020646&TABLE1=OB_Rx. 
  31. ↑ 31.0 31.1 31.2 "Tiagabine". 24 October 2021. https://adisinsight.springer.com/drugs/800001613. 
  32. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/020646s017ltr.pdf
  33. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/020646s020ltr.pdf
  34. ↑ 34.0 34.1 "Tiagabine in the maintenance treatment of bipolar disorder". Cochrane Database Syst Rev 2011 (12). December 2011. doi:10.1002/14651858.CD005173.pub3. PMID 22161389. 
  35. ↑ "Paradoxical pharmacological dissociations result from drugs that enhance delta oscillations but preserve consciousness". Communications Biology 6 (1). June 2023. doi:10.1038/s42003-023-04988-8. PMID 37340024. 



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