Side effects of tiagabine are dose related.[6] The most common side effect of tiagabine is dizziness.[8] 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.[8][9] 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 8mg/day).[8] Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold.[5] There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive.[2][10] Tiagabine can also reportedly interfere with visual color perception.[2]
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.[13][14] 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.[15] However, tiagabine does not decrease neuronal GABA levels and induces compensatory GABA synthesis from glucose or glial glutamine precursors.[16]
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.[14]
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.[17][18]
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.[19]
Pharmacokinetics
Tiagabine has high bioavailability and should not be administered with high fat meals, since it decreases peak plasma concentration achievement time from 45 minutes to 2.5 hours. It is metabolised through two mechanisms in vitro[15]: thiophene ring oxidation through CYP3A liver enzymes, yielding pharmacologically inactive 5-oxo-tiagabine and glucuronidation.
Most of tiagabine is excreted in urine and feces, primary as metabolites. Hepatic enzyme elevation decreased elimination half-life by 50-65%. Interestingly, diurnal circadian rhythm was associated with mean steady-state concentration decrease – nighttime administration resulted in inferior Cmin and AUC values.[15]
Effect on cardiac ion channels
The fact that tiagabine does not adversely affect cardiac ion channel output renders it safe in patients with cardiovascular problems, including QT prolongation. It does not induce arterial vasorelaxation. Tiagabine's affinity towards hNav1.5, hCav1.2 and hKv11.1 (hERG) channels falls below the activity threshold of pKi equal to 4 and has low hydrogen bond energy. This effect is confirmed by comparison to nifedipine, terfenadrine and batrachotoxin. However, the stereoisomerism of tiagabine influences binding pocket alingment, but does not introduce variable ion channel blocade.[20]
Tiagabine cardiac ion channel binding affinity
Ion channel
Ligand
pKi
Binding energy [kcal/mol]
Blocking activity
hNav1.5
(R)-tiagabine
3.74
–5.01
inactive (pKi < 4)
(S)-tiagabine
3.82
–5.21
inactive (pKi < 4)
batrachotoxin
6.68
–9.01
active (pKi > 4)
hCav1.2
(R)-tiagabine
3.70
–5.05
inactive (pKi < 4)
(S)-tiagabine
3.50
–4.77
inactive (pKi < 4)
batrachotoxin
5.25
–7.17
active (pKi > 4)
hKv11.1 (hERG)
(R)-tiagabine
3.32
–5.40
inactive (pKi < 4)
(S)-tiagabine
3.14
–5.20
inactive (pKi < 4)
batrachotoxin
4.95
–6.75
active (pKi > 4)
Even though tiagabine's influence on these receptors is negligible, a pharmacophore model was deduced from computerized molecular docking studies. (R)-tiagabine does not interact with the hERG channel in this model (hydrogen bond energy approximately equal to –7/32 kcal/mol, which is less than for (S)-tiagabine, where it is approximately –5.54 kcal/mol), which confirms the lack of QT segment changes associated with tiagabine treatment in clinically important concentrations.[20]
Tiagabine's binding pocket in cardiac ion channels
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.[21] 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.[citation needed]
US patents on tiagabine listed in the Orange Book expired in April 2016.[22]
Research
Effects on cortical delta oscillations
Tiagabine enhances the power of cortical delta (< 4 Hz) oscillations up to 1000% 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.[23] 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.
Tiagabine (15 mg) enhances MEGdelta power in healthy volunteers.
1 2 Stahl SM (2009). Stahl's essential psychopharmacology: the prescriber's guide; antipsychotics and mood stabilizers (3rded.). New York, NY: Cambridge University Press. pp.523–526. ISBN978-0-521-75900-7.
1 2 "Tiagabine", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID31643697, retrieved 2021-12-24
1 2 Spiller HA, Winter ML, Ryan M, Krenzelok EP, Anderson DL, Thompson M, etal. (2009). "Retrospective evaluation of tiagabine overdose". Clinical Toxicology. 43 (7): 855–859. doi:10.1080/15563650500357529. PMID16440513. S2CID25469390.
↑ Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, etal. (November 2005). "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. doi:10.4088/JCP.v66n1109. PMID16420077.
↑ Andersen KE, Braestrup C, Grønwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, etal. (June 1993). "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. doi:10.1021/jm00064a005. PMID8510100.
↑ "Search Results for Tiagabine". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. Archived from the original on 22 April 2016. Retrieved 22 March 2016.
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