Tiagabine, sold under the brand name Gabitril, 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 including panic disorder.
Medical uses
Tiagabine is approved by US Food and Drug Administration (FDA) as an adjunctive treatment for partial
in individuals of age 12 and up. It may also be prescribed off-label by physicians to treat anxiety disorders, such as panic disorder, as well as
neuropathic pain (e.g.,
fibromyalgia). For
anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), or
for anxiety, and
,
gabapentin, other anticonvulsants, or
for neuropathic pain.
It is effective as monotherapy and combination therapy with other anticonvulsant drugs in the treatment of
partial seizure.
The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to poor effectiveness and very low quality of evidence.
Side effects
Side effects of tiagabine are dose related.
The most common side effect of tiagabine is
dizziness.
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.
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).
Tiagabine may induce
in those without
epilepsy, particularly if they are taking another drug which lowers the seizure threshold.
There may be an increased risk of
psychosis with tiagabine treatment, although data is mixed and inconclusive.
Tiagabine can also reportedly interfere with visual
color perception.
Overdose
Tiagabine
overdose can produce neurological symptoms such as
lethargy, single or multiple
, status epilepticus,
coma,
confusion, agitation,
,
dizziness,
, abnormal posturing, and
, as well as respiratory depression,
tachycardia, and
hypertension or
hypotension.
Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness.
Pharmacology
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).
Pharmacodynamics
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.
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.
However, tiagabine does not decrease neuronal GABA levels and induces compensatory GABA synthesis from glucose or glial glutamine precursors.
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.
Tiagabine also increases Benzodiazepine' affinity to cortical and limbic GABAA receptor receptors and influences EEG measurements by increasing frontal activity and reducing posterior activity in the brain.
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.
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: 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, Diurnality was associated with mean steady-state concentration decrease – nighttime administration resulted in inferior Cmin and AUC values.
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 hNa
v1.5, hCa
v1.2 and hK
v11.1 (hERG) channels falls below the activity threshold of p
Ki 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.
| +Tiagabine cardiac ion channel binding affinity
!Ion channel
!Ligand
!p Ki
!Binding energy kcal/mol
!Blocking activity |
| hNav1.5 | ( R)-tiagabine | 3.74 | –5.01 | inactive (p Ki < 4) |
| ( S)-tiagabine | 3.82 | –5.21 | inactive (p Ki < 4) |
| batrachotoxin | 6.68 | –9.01 | active (p Ki > 4) |
| hCav1.2 | ( R)-tiagabine | 3.70 | –5.05 | inactive (p Ki < 4) |
| ( S)-tiagabine | 3.50 | –4.77 | inactive (p Ki < 4) |
| batrachotoxin | 5.25 | –7.17 | active (p Ki > 4) |
| hKv11.1 (hERG) | ( R)-tiagabine | 3.32 | –5.40 | inactive (p Ki < 4) |
| ( S)-tiagabine | 3.14 | –5.20 | inactive (p Ki < 4) |
| batrachotoxin | 4.95 | –6.75 | active (p Ki > 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.
History
Tiagabine was discovered at
Novo Nordisk in Denmark in 1988 by a team of medicinal chemists and
Pharmacology under the general direction of Claus Bræstrup.
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.
US patents on tiagabine listed in the Orange Book expired in April 2016.
Research
Effects on cortical delta oscillations
Tiagabine enhances the power of cortical
Delta wave (< 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.
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
External links
