TABLE 1.
Summary of some clinically relevant drugs that can alter tonic inhibition within the brain.
| Drug (trade names) | Mechanism of action | Current drug indications |
|---|---|---|
|
Gabapentin (Fanatrex, Gabarone, Gralise, Neurontin) |
Originally thought to be a GABA mimetic, but mechanism of action is now unclear. Possible enhancement of GABA synthesis could explain why ambient GABA levels in the brain are raised1. |
Partial-onset seizures in adults and the elderly2 Alcohol withdrawal as a combination therapy3 Sleep disorders4 |
|
Vigabatrin (Sabril) |
Irreversible block of GABA transaminase to interfere with GABA cetabolism and, therefore, raise ambient GABA levels. |
Refractory complex partial seizures and infantile spasms5. Not favoured due to visual field loss in some adults and children6. |
|
Tiagabine (Gabitril) |
Blockade of GABA transporters on nerve terminals (predominantly GAT-1) leads to raised ambient GABA levels. |
Partial seizures Generalized anxiety disorders/panic disorders7 |
|
Pregabalin (Lyrica) |
Enhances the activity of glutamic acid decarboxylase (GAD) leading to increased GABA synthesis and, therefore, raised ambient GABA levels. |
Partial seizures with or without secondary generalization8 Neuropathic pain in diabetese, post herpetic neuralgia and fibromyalgia8. Generalized anxiety disorder8. |
| Gaboxadol | Selective orthosteric agonist at δ-GABAARs leading to specific enhancement of the tonic conductance. |
Sleep enhancer, but withdrawn from Phase III clinical trials due to poor risk-to-benefit ratio9. |
| L-655,708 | High-affinity negative allosteric modulator of α5-GABAARs that will reduce tonic conductances. |
Cognitive enhancer but not thought to be suitable for human use due to anxiogenic properties10. |
| Ganaxolone | Positive allosteric modulator of most GABAARs with greater potency at δ-GABAARs leading to selective enhancement of the tonic conductance. |
Catemenial epilepsy11 |
|
Alphaxalone (Althesin, Saffan) |
Positive allosteric modulator of most GABAARs with greater potency at δ-GABAARs leading to selective enhancement of the tonic conductance. |
Anaesthetic12 and sedative in long-term intensive care patients13. Was withdrawn from clinical practice due to complications with the vehicle, Cremophor EL. Re-branded as Saffan and widely used as an anaesthetic in veterinary surgery. |
|
Propofol (Diprivan) |
Positive allosteric modulator of most GABAARs including α5 and δ-GABAARs leading to enhanced tonic conductance. |
Widely used as an intravenous anaesthetic. |
Maneuf YP, Gonzalez MI, Sutton KS, Chung FZ, Pinnock RD, Lee K, (2003) Cellular and molecular action of the putative GABAmimetic, gabapentin CMLS, Cell. Mol. Life Sci. 60; 742–750
Beghi E. Treating epilepsy across its different stages. (2010) Ther Adv Neurol Disord. 3(2):85–92.
Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, Randall PK. (2011) Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence. Am J Psychiatry. Mar 31. Epub ahead of print.
Ehrenberg B. (2000) Importance of sleep restoration in co-morbid disease: effect of anticonvulsants. Neurology. 54(5 Suppl 1): S33.
Tolman JA, Faulkner MA. (2009) Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval. Expert Opin Pharmacother. 10(18): 3077–89.
Chiron C, Dulac O. Epilepsy: (2011) Vigabatrin treatment and visual field loss. Nat Rev Neurol. 7(4):189–90.
Pollack MH, Roy-Byrne PP, Van Ameringen M, et al. (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): 1401–8.
Tassone DM, Boyce E, Guyer J, Nuzum D. (2007) Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther. 29(1): 26–48.
Saul S (2007) Merck Cancels Work on a New Insomnia Medication. The New York Times. March 29
Navarro JF, Burón E, Martín-López M (2002). Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABA(A) receptors which contain the alpha-5 subunit, in the elevated plus-maze test". Progress in neuro-psychopharmacology & biological psychiatry 26 (7–8): 1389–92.
Biagini G, Panuccio G, Avoli M (2010) Neurosteroids and epilepsy. Curr Opin Neurol. 23(2):170–6.
Winter L, Nadeson R, Tucker AP, Goodchild CS. (2003) Antinociceptive properties of neurosteroids: a comparison of alphadolone and alphaxalone in potentiation of opioid antinociception, Anesth. Analg. 97 798–805.
Stewart GO, Dobb GJ, Craib IA. (1983) Clinical trial of continuous infusion of alphaxalone/alphadolone in intensive care patients. Anaesth Intensive Care. 11(2):107–12.