Describe the mechanisms of action of the newer antiepileptic drugs, lamotrigine and tiagabine

Introduction

Epilepsy, one of the most common neurological problems, is a condition in which the sufferers have recurring epileptic seizures, due to an excess of electrical activity in the brain. About 1 in 131 people suffer from it, and around 75 new cases are diagnosed every day in the UK (statistics from 2003) (Joint Epilepsy Council 2006). The mechanism of action of antiepileptic drugs (AEDs) is still largely unknown; however three major mechanisms have been distinguished: inhibition of sodium (e.g. phenytoin) and calcium (e.g. ethosuximide) channels and the enhancement of GABA action (e.g. Phenobarbital) (Rang and Dale, 2007). Several of the drugs now in use were tested on animal models. Until 1985 there had been a 25 year gap in the production of new AEDs, but in the last quarter of the twentieth century a new group of drugs was discovered, including Lamotrigine and Tiagabine.

Lamotrigine

Lamotrigine has been proven to be useful in the treatment of both epilepsy and bipolar affective disorders. According to the 2004 NICE recommendations, lamotrigine should be used as a first-line drug for most of the types of epileptic seizures. Its advantages include good tolerability and it can be taken by pregnant women. It is said to be more broad spectrum than carbamazepine, but less than valproate. Nonetheless, it does have some disadvantages, which is why it isn't the first choice drug for all of the cases (Alarcon et al. 2009). Lamotrigine can cause serious allergic reactions and, like carbamazepine or phenytoin, is associated with a rash. With a few exceptions, Lamotrigine doesn't have any serious drug interactions.  Because it has good absorption, linear pharmacokinetics and minimal plasma protein binding, regular dosing alterations are generally needless and therapeutic monitoring is usually not required (Biton V, 2006). In addition, it has a thymoleptic and psychotropic effect (Ketter et al. 2003).

Mechanism of action of Lamotrigine 

Its mechanism of action is complex and mainly involves inhibition of voltage-dependent sodium channels. It also has an antagonistic effect on high-voltage-activated calcium channels, as well as modulation of transient potassium outward current (Wang et al. 2001). These effects give an antiepileptic outcome as they result in the stabilization of the neuronal membrane by inhibiting excitatory neurotransmitter release (2003, Choi et al.). It has been found that lamotrigine inhibits veratrine-evoked amino-acid release, but has no effect on potassium-induced amino-acid release in rat cerebral cortex. These two substances both depolarize the presynaptic cell inducing transmitter release, but by using different mechanisms: veratrine opens up sodium channels, while increased potassium changes the potassium electrochemical gradient. This led to the suggestion that lamotrigine acts at sodium channels (Cheung et al, 1992). Lees and Leach showed that Lamotrigine inhibits burst firing induced by glutamate, mainly by antagonizing sodium and, at higher concentrations, calcium currents, which are responsible for the action potential propagation in a use-dependent way. They also came to the conclusion that Lamotrigine selectively interferes with frequency discharges, which are a common feature of epileptic foci in vivo (Lees et al., 1993). Interestingly, a paper published in the European Journal of Pharmacology states that Lamotrigine evoked an effect on high-voltage-activated calcium currents even in low concentrations. They believe the difference in the findings could be due to the 'age' of the neurons, as one team used adult cortical neurons rather than young cultured ones (1996, Stefani et al.) A different research group proved that Lamotrigine inhibits 4-AP evoked glutamate release, predominantly by reducing Ca2+ release into the nerve terminal by acting on N- and P/Q- type channels, without any effect on synaptosomal excitability (Wang et al., 2001). They found that inhibition of 4-AP-evoked glutamate release by lamotrigine is not a result of a change in membrane depolarization.  They also showed that LAG-mediated inhibition of glutamate release is not as a result of an action on the locations downstream of calcium influx at the level of synaptic vesicle recruitment, docking or exocytosis because lamotrigine has no effect on ionomycin induced release of glutamate (Wang et al., 2001). Finally, whole cell patch clamp recordings from rat hippocampal cells showed that lamotrigine is a possible positive modulator of the transient outward potassium current I_D, therefore restricting excitation in the hippocampus and most likely also in other neuronal networks (Grunze et al., 1998).

Tiagabine

It is an analogue of GABA, with a short plasma life, able to cross the blood-brain barrier (Rang and Dale, 2007). Tiagabine is mainly recommended as add-on therapy in children over 12 years of age and adults with partial onset seizures. It is a narrow spectrum drug, reasonably well tolerated, with side effects being chiefly CNS-relate: including dizziness, drowsiness, confusion and tremor (Adkins JC, Noble S, 1998). It is not indicated in patients with generalized or unclassified types of epilepsy and in patients with liver problems (Schmidt et al., 2000). It has linear pharmacokinetics and there is no evidence that tiagabine changes the plasma concentrations of other epileptic drugs that undergo hepatic metabolism, as it does not inhibit the liver drug metabolizing enzymes (Schmidt et al., 2000).

Mechanism of action of Tiagabine

Its main mechanism of action is the inhibition of GABA uptake in both neuronal and glial cells, especially in areas such as the hippocampus and the thalamus (Angehagen et al. 2003). It inhibits GAT-1, being a potent selective and reversible inhibitor, preventing GABA uptake, making it highly selective. GAT-1 is one of at least four different GABA transporters responsible for the neurotransmitter uptake back into neurons and glial cells after it has been released into the synaptic cleft. As GABA is an inhibitory neurotransmitter, a rise in its concentration in the synapse leads to decreased neural excitability and, consequently, antiepileptic activity (Adkins JC, Noble S, 1998). Tiagabine is not a substrate for the uptake carrier, meaning that it does not act as a false transmitter at GABAergic neurons (Adkins JC, Noble S, 1998). Furthermore, it does not bind to other receptors if given at therapeutic concentrations. This mode of action has two advantages over the direct stimulation by GABA-A receptor agonists and benzodiazepine agonists: a better physiological specificity (because it only has an effect on endogenously released GABA) and a smaller probability for side effects to occur (because enhancement of GABA-receptor-mediated function is restricted by the quantity of GABA released) (Schmidt et al. 2000).

Conclusions

Lamotrigine and Tiagabine are both antiepileptic drugs introduced in the late twentieth century. The former, used mainly as a first-line drug to treat most types of seizures, is a broad spectrum drug with good tolerability. With a couple of exceptions, it doesn't have serious drug interactions, but can be sometimes associated with a rash. Its main mechanism of action is the inhibition of voltage-dependent sodium channels, but it also has an antagonistic effect on high-voltage-activated calcium channels and modulates transient potassium outward currents. Tiagabine is used to treat partial onset seizures as an add-on drug in adults and children over 12 years old. Side effects can include dizziness, tremor and confusion. Its main mechanism of action is the inhibition of GABA uptake leading to decreased neural excitability and in result antiepileptic activity.

References:

v  Adkins JC, Noble S. 1998. Tiagabine. A Review of its Pharmacodynamic and Pharmacokinetic properties and Therapeutic potential in the management of Epilepsy. Drugs 55(3): 437-460. 

v  Alarcon G, Nashef L, Cross H, Nightingale J, Richardson S. 2009. Epilepsy. Oxford University Press.

v  Angehagen M, Ben-Menachem E, Ronnback L, Hansson E. 2003. Novel mechanisms of action of Three Antiepileptic Drugs, Vigabatrin, Tiagabine and Topiramate. Neurochemical Research 28(2): 333-340.

v  Biton V. 2006. Pharmacokinetics, toxicology and safety of lamotrigine in of epilepsy. Expert Opin. Drug Metab. Toxicol. 2(6):1009-1018.

v  Cheung H, Kamp D, Harris E. 1992. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Research 13: 107-112.

v  Choi H, Morrell MJ. 2003. Review of lamotrigine and its clinical applications in epilepsy. 2003. Expert Opinion on Pharmacotherapy 4(2):243-251.

v  Grunze H, Greene RW, Moller HJ, Meyer T, Wladen J. 1998. Lamotrigine may limit pathological excitation in the hippocampus by modulating a transient potassium outward current. Brain Research 791: 330-334.

v  Joint Epilepsy Council. 2006. Epilepsy Prevalence, Incidence and Other Statistics. JEC. Leeds.

v  Ketter TA, Manji HK, Post RM. 2003. Potential Mechanisms of Action of Lamotrigine in the treatment of Bipolar Disorders. Journal of Clinical Psychopharmacology 23(5).

v  Lees G, Leach MJ. 1993. Study on the mechanism of action of the novel anticonvulsant Lamotrigine (Lamical) using primary neuroglial cultures from rat cortex. Brain Research 612: 190-199

v  Rang HP, Dale MM, Ritter MM, Flower RJ. Rang and Dale's Pharmacology. Sixth edition. 2007. Churchhill Livingstone Elsevier

v  Schmidt D, Gram L, Brodie M, Krammer G, Perucca E, Kalviainen R, Elger CE. 2000. Tiagabine in the treatment of epilepsy - a clinical review with a guide for the prescribing physician. Epilepsy Research 41 245-251.

v  Stefani A, Spadoni F, Siniscalhi A, Bernardi G. 1996. Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications. European Journal of Pharmacology 307: 113-116.

v  Wang S, Sihra TS, Gean P. 2001. Lamotrigine inhibition of glutamate release from isolated cerebrocortical nerve terminals (synaptosomes) by suppression of voltage-activated calcium channel activity. Neuroreport 2001 12(10): 2255-2258.