does not increase gaba blood levels in humans. lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect (adrenergic, dopamine d1 and d2, muscarinic, gaba, histaminergic h1, serotonin 5-ht2, and n-methyl-d-aspartate). inhibitory effects on 5-ht, norepinephrine, and dopamine transporters are weak. lamotrigine is a weak inhibitor of dihydrofolate reductase, but whether this effect is sufficient to contribute to a mechanism of action or increases risk to the fetus during pregnancy is not known. early studies of lamotrigine's mechanism of action examined its effects on the release of endogenous amino acids from rat cerebral cortex slices in vitro. as is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine thereby inhibits the release of glutamate and aspartate, which is evoked by the sodium-channel activator veratrine, and was less effective in the inhibition of acetylcholine or gaba release. at high concentrations, it had no effect on spontaneous or potassium-evoked amino acid release. these studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. several electrophysiological studies have investigated the effects of lamotrigine on voltage-gated sodium channels. for example, lamotrigine blocked sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner, at concentrations that are therapeutically relevant in the treatment of human seizures. in cultured hippocampal neurons, lamotrigine reduced sodium currents in a voltage-dependent manner, and at depolarised potentials showed a small frequency-dependent inhibition. these and a variety of other results indicate that the antiepileptic effect of lamotrigine, like those of phenytoin and carbamazepine, is at least in part due to use- and voltage-dependent modulation of fast voltage-dependent sodium currents. however, lamotrigine has a broader clinical spectrum of activity than phenytoin and carbamazepine and is recognised to be protective against generalised absence epilepsy and other generalised epilepsy syndromes, including primary generalised tonic–clonic seizures, juvenile myoclonic epilepsy, and lennox-gastaut syndrome. the basis for this broader spectrum of activity of lamotrigine is unknown, but could relate to actions of the drug on voltage-gated calcium channels. lamotrigine blocks t-type calcium channels weakly, if at all. however, it does inhibit native and recombinant high voltage–gated calcium channels (n- and p/q/r-types) at therapeutic concentrations. whether this activity on calcium channels accounts for lamotrigine's broader clinical spectrum of activity in comparison with phenytoin and carbamazepine remains to be determined. it antagonises these receptors with the following ic50 values: 5-ht3, ic50 = 18 μm σ receptors, ic50 = 145 μm pharmacokinetics the pharmacokinetics of lamotrigine follow first-order kinetics, with a half-life of 29 hours and volume of distribution of 1.36 l/kg. lamotrigine is rapidly and completely absorbed after oral administration. its absolute bioavailability is 98% and its plasma cmax occurs from 1.4 to 4.8 hours. available data indicate that its bioavailability is not affected by food. estimate of the mean apparent volume of distribution of lamotrigine following oral administration ranges from 0.9 to 1.3 l/kg. this is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers. lamotrigine is inactivated by glucuronidation in the liver. lamotrigine is metabolized predominantly by glucuronic acid conjugation. its major metabolite is an inactive 2-n-glucuronide conjugate. lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with carbamazepine, phenytoin and other hepatic enzyme inducing medications may shorten half-life. dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance. the capacity of available tests to detect potentially adverse consequences of melanin binding is unknown. clinical trials excluded subtle effects and optimal duration of treatment. there are no specific recommendations for periodic ophthalmological monitoring. lamotrigine binds to the eye and melanin-containing tissues which can accumulate over time and may cause toxicity. prescribers should be aware of the possibility of long-term ophthalmologic effects and base treatment on clinical response. patient compliance should be periodically reassessed with lab and medical testing of liver and kidney function to monitor progress or side effects. chemistry the first synthesis of lamotrigine was disclosed in a patent filed by the wellcome foundation in 1980. 2,3-dichlorobenzoyl chloride is treated with cuprous cyanide to form an acyl cyanide. this is then reacted with the nitrate salt of aminoguanidine to give an intermediate which is cyclised to the diamino triazine of the drug product. history 1980 — initial patent filings are made by the wellcome foundation. 1990 — lamotrigine is approved for use in ireland to treat epilepsy. 1991 — lamotrigine is used in the united kingdom as an anticonvulsant medication december 1994 — lamotrigine was approved for use in the united states for the treatment of partial seizures. august 1998 — for use as adjunctive treatment of lennox-gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets. december 1998 — for use as monotherapy for treatment of partial seizures in adult patients when converting from a single enzyme-inducing anticonvulsant drug. january 2003 — for use as adjunctive therapy for partial seizures in pediatric patients as young as two years of age. june 2003 — approved for maintenance treatment of bipolar ii disorder; the first such medication since lithium. january 2004 — for use as monotherapy for treatment of partial seizures in adult patients when converting from the anti-epileptic drug valproate (including valproic acid) society and culture brand names lamotrigine is sold under the original brand name lamictal and it is available in generic form under many brand names worldwide. regulatory advisory in 2021 in march 2021, the united states food and drug administration (fda) issued a warning regarding the potential for cardiac arrhythmias in people with pre-existing structural or conduction heart defects. the warning provoked consternation and controversy within the professional community. an in-vitro study conducted in 2011 predicted class ib antiarrhythmic activity at therapeutic concentrations of lamotrigine, due to its sodium channel-blocking activity. thus, lamotrigine use in at-risk populations could prolong the qrs interval on the electrocardiogram, and increase the risk of arrhythmias and sudden death. no references to human studies or postmarket data in at-risk populations (i,e, people with structural heart disease) were cited to support the warning. a study in dogs is mentioned in the prescribing information brochure by the manufacturer. a rapid systematic review concluded that "there is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes….” the fda has recommended that further studies are conducted with lamotrigine and other sodium-channel blocking antiseizure medications.