Lamotrigine , sold as a brand name Lamictal among others, is an anticonvulsant drug used to treat epilepsy and bipolar disorder. For epilepsy, these include focal seizures, tonic-clonic seizures, and convulsions in the Lennox-Gastaut syndrome. In bipolar disorder, it is used to treat episodes of acute depression, rapid bipolar type II cycling, and prevent recurrence of type I bipolar.
Common side effects include drowsiness, headache, vomiting, coordination problems, and rashes. Serious side effects include lack of red blood cells, increased risk of suicide, Stevens-Johnson syndrome, and allergic reactions. There are concerns that use during pregnancy or breast-feeding can result in harm. Lamotrigine is a feniltriazine, making it chemically different from other anticonvulsants. The way it works is not so clear. It appears to increase the action of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system and reduce the sodium voltage sensitive channels.
Lamotrigine was first marketed in the UK in 1991 and was approved for use in the United States in 1994. It is a List of Essential Medicines of the World Health Organization, the most effective and safest drugs needed in the health system. Wholesale costs in developing countries are around 3.57 USD per month by 2015. In the United States, this amount has a wholesale cost of about 4.64 USD.
Video Lamotrigine
Medical use
Epilepsy
Lamotrigine is used for the treatment of partial seizures. This drug is considered to be the first-line treatment for primary generalized tonic-clonic seizures (including simple partial seizures, partial complexes and secondary secondary), and as adjuvant therapy in partial seizures (focal tonic-clonic onset, no atypical, myoclonic, Lennox-Gastaut syndrome). It is also used as an alternative medicine for seizures of atypical absence and absence, myoclonic, and atonic seizures.
It is also appropriate for the treatment of Lennox-Gastaut syndrome. This is one of a small number of FDA-approved therapies for this severe form of epilepsy. Lamotrigine reduces the frequency of LGS seizures, and is one of two drugs known to reduce the severity of drop attacks. Combinations with valproate are common, but this increases the risk of rashes due to lamotrigine, and requires dose reduction due to the interaction of these drugs.
Bipolar disorder
Lamotrigine is approved in the US for treatment of bipolar I disorder and bipolar II disorder. While anticonvulsant carbamazepine and valproate are predominantly antimanics, lamotrigine is most effective at preventing recurrent episodes of bipolar depression. These drugs appear to be ineffective in the treatment of acute mania, current cycling, or acute depression in bipolar disorder; However, it is effective to prevent or delay manic episodes, depressive, or fast cycling. According to research in 2007, lamotrigine can treat bipolar depression without triggering mania, hypomania, mixed state, or fast cycling.
There is little evidence of therapeutic benefits when lamotrigine is used to treat current mood episodes. This has not shown effectiveness in treating acute mania, and there is controversy over the effectiveness of drugs in treating acute bipolar depression. While the 2002 American Psychiatric Association (APA) guidelines recommend lamotrigine as a first-line treatment for acute depression in bipolar disorder II, the APA website notes that the guidelines, which are over the age of five, "can no longer be considered today." Paper written in 2008 by Nasser et al. reviewing evidence from unpublished trials and not referenced in APA 2002 guidelines, and concluded that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar depression". Paper of 2008 by Calabrese et al. examined much of the same data, and found that in five placebo controlled studies, lamotrigine did not differ significantly from placebo in the treatment of bipolar depression. However, in a meta-analysis of a study conducted in 2008, Calabrese found that lamotrigine was effective in individuals with bipolar depression, with the amount needed to treat (NNT) of 11, or 7 in severe depression.
A 2013 review of lamotrigine concluded that it is recommended in bipolar treatment when depression stands out and that further research is needed in terms of its role in the treatment of acute bipolar depression and unipolar depression. In addition, there is no information to recommend its use in other psychiatric disorders found.
Other uses
The use of off-label includes the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reduced neuropathic pain. Although a systematic review conducted in 2013 concluded that well-designed clinical trials showed no benefit for lamotrigine in neuropathic pain. The use of off-label psychiatry includes treatment of obsessive-compulsive disorder treatment, depersonalization disorder, persistent hallucinatory perceptual disorder, schizoaffective disorder, personality threshold disorder, and post-traumatic stress disorder.
Maps Lamotrigine
Side effects
Lamotrigine prescribes information has a black box warning about life-threatening skin reactions, including Stevens-Johnson syndrome (SJS), DRESS syndrome and toxic epidermal necrolysis (TEN). The manufacturer states that almost all cases appear within the first two to eight weeks of therapy, or if the drug suddenly stops and resumes with a normal dose. Patients should seek medical attention for unexpected skin rashes, since its presence is an indication of the possibility of serious or even deadly side effects. Not all rashes that occur when taking lamotrigine develop into SJS or TEN. Between 5 and 10% of patients will develop a rash, but only one in a thousand patients will experience a serious rash. Rashes and other skin reactions are more common in children, so these drugs are often reserved for adults. For patients whose lamotrigine has stopped after onset of rash, re-challenge with lamotrigine is also a viable option. However, that does not apply to very serious cases.
There is also an increase in the incidence of this eruption in patients who currently, or recently discontinued valproate type anticonvulsant drugs, because these drugs interact in such a way that both cleansing decreases and the effective dose of lamotrigine increases.
Side effects such as rash, fever, and fatigue are very serious, as they may indicate the newly established Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome or aseptic meningitis.
Other side effects include loss of balance or coordination; double vision; cockeye; student constriction; blurred vision; dizziness and lack of coordination; drowsiness, insomnia; anxiety; a real dream or nightmare; dry mouth, mouth ulcers; memory problems; mood changes; itching; runny nose; cough; nausea, indigestion, abdominal pain, weight loss; a missed or painful menstrual period; and vaginitis. Side effect profiles vary for different patient populations. Overall adverse effects in treatment were similar between men, women, geriatric, pediatric and racial groups.
Lamotrigin has been associated with a decrease in the number of white blood cells (leukopenia). Lamotrigine did not extend QT/QTc in TQT studies on a healthy subject.
The case of lamotrigine-induced neuroleptic malignant syndrome has been reported.
In 2018 the FDA requires new warnings for the risk of hemophagocytic lymphohistiocytosis (HLH). This reaction can occur between days to weeks after starting treatment.
Female
Women are more likely than men to have side effects. This is the opposite of most other anticonvulsants.
There is evidence to suggest an interaction between lamotrigine and female hormones, which can be of particular concern to women who use estrogen-containing hormonal contraceptives. Ethinylestradiol, the contraceptive agent, has been shown to decrease serum lamotrigine levels. Women who start OCs containing estrogen may need to increase the dose of lamotrigine to maintain its efficacy level. Likewise, women may experience elevated lamotrigine side effects after pill termination. This may include a "pill-free week" in which serum lamotrigine levels have been shown to double.
Pregnancy and breastfeeding
Many studies have found no association between lamotrigine exposure in utero and birth defects, whereas those who have found a relationship have found little association with small malformations such as the cleft palate. The review study has found that the overall rate of congenital malformations in infants exposed to lamotrigine in utero is relatively low (1-4%), which is similar to the degree of malformation in the general population. It is well known that lamotrigine is a weakly inhibitor of human dihydrofolate reductase (DHFR) and other stronger human DHFR inhibitors such as teratogenic known methotrexate.
Lamotrigine is expressed in breast milk; manufacturers do not recommend breastfeeding during treatment. In "Drugs and Milk Mothers", a review of the frequently updated scientific literature, lamotrigine is considered L3: quite safe.
Other effects type
Lamotrigine binds tissues containing melanin like iris. The long-term consequences of this are unknown.
Some patients reported experiencing concentration loss, even with very small doses. Lamotrigine has been implicated in the neurodegeneration of apoptosis from the developing brain. GlaxoSmithKline investigates lamotrigine for the treatment of ADHD with inconclusive results. No adverse effects on cognitive function were observed; However, the only statistical increase in the symptoms of core ADHD is an increase in the Paced Auditory Serial Addition Test (PASAT) that measures the speed of the auditory process and calculation abilities. Another study reported that lamotrigine may be a safe and effective treatment option for adult comorbid ADHD with bipolar and recurrent depression.
Lamotrigine is known to affect sleep. Studies with a small number (10-15) patients reported that lamotrigine improves sleep stability (increases REM sleep duration, reduces the number of phase shifts and reduces the duration of slow-wave sleep), and that there is no effect on alertness, and daytime sloth and cognitive function. However, a retrospective study of 109 patients' medical records found that 6.7% of patients had "warning effects" that resulted in unbearable insomnia, whose treatment had to be stopped.
Lamotrigine can induce a type of seizure known as myoclonic jerk, which tends to occur immediately after drug use. When used in the treatment of myoclonic epilepsy such as juvenile myoclonic epilepsy, lower doses (and lower plasma levels) are usually necessary, since even moderate doses of these drugs can induce seizures, including tonic-clonic seizures, which can progress to epileptic status, which is a medical emergency. It may also cause status of myoclonic epilepticus.
In overdose, lamotrigine can cause uncontrolled seizures in most people. Results reported in overdoses involving up to 15 g include increased seizures, coma and death.
Pharmacology
Action mechanism
Lamotrigine is a member of the antiepileptic drug group that blocks sodium channels. This can suppress the release of glutamate and aspartate, two of the dominant excitation neurotransmitters on CNS. It is generally accepted as a member of the sodium channel antiepileptic drug group, but may have additional measures because it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and is effective in the treatment of depression. phase of bipolar disorder, whereas other sodium channel antiepileptic drugs are not, possibly because of sigma receptor activity. In addition, lamotrigine has several side effects with other unrelated anticonvulsants known to inhibit the sodium channel, which further emphasizes its unique properties.
It is a triazine derivative that inhibits a voltage-sensitive sodium channel, leading to neuronal membrane stabilization. It also blocks the calcium channels L-, N-, and P-type and has a weak 5-hydroxytryptamin-3 (5-HT3) receptor inhibition. This action is thought to inhibit the release of glutamate on cortical projection in the ventral area of ​​the limbic striatum, and its neuroprotective and antiglutamatergic effects have been shown to be promising contributors to mood stabilizing activity. Observation that lamotrigine is reduced? -aminobutyric acid (GABA) A receptor-mediated neurotransmission in the rat amygdala, indicating that GABAergic mechanisms may also be involved. Apparently lamotrigine does not increase levels of GABA in humans.
Lamotrigine has no obvious effect on any of the usual neurotransmitter receptors (adrenergic, dopamine D1 and D2, muscarinic, GABA, histaminergic H1, serotonin 5-HT2, and N-methyl-D-asparate). Inhibitory effects on the 5-HT transporters, norepinephrine, and dopamine are weak. Lamotrigine is a weak inhibitor of dihydrofolate reductase, but whether this effect is sufficient to contribute to the mechanism of action or increase risk to the fetus during pregnancy is unknown. Early studies of the lamotrigine action mechanism examined their effect on the release of endogenous amino acids from mouse cerebral cortical slices in vitro. As with antiepileptic drugs acting on dependent sodium channels, lamotrigine inhibits the release of glutamate and aspartate induced by the sodium channel veratrine activator and is less effective in inhibiting the release of acetylcholine or GABA. At high concentrations, it has no effect on the release of spontaneous or potassium amino acids.
These studies show that lamotrigine acts presinaptically on a voltage-gated sodium channel to reduce glutamate release. Several electrophysiological studies have examined the effects of lamotrigine on stress-dependent sodium channels. For example, lamotrigine is blocked continuous repetitive shooting in spinal cord neurons of cultured rats in a concentration-dependent manner, at therapeutically relevant concentrations in the treatment of human seizures. In cultured hippocampal neurons, lamotrigine reduces sodium currents in a voltage-dependent fashion, and at depolarization potential indicates a small frequency dependent inhibition. These and various other results suggest that the lepotrigine antiepileptic effects, such as phenytoin and carbamazepine, are at least partly due to modulation of use and stress dependent on fast-dependent sodium currents. However, lamotrigine has a broader spectrum of clinical activity than phenytoin and carbamazepine and is recognized as a protective against the absence of generalized epilepsy and other common epilepsy syndromes, including primary general tonic-clonic seizures, juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome.
The basis for this broader spectrum of lamotrigine activity is unknown, but may be related to drug action on calcium-activated voltage channels. Lamotrigine blocks the weak T-type calcium channels, if at all. However, it inhibits active calcium channels and high-voltage recombinants (N- and P/Q/R-type) at therapeutic concentrations. Whether this activity in the calcium channel contributes to a wider spectrum of clinical activity of lamotrigine compared to phenytoin and carbamazepine remains to be determined.
These following receptor antagonises with the following 50 IC values:
- 5-HT 3 , IC 50 = 18? M
- ? receptor, IC 50 = 145? M
Pharmacokinetics
Lamotrigine pharmacokinetics follows first-order kinetics, with a half-life of 29 hours and a distribution volume of 1.36 L/kg. Lamotrigine is rapidly and completely absorbed after oral administration. Absolute bioavailability is 98% and plasma C max occurs from 1.4 to 4.8 hours. Available data indicate that its bioavailability is not affected by food. Estimated average volume of lamotrigine distribution after oral administration ranges from 0.9 to 1.3 L/kg. It is independent of dose and similar following single and double doses in both patients with epilepsy and in healthy volunteers.
Lamotrigine is inactivated by glucuronation in the liver. Lamotrigine is metabolized mainly by the conjugation of glucuronic acid. Its main metabolite is the inactivated 2-n-glucuronide conjugate. Lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with carbamazepine, phenytoin and drugs induce other liver enzymes may shorten half-lives. Dose adjustments should be made on clinical response, but monitoring may be helpful in assessing adherence.
The available test capacity to detect potentially adverse consequences of melanin binding is unknown. Clinical trials do not include subtle effects and optimal treatment duration. There are no specific recommendations for periodic ophthalmological monitoring. Lamotrigine binds eyes and tissues containing melanin that can accumulate over time and can cause poisoning. Prescribers should be aware of the possibility of long-term ophthalmological effects and basic treatment in clinical response. Patient compliance should be periodically reassessed with laboratory and medical tests of liver and kidney function to monitor progress or side effects.
History
- December 1994 - lamotrigine is approved for the treatment of partial seizures. August 1998 - to be used as an adjunct treatment for Lennox-Gastaut syndrome in pediatric and adult patients, a new dosage form: chewable, dispersable tablets.
- December 1998 - for use as monotherapy for the treatment of partial seizures in adult patients when changing from anticonvulsant drugs that trigger a single enzyme.
- January 2003 - to be used as adjunctive therapy for partial seizures in pediatric patients as young as two years of age.
- June 2003 - approved for treatment of bipolar II disorder; the first such drug since lithium.
- January 2004 - for use as monotherapy for the treatment of partial seizures in adult patients when converting from valproate anti-epilepsy drugs [including valproate acid (Depakene); sodium valproate (Epilim) and sodium divalproex (Depakote)].
Trade name
Lamotrigine was originally brought to market by GlaxoSmithKline, a trademark as Lamictal; it is also available in generic form under many brand names worldwide.
References
External links
- FAQ: Psychological Use of Lamotrigine (Lamictal) - by Ivan K. Goldberg, MD. Includes many references from the medical literature.
- Drug Research and Research Center: Lamictal - documents related to the FDA approval process, including medical review and correspondence letters.
- Epilepsy South Africa: TREATMENT FOR EPILEPSI - Epilepsy FAQ with a list of drugs for its treatment, including lamotrigine under the trade name South Africa Lamictin
- Side Effects - report side effects and side effects.
- US. National Drug Library: Drug Information Portal - Lamotrigine
Source of the article : Wikipedia
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