Anticonvulsants stabilizers

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

First, initiate and/or optimize mood-stabilizing medication lithium3 or lamotrigine6 Alternative anticonvulsants carbamazepine, oxcarbazepine, or valproate... 

Lithium was the first established mood stabilizer and is still considered a first-line agent for acute mania and maintenance treatment of both bipolar I and II disorders. It is the only bipolar medication approved for adults and children 12 years and older. Long-term use of lithium reduces suicide risk. Patients with rapid cycling or mixed states may not respond as well to lithium monotherapy as to some anticonvulsants. 

TDM has improved the performance of anticancer, antidementia, antidepressant, antiepileptic, anticonvulsant, antifungal, antimicrobial, antipsychotic, antiretroviral, anxiolytic, hypnotic, cardiac, addiction treatment, immunosuppressant, and mood stabilizer drags for more than 30 years.2-9 Many analytical procedures evolved as analytical techniques and instrumentation have advanced. This chapter briefly reviews the different types of analytical methods the applications of high-throughput techniques in TDM are discussed in detail. 

A series of branched aliphatic amides were prepared to evaluate the role of amide hydrolysis on the pharmacokinetics and anticonvulsant activity of valpromide analogues. Table 4.1 summarizes the structures investigated, the fraction of amide hydrolyzed (/m), and the stability in blood. These results were obtained after intravenous administration to dogs [6], The structures are classified here in order of decreasing fm. 

T. Murakami, E. Shek, E. Pop, N. Bodor, Improved Anticonvulsant Activity of Pheny-toin by a Redox Brain Delivery System II Stability in Buffers and Biological Materials ,. /. Pharm. Sci. 1989, 78,132-131. 

Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14 R546-R551 Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276 36734-36741... 

Lithium remains the treatment of choice for bipolar patients who experience classic euphoric episodes of mania. Current evidence suggests that those with mixed episodes or rapid cycling episodes respond preferably to anticonvulsants or atypical antipsychotic drugs. In addition to its use as a mood stabilizer, lithium is effective in converting unipolar antidepressant nonresponders to responders. Finally, lithium may also be an effective treatment for patients with clnster headaches. 

Choice of a Mood Stabilizer. With the advance of atypical antipsychotics and an ever-expanding list of anticonvulsants, the number of medications reported to treat acute mania and hypomania continues to grow. In fact, all of the atypical antipsychotics, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole have FDA approval for the treatment of acute mania. Long-term protection against future episodes of illness has also been demonstrated with several of these agents, which can influence the choice of initial therapy. 

Alternate treatments. Mood-stabilization and control of manic or hy-pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively. 

Phenytoin, introduced as an anticonvulsant drug in 1938, remains one of the drugs most frequently prescribed for convulsive disorders. The precise mode of action is unknown, but it appears to inhibit the accumulation of sodium in nerve cells, thus stabilizing hyperexcitable cell membranes (A13)—a property also utilized in the treatment of cardiac arrhythmias. 

Several anticonvulsant medications have mood-stabilizing properties. Valproic acid and carbamazepine are... 

Mechanism of Action An anticonvulsant whose exact mechanism is unknown. May block voltage-sensitive sodium channels, thus stabilizing neuronal membranes and regulating presynaptic transmitter release of excitatory amino acids. Therapeutic Effect Reduces seizure activity... 

Mectianism of Action An anticonvulsant that blocks sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repef if ive neuronal firing, and diminishing synapfic impulses. Therapeutic Effect Prevenfs seizures. Pharmacokinetics Complefely absorbed from GI tract and extensively metabolized in the liver to active metabolite. Protein binding 40%. Primarily excreted in urine. Half-life 2 hr metabolite, 6-10 hr. 

Mechanism of Action An anticonvulsant agent that stabilizes neuronal membranes in motor cortex, and decreases abnormal ventricular automaticity. Therapeutic Effect Limits spread of seizure activity Stabilizes threshold against hyperexcitability. Decreases post-tetanic potentiation and repetitive discharge. Shortens refractory period, QT interval, and action potential duration. 

Diagnostic boundaries in juvenile-onset BD need to be defined, since children with hypomania or manic-like symptoms may be increasingly treated with mood stabilizers. In parallel, this would require more complex algorithms because very few controlled trials have been reported (Walkup, 1995). In contrast to the studies of adults reported in the literature, the pharmacological treatment of childhood bipolarity with anticonvulsants remains an understudied area. Carbamazepine appears to be less efficacious than valproate in adult rapid cycling, yet no studies have identified predictors of treatment response to CBZ or any other mood stabilizer (besides lithium) in a pediatric population. 

Ketter, T.A., Ftye, M.A., Cota-Locatelli, G., Kimbrell, T.A., and Post, R.M. (1999) Metabolism and excretion of mood stabilizers and new anticonvulsants. Cell Mol Neurobiol 19 511-532. 

Controlled trials of combinations of mood stabilizers with single mood stabilizer, or of the newer anticonvulsants (e.g., lamotrigine and topiramate) are in process. Open trials have included add-on medications and heterogeneous samples. 

These data suggest that there is more available information for use of lithium than for other mood stabilizers, and that adolescents hospitalized with adolescent-onset, acute mania have rates of response between 50% and 80%. Supplementation with sedating medication appears to be common but not systematically evaluated. Children hospitalized with mania also respond to lithium, but their comorbid disorders often need separate attention. Open trials with DVP in hospitalized adolescents are also supported. There is much less information on CBZ and there are no data on newer anticonvulsants such as lamotrigine, topiramate, or gabapentin. These data are largely consistent with data from studies of hospitalized adults with classic mania. 

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