Antipsychotics loxapine

Amoxapine Is the N-desmethyl metabolite of the conventional antipsychotic loxapine... 

Although classified as a conventional antipsychotic, loxapine is a potent serotonin 2A antagonist... 

Amoxapine. Consideration of the structure of amoxap-inc. 2-chloro-ll-(l-pipcra/inyl)dibcn/.- b./] l,4 oxuzepinc (Asendin). reinforces the fact that many antidepressants are very closely related to antipsychoties. Indeed,. some, including amoxapine. have significant effects at D. receptors. The Ai-methyl-substituted relative of amoxapine is the antipsychotic loxapine (Loxitane). The H-hydroxy metabolite of amoxapine is reportedly active as an antidepre.ssant and us a Dj receptor blocker. 

With its 2-carbon bridge across the middle, maprotiline (Fig. 12-26) is technically a tetracyclic compound, yet it behaves as a secondary amine TCA (i.e., a relatively selective NE reuptake). The drug s second-generation standing is purely chronological. It has been in the U.S. market since 1981. Amoxapine, which was marketed the same year, is, of course, the N4-demethylated antipsychotic loxapine (Fig. 12-26). It has been suggested the cumulation of the 8-OH metabolite may be responsible for the inhibition of NE uptake and account for the antidepressant effect. Nomifensine, which is a tetrahydroisoquinoline with potential as an inhibitor of NE and DA, but not 5-HT, was withdrawn in 1987 for toxicity reasons. 

Amoxapine is a dibenzoxazepine TCA (Fig. 21.8) with antidepressant and antipsychotic effects that has shown therapeutic effectiveness in patients with delusional depression. Additionally, it is the N-desmethyl metabolite of the antipsychotic loxapine. Amoxapine differs structurally from the other secondary TCAs in that it has both a nitrogen and an oxygen atom in its 7-membered central ring and a piperazinyl ring rather than a propylamino side chain attached to the central ring. 

Current antipsychotics used to treat patients are divided into two classes the first generation antipsychotics (FGA) or typicals (e.g., chlorproma-zine, haloperidol, thioridazine, and loxapine) and the second generation antipsychotics (SGA) or atypicals (i.e., clozapine, olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, and asenapine). 

L The answer is a. (Hardman, p 922) Lactulose is a synthetic disaccharide (galactose-fructose) that is not absorbed. In moderate doses, it acts as a laxative. In higher doses, it is capable of binding ammonia and other toxins that form in the intestine in severe liver deficiency and that are believed to cause the encephalopathy. Loperamide is an antidiarrheal opioid lorazepam is a CNS depressant loxapine is a heterocyclic antipsychotic. 

Whatever the underlying causes may be, neuroleptic medications are the most effective treatment for schizophrenia. All antipsychotic medications have some form of dopamine receptor antagonism and they are distinguished by their chemical class. The phenothiazines include chlorpromazine (Thorazine), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), fluphenazine (Prolixin), and prochlorperazine (Compazine). The thioxanthenes include chlorprohixine (Taractan) and thiothixene (Navane). Butyrophenones are represented by haloperidol (Haldol). Loxapine (Loxitane) is a dibenzoxapine, and molindone (Moban) is a dihydroindolone. 

Other first generation (atypical) antipsychotics include thioxanthenes, haloperidol, pimozide, and loxapine. 

Loxapine (Loxitane). Loxapine is a medium potency antipsychotic, and it has several interesting features. First, it is chemically very similar to clozapine, the first of the atypical antipsychotics. In the test tube, loxapine actually behaves more like an atypical antipsychotic (more on that later), but when patients are treated with it, loxapine acts more like a traditional typical antipsychotic. A second point of interest is that loxapine is actually the major active metabolite of the antidepressant amoxa-pine (Ascendin). As a result, one can use a single medication (amoxapine) to treat both depression and psychosis. In practice, however, the use of what is essentially a fixed dose combination medication should be avoided. Using amoxapine does not allow separate adjustment of the antipsychotic and antidepressant, and most importantly, amoxapine is the only antidepressant associated with the risk of TD. 

As a medium potency antipsychotic, its dose and side effects are intermediate. Sometimes, it may be better to use a medium potency antipsychotic for patients who are especially sensitive to the EPS of high potency antipsychotics. Young, wellmuscled males are particularly prone to EPS and so loxapine may be a good choice for those individuals. 

Several studies have evaluated the use of low doses of the typical antipsychotics. These include studies of high potency antipsychotics such as haloperidol, medium potency antipsychotics such as loxapine, and low potency antipsychotics such as chlorpromazine and thioridazine. In general, the studies have shown that antipsychotics reduce impulsivity and protect from psychotic decompensation. 

Loxapine is a more expressed, active antipsychotic than chlorpromazine. Its sedative effect is inferior to that of chlorpromazine. Indications for its use and side effects correspond with those of phenothiazine derivatives. Loxapine is used for treating psychotic disturbances, in particular cases of chronic and severe schizophrenia. Synonyms of this drug are loxapac and loxitane. 

To date, only one antidepressant, amoxapine, has proven effective in the treatment of PMD as the sole therapy. Amoxapine is a chemical congener of the antipsychotic drug loxapine, so it possesses both dopamine-blocking and monoamine-enhancing properties. One double-blind study has confirmed that amoxapine appears to be as effective as the combination of a TCA and an antipsychotic. R. F. Anton and Burch [1990] randomly selected 46 inpatients with psychotic depression to either amoxapine [to 400 mg/day] or ami-... 

Treatment of the product with phosphorus oxychloride leads to a cyclodehydration reaction possibly via the imino chloride. There is thus obtained the antipsychotic compound loxapine (38-7) [39]. 

Amoxapine has been found to be effective in several double-blind studies (Table 7-4 and Table 7-6). It is a dibenzoxazepine derivative that has both NE and serotonin uptake inhibiting properties. Amoxapine is converted into 8-hydroxyamoxapine, which has considerable dopamine receptor binding properties (i.e., radioreceptor bioassays on patients given amoxapine have found activity levels similar to those of patients on typical antipsychotics), a chemical structure similar to loxapine, and effects similar to antipsychotics (1Q3). As a result of this metabolite, amoxapine theoretically may have unique beneficial effects in psychotically depressed patients. However, this possibility has never been adequately tested. Nevertheless, this metabolite is likely responsible for some of the antidopamine effects reported in patients taking amoxapine, including acute and chronic extrapyramidal side effects and elevated prolactin levels ( 104). Like TCAs, amoxapine can be lethal in... 

Haloperidol is the best-studied antipsychotic medication in children and adolescents with schizophrenia. In a double-blind, placebo- and active-controlled study, haloperidol (2 to 16 mg per day) and loxapine (10 to 200 mg per day) were equally effective and superior to placebo ( 168). This finding was replicated in a placebo-controlled, crossover study of haloperidol (doses of 0.5 to 3.5 mg per day or 0.02 to 0.12 mg/kg per day) in children 5.5 to 12 years of age ( 169). In this study, haloperidol was more effective than placebo in reducing ideas of reference, persecutory ideas, hallucinations, and thought disorder. 

Several open studies have also found antipsychotics useful in BPD (214, 243, 244). For example, Leone (244) found that both loxapine and chlorpromazine were effective and equal in most respects. 

Mirtazapine, amoxapine, and maprotiline have tetracyclic structures. Amoxapine is the /V-methylated metabolite of loxapine, an older antipsychotic drug. Amoxapine and maprotiline share structural similarities and side effects comparable to the TCAs. As a result, these tetracyclics are not commonly prescribed in current practice. Their primary use is in MDD that is unresponsive to other agents. 

The dibenzoxapine loxapine and the indolone molindone are also used as antipsychotics. 

FIGURE 11—36. Structural formulas for clozapine and four other antipsychotics, namely, olanzapine, quetiapine, loxapine, and zotepine. Interestingly, all five of these are also SDAs, but not all of them appear to be atypical antipsychotics (e.g., loxapine is conventional, and zotepine is still being characterized). Abo, clinical properties and pharmacological characteristics vary considerably among those that are clearly atypical (i.e., clozapine, olanzapine, and quetiapine). 

OFFICIAL NAMES Major tranquilizers (neuroleptics/antipsychotics) Chlorpromazine (Thorazine) chlorprothixene (Taractan) clozaril (Clozapine) fluphenazine (Permitil, Prolixin) haloperidol (Haldol) loxapine (Daxolin, Loxitane) mesoridazine (Serentil) molindone (Lidone,... 

Amoxapine is a metabolite of the antipsychotic drug loxapine and retains some of its antipsychotic action and dopamine receptor antagonism. A combination of antidepressant and antipsychotic actions might make it a suitable drug for depression in psychotic patients. However, the dopamine antagonism may cause akathisia, parkinsonism, amenorrhea-galactorrhea syndrome, and perhaps tardive dyskinesia. 

Sedation is usually dose-dependent and may not be experienced at low doses where loxapine may function as an atypical antipsychotic (e.g., <50 mg/day especially 5-25 mg/day)... 

To augment partial responders to an atypical antipsychotic, consider doses of loxapine as low as 5-60 mg/day, but use full doses if necessary... 

When initiating therapy with an atypical antipsychotic in an acute situation, consider short-term intramuscular loxapine to lead in to orally administered atypical e.g., initiate oral dosing of an atypical... 

For previously stabilized patients with breakthrough agitation or incipient decompensation, top-up the atypical antipsychotic with as-needed intramuscular or oral single doses of loxapine... 

Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmenfafion wifh a convenfional antipsychotic such as loxapine or from switching to a conventional antipsychotic such as loxapine... 

However, long-term polypharmacy with a combination of a convenfional antipsychotic such as loxapine with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of eifher... 

Other, chemically distinct dopamine blockers were then developed, such as thiothixene, haloperidol, loxapine, molindone, and pimozide. All of these antipsychotics are potent dopamine blockers and collectively were called neuroleptics because they inadvertently cause certain neurological side effects (discussed below). More recently, atypical antipsychotic medications have been developed (clozapine and risperidone), which are effective antipsychotics yet are weak dopamine blockers and cause minimal neurological side effects. This group is discussed separately below. 

A dtbenzoxazepinc derivative in use is loxapine succinate, 2-chloro-11-(4-methyl-1-pipcrazinyl)dibmzlb. / l. 4]oxazepine succinate (Daxoliit). The structural relationship to the phenothiazine antipsychotics is apparent. It is an effective antip.sychotic and has side effects similar to those ic-ported for the phenothiazines. 

Amoxepine is a structurally interesting agent because of the introduction of an electron-withdrawing group. As already mentioned, the orientation of the tricyclic system does not seem crucial to antidepressant (or antipsychotic) activity. Loxapine (48), for exam-... 

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