Butyrophenone antipsychotic drugs

Fexofenadine is a primary oxidative metabolite oftcifciu-dine. Terfenadine was developed during a search for ik butyrophenone antipsychotic drugs as evidenced by thepr -ence of the fV-phcnylhutanol substituent. It also contsuma... 

SAR Terfenadine was discovered in the course of an extensive and intensive search for new butyrophenone antipsychotic drugs as could be seen by the presence of the N-phenylbutanol substituent. It is also studded with a diphenylmethyl piperidine group structural analogous as is normally observed in the piperazine antihistaminies. 

Butyrophenones A family of typical antipsychotic drugs (neuroleptics), the most commonly used being haloperidol. 

Largactil is a proprietary preparation of chlorpromazine, an aliphatic antipsychotic with marked sedation and moderate antimuscarinic and extrapyramidal side-effects. Serenace is a proprietary preparation of haloperidol, a butyrophenone antipsychotic with marked extrapyramidal side-effects, moderate sedation but not very likely to cause hypotension. Tegretol is a proprietary preparation of carbamazepine, an anti-epileptic drug indicated in partial and secondary generalised tonic-clonic seizures, primary generalised tonic-clonic seizures, trigeminal neuralgia and in the prophylaxis of bipolar disorder unresponsive to lithium. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

Alkylation of the basic amino group in (19-6) with butyrophenone (20-1), available from the acylation of fluorobenzene with 4-chlorobutyryl chloride, affords the antipsychotic drug droperidol (20-2) [21]. Alkylation of the fully reduced intermediate (19-7) with a side chain (20-3) yields pimozide (20-4) [22]. 

Antipsychotic drugs include the older phenothiazines and butyrophenones, as well as newer atypical drugs. All of these can cause CNS depression, seizures, and hypotension. Some can cause QT prolongation. The potent dopamine D2 blockers are... 

Phenothiazines and butyrophenones can counteract intoxication from lysergic acid diethylamide (LSD) benzodiazepines can inhibit this useful effect of antipsychotic drugs (151). 

All basic and advanced life-support measures should be implemented. Gastric decontamination should be performed. Butyrophenones are readily absorbed by activated charcoal. Aggressive supportive care should be instituted. Dystonic reactions respond well to intravenous benztropine or diphenhydramine. Oral therapy with diphenhydramine or benztropine should be continued for 2 days to prevent recurrence of the dystonic reaction. For patients suffering from neuroleptic malignant syndrome, a potentially fatal condition associated with the administration of antipsychotic drugs, dantrolene sodium, and bromocriptine have been used in conjunction with cooling and other supportive measures. Arrhythmias should be treated with lidocaine or phenytoin. Diazepam is the drug of choice for seizures phenytoin is used to prevent recurrence. Hemodialysis and hemoperfu-sion have not been shown to be effective. 

Antipsychotic drugs currently approved for clinical use in the United States are summarized in Table 10.1. Drugs classified as typical include the following several phenothiazine derivatives (1-9), the thioxanthene, thiothixene (10), the butyrophenone, haloperidol(ll),... 

The present view is that D-2, as a high-affinity species, represents the presynaptic autoreceptor in the CNS. The low-affinity D-2 receptor, then, is postsynaptic. D2 receptors are not coupled to c-AMP as a secondary messenger. Their mass is estimated as 136,700 daltons. The structural variety of D-2 antagonists varies considerably and includes many clinically important groups of antipsychotic drugs the phenothiazine tranquilizers and several of their bioisosteres (the butyrophenones), a dibenzodiazepine (clozapine), the indole derivative molindone, and a benzamide (sulpiride), all to be discussed later. The ergot alkaloids represent D-2 agonists. 

Adverse Neurological Effects Many neurological syndromes, particularly involving the extrapyramidal motor system, occur following the use of most antipsychotic drugs, especially with the high-potency D -receptor antagonists (tricyclic piperazines and butyrophenones). Acute adverse extrapyramidal effects are less likely with aripiprazole, clozapine, quetiapine, thioridazine, and ziprasidone, or low doses of olanzapine or risperidone. 

A. Classification The major chemical subgroups of antipsychotic drugs are the phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine) the thioxanthenes (eg, thiothixene) and the butyrophenones (eg, halopeiidol). 

Dopamine Receptors - All antipsychotic drugs (neuroleptics) are known to block DA receptors. The number of receptor subtypes claimed for DA, based on binding studies, include "D-1, D-2, D-3 and D-4". 5 However, only the postsynaptic D-2 receptors (labeled by 3[H]butyrophenones) are most consistently relatable to the effects of drugs. The D-1 subtype, a DA-stimulated adenylate cyclase site, has no clearcut function in brain. 46 Recent studies on agonist binding disclosed that 3[h]DA binds to two sites, both postsynaptic one is related to D-2 sites and the other to D-1 sites. 47... 

The antipsychotics are represented by chlorpromazine (and other pheno-thiazines), haloperidol (and other butyrophenones) and thioxanthenes, and the atypical, or newer, antipsychotic drugs, such as clozapine and risperidone. Their major use is in the treatment of psychoses such as schizophrenia and mania. These are listed in Table 20.1 , (below). Some of the antipsychotics are also used as antiemetics, and for motor tics and hiccups. 

Another form of parkinsonism is drug-induced, that is, iatrogenic parkinsonism, which often is a comphca-tion of antipsychotic therapy, especially following the use of the butyrophenone and phenothiazine drug classes (see Chapter 34). Unlike idiopathic parkinsonism, striatal content of dopamine is not reduced by administration of these drugs. In contrast, they produce a functional decrease in dopamine activity by blocking the action of dopamine on postsynaptic dopamine receptors. 

The introduction of the phenothiazine derivative, chlorpromazine, has started a dramatic improvement in the clinical treatment of schizophrenia. During the past four decades, beside phenothiazines, various antipsychotics having different chemical structures have been identified and introduced into clinical practice (e.g., butyrophenones and benzamides). These drugs ( typical antipsychotics ) decreased the duration of hospitalizations and, with maintenance treatment, reduced the risk of relapse and re-hospitalization. However, they had significant adverse side effects such as tardive dyskinesia, orthostatic hypotension, prolactin increase, and QT prolongation. 

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