Butyrophenone haloperidol

Clomethiazole has an elimination half-life of about 4 hours after a single bolus. When administered by intravenous infusion half-lives approaching 20 hours have been reported. The drug is a very powerful inhibitor of the cytochrome P-450 system. It occasionally causes haemolysis. BUTYROPHENONES Haloperidol... 

Butyrophenone Haloperidol Medium High Very high Low Very low... 

Butyrophenone Haloperidol Parenteral form also available generic Severe extrapyramidal syndrome... 

Butyrophenones Haloperidol, droperidol and domperidone act by blocking dopamine receptors. The butyrophenones are moderately effective antiemetics, but high-dose haloperidol was found to... 

In a clinical study, several patients with neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure were treated with phenothiazine, butyrophenone (haloperidol), benzamide, iminomide, benzisox-azole, antidepressants and hypnotics (benzodiazepine and barbiturate) for the treatment of schizophrenia [ 184], The clinical manifestations of neuroleptic malignant syndrome were characterized by altered consciousness, muscle rigidity and weakness, fever and excessive perspiration. All patients were successfully cured of acute renal failure by haemodialysis or haemodiafiltration. 

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),... 

Janssen, R A. J. The evolution of the butyrophenones, haloperidol and trifluperidol, from meperidine-like 4-phenylpiperidines. Int. Rev. Neurobiol. 1965, 8,221-263. 

Butyrophenones haloperidol high less autonomic effects, low sedation, severe extrapyramidal effects... 

Nonphenothiazines include butyrophenone haloperidol (Haldol) whose pharmacologies are similar to phenothiazines as it alters the effects of dopamine by blocking the dopamine receptor sites. 

The role of fluonne in the development of CNS agents has been reviewed [14] Ruonnated phenothiazines, typified by fluphenazine (7[Pg.1121]

In 1952 reserpine, an alkaloid extract from the Indian snakewort plant, Rauwolfia serpentina, which had been used in that country to treat madness , was first tried in schizophrenia. The beneficial impact on patients and the hospital wards was dramatic, as was that a year later of chlorpromazine, a phenothiazine derivative and haloperidol, a butyrophenone. These latter two drugs and closely related derivatives remained the mainstay of therapy for almost 40 years. 

Yet another (see lenperone) butyrophenone related to haloperidol is pipamperone (64). N-benzyl-4-piperidone (60) has a venerable history as starting material for both central analgesics and CNS drugs. This synthon has been used by the Janssen group as a building block for numerous such drugs. Reaction of... 

Chlorpromazine is technically described as a phenothiazine, as are thioridazine and fluphenazine. Together with their structural analogues the thioxanthenes (e.g., clopenthixol) and the butyrophenones (e.g., haloperidol), the phenothiazines comprise the three major families of typical neuroleptics. They were developed in the late 1950s and early 1960s (Table 11.3). All these drugs block dopamine receptors, principally the D2 subtypes, with an affinity that correlates highly (r = +0.90) with their clinical... 

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

The answer is b. (Katzung, p 4822) Haloperidol, a butyrophenone, is by far the most likely antipsychotic to produce extrapyramidal toxicides Other agents, such as piperazine (an aromatic phenothiazine), thiothixene (a thioxanthene), and pimozide (a diphenylbutyropiperidine) are comparitively less likely to produce extrapyramidal toxicity than haloperi-dol. The antagonism of dopamine in the nigrostriatal system might explain the Parkinson-like effects Both haloperidol and pimozide act mainly on D2 receptors, whereas thioridazine and piperazine act on ooadrenergie receptors, and have a less potent but definite effect on D2 receptors. 

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. 

In the 1960s, potent major tranquilizers such as haloperidol (Haldol) and fluphenazine (Prolixin) were new on the psychiatric scene. Many of these synthetic butyrophenones were sufficiently potent to warrant at least preliminary testing in our program. Fluphenazine and 302034 (haloperidol) both impaired NF performance... 

Two types of dopamine receptors have been characterized in the mammalian brain, termed and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

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. 

Haloperidol is a butyrophenone that is associated with a high incidence of extra pyramidal side-effects. It brings about a rapid control of agitation and restlessness and is preferred to chlorpromazine in the elderly because it causes less hypotension. 

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. 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

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