Haloperidol Opiates

There is an increased central nervous system (CNS) depressant effect when the skeletal muscle relaxants are administered with other CNS depressants, such as alcohol, antihistamines, opiates, and sedatives. There is an additive anticholinergic effect when cyclobenzaprine is administered with other drugs with anticholinergic effects (eg, antihistamines, antidepressants, atropine, haloperidol). See Chapter 30 for information on diazepam. 

Tam, S.W., and Cook, L. Sigma opiates and certain antipsychotic drugs mutually inhibit (+)3H-SKF-10,047 and 3H-haloperidol binding in guinea-pig brain membranes. Proc Natl Acad Sci USA 81 5618-5621, 1984. 

The first agent of this class to be introduced in the clinic, haloperidol (18-8), interestingly shares the 4-phenylpiperidine structural fragment found in the central analgesic agent meperidine and its derivatives (see Chapter 7). The former compound may well have been discovered in the course of further SAR studies on the opiate [20]. An unusual synthesis of haloperidol starts with the product (18-1) from Friedel-Crafts acylation of 4-fluorobenzene with succinic anhydride. Successive protection of the... 

The majority of experimental evidence supports the conclusion that bombesin-like peptides stimulate the activity of TIDA neurons and thereby inhibit pituitary prolactin secretion. Indeed, bombesin administration does not suppress a-methyltyrosine- or haloperidol-induced prolactin secretion suggesting that pharmacological impairment of TIDA neuronal function prevents the prolactin inhibitory actions of bombesin (Collu et al., 1983 Buydens et al., 1988). Moreover, bombesin-like peptides block both opiate -and stress-induced prolactin secretion (Tache et al., 1979 Matsushita et al., 1983 Buydens et al., 1988), prolactin secretory responses known to be due, at least in part, to suppression of the activity of TIDA neurons (Moore and Lookingland, 1995). Central administration of bombesin increases DA synthesis and metabolism in whole hypothalamus (Widerlov... 

CYP2D6 Antidepressants amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, trimipramine, N-desmethyl-clomipramine, fluoxetine, norfluoxetine, paroxetine, venlafaxine, sertraline Neuroleptics chlorpromazine, thioridazine, perphenazine, haloperidol, reduced haloperidol, risperidone, clozapine, sertindole Others codeine, opiate, propranolol, dextromethorphan 4 no activity 25% in Caucasians 0%-10% in others 5 no activity 2%-10% in all groups 10 reduced activity 47%-70% in Asians <5% in others 17 reduced activity 25%-40% in blacks 0% in others 2XN increased activity 19%-29% in Arabs and Ethiopians <5% in others... 

FIGURE 6.19 The passage from pethidine-related opiate analgesics to the dopaminergic antagonist haloperidol. 

Dopamine antagonists (e.g., phenothiazines, haloperidol, methyidopa) Opiates Estrogens H2-antagonists (e.g., cimetidine) MAO inhibitors Dopamine agonists (e.g., levodopa, bromocriptine, pergolide, cabergoline) ... 

One can use a low spatial resolution detector system, because the naltrexone blocks all p opiate receptors in the brain regardless of their location, and they are widespread throughout the brain. Probe devices for use with positron-emitting tracers have been used frequently to study mice, rats, dogs, baboons, and humans. In living mice, it was possible to obtain a dose-response curve for haloperidol on the binding of [ C]M-methyl spiperone. Similar dose/response curves were obtained in humans, and the results correlated well with PET imaging studies of the same persons. 

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