Therapeutically neuroleptics

PET studies show that at effective therapeutic plasma concentrations most neuroleptics occupy some 80% of brain Dj receptors (in the striatum at least) and this is therefore considered to be a requirement for efficacy (Pilowsky, Costa and Eli 1992 Farde 1996). If that is so then clozapine, which occupies only 20-40% of the Dj receptors at a therapeutic concentration, must have some other action which accounts for its therapeutic effectiveness. 

Among the D2 family of receptors (D2, D3 and D4) the D2 receptor itself seems to be the most important. At a therapeutic concentration, most neuroleptics, except clozapine (and risperidone), should, according to in vitro binding studies, be occupying 50-70% of brain D2 receptors. The picture is similar for D3 receptors but only clozapine (and... 

Seeman, P (1992) Dopamine receptor sequences therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 7 261-284. 

Dopamine receptor blocking agents. Many of the neuroleptics used in the treatment of schizophrenia frequently produce parkinsonian symptoms as unwanted effects. Neuroleptics block dopamine receptors and their therapeutic effect seems to be related to this action. Although these drugs act on DA systems without distinction, some are more selective. Thioridazine, clozapine and molindone, for example, have electrophysiological effects in the limbic region of the brain but little action in the nigro-striatal area. This selectivity may be related to receptor subtype specificity (see Chs 12 and 54). 

Neuroleptics at therapeutic doses elicit Parkinsonian effects. 

Many antipsychotics show great interindividual variation in plasma levels and so analysis of therapeutic levels can be important clinically as well as in the research laboratory. In addition, nonresponse to the drugs may actually be due to excessive levels of neuroleptics, a paradoxical situation that requires analysis to identify (Rockland, 1986). Several methods using FID were cited in the previous edition of the Handbook of Neurochemistry but ECD and NPD have both shown utility for the typically low therapeutic levels (Cooper, 1988). GC-FID has been used to analyze levels of clozapine in blood, gastric, and urine samples in fatal cases of overdose with this drug (Ferslew et al., 1998), and olanzapine has been measured in blood and urine samples by GC-NPD in overdoses (Stephens et al., 1998). 4-(4-Chlorophenyl)-4-hydroxypiperidine, a metabolite of haloperidol, was analyzed in urine, plasma, brain, and liver from haloperidol-treated rats by GC-ECD, after derivatization with PFBC under aqueous conditions (Fang et al., 1996). 

Gutteck U, Rentsch KM. 2003. Therapeutic drug monitoring of 13 antidepressant and five neuroleptic drugs in serum with liquid chromatography-electrospray ionization mass spectrometry. Clin Lab Med 41 1571. 

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. 

The D2 receptor types, besides being subdivided into D3 and D4 types, are further divided into the D2 long and D2 short forms. D2 antagonists, in addition to virtually all therapeutically active neuroleptics, also include such novel drugs as raclopride, eticlopride and sniperone while quinpirole is an example of a specific D2 receptor agonist. The latter drugs are not available for therapeutic use. A malfunction of the D2 receptors has been associated with psychosis, extrap)n amidal side effects and hyperprolactinaemia. 

Relationship between plasma neuroleptic concentrations and the therapeutic response... 

Unfortunately, few of the studies that have attempted to relate the blood concentrations of neuroleptics to therapeutic response have fulfilled all these criteria. There is a suggestion that a "thera peutic window" exists for some phenothiazine neuroleptics. A therapeutic window is a range of concentrations of a drug measured in the blood that are associated with a good therapeutic response. Plasma concentrations outside this range are either too low to ensure a therapeutic response or so high that they induce toxic side effects. Despite the numerous studies of the relationship between the plasma concentration and the therapeutic response for a number of "standard" neuroleptics, it would appear that such correlations rarely account for more than 25% of the variance in clinical response to treatment. The existence of a therapeutic window for neuroleptics would therefore appear to be unproven. However, there could be ranges of plasma concentrations associated with optimal antipsychotic action, but these... 

In SUMMARY, it would appear that a detailed knowledge of the pharmacokinetics of the main groups of psychotropic drugs is only of very limited clinical use. This is due to limitations in the methods for the detection of some drugs (e.g. the neuroleptics), the presence of active metabolites which make an important contribution to the therapeutic effect, particularly after chronic administration (e.g. many antidepressants, neuroleptics and anxiolytics), and the lack of a direct correlation between the plasma concentration of the drug and its therapeutic effect. Perhaps the only real advances will be made in this area with the development of brain imaging techniques whereby the concentrations of the active drug in the... 

In CONCLUSION, lithium is universally accepted as a mood-stabilizing drug and an effective antimanic agent whose value is limited by its poor therapeutic index (i.e. its therapeutic to toxicity ratio). Neuroleptics are effective in attenuating the symptoms of acute mania but they too have serious adverse side effects. High potency typical neuroleptics appear to increase the likelihood of tardive dyskinesia. Of the less well-established treatments, carbamazepine would appear to have a role, particularly in the more advanced stages of the illness when lithium is less effective. 

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. Hi-antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, clemastine, dimethindene, mebhydroline pheniramine) as antiemetics (meclizine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhydramine, p. 222). Promethazine represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most Hi-antihistamines are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. Hj-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 

Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include antipsychotic efficacy (symbolized by the arrow) the extent of sedation and the ability to induce ex-trapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and oonditlons of lloense. 

For more than 40 years, Li+ has been used to treat mania. While it is relatively inert in individuals without a mood disorder, lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment. Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lo-razepam) and antipsychotics (e.g. haloperidol) to stabilize the behavior of the patient. Over time, increased therapeutic responses to Li+ allow for a gradual reduction in the amount of anxiolytic or neuroleptic required, so that eventually Li+ is the sole agent used to maintain control of the mood disturbance. 

Tourette s syndrome. Administration of nicotine (either 2 mg nicotine gum or 7 mg transdermal nicotine patch) potentiated the therapeutic properties of neuroleptics in treating patients with Tourette s syndrome, and a single patch may be effective for a variable number of days. These findings suggest that transdermal nicotine could serve as an effective adjunct to neuroleptic therapy . 

Neuroleptic drugs are used in the treatment of psychosis, such as schizophrenia they are generally antagonist ligands of dopamine at the central nervous system level. " Indications and therapeutic effects of the various families of neuroleptics result from two factors. The first one is the specifity of the ligand toward the different types of dopaminergic receptors, which are unequally distributed in the... 

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