Neuroleptics pharmacologic effects

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. 

Although the serotonin hypothesis of schizophrenia was formulated at approximately the same time as the discovery of the first neuroleptics, it had no direct connection with the pharmacological propraties of these drugs. The situation is different in the case of the dopamine hypothesis because all known neuroleptics have some inhibitory action on dopaminergic neurons, even though they vary considerably with regard to other pharmacological effects. 

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (ctj and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors. 

Five years later, the American Psychiatric Association (APA, 1975) published The Current Status of Lithium Therapy Report of the APA Task Force. Without citing evidence, the authors stated, The task force has concluded that lithium is a more specific anti-manic agent than neuroleptics and that its therapeutic results are achieved in a unique pharmacologic effect rather than nonspecific calming action. ... 

Naloxone is being used to reverse the potentially lethal respiratory depression caused by neurolept analgesia or opioid overdose. Among other pharmacological effects, naloxone antagonizes the blood pressure drop in various forms of shock [29-32], reverses neonatal hypoxic apnoea [26], counteracts chronic idiopathic constipation [34], reduces the food intake in humans [35, 36] and shows beneficial effects in CNS injuries [37]. 

The stability of oils is very important in pharmaceuticals since nonpolar drugs (for example, contraceptive steroids and neuroleptic tranquillisers) are often formulated in oily injection vehicles for intramuscular or depot injection. Injections of this type can be given, for example, once a month, and the drug exerts its pharmacological effect as it leaches out of the injection site into the bloodstream. Oils used as injection vehicles include arachis oil, from the peanut plant, olive oil, castor oil and ethyl oleate, the ethyl ester of the 18-carbon fatty acid oleic acid (Figure 8.16). 

Meanwhile, antagonism of dopamine D2-type receptors in the chemoreceptor trigger zone in the brainstem is responsible for beneficial antiemetic effects produced by neuroleptics. Several phenothiazines (e.g., promethazine and prochlorperazine) are marketed to exploit this pharmacological effect. 

Other drugs such as the neuroleptic, haloperidol, inhibit the induction of hsp70 mRNA in rodent neurons (Sharp et al.. 1992). Although this observation needs to be confirmed in the human population, it raises the possibility that an age-dependent defect in the production of HS proteins is exacerbated by a drug which is commonly used in demented elderly patients. The potential for certain pharmacologic agents to inhibit the HS response could increase the risk for untoward effects of atherosclerosis and hypoxia. A similar concern may be raised with certain calcium channel blockers which also have been found to reduce the synthesis of HS proteins in cardiac myocytes (Low-Friedrich and Schoeppe, 1991). 

Within the area of biological treatments it is especially important to analyze the non-pharmacological factors of psychopharmacology, which include the fact that prescription patterns vary from one ethnic group to another colored patients in the United States receive greater doses of neuroleptic drugs and injectable or depot forms are more frequent than oral medication (Alarcon, 2005) how side effects are perceived and reported are strongly affected by the patient s (culturally... 

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. 

Among the difficulties in pharmacological treatment is the frequent non-compliance. The biggest determinant of compliance is the quality of a patient s relationship with his doctor. But a further way to handle the issue has involved the development of long acting products (depot neuroleptics), even though their effectiveness in the absolute or compared to oral preparations has not been adequately explored. The most commonly used depot agents are fluphenazine and haloperidol decanoate (see David et al., 2004). 

Richelson, E. (1999) Receptor pharmacology of neuroleptics relation to clinical effects. / Clin Psychiatry 60(Suppl 10) 5-14. 

The pharmacology of all these neuroleptics is extremely complex. Briefly, phenoth-iazines and related drugs have a calming effect on psychotic patients, without producing excessive sedation. Other central effects include the important antiemetic effect in disease-, drug-, or radiation-induced nausea, but not so much in motion sickness. Butyrophenones are more effective antiemetics than phenothiazines and also potentiate the activity of anesthetics. 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

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