Tranquillizers, major

Neuroleptic analgesia is so called because the combination of a major tranquilizer, a neuroleptic dmg, and a potent opiate produces an anesthetic state characterized by sedation, apathy, and mental detachment (see Psychopharmacological agents) (152). Iimovar [8067-59-2] a combination of droperidol [648-72-2], C22H22FN2O2, (19) and fentanyl (9) citrate, is used for procedures that do not require muscle relaxation. However, the onset of action is slow. 

Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the... 

The initial series of major tranquilizers consists of alkylated derivatives of 4-aryl-4-hydroxypiperidines. Construction of this ring system is accomplished by a set of rather unusual reactions. Condensation of methylstyrenes with formaldehyde and ammonium chloride afford the corresponding hexahydro-1,3-oxazines (119). Heating these oxazines in the presence of acid leads to rearrangement with loss of water to the tetrahydropyridines. Scheme 1 shows a possible reaction pathway for these transformations. Addition of hydrogen bromide affords the expected 4-bromo compound (121). This last is easily displaced by water to lead to the desired alcohol (122) The side chain (123) is obtained by Friedel-Crafts acylation of p-fluorobenzene with 4-chloro-butyryl chloride. Alkylation of the appropriate arylpiperidinol with 123 affords the desired butyrophenone derivative. Thus,... 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

An intermediate used in the preparation of the antihistamine, propiomazine, serves as starting material for a 2-substi-tuted major tranquilizer as well. Thus, reaction of the phosgene... 

Incorporation of a second nitrogen atom in the side chain, particularly when that atom is part of a piperazine ring, was found to give a series of major tranquilizers similar in biologic activity to chlorpromazine, but of much increased potency. Alky-... 

That this is not a general observation is indicated by the fact that piperactizine (95), in which carbon again replaced nitrogen, obtained by alkylation of amino alcohol, 94, with the halide (73) is used mainly as a major tranquilizer. 

Major tranquilizer. A drug useful in the control of schizophrenia. Also referred to as neuroleptic or antipsychotic. 

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term neuroleptic is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound s ability to produce EPSs than to treat schizophrenia. Antipsychotic is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an antischizophrenic just as we use the terms antidepressant or antiepileptic irrespective of how the drug works. Despite such personal reservations, the term neuroleptic will be used in this text. 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

Nor were there effective antidotes to the cognitive effects of major tranquilizers such as Prolixin, or sedatives such as Seconal. I m not sure why the IG did not apply their criticism about the lack of an LSD antidote to our much more extensive work with belladonnoids. Until THA and physostigmine came along, I always knew, after giving BZ that I would have to let it run its course. Fortunately, there were no major crises. 

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... 

I particularly recalled my clinical work in 1958 and early 1959, when my assignment was to care for hospitalized soldiers and their dependents. We had few drugs to work with in those days. We relied mainly on Thorazine in the treatment of psychotic patients. It was the first major tranquilizer and preceded by decades the wonder drugs used today. For less severely disturbed patients we used meprobamate (Equanil) which has all but disappeared from today s pharmacies. In fact, the value of lithium, for mood swings, was just beginning to be accepted. 

As a group, these medications have been known by several names. They have been called major tranquilizers. This is not altogether inaccurate these medications do calm or tranquilize. Physicians still use this name sometimes, especially when they re reluctant to use the word psychotic in a discussion with a new patient or his/her family. These medications have also been called neuroleptic, literally meaning seize the nerve cell, in the original Greek. This term is derived from the potential for the medications to cause extrapyramidal side effects. Finally, and most accurately we contend, these medications are called antipsychotics. 

Typical Antipsychotics. The high potency antipsychotic haloperidol (Haldol) and low potency antipsychotics chlorpromazine (Thorazine) and thioridazine (Mellaril) have also been used to treat ADHD. Although they provide a tranquilizing effect (they are in fact sometimes called major tranquilizers ) that can reduce hyperactivity and impulsivity, antipsychotics remain markedly less effective than stimulants. Antipsychotics do not noticeably improve attention in patients with ADHD, and at this time the typical antipsychotics cannot be considered a reasonable monotherapy in uncomplicated ADHD. 

Antipsychotics. Antipsychotic medications are also called major tranquilizers. It is for the tranquilizing effect that they have been used to treat agitation. The earliest antipsychotics, especially thioridazine (Mellaril), proved to be effective in reducing agitation however, this comes at the price of further impairing cognition due to its profound anticholinergic effects. 

Other plants known to contain psychoactive compounds include hellebore, which was used for centuries in Europe to treat mania, violent temper, mental retardation and epilepsy. However, a drug of major importance in modern psychopharmacology arose from the discovery by medicinal chemists of the alkaloids of Rauwolfia serpentina, a root which had been used in the Indian subcontinent for centuries, not only for the treatment of snake bite but also for alleviating "insanity". Understandably, the mechanism of action of reserpine, the alkaloid purified from Rauwolfia serpentina, helped to lay the basis to psychopharmacology by demonstrating how the depletion of central and peripheral stores of biogenic amines was correlated with a reduction in blood pressure and tranquillization. 

The unusual combination of release and antagonism of noradrenaline has been noted above, while another property separating oxypertine from other major tranquillizers is that it does not potentiate the analgesia produced by morphine or pethidine [161]. The compound is anti-emetic and weakly antihistaminic [160-2]. 

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