Tranquilizers chlorpromazine

The strength of the NMR method is made evident, for example, in the study of the behavior of phenothiazine derivatives and their EDA complexes in solution [89]. First, the solution properties of, for example, the tranquilizer chlorpromazine hydrochloride and base in a variety of solvents were established leading to the unambiguous notion of self-association and micellization, with the HC1 form being the more stable. Second, the conformation of these compounds in self-adducts were discovered to be virtually unchanged as a function of temperature in the range 20 to 60°C. Iodine stabilized both molecular forms. Third, the complexation sites in these molecules were clearly established, as well as the stoichiometry of the complexes. The stability of these CTC can be followed with time. 

One of the earliest demonstrations by ESR of the peroxidase oxidation of drugs involved the tranquilizer, chlorpromazine [171]. The stoichiometry of the reaction forming the chlorpromazine radical cation (13) was established, and kinetics of the transient radical were shown to be identical to those of an optically detected intermediate absorbing at 530 nm. Measurements were made of the pH-dependent radical dismutation rate and the rate of reaction of compound II with chlorpromazine. At high enzyme concentrations and low dismutation rates, the radical cation undergoes further oxidation by the enzyme, to form the thionium ion. 

In the otherwise unmedicated animal, imipramine and its related compounds have even fewer behavioural effects than the monoamine oxidase inhibitors. Such changes as have been recorded, using conditioned avoidance and escape techniques, suggest that behaviourally the drugs resemble the tranquillizers . Chlorpromazine and amitriptyline have similar depressant effects on the electrical activity of the brain, reducing the frequency of the spontaneous rhythms. Amitriptyline has been used for treating patients in whom depression and anxiety occur together. 

N-substituted phenothiazines with basic side chains (e.g. the antihistamine promethazine, and the tranquillizer chlorpromazine) are accumulated in the eyes of all mammals. A concentration 50 times as great as in other tissues is often reached (Potts, 1962). 

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). ... 

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-... 

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. 

Thorazine was usually the therapy of choice at that time. Later, diazepam (Valium) and other benzodiazepines such as lorazepam (Ativan) became more widely used. These tranquilizers evoked fewer complaints such as I feel like LSD on the inside and Thorazine on the outside sometimes voiced by patients treated with chlorpromazine. 

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. 

Chlorpromazine was the first, and probably is still the most widely used, major tranquilizer. Although 95-98 of the drug in plasma is bound to protein, it is extensively and rapidly metabolized within the body into a large number of metabolites. Much of the metabolism may indeed take place in the gut before, or in the gut mucosa during absorption. 

The discoveries of chlorpromazine and imipramine are generally regarded as greater scientific advances than that of the tranquillizers. However, in making the public aware of the fact that mental disturbances can be treated with... 

Similar examples abound in most fields of therapeutics. For example, the major tranquilizer chlor-promazine—the first drug found to have true antipsychotic properties—is a trivial modification of phenothiazine, which was known for decades and used as a de-wormer for livestock. The parent phenothiazine, and many of its structural modifications, have no antipsychotic activity at all it is only certain minor structural modifications that have the essential pharmacologic and therapeutic properties. (Chlorpromazine also happens to be a classic example of the serendipitous empirical-clinical method of discovery of a drug s unique therapeutic value, a method described below.)... 

Chlorpromazine (Thorazine ) ushers in the widespread use of tranquilizers for victims of mental disease. 

Chlorpromazine is a tranquilizing and antiemetic agent that may cause a number of side effects in the circulatory and nervous system and adverse effects on blood cells, skin, and the eye. Recent studies suggest a possible genotoxic activity for chlorpromazine, whereas it has been established that certain reactive metabolic intermediates are capable of binding with macromolecules including DNA. 

In Poland, samples of muscle, kidneys, and liver from cattle, swine, horses, and poultry are taken four times per year by veterinary inspectors at slaughterhouses to be analyzed for drug residues. Between 1992 and 1996, 5733 samples of cattle, swine, horse, and chickens muscle were analyzed to determine residues of sulfonamides, nitrofurans, and nitroimidazoles 2613 samples of cattle and swine liver to determine -agonists and 1661 samples of cattle and swine kidney to determine violative levels of tranquilizers and -blockers. No residues of the mentioned groups of drugs above MRL were detected in the examined samples (42). However, nonviolative residues of sulfamethazine, sulfadimethoxine, sulfathiazole, furazolidone, nitrofurazone, nitrofurantoin, metronidazole, dimetridazole, azaperone, chlorpromazine, propiopromazine, carazolol, clenbuterol, and salbutamol could be detected in the corresponding target samples. 

The tricyclic antidepressants (Table 6—5) were so named because their organic chemical structure contains three rings (Fig. 6—25). The tricyclic antidepressants were synthesized about the same time as other three-ringed molecules that were shown to be effective tranquilizers for schizophrenia (i.e., the early antipsychotic neuroleptic drugs such as chlorpromazine) (Fig. 6—26). The tricyclic antidepressants were a disappointment when tested as antipsychotics. Even though they have a three-ringed structure, they were not effective in the treatment of schizophrenia and were almost... 

OFFICIAL NAMES Major tranquilizers (neuroleptics/antipsychotics) Chlorpromazine (Thorazine) chlorprothixene (Taractan) clozaril (Clozapine) fluphenazine (Permitil, Prolixin) haloperidol (Haldol) loxapine (Daxolin, Loxitane) mesoridazine (Serentil) molindone (Lidone,... 

Other psychiatrists noted early on how it produced a calming effect with a minimum of drowsiness and confusion (Hoch, Lesse, Malitz 1956), psychic indifference (Anton-Stephens 1954) and a pathological tranquillity of mind (Winkelman, Jr. 1957). Hans Lehmann, the first North American psychiatrist to use chlorpromazine described it as having the power to quiet severely excited patients without rendering them... 

Wittrig, J., Coopwood, W. E. (1970). Lithium versus chlorpromazine for manics Initiative and productivity versus tranquilization and hospitalization. Diseases of the Nervous System, 31, 486-489. 

---