Phenothiazines tranquilizing drugs

C.d., U.V., and n.m.r. spectroscopy have been used to investigate the inclusion of iV-substituted phenothiazines (tranquillizing drugs) by cyclohepta-amylose in aqueous solution. Formation constants were calculated for the 1 1 complexes obtained. The spectral changes produced on complexation... 

Tranquillizing drugs based on the phenothiazine nucleus potentiate the action of narcotic analgesics [157] although there are some reports to the contrary [158] and certain derivatives, notably methotrimeprazine (levomepromazine, Levo-prome, Veractil) (—)-(LV), are claimed to have intrinsic analgesic activity. In mice, (-)-(LV) is more potent than morphine in a variety of tests [159, 160] for example hot-plate EDso value of 1.02 mg/kg, that of morphine 2.1 mg/kg. 

Phenothiazines are tranquilizing drugs in wWch the basic structure consists of two benzene rings fused to a central six-membered ring containing a sulfur and a nitrogen. They are sometimes administered as the hydrochloride salt by quaternarization of the side chain nitrogen. 

Bromocriptine is also available as an oral formulation, but oral administration to horses has not been reported. This drug should not be used in pregnant or lactating animals because of its effects on prolactin and lactation. Concomitant administration of bromocriptine and the phenothiazine tranquilizers or reserpine is contraindicated. 

The following is a partial list of those drugs that can cause various pigmentary changes anticonvulsants, antimalarials, cytostatics, hormones, metals, tetracyclines, phenothiazine tranquilizers, psoralens, amiodarone, etc. 

Murray, M. (1989) Inhibition of hepatic drug metabolism by phenothiazine tranquilizers quantitative structure-activity relationships and selective inhibition of cytochrome P-450 isoform-specific activities. Chcm. Res. Toxicol., 2, 240-246. 

The phenothiazine tranquilizers presumably act by interaction with cellular receptor sites in the central nervous system, although the mechanisms involved and the nature of the drug receptors are unknown. However, for the... 

The present view is that D-2, as a high-affinity species, represents the presynaptic autoreceptor in the CNS. The low-affinity D-2 receptor, then, is postsynaptic. D2 receptors are not coupled to c-AMP as a secondary messenger. Their mass is estimated as 136,700 daltons. The structural variety of D-2 antagonists varies considerably and includes many clinically important groups of antipsychotic drugs the phenothiazine tranquilizers and several of their bioisosteres (the butyrophenones), a dibenzodiazepine (clozapine), the indole derivative molindone, and a benzamide (sulpiride), all to be discussed later. The ergot alkaloids represent D-2 agonists. 

Epinephrine reversal is occasionally seen as an unexpected (but predictable) effect of drugs for which alpha blockade is an adverse effect (eg, some phenothiazine tranquilizers, antihistamines). 

Reserpine is an important hypotensive drug that was used clinically and that also possesses sedative activity. Reserpine is a major tranquilizer because it exhausts the noradrenaline (NAdr = norepinephrine, NE) of the adrenergic nerve and suppresses the function of the sympathetic nerves. In particular, the incorporation of dopamine, the precursor of NE, is inhibited. On the other hand, stored NE is emitted by the excitement of the sympathetic nerve, and is destroyed by monoamine oxidase (MAO). Thus the amount of NE is gradually reduced, and, as the NE in the nerve ending is depleted, the sedative and hypotensive activities occur. Reserpine is rarely used clinically in the field of psychiatry now because of the availability of the phenothiazine-type drugs. 

General consideration oxymorphone should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other CNS depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. 

Phenothiazine tranquilizers, when quaternized with phenacyl brcxaide oxime, are reported to give products almost as potent as the parent drug but which produce less catatonia and other activity associated with extrapyramidal side effects in man Quaternization of chlorpromazine with methyl chloride, on the other hand, produces a compound with markedly more toxic and less sedative effects in rodents ... 

Work on the phenothiazine tranquilizers was begun in our laboratory late in 1956 and was carried on over a period of almost two years. At that time no official methods existed for any of these important drugs and even to the present time I think there are only two that have attained official status. 

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... 

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.)... 

---