Chlorpromazine development

The human literature consists primarily of case reports. A woman treated for 6 years with chlorpromazine developed multifocal tics and vocalizations following discontinuation of the chlorpromazine therapy. These symptoms suggest that chronic receptor site blockade can result in hypersensitivity of dopamine receptor sites. 

Three patients treated with various antipsychotics (fluphenazine, ha-loperidol, trifluoperazine, chlorpromazine) developed Stevens-Johnson syndrome within 8 to 14 days of starting to take carbamazepine. All 3 had erythema multiforme skin lesions and at least two mucous membranes were affected. After treatment, all 3 were restarted on all their previous drugs, except carbamazepine, without problems. Another case of Stevens-Johnson syndrome has been reported in a patient taking carbamazepine, lithium carbonate, haloperidol and trihexyphenidyl. The reasons are not understood. Stevens-Johnson syndrome with carbamazepine alone is rare, and the risk appears to be mostly confined to the first 8 weeks of treatment. It may be more common in patients being treated for conditions other than epilepsy. It is not possible to say whether the concurrent use of antipsychotics increases the risk of its development, but until more is known it would be prudent to monitor the outcome, particularly during the first 2 weeks of combined use. 

The role of fluonne in the development of CNS agents has been reviewed [14] Ruonnated phenothiazines, typified by fluphenazine (7[Pg.1121]

Chlorpromazine is technically described as a phenothiazine, as are thioridazine and fluphenazine. Together with their structural analogues the thioxanthenes (e.g., clopenthixol) and the butyrophenones (e.g., haloperidol), the phenothiazines comprise the three major families of typical neuroleptics. They were developed in the late 1950s and early 1960s (Table 11.3). All these drugs block dopamine receptors, principally the D2 subtypes, with an affinity that correlates highly (r = +0.90) with their clinical... 

The 1950s represented a golden age for pharmacotherapy. The first antipsychotic drug, chlorpromazine, was developed in the first few years of that decade (Chapter 11), the... 

Phenothiazines The phenothiazines (PTZs) undergo extensive metabolism. Metabolic routes include S-oxidation, aromatic hydroxylation, N-dealkylation, N-oxidation, and a combination of these processes. Chlorpromazine, for example, possesses 168 possible metabolites, a large proportion of which are pharmacologically active compounds. The development of an HPLC assay capable of resolving a large number of these metabolites is virtually impossible and assays that permit the simultaneous determination of the parent compound and a selected number of active metabolites must suffice. The PTZ group of compounds includes chlorpromazine, thioridazine, fluphenazine, and perphenazine. 

Chlorpromazine (Thorazine). The first of the modem antipsychotics was developed in the early 1950s, not as an antipsychotic but as an antihistamine that could be used during surgery to minimize the amount of anesthesia needed. It was hoped that this would lessen the danger of shock (dangerously low blood pressure) during surgery. It was actually quite successful, but it was soon found to have other benefits. Of key importance, it could relieve the positive symptoms of schizophrenia. In the years to follow, this led to the production of other similar antipsychotics collectively known as the typical antipsychotics. 

Chronic stimulant abuse alters the personality of the abuser. These and related changes are the result of neurotoxicity and are not characterized as either acute drug effects or withdrawal signs. Individuals have delusions of being pursued or persecuted and therefore become suspicious and paranoid. They become self-occupied and hostile toward others. Long-term abuse can produce toxic psychosis that closely resembles schizophrenia and must be treated with neuroleptic drugs (haloperidol, chlorpromazine). This psychosis can develop even within 1 to 2 weeks if the person is on a run of very high doses of stimulants. 

An aqueous solution of chlorpromazine (0.1 mg/mL) gives a pink color when added to 5 mL of 1% (NH4)2S20g solution. Upon addition of 1 mL of 10% NaOH and extraction with ether (3 x 5mL), the organic phase is colorless. After evaporation of the organic phase to dryness on a steam bath, a white residue is obtained. If this residue is dissolved in 3 mL of concentrated HCl, and 5 mL of H2O is added, a violet color is developed after 30 minutes[30]. 

Chlorpromazine hydrochloride in 25-mg tablets has been was determined according to the following scheme [69]. 10 tablets are dissolved in H2O, 5 mL of HNO3 is added, and the solution set aside imtil a yellow color develops. At that point, one adds 25 mL of O.IN AgN03, and lets the solution stand for 15 minutes. The solution is then diluted to 100 mL and filtered. To 50 mL of the filtrate is added 1 mL of 10% aqueous Cu(N03)2... 

HPTLC silica gel 60 plates (Merck) washed with 2 developments of hexane-acetone-diethylainine (80 20 3) and dried for 1 hour Hexane-acetone- diethylamine (80 20 3) Scanning at 254 nm Chlorpromazine could be determined over Ae concentration range of 5-200 ng/ml in the serum 185... 

Acute angle closure and difficulty with accommodation can occur from the anticholinergic effects of antipsychotic agents. In addition, pigment deposits may develop in the cornea and lens. Pigmentary retinopathy has been reported with thioridazine. Keratopathy and corneal edema may occur occasionally during pharmacotherapy with chlorpromazine and fluphenazine... 

Chlorpromazine has direct effects on the CTZ and may also depress temperature control and prevent shivering. The effects are due to inhibition of dopamine centrally. It may potentiate the effects of hypnotics, sedatives and anaesthetic agents. It is rarely used in anaesthetic practice today. Promethazine was first developed for its antihistamine effects but is more commonly used for its sedative/anticholinergic, anti-emetic actions, and prevention of motion-related sickness. The sedative actions are quite marked and last longer than the anti-emetic effects. 

Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs. Those who are made too uncomfortable or who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action. Orthostatic hypotension or impaired ejaculation—common complications of therapy with chlorpromazine or mesoridazine—should be managed by switching to drugs with less marked adrenoceptor-blocking actions. 

A stereotyped compulsive behavior is induced both in humans and in laboratory animals by amphetamines. This provided the basis for a method that has been used to measure the action of drugs on amphetamine-sensitive centers of the brain. A lesion in the nigrostriatal bundle on one side of a rat brain was made by injection of a neurotoxic compound such as 6-hydroxydopamine. This caused degeneration of dopamine-containing neurons on one side of the brain. When rats that had been injured in this way were given amphetamines, they developed a compulsive rotational behavior. Administration of chlorpromazine and several other antipsychotic drugs neutralized this behavior and in direct proportion to the efficacy in clinical use, an observation that also supports the theory that schizophrenia involves overactivity of dopamine neurons. 

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