Chlorpromazine antipsychotic effect

Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphena-zine) have greater antipsychotic potency than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflu-promazine). However, their antipsychotic effects are qualitatively indistinguishable. 

Although normally administered in comparatively large doses the concentration of unaltered chlorpromazine in plasma is usually too low to be measured except by sensitive GLC methods (C6, C15). Using such a technique, Curry et al. (C18) have shown that the optimum antipsychotic effect appears to occur at plasma levels which are lower than those causing side effects in chronically treated patients but higher than those causing these effects in acutely treated patients. ... 

It became known in the same year (1954) that the substance reserpine, derived from the Indian plant Rauxcolfia serpentina, had antipsychotic effects similar to those of chlorpromazine This finding was of interest for two reasons the molecular structure of reserpine has some similarity to that of serotonin and LSD and it was found that reserpine liberates serotonin from presynaptic stores in the CNS and thus produces a short-lived excess supply of functionally available serotonin at the synapse. In the context of a serotonin hypothesis of schizophrenia, it could be postulated that the antipsychotic effect of reserpine was due to its ability to liberate serotonin presynaptically and make it functionally available. However, despite its scientific appeal, the serotonin hypothesis of schizophrenia did not last long because it was in conflict with both psychopathological and pharmacological findings ... 

Several open studies have also found antipsychotics useful in BPD (214, 243, 244). For example, Leone (244) found that both loxapine and chlorpromazine were effective and equal in most respects. 

The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations rather than from scientific knowledge of the neurobiological basis of psychosis or the mechanism of action of effective antipsychotic agents. Thus, the fist antipsychotic drugs were discovered by accident in the 1950s when a putative antihistamine (chlorpromazine) was serendipitously observed to have antipsychotic effects when tested in schizophrenic patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action. 

The synthesis and discovery of the antipsychotic effects of the piperazinyl-dibenzoazepine, clozapine (Fig. 13.1) and its launch in 1972 was an important turning point in the drug treatment of schizophrenia [1-3]. Clozapine was called an atypical antipsychotic as it did not produce side effects characteristic for compounds of the chlorpromazine- or haloperidol-type (i.e., extrapyramidal symptoms) either in animal models or in the clinic. Its use, however, became very limited when it was recognized that clozapine might cause a severe, and sometimes fatal, form of agranulocytosis. 

VASODILATOR ANTIHYPERTENSIVES ANTIPSYCHOTICS Risk of hyperglycaemia when diazoxide is co-administered with chlorpromazine Additive effect both drugs have a hyperglycaemic effect Monitor blood glucose closely, particularly with diabetes... 

At this time, there was no knowledge of the molecular basis of chlor-promazine s effect or the molecular target. Knowledge of the molecular basis came 20 years later in 1972 when Paul Greengard s laboratory established the cormection with the dopamine receptor Dj. This led the whole industry to look for a new antipsychotic better than chlorpromazine and to new agents tested directly in multiple clinical trials. Further research 20 years later showed that much of the antipsychotic effect was through another variant of the dopamine receptor, the D2 receptor, not the originally... 

Chlorpromazine (Thorazine) and thioridazine (Mellaril), both phenothiazine derivatives, are used for their antipsychotic effects in the control of severely disturbed or agitated behavior and in schizophrenia. Thioridazine has a higher incidence of antimuscarinic effects but a lower incidence of extrapyramidal symptoms. Pigmentary changes of the retina have been reported occasionally in association with chlorpromazine therapy, although it is recognized that only thioridazine produces retinal toxicity. 

Since the potency (therapeutic efficacy in relation to weight) of antipsychotic agents varies markedly between compounds, it is useful to think of the effective antipsychotic dose of classical agents in terms of chlorpromazine equivalents (see Table 19.5). For example, haloperidol has a relatively high anh-psychotic potency, such that 2-3 mg is equivalent to chlorpromazine 100 mg, whereas sulpiride 200 mg (low potency) is required for the same antipsychotic effect. 

Key CPZ equiv dose = Chlorpromazine equivalent dose.This concept is of value in comparing the potency of classical antipsychotics. Dose ranges are not specified as they are extremely wide and drugs are normally titrated up from low starting doses (e.g. chlorpromazine 25 mg or equivalent) until an adequate antipsychotic effect is achieved or the maximum dose reached.The chlorpromazine equivalent dose concept is of less value for atypical antipsychotics since minimum effective doses (Min. eff. dose) and narrower therapeutic ranges have been defined. Maximum dose (Max. dose) can be exceeded only under specialist supervision. 

Treatment stop medication, give phentolamine (alpha-blockage) or chlorpromazine (antipsychotic with hypotensive effects)... 

Chlorprothixene (25 to 50 mg p.o. t.i.d.) is indicated in the management of manifestations of psychotic disorders. Chlorprothixene is absorbed rapidly, distributed throughout the body, is bound to plasma protein to the extent of 90 to 95%, and is excreted mostly unchanged via the biliary tract in feces. It exerts its antipsychotic effects in part by blocking dopamine receptors in the mesolimbic and mesocortical systems and like chlorpromazine, it produces movement disorders such as parkinsonism (see also Table 2). 

The appetite suppressant and other effects of amfetamines, chlo-rphentermine and phenmetrazine are opposed by chlorpro-mazine. It seems possible that other phenothiazine will interact similarly. The antipsychotic effects of chlorpromazine can be opposed by dexamfetamine. 

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. 

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