Medicines Neuroleptics

Schizophrenia is perhaps the most debiUtating psychiatric illness in modem medicine, affecting about 1% of the general population. Many of those affected require institutionalization (180). Unfortunately, the compounds available to treat this disorder are not hiUy effective in treating the spectmm of symptoms in all patients. Adverse effects are also a problem (181). In addition, available antipsychotic (neuroleptic) dmgs (Table 5) can at most only provide symptomatic rehef. 

Many DA receptor antagonists (neuroleptics) for treating psychoses (for example, schizophrenia) have become efficient medicines. However, most of them induce severe extrapyramidal side-effects (EPS) akin to parkinsonian symptoms and also, more seriously, they induce tardive dyskinesias (TD). There is a need for improvements in the neuroleptics in the clinic. The substituted benzamides are D2 antagonists, some of which display a high degree of limbic selectivity. Such a regional selectivity has been suggested to be beneficial from the side-effects point of view [11,12]. 

Antipsychotics for the symptomatic treatment of schizophrenia and states of agitation occurring in other psychiatric syndromes these medicines are also occasionally called neuroleptics or major tranquillizers. 

In Chapter 1 of this book, psychopharmaceuticals were introduced as effective medicines that primarily have a symptomatic action but are problematic in several respects. Antipsvchotics can cause serious side effects and antidepressants often exert their therapeutic effects only after a delay of weeks and in many cases have unpleasant side effects. With anxiolytics, hypnotics and, in particular, psychostimulants, there are problems with habituation and the potential of dependency. It is therefore not surprising that psychopharmaceuticals do not enjoy a very high reputation among many doctors and the general public (see Box 8.1) and have been given names such as chemical strait-jackets for the older neuroleptics (Szasz, 1957) or chemical blinkers for the mind for tranquillizers. Elomaa (1993) even posed the question of whether the long-tom use of conventional antipsychotics should be considered a crime against humanity. 

The use of neuroleptics in veterinary medicine to control wild and domestic animals provides another illustration of the deactivation effect and its independence from any presumed mental illness in the individual being treated (Booth, 1977 Hall, 1971 Rossoff, 1974). Hartlage (1965) found that Thorazine dampened the emotional responses of animals, thereby perhaps providing some clue to the widespread acceptance of the drug as effective in psychiatric settings (see also Mirsky, 1970 Slik-ker et al., 1976). Jarvik (1970) pointed out that the neuroleptics produce diminished spontaneous activity and emotional indifference in all animal species, including man, but he nonetheless argued for a specific antipsychotic effect. 

Although estimates vary widely for the rates of neuroleptic-induced akathisia, even the lower estimates pose an astronomical risk to patients. Psychiatry and medicine have paid far too little attention to the suffering inflicted on patients by neuroleptic-induced, and also antidepressant-induced, akathisia. 

In regard to neuroleptics, we found that pioneers in their use were most straightforward about its brain-disabling effects. We find the same phenomenon with lithium. Cade (1949) indicated that lithium, when used for other medicinal purposes, produced actual mental depression in a variety of patients, not just those suffering from mania or manic depression. The drug enforced a so-called quieting effect on persons he considered schizophrenic (dementia praecox, in his nosology) ... 

Guze, B., Baxter, L., Jr. (1985). Neuroleptic malignant syndrome. New England Journal of Medicine, 313, 163-164. 

Stroke is a matter of increasing concern with some antipsychotic drugs, and the Canadian Medicine Agency has issued a warning that there is a risk of stroke with risperidone (116). On April 2005, the FDA issued an alert and asked the company to add the following information to both the oral and depot formulations The FDA has found that older patients treated with atypical neuroleptic drugs for dementia had a higher chance for death than patients who did not take the medicine. This is not an approved use (117). In some countries, the use of... 

A 38-year-old Chinese man responded to risperidone monotherapy for 2 weeks after 19 years of resistance to typical neuroleptic drugs. Three days later he lost his medicine and 2 days later his auditory hallucinations and persecutory delusions recurred. Meanwhile, vivid manic symptoms (such as heightened mood, irritability, reduced need for sleep, hyperactivity, pressured speech, flight of ideas, and grandiosity) emerged for the first time throughout the history of his illness. 

The Committee on Safety of Medicines and the erstwhile Medicines Control Agency in the UK received 999 reports of hemopoietic disorders related to neuroleptic drugs between 1963 and 1996 there were 65 deaths (22). There were 182 reports of agranulocytosis chlorpromazine and thioridazine were associated with the highest number of deaths—27 of 56 and nine of 24 respectively. 

Clozapine (E, cf. p 475) is medicinally used as a neuroleptic. For its synthesis the following sequence of reactions starting from 4-chloro-2-nitroaniline (X) is performed ... 

Dr. Bengt Langstrom of the University of Uppsala developed a method to label methyl spiperone, a neuroleptic drug, with C-11, and taught Hopkins chemists, led by Bob Dannals,how to carry out the synthesis during his visit to the Nuclear Medicine Division at Johns Hopkins. The manufacturer of the cyclotron, Scandatronix, sponsored Bengfs visit to Johns Hopkins. 

The great majority of alkaloids, local anaesthetics, barbiturates, and neuroleptics have values between 6 and 8, so that both ionic and neutral species are present, in equilibrium, at physiological pH values. These substances will be considered in Sections 10.4 and 10.5. Among the alkaloids, atropine (piQ 10) (7.16) and tubocurarine (2.6) are atypical in having a higher degree of ionization. Tubocurarine is a quaternary amine and hence completely ionized at all pH values. Other quaternary amines used in medicine are ... 

Chlorpromazine is used as a neuroleptic agent in psychiatry, but was developed from the antihistamine agent promethazine. This might appear an unexpected thing to do, but it is known that promethazine has sedative side effects and so medicinal chemists modified the structure to enhance the sedative effects at the expense of antihistamine activity (Figure 9.10). 

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