ANTIPSYCHOSIS DRUGS side effects
In the mid-1950s, a large series of pharmacologic agents, originally referred to as tranquilizers (later, as psychotropic or neuroleptic drugs), came into prominent use, mainly for the control of schizophrenia, psychotic states associated with "organic brain syndromes," and affective disorders (depression and bipolar disease). The mechanisms by which these drugs ameliorate disturbances of thought and affect in psychotic states are not fully understood, but presumably they act by blocking the postsynaptic mesolimbic dopamine receptors.ceptor subtypes). The D2 receptors are located mainly in the frontal cortex, hippocampus, and limbic cortex, and the D1 receptors are in the striatum, as discussed in Chap. 4. The blockade of dopamine receptors in the striatum is probably responsible for the parkinsonian side effects of this entire class of drugs, and the blockade of another dopaminergic (tuberoinfundibular) system, for the increased prolactin secretion by the pituitary. These drugs also produce some adrenergic blocking effect. The newer "atypical" antipsychotic drugs, exemplified by clozapine, apparently achieve the same degree of D2 and D3 blockade in the temporal and limbic lobes while exhibiting substantially less antagonistic activity in the striatum—accounting also for their lesser parkinsonian side effects. These drugs also block subsets of serotonin receptors.
Since the introduction in the 1950s of the phenothiazine chlorpromazine as an anesthetic agent and the serendipitous discovery of its antipsychoticeffect on schizophrenia, a large number of antipsychotic drugs have been marketed for clinical use. No attempt is made here to describe or even list all of them. Some have had only an evanescent popularity and others have yet to prove their value. Chemically, these compounds form a heterogeneous group. Eight classes of them are of particular clinical importance: (1) the phenothiazines; (2) the thioxanthenes; (3) the butyrophenones; (4) the rauwolfias alkaloids; (5) an indole derivative, loxapine, and a unique dihydroindolone, molindone; (6) a diphenylbutylpiperidine, pimozide; (7) dibenzodiazepines, typified by clozapine and olanzapine; and (8) a benzisoxazole derivative, risperidone. Molindone and loxapine are about as effective as the phenothiazines in the management of schizophrenia and their side effects are similar, although claims have been made that they are less likely to induce tardive dyskinesias and seizures. Their main use is in patients who are not responsive to the older drugs or who suffer intolerable side effects from them.
The antipsychotic agents in the class of clozapine (which is less used than other agents in the class because of cases of aplastic anemia) have attracted great interest, because—as already mentioned—they are associated with relatively fewer extrapyramidal side effects. For this reason, they are particularly favored in controlling the confusion and psychosis of parkinsonian patients. The other new class of drugs, of which risperidone is the main example, also has fewer extrapyramidal side effects than the phenothiazines and a more rapid onset of action than the traditional antipsychotic medications. All of these newer medications produce the "metabolic syndrome" of weight gain, adverse lipid changes, and glucose intolerance. Pimozidemay be useful in the treatment of haloperidol-refractory cases of Gilles de la Tourette syndrome (Chap. 6); its main danger is its tendency to produce cardiac arrhythmias.
Phenothiazines
This group comprises chlorpromazine (Thorazine), promazine (Sparine), triflupromazine (Vesprin), prochlorperazine (Compazine), perphenazine (Trilafon),fluphenazine (Permitil, Prolixin), thioridazine (Mellaril), mesoridazine (Serentil), and trifluoperazine (Stelazine). In addition to their psychotherapeutic effects, these drugs have a number of other actions, so that certain members of this group are used as antiemetics (prochlorperazine)
