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a central place in the treatment of panic attacks and other anxiety states, as an adjunct in some depressive illnesses, and in the behavioral disturbances in Alzheimer disease It seems, however, to create more dependence than some of the others in its class Other important benzodiazepine drugs are urazepam (Dalmane), triazolam (Halcion), chlorazepate (Tranxene), temazepam (Restoril), and other newer varieties, all widely used in the treatment of insomnia (page 340), and clonazepam (Klonipin), which is useful in the treatment of myoclonic seizures (page 274) and intention myoclonus (page 89) Midazolam (Versed), a short-acting parenteral agent, is given frequently to achieve the brief sedation required for procedures such as MRI or endoscopy and is useful in the treatment of status epilepticus, however, it is known to cause respiratory arrest on occasion Lorazepam (Ativan) and oxazepam (Serax) are said to be preferable to other benzodiazepines in treating the elderly and those with impaired liver function Many other benzodiazepine compounds have appeared in recent years, but a clear advantage over the original ones remains to be demonstrated (Hollister; Pirodsky and Cohn) The popularly used sleeping medication, Zolpidem (Ambien) differs from the benzodiazepines structurally but is pharmacologically similar The benzodiazepine drugs, like barbiturates, have a depressant action on the CNS by binding to speci c receptors on GABA inhibitory systems The benzodiazepines act in concert with GABA to open chloride ion channels and hyperpolarize postsynaptic neurons and reduce their ring rate The primary sites of their action are the cerebral cortex and limbic system, which accounts for their anticonvulsive and anxiolytic effects While quite safe in the recommended dosages, they are far from ideal They frequently cause unsteadiness of gait and drowsiness and at times syncope, confusion, and impairment of memory, especially in the elderly If taken in large doses, the benzodiazepines can depress the state of consciousness, resembling that of other sedative-hypnotic drugs but with less respiratory suppression and hypotension Flumazenil, a speci c pharmacologic antagonist of the CNS effects of benzodiazepines, rapidly but brie y reverses most of the symptoms and signs of benzodiazepine overdose It acts by binding to CNS diazepine receptors and thereby blocking the activation of inhibitory GABA-nergic synapses Flumazenil may also have diagnostic utility in cases of coma of unknown etiology and in hepatic encephalopathy (see page 968) Signs of physical dependence and true addiction, though relatively rare, undoubtedly occur in chronic benzodiazepine users, even in those taking therapeutic doses The withdrawal symptoms are much the same as those that follow the chronic use of other sedative drugs (anxiety, jitteriness, insomnia, seizures) but may not appear until the third day after the cessation of the drug and may not reach their peak of severity until the fth day (Hollister) In chronic benzodiazepine users, the gradual tapering of dosage over a period of 1 to 2 weeks minimizes the withdrawal effects However, we have observed numerous cases over the years in which the cessation of moderate doses of chronically used diazepines has resulted in one or more seizures This is likely to happen when the patient is hospitalized for other reasons and the accustomed sleeping medication is omitted.

These drugs are capable of modest depressant action and are effective in relieving mild degrees of nervousness, anxiety, and mus-

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cle tension Meprobamate (Equanil, Miltown) is the best-known member of this group It was the rst of the new (postbarbiturate) antianxiety drugs, a chemical variant of the weak and ineffective muscle relaxant mephenesin With average doses (400 mg three or four times a day), the patient is able to function quite effectively; larger doses cause ataxia, drowsiness, stupor, coma, and vasomotor collapse Meprobamate has turned out to have the same disadvantages as the barbiturates, including death from overdosage Addiction to meprobamate may occur, and if four or more times the daily recommended dose is taken over a period of weeks to months, withdrawal symptoms (including convulsions) may appear Because of this tendency to produce physical dependence and other disadvantages (serious toxic reactions and a high degree of sedation), meprobamate and its congeners are now seldom used except illicitly Buspirone A new class of antianxiety agents, exempli ed by the selective 5-HT2 serotoninergic agent buspirone (BuSpar), is chemically and pharmacologically different from the benzodiazepines, barbiturates, or other sedatives Its distinctive nature is con rmed by the observation that it does not block the withdrawal syndrome of other sedative-hypnotic drugs Because of its apparently reduced potential for abuse and tolerance, it is not included in the list of controlled pharmaceutical substances in the United States, but adverse interactions with MAO inhibitors are known Its use with other psychotropic drugs is still under investigation

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value Chemically, these compounds form a heterogeneous group Eight classes of them are of particular clinical importance: (1) the phenothiazines; (2) the thioxanthines; (3) the butyrophenones; (4) the rauwol a alkaloids; (5) an indole derivative, loxapine (Loxitane), and a unique dihydroindalone, molindone (Moban); (6) a diphenylbutylpiperidine, pimozide (Orap); (7) dibenzodiazepines, typi ed by clozapine (Clozaril) and olanzapine (Zyprexa); and (8) a benzisoxazole derivative, risperidone (Risperdal) The last four of these drugs were introduced more recently than the others and hence have had a more limited trial 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 have attracted great interest, since 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 Pimozide may be useful in the treatment of haloperidol-refractory cases of Gilles de la Tourette syndrome (page 95); its main danger is its tendency to produce cardiac arrhythmias

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