Phenothiazines are classified on the basis of their chem-istry, pharmacological actions, and potency. Chemical classifications include the aliphatic (e.g., chlorproma-zine; Thorazine), piperidine (e.g., thioridazine; Mellaril), and piperazine subfamilies. The piperazine derivatives are generally more potent and pharmacologically se-lective than the others. The thioxanthenes (e.g., thio-thixene; Navane) are chemically related to the pheno-thiazines and have nearly equivalent potency. Thebutyrophenone haloperidol (Haldol) is structurally dis-tinct from the two preceding groups, offering greater potency and fewer autonomic side effects. The dibenzo-diazepine clozapine (Clozaril) bears some structural re-semblance to the phenothiazine group but causes little extrapyramidal toxicity. The benzisoxazole risperidone (Risperdal) is representative of many of the newer agents in having a unique structure relative to the older groups while retaining antipsychotic potency and a bet-ter side effect profile.
Most of the antipsychotics are readily but incompletely absorbed, and many undergo significant first-pass me-tabolism. The oral bioavailability of chlorpromazine and thioridazine is in the range of 25 to 35%, while that of haloperidol, which is less likely to be metabolized, has an oral bioavailability of about 65%. The antipsychotics are highly lipid soluble and are about 95% bound to pro-teins. Generally they have a much longer clinical dura-tion of action than could be estimated from their plasma half-lives; this is likely due to their sequestration in fat tissue. Depot preparations are more slowly absorbed and longer acting, and thus can be administered par-enterally at intervals up to 3 weeks. The main routes of metabolism are mediated by hepatic oxidative microso-mal enzymes and by glucuronidation. Some metabolites, such as 7-hydroxychlorpromazine, retain measurable ac-tivity, but this effect is not considered to be clinically im-portant; an exception to this observation is the major metabolite of thioridazine, which is more potent than the parent drug. Since drug blood concentrations of the less potent antipsychotics are lower after several weeks of treatment at the same dose, it is believed that these compounds may weakly induce their own metabolism. Also, the ability to metabolize and eliminate these drugs has been shown to diminish with age. Typical elimination half-lives vary from 12 to 24 hours.
Despite differences in potency, all commonly used an-tipsychotic drugs have approximately equal efficacy in equivalent doses. However, individual patients may be more responsive to one drug class than another. Prototype or representative members of the antipsy-chotics are arranged in decreasing order of potency in Table 34.1. While the sedative and autonomic effects of the high-potency drugs are less prominent, these agents are more likely to cause acute extrapyramidal symp-toms. Generally, these trends are reversed as potency decreases.
All antipsychotics block D2-receptors, but the de-gree of blockade in relation to actions on other recep-tors varies greatly. For example, chlorpromazine andthioridazine block α-adrenoceptors (autonomic side effects) more potently than D2-receptors and also block 5-HT2 serotonergic and H1 histamine receptors (sedative side effects) to a significant extent. However, their affinity for D1-receptors is weak. Haloperidol and pimozide (Orap) act mainly on D2-receptors (ex-trapyramidal toxicity) with negligible activity at D1-receptors. Clozapine, risperidone, and olanzapine (Zyprex) show marked clinical differences from the other drugs. Clozapine binds more to D4, 5-HT2, α1-, and H1-receptors (autonomic and sedative side effects) than to either D2 (low extrapyramidal activity) or D1 sites. Risperidone binds primarily to D2-, 5-HT2-, and α1-receptors, retaining high potency with lesser potential for side effects. Current drug development is directed toward a search for atypical antipsychotics like clozap-ine that have a broad spectrum of effects on other neu-rotransmitter receptors.
Antipsychotic drugs produce shifts in the pattern of electrographic (EEG) frequencies, usually slowing them and causing hypersynchrony. This slowing is sometimes focal or unilateral, which may pose diagnostic problems, but the frequency and amplitude changes are readily ap-parent. The hypersynchrony produced by these drugs probably accounts for their activating effect on the EEG in epileptic patients and for the low incidence of seizures in patients with no history of seizure disorders.
Antipsychotics produce striking effects on the re-productive system. Amenorrhea and increased libido have been reported in women, whereas decreased li-bido and gynecomastia have been observed in men. Some of these actions are undoubtedly the result of a drug-associated blockade of dopamine’s tonic normal inhibition of prolactin secretion, but they may also be partially due to an enhanced peripheral conversion of androgens to estrogens.
Orthostatic hypotension and high resting pulse rates can result from the use of the low-potency phenothi-azines. Mean arterial pressure, peripheral resistance, and stroke volume are decreased, while pulse rate is in-creased. Abnormal electrocardiograms (ECGs) have been observed, especially following thioridazine admin-istration. These findings include prolongation of the QT interval and abnormal configurations of the ST segment and T waves, the latter being rounded, flattened, or notched. These effects are readily reversed upon drug withdrawal.
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