Miscellaneous Pharmacological Effects

Interactions of antipsychotic drugs with central neurotransmitters other than DA may contribute to their antipsychotic effects or other actions. For example, many antipsychotics enhance the turnover of acetylcholine, especially in the basal ganglia, perhaps secondary to the blockade of inhibitory dopaminergic heteroceptors on cholinergic neurons. In addition, there is an inverse relationship between antimuscarinic potency of antipsychotic drugs in the brain and the likelihood of extrapyramidal effects. Chlorpromazine and low-potency antipsychotic agents, including clozapine and quetiapine, have antagonistic actions at histamine receptors that probably contribute to their sedative effects.

ABSORPTION, DISTRIBUTION, FATE, AND EXCRETION Some antipsychotic drugs have erratic and unpredictable patterns of absorption after oral administration. Parenteral (intramuscular) administration increases the bioavailability of active drug 4-10-fold. Most antipsychotic drugs are highly lipophilic, highly membrane- or protein-bound, and accumulate in the brain, lung, and other tissues with a rich blood supply. They also enter the fetal circulation and breast milk. It is virtually impossible to remove these agents by dialysis.

Elimination half-lives with respect to total concentrations in plasma are typically 20-40 hours. However, complex patterns of delayed elimination may occur with some drugs, particularly the butyrophenones and their congeners. Biological effects of single doses of most antipsychotics usually persist for at least 24 hours, permitting once-daily dosing once the patient has adjusted to initial side effects. Elimination from the plasma may be more rapid than from sites of high lipid content and binding, notably in the CNS; metabolites of some agents have been detected in the urine several months after drug administration was discontinued. Slow removal of drug may contribute to the typically delayed exacerbation of psychosis after stopping drug treatment. Repository ("depot") preparations of esters of neuroleptic drugs, as well as risperidone incorporated into carbohydrate microspheres, are absorbed and eliminated much more slowly than are oral preparations. For example, half of an oral dose of fluphenazine hydrochloride is eliminated in -20 hours, while the decanoate ester injected intramuscularly has a t1/2 of 7-10 days. Clearance of fluphenazine decanoate and normalization of hyperprolactinemia following repeated dosing can require 6-8 months. Effects of long-acting risperidone (risperidal consta) are delayed for 2-3 weeks because of slow biodegradation of the microspheres and persist for at least 2 weeks after the injections are discontinued.

The antipsychotic drugs are metabolized largely by hepatic CYPs and by glucuronidation, sulfation, and other conjugation processes. Hydrophilic metabolites of these drugs are excreted in the urine and to some extent in the bile. Most oxidized metabolites of antipsychotic drugs are biologically inactive. Less potent antipsychotic drugs like chlorpromazine may weakly induce their own hepatic metabolism, since their concentrations in blood are lower after several weeks of treatment at the same dosage. Alterations of GI motility also may contribute. The fetus, the infant, and the elderly have diminished capacity to metabolize and eliminate antipsychotic agents; young children tend to metabolize these drugs more rapidly than do adults.

With several antipsychotic agents, bioavailability and drug acceptance by hospitalized patients is somewhat increased with liquid concentrates and rapidly disintegrating tablets that yield peak serum concentrations of chlorpromazine and other phenothiazines within 2-4 hours. Intramuscular administration avoids much of the first-pass enteric metabolism and provides measurable concentrations in plasma within 15-30 minutes. Bioavailability of chlorpromazine may be increased up to tenfold with injections, but the clinical dose usually is decreased by only three- to fourfold. GI absorption of chlorpromazine is modified unpredictably by food and probably is decreased by antacids. Antipsychotic agents bind significantly to membranes and to plasma proteins. Elimination kinetics can be multiphasic and variable with dose, and termination of action may rely on clearance of both active metabolites and the parent compound. Approximate elimination half-lives of clinically employed antipsychotic agents are provided in Table 18-2; see also Appendix II, Pharmacokinetic Data in the 11th edition of the parent text.

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