Case: Antipsychotic drugs. Discussion

Class

Antipsychotic drugs can be classified according to chemical structure as phenothiazines, butyrophenones, and an important group with diverse atypical structures. The phenothiazines are further subdivided according to side-chain constituents: aliphatic, piperidine, and piperazine (Table Representative antipsychotic drugs).

Table: Representative antipsychotic drugs (side chains)

Although very similar in their therapeutic efficacy, the “low- (oral-) potency” aliphatic and piperidine phenothiazines have a somewhat different adverse effect profile than the “high-potency” agents that include the piperazine phenothiazines, and also thiothixene, and haloperidol.

The newer, atypical agents have generally unique structures; some studies have suggested that they may have greater therapeutic efficacy with regard to the negative symptoms of schizophrenia. They also have been documented to have superior adverse effect profiles. Recent clinical trials have called into question the safety of several of the newer agents. In summary, individual patient response to antipsychotic agents varies widely and often dictates drug selection.

Administration of the low-potency antipsychotic agents is more likely to result in autonomic adverse effects that include orthostatic hypotension caused by α-adrenoceptor blockade, and dry mouth, urinary retention, and tachycardia resulting from blockade of muscarinic cholinoreceptors. Their blockade of histamine H1 receptors in the CNS results in sedation. The still widely used high-potency agents, for example, haloperidol, are more likely to result in adverse neurologic effects. Among these are the EPSs, acute dystonia, akathisia, and Parkinson syndrome, which occur relatively early in therapy and are thought to be primarily mediated by blockade of dopamine D₂ receptors in the nigrostriatal dopamine pathway of the basal ganglia.

A late-occurring tardive dyskinesia that is often irreversible and that may be a result of the slow development of dopamine receptor supersensitivity also in the basal ganglia is more or less likely to occur with all antipsychotic agents except clozapine. A potentially fatal neuroleptic malignant syndrome is another serious adverse effect of antipsychotic agents in sensitive patients (1 %). Also, hyperprolactinemia in women may occur as a result of enhanced prolactin release from the posterior pituitary, because of antipsychotic drug blockade (phenothiazines, butyrophenones, risperidone) of dopamine D₂ receptors of the tuberoinfundibular dopaminergic pathway, which may lead to amenorrhea, galactorrhea, gynecomastia, decreased libido, and impotence. Weight gain is also a likely effect of many of these antipsychotic agents.

The atypical agents are less likely than the conventional agents to result in adverse EPSs. However, weight gain (clozapine, olanzapine, quetiapine), hypotension, and sedation are not uncommon events. Seizures (2-5%) and agranulocytosis (2% risk, 10% fatality) limit the use of clozapine to patients unresponsive to other agents.

Mechanism of Action

All clinically useful antipsychotic drugs block postjunctional dopamine D₂ receptors, although the degree of blockade among the drugs varies greatly in relation to their action on other neuroreceptors, particularly serotonin 5-hydroxytryptamine 2A (5-HT_2A) receptors and certain other dopamine receptor subtypes. Antipsychotic drugs appear to exert their therapeutic effect, at least in part, by inhibition of dopamine’s action in the mesocortical and mesolimbic dopaminergic pathways of the CNS.

Administration

All antipsychotic agents can be administered by either the oral or parenteral route or both. Fluphenazine decanoate and haloperidol decanoate are available as parenteral depot preparations.

Pharmacokinetics

Most antipsychotic agents are readily but incompletely absorbed. They are highly lipid soluble and have longer clinical duration of action than would be expected from their plasma half-life, probably as a consequence of their deposition in fat tissue.

Thioridazine, which is metabolized to mesoridazine, is the exception to the rule that hepatic metabolism of the antipsychotic agents results in less active metabolites.

Concurrent use of certain antipsychotic agents with other drugs that also block cholinoreceptors may result in additive peripheral and CNS dysfunction.