INTRODUCTION

Developed starting in the 1950s, the typical antipsychotics are effective against the positive signs of psychosis (e.g., delusions, hallucinations, disorganized thought), but they provided no treatment for the negative signs (e.g., avolition, alogia, social withdrawal). In addition, numerous adverse side effects associated with these agents lead to poor patient compliance. The second-generation drugs, or atypical antipsychotics, have been available starting in the 1990s. These drugs are characterized by minimal extrapyramidal side effects when taken at effective dosages and have activity against the negative signs of schizophrenia (Table 180-1). Third-generation agents are being developed to minimize the adverse side effects seen with the first- and second-generation agents.

Antipsychotics were originally referred to as major tranquilizers, because of their ability to calm patients, but because they are not simply sedatives, this term is inappropriate. These drugs were also termed neuroleptics, which refers to their ability to slow movement. With the advent of the atypical antipsychotics, it became clear that antipsychotic properties do not necessarily parallel neuroleptic properties. For this reason, the preferred term is antipsychotics. Although antipsychotic is a useful term, these drugs are sometimes administered to treat other conditions, such as agitation, nausea and emesis, various headache conditions; to suppress hiccups; and to control various involuntary motor disorders, such as Tourette’s syndrome, Huntington’s chorea, and basal ganglia disorders.

PATHOPHYSIOLOGY

Currently more than 50 different antipsychotics are available worldwide. Classification by structure is difficult; a more useful method is classification according to their relative receptor-binding profiles (Table 180-2).¹ In overdose, the clinical toxicity is primarily an exaggerated effect of the pharmacologic activity.

Virtually all antipsychotics bind to (and inhibit) presynaptic and postsynaptic dopamine-2 (D₂) receptors in the CNS. When antipsychotic treatment is initiated, blockade of the D₂ receptor results in increased production and release of dopamine from the presynaptic cell. However, with continued use, depolarization inactivation occurs, and decreased production and release develop, along with continued postsynaptic receptor blockade.

The blockade of dopamine receptors in different regions of the brain produces varying effects. Blockade of D₂ receptors in the mesocortical and mesolimbic system is associated with antipsychotic efficacy, whereas D₂ receptor blockade in the area postrema (chemotactic trigger zone) is responsible for antiemetic activity. Aripiprazole is different for other antipsychotics; it is a partial D₂-agonist, with specific effects dependent on the concentration of dopamine. At low levels of dopamine, aripiprazole will stimulate the D₂ receptors, and at high levels of dopamine, aripiprazole will inhibit the D₂ receptors.

Blockade of the D₂ receptors in other regions of the brain produces many of the adverse effects associated with antipsychotics. Antagonism of the D₂ receptors in the tuberoinfundibular region is associated with hyperprolactinemia, which can cause galactorrhea, gynecomastia, and sexual dysfunction.¹ Blockade of the D₂ receptors in the nigrostriatal region is associated with the development of extrapyramidal symptoms. Agents with greater D₂ receptor affinity (e.g., haloperidol or fluphenazine) have a greater likelihood of inducing extrapyramidal symptoms, whereas agents with less receptor affinity (e.g., clozapine) are less likely to cause extrapyramidal symptoms. Blockade of the D₂ receptors in the anterior hypothalamus (preoptic area) can produce alterations in body temperature.

In addition to blocking dopamine receptors, many antipsychotics have activities at the α-adrenergic, muscarinic, histaminergic, and serotoninergic receptors. Antagonism of the α₁-adrenergic receptors leads to orthostatic hypotension and reflex tachycardia. Antagonism of the muscarinic receptors can produce anticholinergic symptoms, including hyperthermia, tachycardia, mydriasis, dry mucosal membranes, and urinary retention. Blockade of the histaminergic receptors primarily results in sedation.

Among the first-generation antipsychotics, potency is inversely related to the likelihood of sedation but directly correlated with extrapyramidal effects. Therefore, high-potency agents such as haloperidol, fluphenazine, and thiothixene are less sedating but more likely to cause extrapyramidal symptoms than are lower potency agents such as chlorpromazine and thioridazine.

Antagonism of the serotonin receptors is associated with a reduced likelihood of inducing extrapyramidal symptoms.² Because serotonin receptor antagonism inhibits dopamine release in the nigrostriate and prefrontal cortex, blockade of the serotonin subtype 2A (5-HT_2A) receptors is associated with increased efficacy in treatment of negative symptoms, while providing reduced risk of extrapyramidal symptoms. Agents that are partial 5-HT_1A receptor agonists, such as ziprasidone and aripiprazole, have similar effects.

PHARMACOKINETICS

Most of the antipsychotics have similar pharmacokinetic profiles. After oral administration, absorption occurs rapidly, the drugs undergo significant first-pass metabolism, and peak plasma concentrations typically occur within 1 to 6 hours. Following IM injection, peak plasma concentrations typically occur within 60 minutes for immediate-release products, but can be delayed up to 1 day with depot preparations. Nearly all antipsychotics have high protein binding and a large volume of distribution. Metabolism is primarily through the cytochrome P-450 enzyme system, with isoenzymes 2D6, 1A2, and 3A4 accounting for the majority of drug metabolism. Because of the near-complete hepatic metabolism of these drugs, renal impairment rarely requires dosage adjustments (noTable exceptions include sulpiride and remoxipride).

CLINICAL FEATURES

Isolated overdose of antipsychotics is rarely fatal, and most patients develop only mild to moderate symptoms.^3,4,5,6 Toxicity is largely a function of the dose ingested, habituation, comorbid conditions, and age. Following overdose, CNS depression is frequent but is less severe in patients receiving long-term therapy, because tolerance to the sedative effects develops after days to weeks of regular use. CNS effects range from lethargy, ataxia, dysarthria, and confusion to coma with respiratory depression in cases of severe overdose.^5,6 The ingestion of a single pill of some of the atypical or typical antipsychotics can cause significant CNS and respiratory depression in young children.⁷ Respiratory depression is more common in multidrug overdoses.

Paradoxical agitation and delirium may occur in mixed overdoses, especially those involving agents with antimuscarinic properties. Seizures occur in approximately 1% of individuals after overdose, with the incidence higher for loxapine and clozapine. Gastric pharmacobezoars have been reported with quetiapine extended-release overdose.⁸

Many of the antipsychotics have antimuscarinic properties (Table 180-2

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