Antipsychotic Drugs

Classification

The major chemical subgroups of older antipsychotic drugs are the phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine), the thioxanthenes (eg, thiothixene), and the butyrophenones (eg, haloperidol).

Newer “second generation” drugs of varied heterocyclic structure are also effective in schizophrenia, including clozapine, loxapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. In some cases, these atypical antipsychotic drugs may be somewhat more effective and less toxic than the older drugs. However, they are much more costly than standard older drugs, most of which are prescribed generically.

Pharmacokinetics

The antipsychotic drugs are well absorbed when given orally, and because they are lipid soluble, they readily enter the central nervous system (CNS) and most other body tissues. Many are bound extensively to plasma proteins. These drugs require metabolism by liver enzymes before elimination and have long plasma half-lives that permit once-daily dosing. In some cases, other drugs that inhibit cytochrome P450 enzymes can prolong the half-lives of antipsychotic agents. Parenteral forms of many agents (eg, fluphenazine, haloperidol) are available for both rapid initiation of therapy and depot treatment.

Mechanism of Action

The Dopamine Hypothesis

The dopamine hypothesis of schizophrenia proposes that the disorder is caused by a relative excess of functional activity of the neurotransmitter dopamine in specific neuronal tracts in the brain. This hypothesis is based on several observations. First, many antipsychotic drugs block brain dopamine receptors (especially D2 receptors). Second, dopamine agonist drugs (eg, amphetamine, levodopa) exacerbate schizophrenia. Third, an increased density of dopamine receptors has been detected in certain brain regions of untreated schizophrenics. The dopamine hypothesis of schizophrenia is not fully satisfactory because antipsychotic drugs are only partly effective in most patients and because many effective drugs have a much higher affinity for other receptors, including serotonin receptors, than for D2 receptors.

Dopamine Receptors

Five different dopamine receptors (D1-D5) have been characterized. Each is G-protein coupled and contains 7 transmembrane domains. The D2 receptor, found in the caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus, is negatively coupled to adenylyl cyclase. The therapeutic efficacy of the older antipsychotic drugs correlates with their relative affinity for the D2 receptor. Unfortunately, there is also a correlation between blockade of D2 receptors and extrapyramidal dysfunction.

Other Receptors

Most of the newer atypical antipsychotic agents have higher affinities for other receptors than for the D2 receptor. For example, adrenoceptor-blocking action correlates well with antipsychotic effect for many of the drugs (Table 29-1). Clozapine, a drug with significant D4 and 5-HT 2 receptor-blocking actions, has virtually no affinity for D2 receptors. Most of the newer atypical drugs (eg, olanzapine, quetiapine, and risperidone) also have high affinity for 5-HT2A receptors, although they may also interact with D2 and other receptors. Ziprasidone is an antagonist at the D2, 5-HT2A, and 5-HT1D receptors and an agonist at the 5-HT1A receptor. The newer antipsychotic agent aripiprazole is a partial agonist at D2 and 5-HT1A receptors but is a strong antagonist at 5-HT2A receptors. The receptor-binding characteristics of the newer antipsychotic drugs have led to a serotonin hypothesis as an alternative to the dopamine hypothesis of the nature of schizophrenia. Most of the atypical drugs cause less extrapyramidal dysfunction than standard drugs. With the exception of haloperidol, all antipsychotic drugs block H1 receptors to some degree.

TABLE 29-1 Relative receptor-blocking actions of neuroleptic drugs.

Drug D2 Block D4 Block Alpha1 Block 5-HT2 Block M Block H1 Block Most phenothiazines and thioxanthines ++ – ++ + + + Thioridazine ++ – ++ + +++ + Haloperidol +++ – + – – – Clozapine – ++ ++ ++ ++ + Molindone ++ – + – + + Olanzapine + – + ++ + + Quetiapine + – + ++ + + Risperidone ++ – + ++ + + Ziprasidone ++ – ++ ++ – + Aripiprazole a

+ + + ++ – +

aPartial agonist at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

+, blockade; -, no effect. The number of plus signs indicates the intensity of receptor blockade.

Effects

Dopamine receptor blockade is the major effect that correlates with therapeutic benefit for older antipsychotic drugs. Dopaminergic tracts in the brain include the mesocortical-mesolimbic pathways (regulating mentation and mood), nigrostriatal tract (extrapyramidal function), tuberoinfundibular pathways (control of prolactin release), and chemoreceptor trigger zone (emesis). Mesocortical-mesolimbic dopamine receptor blockade presumably underlies antipsychotic effects, and a similar action on the chemoreceptor trigger zone leads to the useful antiemetic properties of some antipsychotic drugs. Adverse effects resulting from receptor blockade in the other dopaminergic tracts, a major problem with older antipsychotic drugs, include extrapyramidal dysfunction and hyperprolactinemia (see later discussion). Note that almost all antipsychotic agents block both 1 and histamine H1 receptors to some extent. The relative receptor-blocking actions of various antipsychotic drugs are shown in Table 29-1.

Clinical Use

Treatment of Schizophrenia

Antipsychotic drugs reduce some of the positive symptoms of schizophrenia, including hyperactivity, bizarre ideation, hallucinations, and delusions. Consequently, they can facilitate functioning in both inpatient and outpatient environments. Beneficial effects may take several weeks to develop. Overall efficacy of the antipsychotic drugs is, for the most part, equivalent in terms of the management of the floridly psychotic forms of the illness, although individual patients may respond best to a specific drug. However, clozapine is effective in some schizophrenic patients resistant to treatment with other antipsychotic drugs. Older drugs are still commonly used partly because of their low cost compared with newer agents. However, none of the traditional drugs has much effect on negative symptoms of schizophrenia. Newer atypical drugs are reported to improve some of the negative symptoms of schizophrenia, including emotional blunting, social withdrawal, and lack of motivation.

Other Psychiatric and Neurologic Indications

The newer antipsychotic drugs are often used with lithium in the initial treatment of mania. Several second-generation drugs are approved for treatment of acute mania; two of these (aripiprazole and olanzapine) are aproved for maintenance treatment of bipolar disorder. The antipsychotic drugs are also used in the management of psychotic symptoms of schizoaffective disorders, in Gilles de la Tourette syndrome, and for management of toxic psychoses caused by overdosage of certain CNS stimulants. Molindone is used mainly in Tourette’s syndrome; it is rarely used in schizophrenia. The newer atypical antipsychotics have also been used to allay psychotic symptoms in patients with Alzheimer’s disease and in parkinsonism.

Nonpsychiatric Indications

With the exception of thioridazine, most phenothiazines have antiemetic actions; prochlorperazine is promoted solely for this indication. H1-receptor blockade, most often present in short side-chain phenothiazines, provides the basis for their use as antipruritics and sedatives and contributes to their antiemetic effects.

Toxicity

Reversible Neurologic Effects

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