Antipsychotics

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182 Antipsychotics

Pharmacology of Antipsychotics

The broad class of medications used to treat psychoses is of interest to intensivists for two reasons. First, some of these medications are useful in the management of agitated or delirious patients in the intensive care unit (ICU). Second, intensivists may need to care for patients with accidental or deliberate overdose of such medications, either alone or in combination with other medications.

The antipsychotics can be divided into three categories based on their chemical structure and receptor-binding activities: phenothiazines, butyrophenones, and atypical antipsychotics. The prototypical antipsychotic agent in the phenothiazine class is chlorpromazine (Thorazine). Its pharmacology is discussed in detail in this chapter and then compared with that of the newer antipsychotic agents.¹ The structures of some commonly used antipsychotics are shown in Figure 182-1.

Figure 182-1 Structures of the antipsychotics discussed in this chapter.

In terms of the number of neurotransmitter systems with which it interacts, chlorpromazine is one of the “dirtiest” drugs in pharmacology. It is a competitive antagonist at the dopamine (D₂), muscarinic, cholinergic, histamine (H₁), α-adrenoceptor, and serotonin (5-HT₂) receptors. It is believed that its primary antipsychotic effect results from dopaminergic blockade, whereas many (but certainly not all) of its adverse effects result from blockade of cholinergic (sedation, dry mouth) and α-adrenoceptor (orthostatic hypotension) receptors. The relative propensities of some of the antipsychotics to cause sedation, extrapyramidal effects, and hypotension are listed in Table 182-1.

TABLE 182-1 Adverse Effects of Some Antipsychotic Medications

When chlorpromazine is given to a “normal” individual, behavior is diminished and responses to stimuli are fewer, slower, and smaller in magnitude. If it is given in high doses, a catatonic state is induced, although consciousness and memory are preserved. In fact, when the drug wears off, individuals can describe in great detail how bad it made them feel, although they are most unlikely to complain of the dysphoria while it is occurring. This pattern is in distinct contrast to the benzodiazepines, which often produce anterograde amnesia.

When chlorpromazine is given to psychotic patients, there usually is improvement in the thought disorder. In patients with schizophrenia, delusions and hallucinations become less pronounced or disappear, and thinking becomes more orderly. Even if some hallucinations remain, the patient is far more likely to recognize them as unreal.

Because of the wide prevalence of dopaminergic neurons in the central nervous system (CNS), chlorpromazine has widespread effects. The specific areas of the brain responsible for the antipsychotic effects remain obscure. Chlorpromazine lowers the seizure threshold and must be used with caution in persons who are prone to seizures. Because dopamine is released by the hypothalamus to inhibit prolactin secretion by the pituitary, chlorpromazine causes an increase in prolactin secretion. Chlorpromazine exerts its antiemetic effect by blocking dopamine receptors in the chemoreceptor trigger zone.

Blockade of dopamine receptors in the basal ganglia leads to extrapyramidal effects: akathisia, dystonia, rigidity, and tardive dyskinesia. Akathisia is an uncomfortable inability to sit still. Patients feel the need to be in constant motion and may appear to be agitated (although they are not). The acute dystonic signs are usually manifested as uncomfortable (and embarrassing) contractions of the muscles of the face and neck. The rigidity that occurs may be clinically indistinguishable from that of Parkinson’s disease. All of these effects occur early in the course of treatment with chlorpromazine and are dose related. In addition, they are readily treated with anticholinergic medications such as benztropine or diphenhydramine (see later discussion).

Tardive dyskinesia may occur after prolonged therapy with chlorpromazine (although it rarely occurs very early after starting treatment with the drug). It is characterized by involuntary repetitive stereotyped movements, usually of the face, such as lip smacking, eye blinking, grimacing, or tongue protruding. Paradoxically, the dyskinetic movements may be suppressed by increasing the dose of chlorpromazine. Tardive dyskinesia is often permanent, persisting after the discontinuation of chlorpromazine.

Neuroleptic malignant syndrome is a rare complication of chlorpromazine therapy and is characterized by hyperthermia (as a result of generalized muscle contracture), stupor, and metabolic abnormalities such as myoglobinemia and elevation of plasma creatine kinase concentration. It resembles malignant hyperthermia, which is a rare adverse reaction to certain anesthetic medications. Treatment of neuroleptic malignant syndrome is discussed later in this chapter.

Because chlorpromazine also blocks muscarinic and α-adrenoceptors, many of its other adverse effects are readily predicted: orthostatic hypotension, nasal stuffiness, dry mouth, blurred vision, and urinary retention. Chlorpromazine (and many other phenothiazines) can cause jaundice. Tolerance does not develop to the antipsychotic effects of chlorpromazine, although tolerance to the sedative effects does occur over a period of a few weeks.

There are many other antipsychotic medications whose effects differ from those of chlorpromazine, primarily on the basis of different degrees of blockade of the various receptor types. In general, medications with greater anticholinergic effects are more sedating and less likely to cause extrapyramidal effects. They also tend to cause more orthostatic hypotension due to α-adrenoceptor blockade. Conversely, those medications with lesser anticholinergic effects tend to be much more potent dopaminergic antagonists and are less sedating, cause less orthostatic hypotension, and are more likely to produce extrapyramidal effects.

Other phenothiazines in common use include thioridazine (Mellaril), trifluoperazine (Stelazine), and fluphenazine (Prolixin). Thioridazine has greater sedating and hypotensive effects than chlorpromazine while causing many fewer extrapyramidal reactions. Trifluoperazine and fluphenazine are less sedating, cause fewer hypotensive effects, and are more likely to cause extrapyramidal reactions than chlorpromazine.

All phenothiazine antipsychotics have antiemetic activity. For reasons related more to brand differentiation than pharmacology, prochlorperazine (Compazine) is marketed as an antiemetic. Its pharmacology is very similar to that of chlorpromazine. It is available in a multitude of preparations to make administration convenient: tablets, liquid, suppository, and injection.

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