Antipsychotics

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182 Antipsychotics

Mark Dershwitz

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.

Haloperidol (Haldol) is in the butyrophenone class. It causes little sedation or hypotension and has high incidence of extrapyramidal effects. Because of its decreased propensity to cause hypotension, especially in hypovolemic patients, haloperidol is the most commonly used antipsychotic in the ICU for the management of delirium or agitation (see Chapter 2). Droperidol (Inapsine) is pharmacologically very similar to haloperidol and is commonly used by anesthesiologists as an antiemetic.

The atypical antipsychotics are “atypical” in that they have less (or no) antagonistic activity at dopaminergic and cholinergic receptors. Their antipsychotic activity is thought to be due to blockade of 5-hydroxytryptamine 2 (5-HT₂) receptors. Because they are also potent α-adrenoceptor antagonists, orthostatic hypotension is a common problem. However, extrapyramidal effects are much rarer than with any of the older antipsychotic agents. Drugs in this class include clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), risperidone (Risperdal), and aripiprazole (Abilify). Clozapine can cause agranulocytosis and seizures; regular monitoring of the white blood cell count is necessary in patients taking the drug. Aripiprazole is an “atypical” atypical antipsychotic in that it is a partial agonist at dopamine D₂, 5-HT_1A, and 5-HT_2A receptors. It is minimally sedating and produces little hypotension and few extrapyramidal effects.

For emergency management of agitation, delirium, or acute psychosis, haloperidol may be given intravenously (IV) or intramuscularly (IM), or chlorpromazine, olanzapine, or ziprasidone may be given IM. Chlorpromazine should rarely be given IV because of its profound vasodilating effect, which is especially pronounced in hypovolemic patients.

Use of Antipsychotics in the Intensive Care Unit

The most common indication for use of antipsychotic medications in the ICU is for treatment of agitation or delirium. Haloperidol is the usual drug of choice for this indication because of intensivists’ familiarity with it and because of its substantial safety record.²

If the need to begin treatment is not urgent, and if gastrointestinal absorption is expected to be reliable, oral haloperidol may be used at a beginning dose of 0.5 to 1 mg and repeated as needed. As the duration of therapy increases, the interval between doses also increases because the terminal half-life of haloperidol is about 1 day in normal persons and may be prolonged in critically ill persons. In the urgent management of severe agitation, the IV (or less desirably, the IM) route may be used. A reasonable starting dose is 2.5 to 5 mg; if an inadequate response is obtained, additional escalating doses (e.g., twice the previously administered dose) may be given every 5 to 10 minutes. Once reasonable efficacy has been achieved, the last administered dose may then be repeated every 4 to 6 hours. Some critically ill patients require hundreds of milligrams daily for the management of agitation or delirium. One alternative to frequent administration of bolus injections of haloperidol is administration of haloperidol by continuous infusion. This method may provide better control of delirium and agitation in some patients and decrease the nursing effort required to prevent self-inflicted injuries.³ After steady-state blood concentrations of haloperidol are approached, days are required for the effects to wane after stopping administration.

Chlorpromazine is usually a less desirable alternative in this scenario because of its tendency to cause hypotension secondary to α-adrenoceptor blockade. Hypotension caused by chlorpromazine is especially pronounced after IV administration, and if the drug must be given by this route, the injection should be made very slowly. In comparison to haloperidol, chlorpromazine is also significantly more sedating, which might be an attractive side effect. In general, addition of a sedative such as a benzodiazepine or propofol to a haloperidol regimen provides superior sedation and control of delirium with fewer hemodynamic effects.

Olanzapine recently has been studied in comparison with haloperidol for treatment of delirium in the ICU.² Overall efficacy was comparable with either medication, and there were fewer extrapyramidal effects with olanzapine.

All phenothiazine and butyrophenone antipsychotic agents have antiemetic activity by virtue of their ability to block the dopamine receptor in the chemoreceptor trigger zone. Antiemetic doses are much lower than usual antipsychotic doses. The most extensively studied antiemetic antipsychotic drug is droperidol. The usual antiemetic dose is 1.25 mg given 2 to 3 times daily. This dose rarely causes sedation or any other adverse effects. If droperidol at this dose does not relieve the emetic symptoms, an antiemetic from a different class (e.g., a 5-HT₃ antagonist) should be given.

Management Of Adverse Effects

The extrapyramidal effects of antipsychotics are uncomfortable but rarely hazardous. The exception is an unusual presentation of acute dystonia manifested as airway compromise. If administration of an anticholinergic agent does not provide rapid relief, paralysis and intubation are required to maintain airway integrity.

For treatment of extrapyramidal effects caused by an antipsychotic drug, a centrally acting anticholinergic is given, usually IV. The usual doses are 1 to 2 mg of benztropine (Cogentin) or 25 to 50 mg of diphenhydramine (Benadryl). Diphenhydramine causes more sedation than benztropine, which may or may not be advantageous in a particular patient. Because the extrapyramidal effects are dose related, decreasing the subsequent dose may lessen the likelihood of recurrence. Alternatively, changing to a different medication with fewer inherent extrapyramidal effects is also an option (see Table 182-1). However, such a change in therapy is likely to result in greater hypotensive effects from the antipsychotic medication, a factor that must be considered in critically ill patients.

Neuroleptic malignant syndrome is a rare and occasionally fatal constellation of symptoms which can include catatonia, stupor, rigidity, hyperthermia, autonomic instability, and rhabdomyolysis, leading to myoglobinemia and elevated circulating levels of creatine kinase. The syndrome is commonly associated with the more potent antipsychotics (e.g., haloperidol), and dopaminergic blockade is thought to be the initial underlying mechanism. However, all atypical antipsychotics have been associated with neuroleptic malignant syndrome.

Treatment requires supportive measures such as cessation of the antipsychotic medication, active cooling, and maintenance of blood pressure and urine output. The efficacy of additional pharmacologic therapy is controversial.⁴ The dopaminergic agonists, amantadine (Symmetrel) and bromocriptine (Parlodel), and dantrolene (Dantrium), a muscle relaxant with an intracellular mechanism of action that is also used to treat malignant hyperthermia, are commonly administered. However, it is unclear whether these agents convey benefits beyond supportive therapy.

Most phenothiazine and butyrophenone antipsychotics are thought to increase the incidence of torsades de pointes, a form of ventricular tachycardia that can deteriorate into ventricular fibrillation.⁵ Cases of torsades de pointes have also been ascribed to therapy with atypical antipsychotics, although the incidence is much lower. Torsades de pointes is usually, but not always, preceded by an increase in the corrected QT interval (QTc) on the electrocardiogram (ECG). QTc prolongation is a known dose-related effect and is common during therapy with thioridazine, chlorpromazine, haloperidol, and droperidol. Torsades de pointes is more likely when the QTc is lengthened beyond 500 msec or when it is prolonged 60 msec or more beyond its usual baseline value. Discontinuation of the antipsychotic agent decreases QTc and the associated risk of torsades de pointes.

Hypotension due to α-adrenoceptor blockade often accompanies therapy with phenothiazines and atypical antipsychotics. The degree of hypotension may be exaggerated in persons with coexisting hypovolemia and those who are receiving therapy with β-adrenoceptor antagonists, because the efferent limb of the barostatic reflex is blocked. Infusion of phenylephrine (Neo-Synephrine), a pure α-adrenoceptor agonist, restores blood pressure without producing other cardiovascular perturbations.

The seizure threshold may be lowered by antipsychotic medications, especially chlorpromazine and clozapine.⁶ However, because the effect is dose dependent, large doses of other antipsychotics also have been associated with seizures, both in persons with a known preexisting seizure disorder and in persons with no prior history. The approach to treatment of an antipsychotic-related seizure is similar to that used with other drug-induced or idiopathic seizures: initial measures to maintain airway patency, along with administration of supplemental oxygen, an anticonvulsant medication (e.g., diazepam [Valium]) if the seizure does not terminate spontaneously, and withdrawal or decrease in the dose of the offending medication (if known).