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Antipsychotic drugs
Essentials
- 1
Antipsychotics can cause numerous adverse effects at therapeutic doses, which may limit compliance.
- 2
Extrapyramidal effects are less pronounced with second-generation antipsychotics.
- 3
Clozapine is associated with agranulocytosis and myocarditis with therapeutic use and requires strict surveillance.
- 4
Following overdose, antipsychotics predominantly cause central nervous system (CNS) depression and cardiovascular effects.
- 5
Amisulpride can cause significant QT prolongation, potentially resulting in torsades de pointes.
- 6
Management of antipsychotic overdose is primarily supportive.
- 7
Neuroleptic malignant syndrome is a rare, idiosyncratic adverse reaction, which may be lethal without timely diagnosis and treatment.
Introduction
Antipsychotics form a heterogeneous group of medications that has evolved since chlorpromazine was first used to treat schizophrenia in the 1950s. The first-generation or ‘typical’ antipsychotics caused many adverse effects, especially movement disorders such as extrapyramidal syndromes (EPS). They also have little efficacy in treating the negative symptoms of schizophrenia. This led to the development of the second-generation or ‘atypical’ antipsychotics in the late 1980s. Generally these drugs have fewer tendencies to cause movement disorders and have efficacy in managing negative symptoms of schizophrenia, while maintaining efficacy in treating acute psychosis. For this reason, they have largely replaced the older antipsychotics as first-line pharmacotherapy for schizophrenia and psychotic disorders.
The previous 30 years has shown an increase in overall prescribing of antipsychotics in Australia (many for off-label indications), along with increasing presentations with self-poisoning. Despite a greater proportion of presentations with overdose of second-generation antipsychotics (particularly quetiapine and olanzapine), which are perceived as safer, there has been no reduction in morbidity or in-hospital mortality.
Pharmacology
There are numerous ways of classifying the antipsychotic drugs: typical or atypical as described above ( Box 25.3.1 ), by their chemical structure, or according to neuroreceptor binding affinity.
Box 25.3.1
Typical and atypical antipsychotic drugs
All antipsychotic drugs produce their beneficial therapeutic effects by antagonizing dopamine D 2 receptors in the mesolimbic system. The first-generation antipsychotics were classified as high or low potency depending on their affinity for these D 2 receptors. However, antagonism of the other D 2 receptors leads to many of the adverse clinical effects. Antagonism of D 2 receptors in the nigrostriatal pathway leads to movement disorders, antagonism of the D 2 receptors in the mesocortical area can contribute to the negative symptoms, and antagonism of D 2 receptors in the anterior pituitary stimulates prolactin secretion potentially causing gynaecomastia and galactorrhoea. Blockade of D 2 receptors in the anterior hypothalamus may affect temperature regulation, leading to hypo- or hyperthermia, and may be involved in the development of neuroleptic malignant syndrome (NMS). The antiemetic effect of some of the antipsychotics is due to antagonism of the D 2 receptors in the chemoreceptor trigger zone in the medulla.
Second-generation antipsychotics also derive therapeutic efficacy from affinity and antagonism at various serotonin (5-HT) receptors. Antagonism at the 5-HT 2A receptor is implicated both in increasing efficacy of treating negative symptoms of schizophrenia, and also in reducing the incidence of EPS.
Agents with high antagonism of muscarinic M 1 and M 2 receptors (e.g. olanzapine, quetiapine) can cause an agitated delirium and peripheral features characteristic of anticholinergic toxicity. Drugs that have a higher anticholinergic activity than dopaminergic tend to cause fewer extrapyramidal effects. High relative antagonism of histamine H 1 receptors leads to sedation and, to a lesser extent, hypotension. Antagonism at the α 1 -adrenergic receptor can result in hypotension (e.g. clozapine, quetiapine). Clozapine also antagonizes the α 2 -receptor, although the clinical significance of this is uncertain.
Some first-generation antipsychotics can block voltage-gated fast sodium channels, which in overdose, can lead to slowing of cardiac conduction, widening the QRS complex, and impairing myocardial contractility. Blockade of the delayed rectifier potassium channel causes delayed repolarization leading to QT prolongation.
Despite the heterogeneous nature of the antipsychotics, in general, they share similar pharmacokinetic properties. They are well absorbed after oral administration, with peak serum concentrations usually occurring within 2 to 6 hours of ingestion. This may be delayed following overdose of agents with significant anticholinergic properties. They are lipophilic, have large volumes of distribution and the majority of the agents are highly protein bound. They are extensively metabolized in the liver, with some having active metabolites.
Clinical effects
Adverse effects
Adverse effects at therapeutic doses may be dose related or idiosyncratic.
Extrapyramidal syndromes
These are a heterogeneous group of disorders characterized by abnormal neuromuscular activity. They can be particularly distressing to patients and may lead to difficulties with compliance. There are four well-recognized syndromes—acute dystonia, akathisia, parkinsonism and tardive dyskinesia. Of these, the first three are usually reversible, whereas tardive dyskinesia is irreversible, but occurs late, usually after months to years of treatment.
EPS are more common among the first-generation antipsychotics, especially those with high potency, such as haloperidol. Second-generation antipsychotics are associated with a lower incidence of EPS, although it must be appreciated that EPS can occur with the use of any antipsychotic. Reactions are usually idiosyncratic, although can occur following overdose.
Acute dystonia is characterized by sustained involuntary muscle contraction, which commonly involves the face, head and neck, but can also involve the extremities. Rarely, the larynx can be involved, which may be life threatening. Risk factors for developing dystonia include male gender, young age and previous history of dystonic reaction. Onset is usually within a few hours of exposure, but may be delayed for several days.
Akathisia is characterized by an unpleasant sensation of restlessness or unease and, often, the patient is unable to remain still. It can be difficult to diagnose and is sometimes attributed to the underlying psychiatric condition rather than to the treatment.
Drug-induced parkinsonism is similar to idiopathic Parkinson disease, with rigidity and bradykinesia, although the characteristic tremor may be less pronounced. It is more common in older patients and patients on high potency agents.
Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements, classically involving the muscles of the face and mouth, although the limbs and trunk may be involved. It usually appears after months or years of therapy with antipsychotics and is usually resistant to treatment.
Cardiovascular effects
Cardiovascular effects of antipsychotics with therapeutic use include tachycardia, postural hypotension and ECG changes. Postural hypotension may be multifactorial, with α 1 -adrenergic blockade and direct myocardial depression playing a role. ECG changes may be diverse, with QRS prolongation, QT prolongation and non-specific ST-segment and T-wave changes being reported.
Seizures
All antipsychotics can lower the seizure threshold. However, seizures rarely complicate therapeutic use of antipsychotics, unless the patient has underlying risk factors, such as organic brain disease or epilepsy.
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