Antipsychotics, first-generation (typical)

Key examples

• Haloperidol
• Chlorpromazine
• Prochlorperazine 

 

Common indications

1. Urgent treatment of severe psychomotor agitation that is causing dangerous or violent behaviour, or to calm patients to permit assessment.
2. Schizophrenia, particularly when the metabolic side effects of second-generation (atypical) antipsychotics are likely to be problematic.
3. Bipolar disorder, particularly in acute episodes of mania or hypomania.
4. Nausea and vomiting, particularly in the palliative care setting.

 

Mechanisms of action

• Antipsychotic drugs block post-synaptic dopamine D2 receptors. There are three main dopaminergic pathways in the central nervous system. The mesolimbic/mesocortical pathway runs between the midbrain and the limbic system/frontal cortex. 
• D2 blockade in this pathway is probably the main determinant of antipsychotic effect, but this is incompletely understood. The nigrostriatal pathway connects the substantia nigra with the corpus striatum of the basal ganglia. The tuberohypophyseal pathway connects the hypothalamus with the pituitary gland. 
• D2 receptors are also found in the chemoreceptor trigger zone, where blockade accounts for their use in nausea and vomiting. All antipsychotics, but particularly chlorpromazine, have some sedative effect. This may be beneficial in the context of acute psychomotor agitation.

 

Important adverse effects

• Extrapyramidal effects – movement abnormalities that arise from D2 blockade in the nigrostriatal pathway – are the main drawback of first-generation antipsychotics. They take several forms: acute dystonic reactions are involuntary parkinsonian movements or muscle spasms; akathisia is a state of inner restlessness; and neuroleptic malignant syndrome is rare but life-threatening side effect characterised by rigidity, confusion, autonomic dysregulation and pyrexia. These all tend to occur early in treatment. 
• By contrast, tardive dyskinesia is a late adverse effect (tardive, late), occurring after months or years of therapy. This comprises movements that are pointless, involuntary and repetitive (e.g. lip smacking). It is disabling and may not resolve on stopping treatment. Other adverse effects include drowsiness, hypotension, QT-interval prolongation (and consequent arrhythmias), erectile dysfunction, and symptoms arising from hyperprolactinaemia due to tuberohypophyseal D2 blockade (e.g. menstrual disturbance, galactorrhoea and breast pain).

 

Warnings

• Elderly patients are particularly sensitive to antipsychotics, so start with lower doses. 
• Antipsychotics should ideally be avoided in dementia, as they may increase the risk of death and stroke. 
• They should be avoided if possible in Parkinson’s disease due to their extrapyramidal effects.

 

Important interactions

• Consult the BNF when prescribing for a patient taking antipsychotics as there is an extensive list of interactions. 
• Prominent among these are drugs that prolong the QT interval (e.g. amiodarone, macrolides).