19th May 2025

First generation anti-psychotic drugs

Antipsychotic medications, used in the treatment of acute psychosis, chronic schizophrenia, bipolar disorder and treatment-resistant depression, are divided into two classes: first-generation (or “typical”) antipsychotics, and second-generation (or “atypical) antipsychotics. 

First- and second-generation antipsychotics differ both in their mechanism of action, and in their side effect profile; however, it should be noted that there exist significant areas of overlap with regards to adverse drug effects between the two classes. Furthermore, individual drug types exhibit differences in their side effect profiles when compared with other members of the same antipsychotic class. Generally speaking, first-generation antipsychotics (FGAs) are more likely to cause extra-pyramidal side effects (EPSEs) and tardive dyskinesias than second-generation antipsychotics (SGAs). While metabolic disturbance is more typically associated with SGAs than FGAs, emerging evidence suggests this in fact occurs in both classes with similar frequency.

Mechanism of action

The primary mechanism of action of FGAs is thought to be via neuronal dopamine-2 (D2) receptor antagonism; activity at muscarinic, histaminergic, 5-HT2a and alpha-1 receptors is also seen. 

Examples

• Haloperidol
• Fluphenazine
• Perphenazine 
• Pimozide
• Thiothixene
• Chlorpromazine
• Thioridazine

Adverse effects

• Extrapyramidal side effects (EPSEs) 
  • Akathisia – motor disturbance resulting in restlessness, an urge for constant movement, often accompanied by visibly excessive movements
  • Parkinsonism – rigidity, tremor, bradykinesia, cogwheeling, hypomimia 
  • Acute dystonias – this refers to involuntary contraction of a muscle group or groups, which is frequently distressing to the patient. Examples include oculogyric crisis, torticollis, opisthotonos and laryngospasm (which may be fatal without appropriate and swift management). 
• Tardive dyskinesias
  • This refers to involuntary, repetitive movements, which may involve the tongue, lips (e.g. lip-smacking), jaw, trunk, and limbs. ‘Writhing’ movements of the torso, limbs or tongue may be seen
  • Often of little concern to the patient
  • Long-term disability or cosmetic deformity may occur if not addressed.
• Metabolic complications – includes weight gain, hyperlipidaemia, diabetes mellitus and cardiovascular sequelae.
• Neuroleptic malignant syndrome – the characteristic features are muscle rigidity, altered mental status, fever and dysautonomia. Rhabdomyolysis may occur. The aetiology is unclear but a previous episode of neuroleptic malignant syndrome appears to be the biggest risk factor. 
• QT prolongation / sudden cardiac death – haloperidol, chlorpromazine and thioridazine are associated with particularly increased risk of QT prolongation. The increased incidence of sudden cardiac death seen with FGAs is attributed to prolonged QT interval. Baseline ECG and annual monitoring of the QT interval is recommended. 
• Anticholinergic side effects – such as dry mouth, urinary retention, constipation, and blurred vision; particularly seen in association with chlorpromazine and thioridazine. 
• Postural hypotension – seen most with chlorpromazine and thioridazine. The mechanism is believed to be secondary to alpha-adrenergic receptor antagonism.
• Agranulocytosis – FGAs carry a very small risk of agranulocytosis, the development of which may be fatal. It has been reported with the use of chlorpromazine, fluphenazine and thioridazine.  
• Hyperprolactinaemia – this may present with menstrual cycle abnormalities, galactorrhoea, and sexual dysfunction. It occurs secondary to dopamine inhibition, hence reducing the dopaminergic inhibition of prolactin release from the anterior pituitary gland.

Other side effects of FGAs include falls, seizures, increased mortality, sexual dysfunction, retinitis pigmentosa, and cholestatic jaundice.