Dopamine receptor antagonism
The primary action of benperidol is blockade of dopamine D2 receptors in the brain. This inhibits dopaminergic neurotransmission, especially in the mesolimbic pathway. Hyperactivity of this pathway is associated with positive symptoms of psychosis such as delusions, hallucinations, and disorganized thinking.
By blocking D2 receptors, benperidol interferes with this hyperactive dopaminergic signaling, thereby reducing positive psychotic symptoms. This D2 antagonism is a shared mechanism among typical antipsychotics like benperidol and underlies their antipsychotic efficacy.
However, D2 antagonism is also responsible for many of the extrapyramidal side effects of benperidol like Parkinsonism, akathisia, and tardive dyskinesia. Lower potency at D2 receptors is related to lower risk of these movement disorders.
Serotonin receptor antagonism
In addition to dopamine receptors, benperidol also blocks serotonin 5-HT2A receptors. Antagonism of 5-HT2A receptors may contribute to its antipsychotic effects, especially reduction of negative symptoms and cognitive symptoms in schizophrenia.
5-HT2A antagonism may also lower the risk of extrapyramidal side effects compared to D2 antagonism alone. However, it produces other side effects such as sedation, weight gain, and sexual dysfunction. The balance of dopamine and serotonin receptor blockade is important for maximizing the therapeutic effects of antipsychotics while limiting adverse effects.
Histamine receptor antagonism
Benperidol blocks H1 histamine receptors, which causes sedation and drowsiness, especially at high doses or initial use. H1 antagonism may augment the antipsychotic effects, but also contributes greatly to sedation with benperidol.
Benperidol inhibits muscarinic M1 receptors, producing anticholinergic effects such as dry mouth, blurred vision, urinary retention, and constipation. This can exacerbate cognitive problems in schizophrenia and cause confusion in elderly patients or at high doses. Central anticholinergic effects also contribute to sedation with benperidol.
Benperidol demonstrates some affinity for adrenergic α1 and α2 receptors which can influence blood pressure. It also mildly blocks reuptake of noradrenaline and dopamine, although its primary mechanism remains receptor antagonism. Lower potency for these additional mechanisms may explain the tendency for less orthostatic hypotension and elevation of prolactin with benperidol compared to other typical antipsychotics.
In summary, the antipsychotic activity of benperidol arises from its ability to block dopamine D2 and serotonin 5-HT2A receptors, while its side effect profile stems from blockade of D2, 5-HT2A, H1 histamine and muscarinic M1 receptors. Receptor binding at other sites also contributes to its pharmacological effects. The benefits and risks of benperidol must be weighed carefully based on individual patient characteristics and severity of psychosis.