What are the pharmacodynamics of haloperidol (antipsychotic medication)?

From the Guidelines

Haloperidol is a first-generation (typical) antipsychotic that primarily works by blocking dopamine D2 receptors in the brain, with high affinity for D2 receptors in the mesolimbic and nigrostriatal pathways, explaining both its therapeutic effects and side effects. The pharmacodynamics of haloperidol involve the blockade of dopamine receptors in the mesolimbic pathway, which helps reduce positive symptoms of psychosis such as hallucinations and delusions.

Key Points

• Haloperidol blocks D2 receptors in other brain regions, including the tuberoinfundibular pathway, leading to hyperprolactinemia, and the nigrostriatal pathway, causing extrapyramidal symptoms like parkinsonism, akathisia, and dystonia 1.
• Unlike atypical antipsychotics, haloperidol has minimal activity at serotonin receptors, which explains its higher propensity for movement disorders.
• It also has some anticholinergic and antihistaminic properties, though these are relatively weak compared to its dopamine antagonism.
• Haloperidol has a high potency, meaning it produces significant antipsychotic effects at relatively low doses, and its D2 receptor occupancy typically exceeds 70-80% at therapeutic doses, which is necessary for antipsychotic efficacy but also increases the risk of extrapyramidal side effects.

Side Effects

• The most common side effects of haloperidol include extrapyramidal symptoms, such as parkinsonism, akathisia, and dystonia, as well as hyperprolactinemia and weight gain.
• Other potential side effects include sedation, orthostatic hypotension, and anticholinergic effects such as dry mouth and constipation.
• The risk of extrapyramidal side effects is higher with haloperidol compared to atypical antipsychotics, such as risperidone, which has a lower propensity for movement disorders 1.

From the FDA Drug Label

Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients.

The pharmacodynamics of haloperidol involve the elevation of prolactin levels, which can lead to various disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence. The clinical significance of elevated serum prolactin levels is unknown for most patients. 2

From the Research

Pharmacodynamics of Haloperidol

The pharmacodynamics of haloperidol involve its mechanism of action as a dopamine D2 receptor antagonist. Key aspects of its pharmacodynamics include:

• Dopamine D2 receptor occupancy: Haloperidol's antipsychotic effect is thought to be mediated by its ability to occupy dopamine D2 receptors in the brain 3, 4, 5, 6.
• Antipsychotic potency: The potency of haloperidol as an antipsychotic is directly related to its ability to bind to D2 receptors 3.
• Therapeutic concentrations: The concentrations of haloperidol found in the plasma water of treated patients closely match the predicted therapeutic absolute concentrations, adjusted for the 60-75% D2 occupancy needed for clinical efficacy 3.
• Receptor binding kinetics: Antipsychotics that elicit low or no Parkinsonism or prolactinaemia are loosely attached to D2 and rapidly dissociate from D2, whereas those eliciting Parkinsonism stay tightly attached to D2 for many hours 3.

Effects on Striatal Medium Spiny Neurons

Haloperidol's effects on striatal medium spiny neurons include:

• Reduction of excitability: Haloperidol reduces the excitability of striatal medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) 7.
• Increase in inhibitory/excitatory synaptic transmission ratio: Haloperidol affects D1-MSNs by increasing the ratio of inhibitory/excitatory synaptic transmission (I/E ratio) specifically onto D1-MSNs but not D2-MSNs 7.

Relationship with Clinical Efficacy and Side Effects

The relationship between haloperidol's pharmacodynamics and its clinical efficacy and side effects includes:

• Correlation with delirium agitation scores: Variations in dopamine receptor occupancy correlate with changes in Richmond Agitation-Sedation Scale (RASS) scores in individuals with hyperactive delirium 5.
• Risk of extrapyramidal symptoms (EPS): There is a linear association between the odds ratio of developing EPS and peak D2LR antagonism as functions of dopamine receptor occupancy 5.
• Comparison with other antipsychotics: Olanzapine leads to a lower striatal D2 receptor occupancy than haloperidol, which may contribute to its lower incidence of EPS 4, 6.