Antipsychotics: The EssentialsModule 2

Mechanism of Action of Aripiprazole

Flavio Guzmán, MD

Aripiprazole is a partial agonist that acts on mesolimbic and mesocortical dopamine

pathways.

What is an partial agonist?

Aripiprazole as partial agonist

Partial agonism in the mesolimbic pathway

Dopamine Activity in Healthy Individuals

Basal Activity

Maximal Activity

Normal Activity

Dopaminergic neurotransmission

log [drug]

Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Schizophrenia: overactivity of the mesolimbic pathway

Basal Activity

Maximal Activity Schizophrenia

log [drug]

Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Dopaminergic neurotransmission

Aripiprazole therapy

Basal Activity

Maximal Activity

Dotted sigmoidal line: actions of partial agonist in the presence of endogenous concentrations of dopamine.

Schizophrenia

log [drug]

Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Dopaminergic neurotransmission

Partial agonism in the mesocortical pathway

Dopamine Activity in Normal Circumstances

Basal Activity

Maximal Activity

Normal Activity

log [drug]Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Dopaminergic neurotransmission

Dopamine System in Schizophrenia

Basal Activity

Maximal Activity

Normal Activity

Schizophrenia

log [drug]

Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Aripiprazole Therapy

Basal Activity

Maximal Activity

Normal Activity

Schizophrenia

log [drug]Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Dopaminergic neurotransmission

Aripiprazole effects on other dopamine pathways

Tuberoinfundibular Pathway Nigrostriatal Pathway

Less risk of hyperprolactinemia Less risk of EPS

Other pharmacological properties

Key Points• Aripiprazole is a partial agonist at D2 receptors.• It may act as an antipsychotic by:

– Lowering dopaminergic neurotransmission in the mesolimbic pathway.

– Enhancing dopaminergic activity in the mesocortical pathway.

• It has a lower risk of EPS and hyperprolactinemia than other antipsychotics