Second generation antipsychotics: mechanism of action
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A Simplified Guide to Oral Antipsychotic Medications – Mechanism of Action, Side Effects and Need to Know PointsPosted on:April 29, 2018 Last Updated: December 26, 2021 Time to read: 10 minutesAntipsychotic medications were discovered serendipitously in the 1950’s, when Chlorpromazine, which has antihistaminic properties was also observed to have antipsychotic effects when prescribed in patients with schizophrenia. Antipsychotic medications were predominantly used in the treatment of schizophrenia, however, nowadays they are used in a range of disorders and are evidence-based in the treatment of bipolar disorder, schizoaffective disorder and are used off-label for other disorders, such as post-traumatic stress disorder and eating disorders. Antipsychotic medications are broadly divided into typical and atypical antipsychotics although this distinction does not necessarily take into account the individuality in receptor profiles of the individual antipsychotic medications. In this particular summary, we focus on the commonly used oral atypical antipsychotic medications that are used in schizophrenia and highlight the key receptor profiles. It is important to note there may be several other receptors involved. However, we focus on the most important ones that are responsible for efficacy and tolerability. Each antipsychotic has a link to the full product information from the Therapeutic Goods Administration (TGA) for products available in Australia. CONVENTIONAL OR TYPICAL OR FIRST GENERATION ANTIPSYCHOTICA conventional, typical or first-generation antipsychotic is defined by the ability to block dopamine (D2) receptors. They also have in, varying degrees, M1, Alpha-1 and H1 receptor blockade. Typical antipsychotics:
How does dopamine blockade treat psychosis? Blocking Dopamine receptors in the mesolimbic area treats psychotic symptoms. However because the mesolimbic pathway is also a reward pathway, D2 antagonism can result in patients having apathy, anhedonia, and amotivation. Why does D2 blockade result in side effects? When a typical antipsychotic which is a dopamine antagonist is prescribed, it cannot selectively block the D2 in the mesolimbic area while sparing the D2 receptors in other areas. Therefore, prescription of a D2 antagonist can block Dopamine receptors in other areas, resulting in side effects. 1.Cognitive Side Effects 2. Depressed mood and secondary negative symptoms 3. Extrapyramidal side effects (EPSEs) 4. Raised Prolactin UNCONVENTIONAL
OR ATYPICAL OR SECOND GENERATION ANTIPSYCHOTICSThe atypicality of the atypical antipsychotics has been attributed to the combination of the D2 antagonism with the 5HT2A antagonism. There are other antipsychotics that derive their atypicality from other receptor mechanisms which we outline below. How does the 5HT2A receptor make the antipsychotic atypical? The 5HT2A receptor can be considered to be a break on the Dopamine release, i.e., if the 5HT2A receptor is activated it blocks Dopamine release. Thus, 5HT2A antagonism stimulates Dopamine release in a range of pathways, thus reducing the side effects that a typical Dopamine blocker would cause.
What are partial dopamine agonists? Partial dopamine agonists are also atypical antipsychotics and are also called third-generation antipsychotics. Aripiprazole, Brexpiprazole and Cariprazine fall under this category. Partial dopamine agonists have a lower intrinsic activity at dopamine receptors than full agonists, allowing them to act either as a functional dopamine agonist or a functional dopamine antagonist (Goldilocks effect / Dimmer Switch Effect), depending on the surrounding levels of dopamine (full agonist). In the absence of dopamine agonist activity, partial agonists show functional agonist activity, binding to the dopamine receptor to produce a response. In the presence of excessive dopamine agonist activity, partial agonists show functional antagonist activity. How are atypical antipsychotics classified? The atypical antipsychotics can be divided into the dones, the pines, two pips and a rip. Below we cover the main receptor profiles of the different antipsychotics that are relevant to clinical practice as opposed to outlining every single receptor binding. THE PINES OLANZAPINENeed to know:
QUETIAPINENeed to know:
ASENAPINENeed to know:
CLOZAPINENeed to know:
Common side effects:
Serious side effects:
THE DONES LURASIDONENeed to know:
RISPERIDONENeed to know:
PALIPERIDONENeed to know:
ZIPRASIDONENeed to know:
THE PIPS ARIPIPRAZOLENeed to know:
BREXPIPRAZOLENeed to know:
THE RIP CARIPRAZINENeed to know:
OTHERS AMISULPRIDE |