in this lecture we are going to cover pharmacology of antipsychotics so antipsychotics are a class of drugs used primarily to treat psychotic disorders such as schizophrenia mania due to bipolar disorder and severe depression now in order to gain better understanding of mechanism of action of antipsychotic drugs first we need to discuss the role of dopamine in the development of psychosis so the monoamine neurotransmitter dopamine plays a key role in the so called dopamine hypothesis which argues that the unusual behavior and experiences associated with psychosis can be largely explained by changes in dopamine function in the brain now dopamine has four major pathways by which it affects the brain number one the mesolimbic pathway which is thought to be hyperactive in schizophrenia and to mediate positive symptoms of psychosis such as delusions and hallucinations number two mesocortical pathway which is thought to be under active in schizophrenia and thus mediate negative psychotic symptoms such as loss of motivation and social withdrawal number three the nigrostriatal pathway which is part of the extrapyramidal nervous system and controls motor function and movement deficiency of dopamine in this pathway can lead to dystonia and parkinsonian symptoms while excess of dopamine can lead to hyperkinetic movements such as tics and dyskinesias the last major pathway number four is the tuberoinfundibular pathway which controls prolactin secretion specifically dopamine in this pathway inhibits prolactin release and as a reminder prolactin is a hormone that enables milk production and is also involved in the control of sexual desire and regulation of immune system now within those different pathways dopamine interacts with specific receptors that mediate functional effects of dopamine there are five primary types of dopamine receptors known as D1 D2 D3 D4 and D5 out of the five D1 and D2 receptors are found in the highest density in nearly all of the pathways involved in psychotic disorders however D2 receptors are the most clinically relevant because they are the main targets of antipsychotic drugs now antipsychotics can be grouped into older first generation agents known as typicals and the newer second-generation agents known as atypicals the first generation typical antipsychotics all share the same main therapeutic goal that is to block D2 receptors furthermore typical antipsychotics are not selective for any of the four dopamine pathways and thus will block D2 receptors in almost all areas of the brain this has positive as well as negative consequences so blockade of dopamine receptors in the mesolimbic pathway reduces positive symptoms such as delusions and hallucinations which is beneficial however blockade of dopamine receptors in the mesocortical pathway that is already underactive in schizophrenia may cause worsening of negative symptoms and thus lead to diminished energy lack of motivation restrictions in emotional and verbal expressiveness and social disengagement furthermore blockade of dopamine receptors in the nigrostriatal pathway may lead to extrapyramidal disorders tardive dyskinesia and parkinson's-like symptoms such as tremors muscle rigidity and difficulty in starting and stopping movements lastly blockade of dopamine receptors in the tuberoinfundibular pathway may cause increase in blood prolactin levels which then may lead to galactorrhea gynecomastia and sexual dysfunction now based on their affinity for D2 receptors typical antipsychotics are often subclassified as high potency or low potency the examples of high potency antipsychotics are Haloperidol Fluphenazine Prochlorperazine and Trifluoperazine the example of low potency antipsychotic is Chlorpromazine so generally speaking the high potency agents produce stronger antipsychotic effect at relatively low doses however they also tend to cause more extrapyramidal side effects and greater increase in prolactin levels on the other hand the less selective low potency agents do not bind to D2 receptor as tightly as the high potency agents and generally affect a range of other receptors including alpha-adrenergic cholinergic and histamine receptors this can result in a variety of side effects for example blockade of alpha-adrenergic receptors can lead to orthostatic hypotension blockade of muscarinic receptors can lead to anticholinergic symptoms such as dry mouth blurred vision difficulty urinating and constipation and blockade of H1-histamine receptors can lead to sedation and some weight gain now let's move on to the second generation atypical antipsychotics in contrast to typical antipsychotics that primarily block only D2 receptors atypical agents appear to block both D2 receptors as well as serotonin receptors subtype 2A because serotonin inhibits dopamine release agents that block serotonin receptors may increase dopamine levels in brain areas that need it furthermore atypicals occupy D2 receptors transiently and dissociate quickly allowing for relatively normal dopamine neurotransmission this modest D2 receptor blockade in combination with serotonin receptor blockade is thought to significantly lower the incidence of extrapyramidal side effects as well as decrease negative symptoms and improve cognition compared to typical agents the examples of atypical antipsychotics are Aripiprazole Clozapine Lurasidone Olanzapine Quetiapine Risperidone and Ziprasidone now in addition to dopamine and serotonin 2A receptor blockade atypical antipsychotics also bind to many other targets including other subtypes of serotonin receptors as well as histamine alpha-adrenergic and muscarinic receptors as a result the side-effects of second-generation agents can vary depending on the drug's receptor binding profile so for example atypical antipsychotics that have strong affinity for serotonin receptors subtype 2C such as Clozapine and Olanzapine may cause metabolic side effects including weight gain hyperglycemia and dyslipidemia agents that have strong affinity for H1 receptors such as Clozapine Olanzapine and Quetiapine may cause sedation and may also contribute to weight gain agents that have significant affinity for alpha-1-adrenergic receptors such as Clozapine and Risperidone may cause orthostatic hypotension in addition to that out of all second-generation agents Risperidone seems to have the strongest affinity for D2 receptors and because of that it has the highest potential to induce extrapyramidal side effects and hyperprolactinemia lastly Clozapine is the only antipsychotic that can cause serious condition called agranulocytosis that occurs when the bone marrow does not produce enough white blood cells called granulocytes because this condition can be fatal periodic blood cell counts must be performed to ensure patient safety and with that I wanted to thank you for watching I hope you enjoyed this video and as always stay tuned for more