Pharmacology - ANTIPSYCHOTICS (MADE EASY)

Antipsychotics are medications primarily used to treat psychotic disorders like schizophrenia, bipolar mania, and severe depression. Their mechanism of action is closely tied to the dopamine hypothesis, which suggests that altered dopamine function in the brain underlies many symptoms of psychosis. Understanding this connection provides insight into how these drugs alleviate unusual behaviors and experiences associated with such conditions.

Dopamine influences the brain through four key pathways. The mesolimbic pathway, hyperactive in schizophrenia, mediates positive psychotic symptoms like delusions and hallucinations. The mesocortical pathway is underactive in schizophrenia, leading to negative symptoms such as lack of motivation and social withdrawal. The nigrostriatal pathway governs motor function; dopamine deficiency here causes dystonia or Parkinsonian traits while excess leads to tics or dyskinesias. Lastly, the tuberoinfundibular pathway regulates prolactin secretion by inhibiting its release, impacting milk production and sexual desire.

Dopamine interacts with five primary receptors: D1, D2, D3, D4, and D5. Among these, the highest density of activity is found in pathways involving psychotic disorders through the action of primarily the D1 and especially clinically significant D2 receptors. These are key targets for antipsychotics which are categorized into older first-generation (typicals) drugs and newer second-generation agents.

Mechanism and Effects of First-Generation Antipsychotics First-generation antipsychotics aim to block D2 dopamine receptors across all brain pathways, yielding both therapeutic benefits and adverse effects. Blocking the mesolimbic pathway alleviates positive symptoms like delusions but blocking the mesocortical pathway can worsen negative symptoms such as lack of motivation or social withdrawal. Dopamine blockade in the nigrostriatal pathway may cause movement disorders, while interference in the tuberoinfundibular pathway raises prolactin levels leading to hormonal side effects.

Potency Classification and Side Effects High-potency agents like Haloperidol are effective at low doses but often result in severe extrapyramidal side effects and increased prolactin levels. Low-potency drugs such as Chlorpromazine bind less tightly to D2 receptors yet affect other receptor types causing diverse issues including orthostatic hypotension from alpha-blockade or dry mouth due to muscarinic receptor inhibition.

Second-generation atypical antipsychotics block both D2 dopamine receptors and serotonin 2A receptors, which can increase dopamine in specific brain areas while reducing extrapyramidal side effects. These drugs transiently occupy D2 receptors, allowing normal dopamine transmission that improves cognition and reduces negative symptoms compared to typical agents. They also bind to other receptor types like histamine, alpha-adrenergic, muscarinic, and various serotonin subtypes causing diverse side effects depending on the drug's binding profile. Clozapine and Olanzapine may lead to metabolic issues such as weight gain due to strong affinity for serotonin 2C or H1-histamine receptors; Risperidone has a high potential for extrapyramidal symptoms because of its strong D2 receptor affinity; Clozapine uniquely risks agranulocytosis requiring regular blood monitoring.