This article provides a detailed overview of antipsychotic medications, focusing on both first-generation (typical) and second-generation (atypical) agents. It explores their clinical indications, mechanisms of action, receptor pharmacology, and pharmacokinetic properties. Additionally, it explains how dopamine pathways contribute to therapeutic effects and adverse reactions. For more information on the clinical safety of antipsychotics, please visit the article linked. Indications for Use Antipsychotics are used to treat schizophrenia, bipolar disorder (including mania), and acute agitation. They are also used for rapid tranquillisation and in palliative care for symptoms such as nausea, vomiting, and restlessness. Some agents have additional uses, including generalised anxiety disorder, intractable hiccups, and agitation in elderly patients, while clozapine is reserved for treatment-resistant schizophrenia. Mechanism of Action Antipsychotics primarily act as postsynaptic dopamine D2 receptor antagonists. First-generation antipsychotics tend to have strong D2 blockade and are less receptor-selective. Second-generation antipsychotics tend to act on multiple receptors, including: Dopamine (D2) Serotonin (5-HT1A, 5-HT2A) Histamine (H1) Muscarinic (M1) α-adrenergic receptors Imaging studies suggest 80% blockade of D2 receptors is required to elicit an antipsychotic response. The table below describes the three main dopamine pathways in the brain, which explains the pharmacological effect and some adverse effects that can occur with antipsychotic treatment. Dopamine blockade in the chemoreceptor trigger zone also accounts for side effects such as nausea and vomiting. Name Brain area Impact of D2 blockade Mesolimbic/mesocortical pathway Between midbrain and limbic system/frontal cortex Associated with schizophrenia Reduces positive symptoms in schizophrenia Nigrostriatal pathway Between substantia nigra and corpus striatum of basal ganglia Causes extrapyramidal side effects (EPSE) Tuberohypophyseal pathway Between hypothalamus and pituitary gland Increases prolactin secretion Blockade of the D2 receptors in the mesolimbic pathway is thought to treat positive symptoms in schizophrenia. Created in https://BioRender.com Fig 1: Dopamine pathways brain Symptoms of Schizophrenia Positive Symptoms (excess function) Hallucinations Delusions Catatonia Negative Symptoms (loss of function) Social withdrawal Flattened affect Anhedonia Reduced motivation The sedating effects of antipsychotics are immediate, whereas the onset of antipsychotic activity is thought to have a delayed onset (days to weeks). Serotonin Receptors Some second-generation antipsychotics also have activity at serotonin receptors. It is thought that the 5HT-1a and 5HT2a receptors have a role to play in schizophrenia. In the nigrostriatal pathway, 5-HT2a receptors control the release of dopamine. Olanzapine and risperidone are 5HT-2a antagonists contributing to a reduction in extrapyramidal side effects (EPSE), possibly due to the following effects: Enhanced dopamine release in the striatum D2 and 5HT-2a antagonism counteract increased dopamine in the mesolimbic pathway 5-HT2a antagonism also enhances dopamine and glutamate release in the mesocortical circuit which may improve negative symptoms of schizophrenia. Quetiapine and aripiprazole are partial 5HT1a agonists which may reduce 5HT release leading to enhanced dopamine release in the striatum and prefrontal cortex. Muscarinic Receptors Olanzapine, quetiapine, clozapine, chlorpromazine are all antagonists at muscarinic receptors which may be a possible mechanism for a reduction in EPSE. Blockade of D2 receptors in the striatum leads to increased acetylcholine action at muscarinic receptors leading to EPSE, therefore antagonist action at the muscarinic receptors will reduce this effect. The effect of quetiapine at H1 receptors causes drowsiness and helps to treat insomnia. Pharmacokinetics First-generation antipsychotics are more selective for D2 receptors, whereas second-generation antipsychotics generally display broader receptor binding, thought to contribute to a reduction in EPSE. The following table includes key pharmacokinetic drug summaries for first- and second-generation antipsychotics. First-Generation Antipsychotics Drug (available route) Receptor activity Absorption Distribution Metabolism Excretion Chlorpromazine (PO, PR) Blockade of α1-adrenergic, M, D1-5, 5HT-2a and H1 F ~32% Tmax 2-4 hours Erratically absorbed with a high variation in Cmax Extensive distribution 95-98% plasma protein binding Diffuses across placenta Excreted in breast milk Metabolised in liver via oxidation Excreted via kidneys and bile Half life (t½) ~ 30 hours Levomepromazine (parenteral/PO) Blockade of α1-adrenergic, α2-adrenergic, M1, H1 and D2 F=50% Tmax 2-3 hours (parenteral/oral) Vd = 23-42L/kg Metabolised by CYP3A4 (major) and CYP1A2 (minor) in liver Excreted via kidneys and bile T ½ = 15-30 hours Haloperidol (parenteral/PO) Blockade of α1-adrenergic, D1-5, 5HT-2a and H1 Used for rapid tranquilisation when used intramuscular injection (IM); Tmax = 20-40 minutes (IM) Tmax = 2-6 hours (PO) F = 60-70% Extensive distribution Vd = 8-21L/kg 88-92% plasma protein binding Extensive metabolism by CYP3A4 and CYP2D6 in liver (dose reduction required in liver impairment, caution in known poor metabolisers of CYP2D6) Excreted via kidneys and bile T ½ = 21 hours (IM), 24 hours (PO) Second-Generation Antipsychotics Drug (available route) Receptor activity Absorption Distribution Metabolism Excretion Quetiapine (PO) Blockade of α1-adrenergic, M, D1, D2, 5HT-2a and H1, Partial agonist at 5-HT1a. Active metabolite norquetiapine is active muscarinic agonist Well absorbed Plasma protein binding: 83% Extensively metabolised by CYP3A4 T½ = 6hrs Dose adjustment not required in renal impairment, however may be required in hepatic impairment due to extensive metabolism Aripiprazole (PO, parenteral (including MR injection)) Blockade of α1-adrenergic, D1, D2, 5HT-2a and H1 Partial agonist at D2 and 5HT-1a receptors Well absorbed Tmax = 3-5 hours F = 87% Widely distributed Plasma protein binding >99% Extensively metabolised by CYP2D6 and CYP3A4 to active metabolite T½ = 75 hours (CYP2D6 extensive metabolisers) T ½ = 146 hours (poor metabolisers CYP2D6) 27% renal excretion and 60% faeces Risperidone (MR injection, PO) Blockade of α1-adrenergic, D1, D2, 5HT-2a and H1 Potent at D4 receptors Tmax = 1-2 hours F = 70% Relative oral bioavailability of tablet is 94% compared to liquid Css = 1 day (risperidone) Css= 4-5 days (paliperidone) Vd = 1-2L/kg Plasma protein binding = 90% (risperidone), 77% (paliperidone) Metabolised to paliperidone (9-hydroxy-risperidone) by CYP2D6 Minor metabolism via CYP3A4 T½ = 3 hours (risperidone), 24 hours (paliperidone) Exposure can be increased in renal and hepatic impairment – lower starting doses should be considered Amisulpride (PO) High affinity D2/D3 receptors F = 48% Two absorption peaks observed at 1 hour and at 3-4 hours Vd = 5.8L/kg Protein plasma binding: 16% Weakly metabolised to inactive metabolites T ½ = 12 hours Eliminated renally Dose reduction required in renal impairment but not in hepatic impairment Clozapine (PO) Blockade of α1-adrenergic, M, 5HT-2a and H1 Weak antagonist activity at receptors D1, 2, 3 and 5, but high potency for the D4 receptor. F = 50-60% (moderate first pass metabolism) Tmax = 2/1 hours Linear pharmacokinetics Vd = 1.6L/kg Protein plasma binding: 95% Extensive metabolism by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6 One metabolite is active but less potent and short T1/2 T ½ = 14.2 hours once at steady state 50% excreted via urine and 30% faeces Olanzapine (PO, parenteral) Blockade at D1-5, M1-M5, α1-adrenergic, 5HT-2a/2c, 5HT-3, 5HT-6, H1 Tmax = 5-8 hours Plasma protein binding = 93% Metabolised by CYP1A2 and CYP2D6 T ½ varied depending on age and gender, ranges from 32.3-51.8 hours References Clozaril 25 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 4411 Accessed 18/04/26 Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier. Clozapine: reminder of potentially fatal risk of intestinal obstruction, faecal impaction, and paralytic ileus – GOV.UK. MHRA. Published 26 October 2017 Chlorpromazine 100mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 3476 Accessed 24/4/26 Chlorpromazine Hydrochloride 100mg/5ml Oral Syrup – Summary of Product Characteristics (SmPC) – (emc) | 6696 Accessed 24/4/26 Levomepromazine Hydrochloride 25mg/ml Solution for Injection – Summary of Product Characteristics (SmPC) – (emc) | 3014 Accessed 24/4/26 Haloperidol 5 mg/ml solution for injection – Summary of Product Characteristics (SmPC) – (emc) | 100592 Accessed 24/4/26 HALDOL 2 mg/ml oral solution – Summary of Product Characteristics (SmPC) – (emc) | 15252 Accessed 24/4/26 Aripiprazole 10mg tablets – Summary of Product Characteristics (SmPC) – (emc) | 7074 Accessed 27/4/26 Quetiapine 25 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 3079 Accessed 27/4/26 https://www.medicines.org.uk/emc/product/11871/smpc Accessed 27/4/26 Amisulpride 100 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 101726 Accessed 29/04/26 Olanzapine 10 mg tablets – Summary of Product Characteristics (SmPC) – (emc) | 3070 Accessed 30/04/26 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Pharmacology of Antipsychotics Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 200 multiple-choice questions to reinforce learning. Learn More Rate This Article