Second-generation antipsychotics (SGAs) are also called atypical antipsychotics Atypical Antipsychotics Antiemetics. Medications in this class include aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, and ziprasidone. The SGAs act primarily by antagonizing dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS (D2) and serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS ( 5-hydroxytryptamine 5-hydroxytryptamine A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS 2 (5-HT2)) receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors. Clinical indications include the treatment of schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia, bipolar disorder Bipolar disorder Bipolar disorder is a highly recurrent psychiatric illness characterized by periods of manic/hypomanic features (distractibility, impulsivity, increased activity, decreased sleep, talkativeness, grandiosity, flight of ideas) with or without depressive symptoms. Bipolar Disorder, and treatment-resistant depression. In comparison to 1st-generation antipsychotics ( FGAs FGAs Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics), the SGAs cause fewer extrapyramidal symptoms Extrapyramidal Symptoms Ataxia-telangiectasia but more metabolic adverse effects.
Last updated: 28 Apr, 2022
Structure of clozapine, the 1st atypical (2nd-generation) antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics.
Image: “Clozapine” by Harbin. License: Public DomainThe 2nd-generation antipsychotics (SGAs) differ significantly from one another in pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics. These agents are available as oral tablets/capsules (asenapine is a sublingual tablet or transdermal patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes), and some are also available as IM injections. Most SGAs are metabolized by the hepatic microsomal enzyme system called cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury (abbreviated CYP followed by numbers and letters for the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics family and subfamily).
The 2nd-generation antipsychotics have comparable efficacy for psychosis; clozapine is also effective in treating schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia, specifically treatment-resistant cases.
Although extrapyramidal symptoms Extrapyramidal Symptoms Ataxia-telangiectasia (EPS) do occur with SGAs, the rates are lower than with FGAs FGAs Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics. However, SGAs have more metabolic side effects, including hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus, hyperlipidemia, and weight gain. All have the serious potential adverse effects of neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome, hyperthermia, and tardive dyskinesia.
Serious adverse effects:
Other frequent side effects:
Aripiprazole and risperidone are primarily metabolized by CYP2D6 and CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers).
Asenapine and olanzapine are primarily metabolized by CYP1A2; avoid combining with CYP1A2 inhibitors.
Avoid SGAs in combination with other drugs that prolong the QT interval QT interval Electrocardiogram (ECG).
Drug | Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics after oral administration | Primary metabolism | Adverse effects* |
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Aripiprazole |
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Hepatic cytochrome enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes CYP2D6 and 3A4 to active and inactive metabolites |
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Asenapine | 24 hours | CYP1A2 and UGT glucuronidation |
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Brexpiprazole | 94 hours | CYP2D6 and 3A4 |
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Cariprazine |
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CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) to active and inactive metabolites |
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Clozapine (restricted distribution in the United States) | 12 hours | CYP1A2, other CYPs, and UGT glucuronidation |
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Iloperidone | 18–26 hours | CYP2D6 and other CYPs to active and inactive metabolites |
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Lumateperone | 18 hours after IV administration |
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Lurasidone | 29–37 hours at steady state Steady state Enzyme Kinetics | CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) to active and inactive metabolites |
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Olanzapine | 30–38 hours | CYP1A2 and UGT glucuronidation |
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Paliperidone (oral, also extended- release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology 1-, 3-, and 6-month injectable forms) | 23 hours | CYP2D6 and 3A4 |
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Pimavanserin |
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CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) and 3A5 to the active metabolite | 5%–10%:
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Quetiapine | 6–12 hours | CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) |
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Risperidone | 20 hours | CYP2D6 to active (paliperidone) and inactive metabolites |
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Ziprasidone |
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CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) |
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