First-Generation Antipsychotics

Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, mania Mania A state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases). Bipolar Disorder, and aggression Aggression Behavior which may be manifested by destructive and attacking action which is verbal or physical, by covert attitudes of hostility or by obstructionism. Oppositional Defiant Disorder. Antipsychotics are notable for their use 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 and 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 are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. Drugs from both classes act on 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 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. Notable side effects from antipsychotic agents include movement disorders, dose-related sedation, and metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome. A serious long-term side effect to be cautious of is tardive dyskinesia, which is characterized by repetitive involuntary movements.

Last updated: Sep 1, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Neurotransmitters that may be modulated by antipsychotics for a therapeutic effect include 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, 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 (also called 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 ( 5-HT 5-HT 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)), and norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS (NE).

Mechanism of action

  • Blockade of postsynaptic 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 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 in the mesolimbic pathway → relief of psychotic symptoms Psychotic symptoms Brief Psychotic Disorder
  • Blockade in mesocortical, nigrostriatal, and tuberoinfundibular pathways → adverse effects
  • Low-potency agents have a greater affinity for:
    • Alpha-adrenergic 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
    • Histaminergic 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
    • Muscarinic receptors Muscarinic Receptors Asthma Drugs

Physiologic effects

  • Dopaminergic receptors Dopaminergic receptors Cell-surface proteins that bind dopamine with high affinity and trigger intracellular changes influencing the behavior of cells. Receptors and Neurotransmitters of the CNS:
    • Subtypes D1 and D2 are pharmacologic targets.
    • D1-like 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 are excitatory.
    • D2-like 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 are inhibitory.
    • D2 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 are expressed on dopaminergic neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology as presynaptic and postsynaptic 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.
  • 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 hypothesis Hypothesis A hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis. Statistical Tests and Data Representation 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:
    • 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 hyperfunction in the striatum Striatum Striped gray matter and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. Basal Ganglia: Anatomy (mesolimbic tract) → “positive symptoms”; 1st-generation antipsychotics (FGAs) reduce:
      • Delusions
      • Hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia
      • Paranoia
      • Mania Mania A state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases). Bipolar Disorder
      • Aggressiveness
    • 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 hypofunction in the prefrontal cortex (mesocortical tract) → negative and cognitive symptoms:
      • Blunted affect, anhedonia Anhedonia Inability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia). Schizophrenia, avolition Avolition Lack of initiative. Schizophrenia, social withdrawal
      • Impairment of attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment, working memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment, and executive function
    • High doses of psychostimulants can cause psychosis.
  • Effects of increasing 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 in the other 2 dopaminergic tracts in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification:
    • In the nigrostriatal tract: improves extrapyramidal function such as symptoms of Parkinson’s disease
    • In the chemoreceptor zone ( vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia center of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification): anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics/ vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Serotonergic ( 5-HT 5-HT 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) 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:
    • Major serotonin-producing neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology are located in the raphe Raphe Testicles: Anatomy nuclei in the brainstem.
    • 5-HT 5-HT 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 is synthesized in serotonergic nerve terminals:
      • Upon the propagation Propagation Propagation refers to how the electrical signal spreads to every myocyte in the heart. Cardiac Physiology of an action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential down the neuron → storage vesicles Vesicles Female Genitourinary Examination fuse with the presynaptic membrane Presynaptic membrane Synapses and Neurotransmission 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 neurotransmitters into the synaptic cleft Synaptic cleft Synapses and Neurotransmission 
      • 5-HT 5-HT 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 activity is terminated by the 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 transporter → reuptake of 5-HT 5-HT 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 into the serotonergic nerve terminal
      • 5-HT 5-HT 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 can then be reloaded into vesicles Vesicles Female Genitourinary Examination or metabolized on the outer mitochondrial membrane in nerve terminals.
  • 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 hypothesis Hypothesis A hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis. Statistical Tests and Data Representation 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: Hyperactivation of cortical 5-HT 5-HT 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 CNS2A 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 on glutamatergic pyramidal neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology → ↑ glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids 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 in the ventral tegmental area (VTA) → overactivation of the mesolimbic pathway → ↑ 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 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 in the striatum Striatum Striped gray matter and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. Basal Ganglia: Anatomy

Pharmacokinetics and Classification

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

There are numerous medications with unique 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.

  • FGAs act at the D2 receptor Receptor 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.
  • Well absorbed:
    • Cross the blood-brain barrier Blood-brain barrier Specialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Systemic and Special Circulations easily
    • Have long half-lives:
      • Half-lives of orally administered drugs vary from 2 hours (chlorpromazine) to 55 hours (pimozide).
      • IM dosing of some FGAs (e.g., the 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 of IM haloperidol decanoate is 3 weeks; dosed monthly)
    • 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 (CYP) inhibitors will prolong the action of FGAs:
      • Different FGAs use any or all of the CYP2D6, 3A4, and 1A2 pathways.
      • Other medications that are substrates for these pathways may cause overdose symptoms.
  • FGAs need 1–2 weeks for full effect.
  • All FGAs except haloperidol block the H1 histamine receptor Receptor 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.
  • Highly lipid-soluble compounds, some of which can be used as a long-acting injection (every 2–4 weeks)
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy: excreted in the urine and feces

Classification

The FGAs can be classified based on their potency:

  • High-potency FGAs:
    • Low activity at the histaminic and muscarinic receptors Muscarinic Receptors Asthma Drugs
    • Minimally associated with the following adverse effects:
      • Sedation
      • Weight gain
      • Anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs activity
    • High risk for extrapyramidal side effects (EPS) with all of the high-potency FGAs:
      • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
      • Bradykinesia Bradykinesia Parkinson’s Disease
      • Akathisia
    • Examples:
      • Fluphenazine (Prolixin)
      • Haloperidol (Haldol)
      • Loxapine (Loxitane)
      • Perphenazine (generic)
      • Pimozide (Orap)
      • Thiothixene (Navane)
      • Trifluoperazine (Stelazine)
  • Low-potency FGAs:
    • Lower affinity for 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 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; thus, higher doses are needed
    • Higher incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs and antihistamine side effects
    • Lower incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of EPS and 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 ( NMS NMS 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)
    • Examples:
      • Chlorpromazine (Thorazine)
      • Thioridazine (formerly Mellaril, the branded product Product A molecule created by the enzymatic reaction. Basics of Enzymes was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.)

Indications

  • Conditions treated using high-potency antipsychotics: 
    • 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:
      • Reduces the “positive” symptoms (e.g., delusions, aggressiveness)
      • FGAs have few effects on the “negative” symptoms (e.g., anhedonia Anhedonia Inability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia). Schizophrenia, social withdrawal).
      • 2nd-generation antipsychotics: more effective at reducing neurocognitive impairment
    • Psychosis
    • Mania Mania A state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases). Bipolar Disorder associated with 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:
      • Used in conjunction with mood stabilizers (e.g., lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly, valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs, and lamotrigine Lamotrigine A phenyltriazine compound, sodium and calcium channel blocker that is used for the treatment of seizures and bipolar disorder. Second-Generation Anticonvulsant Drugs)
      • FGAs act rapidly → antimanic effect (mood stabilizers have a latency period before they take effect)
    • Tic disorder ( Tourette syndrome Tourette Syndrome A neuropsychological disorder related to alterations in dopamine metabolism and neurotransmission involving frontal-subcortical neuronal circuits. Both multiple motor and one or more vocal tics need to be present with tics occurring many times a day, nearly daily, over a period of more than one year. The onset is before age 18 and the disturbance is not due to direct physiological effects of a substance or another medical condition. The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning. Tics and Tourette Syndrome)
    • Treatment-resistant depression: adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy in combination with an antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressants
    • Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders:
      • Used cautiously in individuals with severe dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders
      • Used in individuals who are aggressive or pose danger to themselves or others
  • Low-potency antipsychotics: chlorpromazine (Thorazine)
    • Used for the same conditions listed above
      • Used to relieve prolonged hiccups
      • Used to treat severe behavioral problems in children
    • Reduces aggressive behavior, hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia, suicidal/homicidal thoughts

Adverse Effects

The adverse effects of FGAs are due to 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 blockade.

  • Low-potency FGAs (chlorpromazine and thioridazine) can cause:
    • Sedation
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs side effects:
      • Dry mouth
      • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
      • Blurred vision Vision Ophthalmic Exam
      • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
      • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
      • Hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia
  • High-potency FGAs have a high risk of EPS:
    • Acute dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia: prolonged tonic muscle spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy of rapid onset upon initiating (1st 4 days) or increasing the dose of antipsychotics
    • Bradykinesia Bradykinesia Parkinson’s Disease (Parkinsonian symptom)
    • Akathisia (feeling of restlessness)
    • Perphenazine (generic): associated with a lower rate of extrapyramidal symptoms Extrapyramidal Symptoms Ataxia-telangiectasia than that with high-potency FGA haloperidol; comparable with risperidone Risperidone A selective blocker of dopamine D2 receptors and serotonin 5-HT2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia. Second-Generation Antipsychotics
  • Weight gain
  • Elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy 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
  • Ophthalmologic problems:
    • Retinitis pigmentosa (rare)
    • Worsened glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
  • “Anti-HAM” symptoms:
    • H: Anti-Histamine symptoms:
      • Sedation
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
      • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
      • Dry mouth
    • A: Anti-Alpha-adrenergic symptoms:
      • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
      • Arrhythmias
      • Sexual dysfunction Sexual dysfunction Physiological disturbances in normal sexual performance in either the male or the female. Sexual Physiology
    • M: Anti-Muscarinic symptoms:
      • Dry mouth
      • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
      • Urinary retention Urinary retention Inability to empty the urinary bladder with voiding (urination). Delirium
      • Blurred vision Vision Ophthalmic Exam
      • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Tardive dyskinesia:
    • Due to postsynaptic 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 receptor Receptor 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 hypersensitivity
    • May take years or decades to appear
    • Usually permanent and distressing to affected individuals
    • Manifestations:
      • Abnormal, involuntary, hyperkinetic movements
      • Usually affects the mouth and tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, but can also affect the trunk
      • Irreversible facial disfiguration
  • NMS NMS 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:
    • Life-threatening reaction to FGAs
    • Causes hyperthermia (very high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever)
    • Other symptoms:
      • Confusion
      • Muscle rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon
      • Diaphoresis
      • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
  • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia (and galactorrhea Galactorrhea Excessive or inappropriate lactation in females or males, and not necessarily related to pregnancy. Galactorrhea can occur either unilaterally or bilaterally, and be profuse or sparse. Its most common cause is hyperprolactinemia. Hyperprolactinemia in both women and men)

Drug-Drug Interactions and Contraindications

Drug-drug interactions

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Beers list: a list of potentially inappropriate medications for use in the elderly
    • Originally published in 1991 and updated regularly
    • All antipsychotics are listed in the Beers list.
  • General black-box warning: All antipsychotics increase the risk of death in older individuals with dementia-related psychosis.
  • CNS:
    • Individuals who are in a coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma or with CNS depression
    • Concomitant high-dose hypnotics
    • Parkinson’s disease
  • Cardiovascular:
    • Arrhythmias
    • Congenital Congenital Chorioretinitis long QT syndrome Long QT syndrome Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization that produces QT prolongation on electrocardiogram (ECG). Long QT syndrome is associated with an increased risk of developing life-threatening cardiac arrhythmias, specifically torsades de pointes. Long QT Syndrome
  • Hematologic:
    • Blood dyscrasias
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow depression

References

  1. Meyer, J.M. (2018). Pharmacotherapy of Psychosis and Mania. In Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.) Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. New York, NY: McGraw-Hill. 
  2. Nelson, L.S., et al. (2019). Neurotransmitters and Neuromodulators. In Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill.
  3. Schatzberg, A.F., DeBattista, C. (2019). Schatzberg’s Manual of Clinical Psychopharmacology, 9e. Washington, DC: American Psychiatric Association Publishing.
  4. Kaar, S.J., et al. (2020). Antipsychotics: Mechanisms underlying clinical response and side effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 172, 107704. https://doi.org/10.1016/j.neuropharm.2019.107704 
  5. Mandrioli, R., et al. (2015). Evaluation of the pharmacokinetics, safety, and clinical efficacy of ziprasidone for the treatment of schizophrenia and bipolar disorder. Expert Opinion on Drug Metabolism and Toxicology. 11, 149–174. https://doi.org/10.1517/17425255.2015.991713 
  6. Citrome, L. (2015). The ABCs of dopamine receptor partial agonists — aripiprazole, brexpiprazole, and cariprazine: the 15-min challenge to sort these agents out. The International Journal of Clinical Practice. 69, 1211–1220. https://doi.org/10.1111/ijcp.12752 
  7. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA, American Psychiatric Association.
  8. Hasin, D.S., et al. (2005). Epidemiology of major depressive disorder: Results from the national epidemiologic survey on alcoholism and related conditions. Archives of General Psychiatry. 62, 1097–1106. https://doi.org/10.1001/archpsyc.62.10.1097 
  9. American Geriatrics Society. (2019). 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatric Society. 67, 674–694. https://doi.org/10.1111/jgs.15767 
  10. Jibson, M.D. (2020). First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects. UpToDate. Retrieved August 13, 2021, from https://www.uptodate.com/contents/first-generation-antipsychotic-medications-pharmacology-administration-and-comparative-side-effects
  11. Lexicomp, Inc. (2021). Pimozide: Drug information. UpToDate. Retrieved August 14, 2021, from https://www.uptodate.com/contents/pimozide-drug-information

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