Medicine & USMLE

Typical Antipsychotics

Psych Pharm
  1. Lithium
  2. Typical Antipsychotics
  3. Atypical Antipsychotics
  4. SSRIs
  5. SNRIs
  6. Tricyclic Antidepressants (TCAs)
  7. Monoamine Oxidase Inhibitors (MAOIs)
  8. Bupropion
  9. Mirtazapine
  10. Trazadone
  11. Vilazodone
  12. Vortioxetine
  13. Buspirone
  14. Varenicline


Typical antipsychotics, also known as first-generation antipsychotics (FGAs), are a class of drugs used to treat psychosis. They are separated into two groups, the high potency and low potency typical antipsychotics. Important high potency drugs to know are haloperidol and fluphenazine, while low potency antipsychotics include chlorpromazine. All of these drugs function by blocking D2 dopamine receptors. Typical antipsychotics are typically used to treat patients with psychotic disorders such as schizophrenia, or to calm patients with acute agitation. High potency antipsychotics are associated with the development of extrapyramidal symptoms, including akathisia, parkinsonism, acute dystonia, and tardive dyskinesia. In contrast, low potency antipsychotics are more associated with anticholinergic and antihistaminic side effects. Both high and low potency antipsychotics can cause hyperprolactinemia, neuroleptic malignant syndrome (NMS), and long QT syndrome. 

Key Points

  • Typical Antipsychotics
    • Also known as first-generation antipsychotics (FGA)
    • High potency
      • Haloperidol
      • Fluphenazine
      • Pimozide
    • Low potency 
      • Chlorpromazine
      • Thioridazine
      • Trifluoperazine
    • Mechanism
      • D2 (dopamine) receptor antagonist
        • Blocks effects of dopamine released by dopaminergic neurons in the brain, primarily affecting the following known pathways:
          • Mesolimbic
            • This dopaminergic pathway is involved in reward-seeking and a dopaminergic imbalance in this region is thought to be the cause of psychosis.
          • Nigrostriatal
            • The nigrostriatal pathway plays a key role in regulating movement as part of the basal ganglia. Inhibiting the effects of dopamine in this pathway leads to movement abnormalities, including Parkinsonism.
          • Tuberoinfundibular
            • Dopamine released by the dopaminergic neurons of the tuberoinfundibular pathway normally act on the anterior pituitary to inhibit prolactin secretion. Blocking the effect of dopamine in this pathway leads to hyperprolactinemia.
        • Blocking D2 receptors (Gi subunit-coupled receptor) causes an increase in intracellular cAMP levels
        • Lipid-soluble
          • Slow release from fatty tissue stores allows for long-lasting effects.
    • Clinical Use
      •  Psychotic states
        • Schizophrenia
          • Typical antipsychotics are not considered first-line
            • Treat positive symptoms (delusions, hallucinations, thought disorders), but have minimal effect on negative symptoms (flat affect, apathy, anhedonia, minimal speech, anti-social behavior)
        •  Mania with psychotic symptoms
          • Bipolar Type I
        • Psychotic episodes during pregnancy
          • Typical antipsychotics preferred over atypical antipsychotics
      • Acute agitation
        • Haloperidol is often used to treat delirium, agitation secondary to delusional states, or agitation provoked by substance use
      • Treatment-resistant tics in Tourette syndrome
        • High-potency antipsychotics (haloperidol, fluphenazine, pimozide)
      • Huntington disease
        • Suppresses involuntary movements by inhibiting dopamine in basal ganglia pathways.
      • Disruptive mood dysregulation disorder
    • Adverse Effects
      • Neuroleptic malignant syndrome
        • Life-threatening reaction to antipsychotics characterized by:
          • Fever
          • Muscle rigidity (“lead pipe” rigidity)
            • Often accompanied by an increase in creatinine kinase (CK)
          • Altered mental status
          • Autonomic dysfunction
            • Unstable vitals (BP, HR)
        • Tip: can differentiate from serotonin syndrome by lack of hyperactive reflexes (i.e. no clonus/hyperreflexia)
        • Treat with dantrolene and supportive care
      • Extrapyramidal symptoms
        • More common with high potency antipsychotics
        • Disordered movements related to the effect of D2 antagonism on nigrostriatal pathways
        • Acute (hours to days)
          • Acute dystonia
            • Muscle spasm/stiffness
              • Ex) Neck twisted to one side
            • Oculogyric crisis
              • Eyes stuck looking upwards
            • Risk of laryngospasm
            • Treatment: Anticholinergics (benztropine, trihexyphenidyl), antihistamines (diphenhydramine)
        • Subchronic (days to months)
          • Akathisia 
            • Restlessness/urge to move
            • Treat with beta-blockers, benztropine, benzodiazepines
          • Parkinsonism
            • Bradykinesia, cogwheel rigidity, tremor, shuffling gait
            • Treat with benztropine or amantadine
        • Chronic (months to years)
          • Tardive dyskinesia
            • Involuntary repetitive movements, primarily of the face, tongue, and neck (lip smacking, sticking out tongue, grimacing)
            • Often irreversible
      • Hyperprolactinemia
        • D2 antagonism prevents normal dopamine inhibition of prolactin secretion from lactotrophs of the anterior pituitary, leading to galactorrhea, gynecomastia, oligomenorrhea, impotence, and low libido
        • High levels of prolactin can suppress GnRH, leading to secondary hypogonadotropic hypogonadism
      • Anticholinergic effects
        • More common with low potency antipsychotics
        • Symptoms include tachycardia, confusion, constipation, urinary retention, dry mouth, increase in pupil size (mydriasis), dry skin
      • Antihistaminic effects (Sedation)
        • More common with low potency antipsychotics
      • Orthostatic hypotension
        • More common with low potency antipsychotics
        • Due to blockade of alpha-1 adrenergic receptors
      • Prolonged QT
      • Ocular deposits
        • Chlorpromazine leads to corneal deposits
        • Thioridazine leads to retinal deposits
      • Metabolic syndrome
        • Weight gain
        • Dyslipidemia
        • Hyperglycemia