How Do First-Generation Antipsychotics Work?

First-generation antipsychotics are medications used in the treatment of schizophrenia and psychosis. First-generation antipsychotics, also known as typical or conventional antipsychotics are the initial class of drugs developed to treat psychotic disorders.

First-generation antipsychotics primarily work by reducing the activity of dopamine, one of the chemicals (neurotransmitters) released in the brain by nerve cells (neurons) to transmit signals. Some of the first-generation antipsychotics also have effects on other neurotransmitters such as norepinephrine and acetylcholine.

• Dopamine has many functions, including pleasure sensation, mood, learning, and memory.
• Norepinephrine improves energy and attention.
• Acetylcholine is responsible for muscle contraction and treats nervous system disorders that cause uncontrolled muscle contractions. 

First-generation antipsychotics work by blocking D2 dopamine receptors, protein molecules on neuronal membranes that initiate excitatory action when stimulated by dopamine. The first-generation antipsychotics also depress the release of hormones by the hypothalamus and pituitary gland.

One of the first-generation antipsychotics, loxapine, in addition to D2 receptors, blocks the activity of serotonin 5-HT2A receptors.  Serotonin is another neurotransmitter that regulates mood and behavior, blocks 5-HT2A receptors which are excitatory, reduces aggression, and has a calming effect.

First-generation antipsychotics may be administered as:

• Oral tablets, capsules, solutions, or oral inhalations
• Intramuscular (IM), intravenous (IV), or subcutaneous (SC) injections

First-generation antipsychotics are used to treat the following conditions:

FDA-approved:

• Psychotic disorders
• Schizophrenia
• Sedation for psychosis
• Acute agitation
• Behavioral disorders
• Schizophrenia and bipolar I agitation
• Non-psychotic anxiety
• Tourette syndrome (a nervous system disorder involving repetitive movements or unwanted sounds)
• Nausea and vomiting

Off-label uses:

• Intractable hiccups

Side effects of first-generation antipsychotics may include the following:

• Extrapyramidal symptoms, which are drug-induced movement disorders such as:
  • Akathisia
  • Dystonia
  • Dyskinesia
  • Akinesia
  • Muscle stiffness
  • Neuroleptic malignant syndrome (rare, life-threatening reaction)
  • Parkinsonism
  • Tardive dyskinesia
• Anticholinergic effects such as:
  • Constipation
  • Urinary retention
  • Blurred vision
  • Xerostomia (dry mouth)
• Sedation
• Confusion
• Drowsiness
• Dizziness
• Headache
• Insomnia
• Weakness
• Depression
• Hyperactivity
• Euphoria
• Nervousness
• Agitation
• Anxiety
• Seizure
• Cerebral edema
• Peripheral edema
• Poikilothermia (inability to regulate core body temperature)
• Impaired regulation of body temperature
• Hyperpyrexia (high temperature)
• Heat stroke
• Increased appetite
• Increased thirst
• Weight gain
• Decreased gag reflex
• Diminished sweating
• Nasal congestion
• Hypotension (low blood pressure)
• Orthostatic hypotension (blood pressure drop when standing up from sitting or lying down)
• Abnormal ECG results
• Torsades de Pointes (irregular heart rhythm in which the ventricles beat faster and out of synchronization with the atria)
• Tachycardia (rapid heartbeat)
• Respiratory adverse effects in patients with COPD (with oral inhalations)
• Speech disorder
• Dysgeusia (taste disorder)
• Throat irritation
• Bronchospasm
• Visual disturbance
• Oculogyration (prolonged upward deviation of the eyes)
• Lens opacity
• Retinal disorders such as:
  • Pigmentary retinopathy
  • Retinitis pigmentosa
• Nausea
• Salivation
• Diarrhea
• Paralytic ileus (intestinal blockage due to paralysis of intestinal muscles)
• Obstipation (a severe form of constipation)
• Anorexia (loss of appetite)
• Dyspepsia (indigestion)
• Hypersensitivity reactions such as:
  • Rash
  • Pruritus (itching)
  • Allergic dermatitis
  • Light sensitivity
• Drug-induce systemic lupus erythematosus (SLE), an autoimmune condition
• Blood disorders such as:
  • Leukopenia (low count of leukocytes)
  • Agranulocytosis (low granulocytes, immune cells with granules)
  • Thrombocytopenia (decrease in platelet count)
  • Hematopoietic disorder (impairment in the production of blood cells)
• Abnormal liver function test results
• Obstructive hyperbilirubinemia (buildup of bilirubin, a type of jaundice)
• Cholestatic jaundice (jaundice due to impaired bile flow)
• Erectile dysfunction
• Priapism (persistent and painful erection)
• Ejaculatory disorder
• Impotence
• Increased libido
• Impaired, irregular, or absent menstruation
• Gynecomastia (breast tissue growth in males)
• Galactorrhea (abnormal milk production and leakage)
• Rhabdomyolysis (breakdown of skeletal muscle cells)
• Falls
• Death

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of first-generation antipsychotic drugs include:

• Adasuve
• fluphenazine
• Haldol
• Haldol Decanoate
• haloperidol
• Haloperidol LA
• loxapine
• loxapine inhaled
• molindone
• perphenazine
• pimozide
• thiothixene
• trifluoperazine