How Do Phenothiazine Antipsychotics Work?

Phenothiazine antipsychotics are medications used in the treatment of schizophrenia and other psychotic disorders. Some of the phenothiazine antipsychotics are used for sedation and to treat severe hiccups, nausea and vomiting.

Phenothiazine antipsychotics inhibit the activity of dopamine, a chemical (neurotransmitter) released in the brain by nerve cells (neurons) to transmit signals. Known as the “happy hormone,” dopamine regulates the brain’s reward system and is responsible for many essential functions including movement, emotions and cognition.

Phenothiazine antipsychotics work by blocking D2 dopamine receptors, protein molecules on neuronal surfaces that initiate excitatory action when stimulated by dopamine. Inhibiting D2 receptors reduces aggression and agitation.  

Some phenothiazine antipsychotics work as antiemetics by blocking the vagus nerve in the gastrointestinal (GI) tract. In addition to D2 receptors, phenothiazines block the activity of H1 histamine receptors and M1 muscarinic receptors which stimulate GI smooth muscle contraction.

Phenothiazine antipsychotics also depress the release of hormones by the hypothalamus and pituitary gland, which stimulate other glands in the body to release hormones. Phenothiazine antipsychotics have sedative effects and are used to relieve anxiety.

Phenothiazine antipsychotics are available as:

• Oral tablets, solution, elixir and syrup
• Rectal suppositories
• Intramuscular (IM), intravenous (IV) or subcutaneous (SC) injections

Phenothiazine antipsychotics are used to treat the following conditions:

FDA-approved:

• Psychotic disorders
• Schizophrenia
• Preoperative apprehension
• Intraoperative sedation
• Intractable hiccups
• Acute intermittent porphyria (a rare metabolic disorder)
• Behavioral disorders and hyperactivity
• Nausea and vomiting
• Prophylaxis for intraoperative nausea and vomiting
• Depressive disorders
• Non-psychotic anxiety

Off-label uses:

• Migraine headache
• Nonpsychotic dementia behavior

Side effects of phenothiazine antipsychotics may include the following:

• Extrapyramidal symptoms, which are drug-induced movement disorders such as:
  • Akathisia
  • Dystonia
  • Dyskinesia
  • 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
• Weight gain
• Decreased gag reflex
• Erectile dysfunction
• Oligomenorrhea/amenorrhea (Irregular/absent menstruation)
• Cerebral edema
• Orthostatic hypotension (blood pressure drop when standing up from sitting or lying down)
• Tachycardia (rapid heartbeat)
• Poikilothermia (inability to regulate core body temperature)
• Insomnia
• Agitation
• Anxiety
• Depression
• Euphoria
• Dizziness
• Weakness
• Headache
• Anorexia (loss of appetite)
• Dyspepsia (indigestion)
• Diarrhea
• Ileus (temporary lack of intestinal muscle contraction)
• Lens opacities (with prolonged use)
• ECG changes
• Photosensitivity
• Pruritus (itching)
• Galactorrhea (abnormal milk production and leakage)
• Gynecomastia (breast tissue growth in males)
• Ejaculatory disorder
• Blood dyscrasias (disorders) such as
  • Leukopenia (low count of leukocytes)
  • Agranulocytosis (low granulocytes, immune cells with granules)
• Seizure
• Priapism (persistent and painful erection)
• Cholestatic jaundice (jaundice due to impaired bile flow)
• Hepatotoxicity (toxicity to the liver)
• Hypotension (low blood pressure)
• Hypertension (high blood pressure)

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 phenothiazine antipsychotic drugs include:

• chlorpromazine
• Compro (prochlorperazine maleate rectal suppository)
• fluphenazine
• perphenazine
• prochlorperazine
• prochlorperazine edisylate
• prochlorperazine mesylate
• Procomp (prochlorperazine rectal suppository)
• thioridazine
• Thorazine
• trifluoperazine