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Chlorpromazine


Chlorpromazine

Article Author:
Sukhmanjeet Kaur Mann
Article Editor:
Raman Marwaha
Updated:
5/23/2020 7:25:01 PM
For CME on this topic:
Chlorpromazine CME
PubMed Link:
Chlorpromazine

Indications

Chlorpromazine is a typical antipsychotic used for the treatment of:

  • Schizophrenia (primarily the positive symptoms)
  • Bipolar I acute manic type of manic-depressive illness
  • Acute agitation marked by explosive hyperexcitable behavior out of proportion to the initial provocation
  • To control nausea and vomiting
  • Persistent singultus (chronic hiccups)
  • Relief of apprehension before surgery

The efficacy of chlorpromazine in bipolar disorder was mainly established to control the manic episode of bipolar illness such as excessive energy, decreased need for sleep, increased excitability and impulsivity, and grandiose ideations. Chlorpromazine is the Food and Drug Administration (FDA)-approved treatment for persistent singultus, which is a medical problem where the hiccupping can lasts for more than 48 hours. In regards to acute psychosis, studies have shown that chlorpromazine has been effective as a short-term treatment in controlling the combativeness and aggressive behavior in children.[1][2][3]

Mechanism of Action

Chlorpromazine belongs to the category of typical antipsychotics or neuroleptics, also known as first-generation antipsychotics (FGAs). It produces its antipsychotic effect by the post-synaptic blockade at the D2 receptors in the mesolimbic pathway. However, the blockade of D2 receptors in the nigrostriatal pathway is responsible for its extrapyramidal side effects. 

The antiemetic effect of chlorpromazine stems from the combined blockade at histamine H1, dopamine D2, and muscarinic M1 receptors in the vomiting center.

Administration

The medication is available in the form of tablets (10 mg, 25 mg, 50 mg, 100 mg, 200 mg) for oral intake and can also be administered as intramuscular and intravenous injections. Dosage decisions are on a patient-by-patient basis.[4]

For the treatment of schizophrenia, the patient is initially started on 25 to 75 mg/day orally twice a day and maintained at 200 mg/day. However, the maximum dose per oral can be up to 800 mg/day. If given by intramuscular or intravenous route, it is initially started at 25 mg, followed as needed by 25 to 50 mg after 1 to 4 hours. The usual dose can be 300-800 mg/day.

For the treatment of nausea and vomiting, chlorpromazine dose can range from 10 to 25 mg orally every 4 to 6 hours as needed. If used as an intramuscular or intravenous injection, the dose can range from 25 to 50 mg every 4 to 6 hours as needed.

Persistent singultus can be treated by giving 25 to 50 mg of chlorpromazine orally every 6 to 8 hours. If hiccups persist even after oral treatment of 2 to 3 days, then chlorpromazine is given as intramuscular or intravenous dose.

To control preoperative apprehension, the dose for chlorpromazine can range from 25 to 50 mg orally and 12.5 to 25 mg intramuscularly given 2 to 3 hours before surgery.

Adverse Effects

Chlorpromazine is a low-potency antipsychotic that mainly causes non-neurologic side effects. It is highly lipid-soluble and stored in body fats, thus very slow to be removed from the body. Being a low-potency typical antipsychotic, it primarily causes dry mouth, dizziness, urine retention, blurred vision, and constipation by blocking the muscarinic receptors. There is a risk of angle-closure glaucoma in the elderly. It also causes sedation due to the blockade of histamine H1 receptors.

Antagonism at the D2 receptors in the tuberoinfundibular pathway is believed to be responsible for the increase in the prolactin level. This hyperprolactinemia can cause several endocrinal side effects, such as a decrease in libido in both the genders. In males, increased prolactin may cause gynecomastia, galactorrhea, and erectile dysfunction. Rarely, it may cause priapism. In females, an increase in prolactin levels may result in irregular menstruation, oligomenorrhea, amenorrhea, and galactorrhea. 

When administered as intramuscular or intravenous injections, it may cause hypotension and headache. Prolonged use of chlorpromazine may cause corneal deposits and lens opacity. It may prolong the QT interval. Studies have shown that chlorpromazine may also result in cholestatic jaundice by impairing the bile flow. The drug-induced hepatotoxicity results from inflammation and injury to the liver, which may significantly increase the alanine aminotransferase level (ALT). It can be prevented by regular monitoring with liver function tests, and in case of the early detection of liver injury, the drug should be stopped, and symptomatic management should start.[5][6]

Despite being a low-potency drug, chlorpromazine can still cause extrapyramidal side effects (EPS) such as acute dystonia, akathisia, parkinsonism, and tardive dyskinesia (TD). The evolution of EPS side effects can occur through hours to days. Acute dystonia refers to muscle stiffness or spasm of the head, neck, and eye muscles that can start hours after starting the medication. Akathisia includes restlessness and fast pacing. Parkinsonism includes bradykinesia, "cogwheel" rigidity, and shuffling gait. TD results from prolonged exposure to antipsychotic drugs and includes involuntary, repetitive abnormal movements of the face and extremities. Patients are at risk of developing neuroleptic malignant syndrome (NMS), which is a life-threatening manifestation, where the patient presents with "lead-pipe" muscle rigidity, autonomous instability, hyperpyrexia more than 40 degrees Celsius, altered mental status, leukocytosis, and elevated serum creatinine kinase.[7][8]

Contraindications

Chlorpromazine should not be given if there is a known hypersensitivity or allergy to phenothiazines. The drug should be used cautiously in patients who are on antihypertensive medications due to the risk of developing severe hypotension. It should not be administered concurrently with drugs that depress the central nervous system or in patients with a poorly controlled seizure disorder. The drug does not have approval for the treatment of dementia-related psychosis. Chlorpromazine's D2 receptor blockade action may affect the therapeutic efficacy of the medications with dopamine agonist action such as levodopa or cabergoline. Selective-serotonin reuptake inhibitors such as citalopram and escitalopram are contraindicated to use along with chlorpromazine. Studies have shown that chlorpromazine qualifies as a potential drug for use during breastfeeding, but under medical supervision, if the benefits outweigh risks.[9]

Monitoring

The hepatic P450 enzyme CYP2D6 metabolizes the drug, and its half-life is approximately 30 hours. It gets excreted from the body via urine and in bile. Studies have shown the correlation between chlorpromazine's therapeutic level and the improvement of the psychiatric symptoms. Researchers have noted that the patients receiving chronic treatment with chlorpromazine have lower plasma levels as compared to the patients acutely treated on an oral dose of chlorpromazine. Also, the concomitant use of anticholinergics can affect the plasma concentration of chlorpromazine. However, the plasma level and the response threshold for clinical improvement of symptoms and toxicity with the use of chlorpromazine differs both for children and adults.[10]

Toxicity

Patients who are allergic to phenothiazines can develop hypersensitive anaphylactic reactions with chlorpromazine. Such patients can be treated by discontinuing the drug and administering steroids or antihistaminic drugs. Chlorpromazine use also requires caution in patients with cerebrovascular and cardiovascular diseases. Patients should start on a low dose of chlorpromazine as an initial dosage, and the increase in subsequent dosing should be gradual. However, treatment should be discontinued if the patient develops agranulocytosis.

In the event of overdose, ensure adequate ventilation. No specific antidote is available, and treatment is mostly symptomatic with regular cardiac and respiratory monitoring. Gastric lavage may be attempted if the patient presents to the emergency department within the first 4 to 6 hours. Activated charcoal is also an option. ECGs are necessary to assess for arrhythmias or QT-interval prolongation. NMS should be treated supportively with cooling and by giving dantrolene sodium. Treatment for TD can be done by discontinuing chlorpromazine and starting a second-generation antipsychotic along with valbenazine or deutetrabenazine. 

Enhancing Healthcare Team Outcomes

Chlorpromazine is a low-potency antipsychotic drug that is usually started by a psychiatrist. However, the follow-up of the patient on the drug can involve many healthcare professionals on the interprofessional team, which include primary care providers, psychiatrists, pharmacists, nurse practitioners, or the emergency department. Psychiatric nurses monitor patients and provide education, informing the prescriber of any concerns such as adverse events or therapeutic ineffectiveness. Pharmacists review the dosage, perform drug interaction checks, and also educate patients about the importance of compliance and side effects. Adequate communication is necessary among the providers for effective patient care and to limit any medical error. Patients should be assessed for any movement disorder and also blood work, ECGs should be obtained at regular visits. At any level, if the side effects are present, effective communications should take place, and referrals made to help the patients maintain an adequate quality of life. Patients should understand to limit the consumption of alcohol and consume a healthy meal while on the drug. Interprofessional teamwork is a necessary component of successful therapy with chlorpromazine. [Level 5]


References

[1] Jufe GS, [Evolution of antipsychotics and their use in the treatment of schizophrenia. What's up, doc?]. Vertex (Buenos Aires, Argentina). 2011 Nov-Dec;     [PubMed PMID: 22799143]
[2] Valdovinos EM,Frazee BW,Hailozian C,Haro DA,Herring AA, A Nonopioid, Nonbenzodiazepine Treatment Approach For Intractable Nausea and Vomiting in the Emergency Department. Journal of clinical gastroenterology. 2019 Sep 17;     [PubMed PMID: 31567626]
[3] Kohse EK,Hollmann MW,Bardenheuer HJ,Kessler J, Chronic Hiccups: An Underestimated Problem. Anesthesia and analgesia. 2017 Oct;     [PubMed PMID: 28759492]
[4] Choi M,Barra ME,Newman K,Sin JH, Safety and Effectiveness of Intravenous Chlorpromazine for Agitation in Critically Ill Patients. Journal of intensive care medicine. 2018 Dec 17;     [PubMed PMID: 30558470]
[5] Velayudham LS,Farrell GC, Drug-induced cholestasis. Expert opinion on drug safety. 2003 May;     [PubMed PMID: 12904107]
[6] Morgan K,Martucci N,Kozlowska A,Gamal W,Brzeszczyński F,Treskes P,Samuel K,Hayes P,Nelson L,Bagnaninchi P,Brzeszczynska J,Plevris J, Chlorpromazine toxicity is associated with disruption of cell membrane integrity and initiation of a pro-inflammatory response in the HepaRG hepatic cell line. Biomedicine     [PubMed PMID: 30841456]
[7] Patterson-Lomba O,Ayyagari R,Carroll B, Risk assessment and prediction of TD incidence in psychiatric patients taking concomitant antipsychotics: a retrospective data analysis. BMC neurology. 2019 Jul 20;     [PubMed PMID: 31325958]
[8] Morris E,Green D,Graudins A, Neuroleptic malignant syndrome developing after acute overdose with olanzapine and chlorpromazine. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2009 Mar;     [PubMed PMID: 19191213]
[9] Klinger G,Stahl B,Fusar-Poli P,Merlob P, Antipsychotic drugs and breastfeeding. Pediatric endocrinology reviews : PER. 2013 Mar-Apr;     [PubMed PMID: 23724438]
[10] Rivera-Calimlim L, Problems in therapeutic blood monitoring of chlorpromazine. Therapeutic drug monitoring. 1982;     [PubMed PMID: 7041337]