CHLORPROMAZINE
Chlorpromazine is a first-generation antipsychotic medication commonly known for the treatment of psychosis, manic episodes and Schizophrenia; additionally, known for its anti-emetic properties and treatment of nausea and vomiting. For this reason, it can be classed as either an antipsychotic or a gastrointestinal agent. Trade marketed as thorazine, chlorpromazine can be found under several names including Largactil, Contomin and Chlorderazin. It affects dopamine receptors in neurotransmitters. This drug has multiple other uses like the treatment of Porphyria, tetanus and many more. Chemically it is classified as a phenothiazine with an allopathic side chain, meaning it does not contain benzene rigs and thus is free to react more easily in a system.
Chlorpromazine’s IUPAC name is 3-(2-chlorophenothiazin-10-yl)-N,N-dimethylpropan-1-amine. This medication has a molecular weight of 318.863 g/mol, showing 3 hydrogen bond acceptors and zero donors, with 4 rotatable bonds following Lipinski’s rules for a successful chemical compound.
DISCOVERY AND DEVELOPMENT
At the end of the 19th century, the first family of antipsychotic drugs was discovered, such being phenothiazines. Chlorpromazine is a synthetic dimethylamine derivative of such compound. These drugs treated diverse illnesses such as Malaria and microbial infections before treating psychotic diseases. A pharmaceutical company in France called Rhône-Poulenc at the time wanted to develop anti-histamine drugs that target the central nervous system. They aimed to develop a drug that could be taken prior to surgery to calm down patients. After development and testing, chlorpromazine was found to cause patients to tranquilize without the effect of sedation. They believed that this drug could have a large impact in psychiatry especially after World War II. During this time, the development of anti-psychotic drugs was increasing.
Jean Delay and Pierre Deniker were the two psychiatrists in Paris that began to use Chlorpromazine in patients at the St. Anne’s Hospital in France in 1952. Chlorpromazine was tested directly on patients skipping animal and clinical trials. After a period of testing inpatients, the psychiatrists reached the conclusion that this drug was highly effective in patients with Schizophrenia and published their findings the same year.
It wasn’t until 1954 when Chlorpromazine was introduced to North America. At the time, Europe and America had very different views on psychology; while Europe was focused on social psychology, America leaned towards psychoanalysis. Thus, the introduction of Chlorpromazine came later.
PATIENTS
The principal pharmacological use of chlorpromazine is mostly psychotropic, meaning that it treats mental illness. Mental illnesses like psychosis, bipolar disorder and Schizophrenia are treated with chlorpromazine being the first drug to ever treat Schizophrenia. In addition, it treats behavior problems in children as it tranquilizes without fully sedating patients and nausea as it has anti-emetic properties. Other symptoms like prolonged hiccups, and tetanus (paired with other medications), may be treated with this medication.
Patients range from children all the way to elders. Children from the early age of 6 months to 12 years that present aggressive behaviors, nausea, vomiting or tetanus are treated with chlorpromazine. Adults usually take this drug for manic episodes, sedation, continuous hiccups (<1 month), Schizophrenia and tetanus.
Patients taking this drug should avoid alcohol as it may increase side effects by prolonging the effects on the central nervous system as it is a depressant. In addition, they should avoid sun exposure as chlorpromazine makes the skin more sensitive and susceptible to burning easily. Effects of chlorpromazine differ between each patient, contrasting significantly between normal (non-psychotic) and psychotic individuals. In normal individuals taking chlorpromazine for its anti-emetic properties, a development of indifference to the surroundings, reduced speed, quietness and reduced sleepiness is seen. Spontaneity is minimized as well. In psychotic individual’s irrational behavior, aggressiveness, negative/anxious thoughts and behaviors are normalized reducing psychotic symptoms. For Schizophrenia patients, hallucinations and delusions are inhibited.
TARGET
According to International Programme on Chemical Safety (IPCS), Chlorpromazine has actions at all levels of the central nervous system – primarily at subcortical levels – as well as on multiple organ systems. The main target for Chlopromazine is D2 dopamine receptors in neurotransmitters in the brain. Pharmacokinetic research of this medication shows that it binds to plasma proteins easily ranging from 92% to 97% in trialed blood concentrations. Chlorpromazine is distributed around the body crossing the blood brain barrier to the point where there are higher concentrations of the drug in the brain than in the plasma. Two to three hours after consumption of chlorpromazine, plasma levels peak. Peak concentrations are reached much faster if drug is taken IV or IM in contrast to orally. Plasma levels decrease if patient consumes food or any anticholinergic drugs prior to taking chlorpromazine; the effects of the drug are reduced or prolonged.
MECHANISM OF ACTION
Chlorpromazine is a competitive inhibitor for several receptors in the body however, its antipsychotic properties mainly compete for D2 dopamine receptors in neurotransmitters in the mesolimbic system of the brain.
SIDE EFFECTS
Side effects are most commonly seen in adults. Aside from allergic reactions in patients to phenothiazines, this drug has a series of side effects, some harsher than others. The less serious side effects may include: dizziness, anxiety, insomnia, changes in menstrual period, breast swelling, dry mouth, stuffy nose, constipation or impotence. However, there are more serious side effects that may be life threatening if not treated rapidly or accordingly. For instance, ceasing urination, decreased vision, uncontrollable movements in certain parts of the body like eyes, lips and legs (twitching), tremors, restlessness, difference in heart rate and light headedness. As this medication is a first-generation drug, it is associated with movement disorders. In addition, other serious side effects may include: flu symptoms, fever, itching, slow heart and breathing rates, confusion and stiff muscles.
Chlorpromazine can cause enzyme levels to increase, altering metabolic functions and can cause acute and chronic cholestatic liver injuries as well as heart failure. For this reason, this drug should be administered carefully to patients with any of these diseases or risks.
A patient with dementia cannot take Chlorpromazine as side effects include heart failure, pneumonia or even sudden death.
A doctor must document all medications, treatments and diseases a patient has or has had before prescribing chlorpromazine. Patients with history of diverse illnesses like liver or kidney disease, glaucoma, heart disease, amongst many more may be more susceptible to harsh side effects. Doctors evaluate each patient case carefully to determine if chlorpromazine is the correct option.
Pregnant woman should not take chlorpromazine as they may undergo feelings of withdrawal, breathing and feeding problems and stiff muscles. However, a woman who has been taking it during pregnancy should not stop midway but should talk to the primary care physician for more specific recommendations.
DOSAGE
Chlorpromazine may be taken orally, intravenously (IV), intramuscularly (IM) or rectally depending on the recommendations stated by a doctor. Oral intake is via tablet or syrup form. It is recommended not to crush tablets as this increases the rate of metabolism in the stomach, reducing the bioavailability of the drug. Both IM and IV doses are injected in the deltoid muscle (shoulder) or the gluteus maximus muscle (buttock). IV injections are diluted forms of the drug which are beneficial for patients that acquire an allergy from IM insertion. Rectal intake of chlorpromazine is via suppositories.
Dosage depends on the illness intending to treat, the age and weight of the patient and the mechanism of intake (oral, intravenous or intramuscular). For the treatment of psychotic illnesses in adults, dosages are higher than when treating tetanus, nausea, hiccups, etc. For children, the dosage for the treatment of aggressive behavior, hyperactivity (and its commonly manifested behaviors ie. Impulsivity, poor frustration tolerance, etc.), tetanus, nausea or sedation does not vary significantly.
For example, for an adult in a hospital presenting an Acute Manic episode the average dosage is about 500mg orally per day. For patients coming out of the hospital (at home), the average is an initial dose of 25mg orally three times a day and then a maintenance dose of 400mg orally per day. Patients in need of immediate tranquilization may receive up to 1000mg/day to achieve cooperativeness. In treating psychotic illnesses like the previously mentioned manic episodes, schizophrenia or psychosis, chlorpromazine is dosed similarly. To find the perfect dose for a patient, doctors increase a drug dose gradually for a period and then start decreasing it until achieving the most beneficial dosage for the specific patient. Every patient has their own optimum dose.
Contrary to the high dosages of psychotic episodes, adults presenting symptoms like nausea and vomiting require a much smaller dose of chlorpromazine. With 10 mg to 25 mg dose of this drug every 4 to 6 hours, a patient suffering from emesis will no longer present the symptoms.
For children presenting aggressive behavior the average dose is about .55mg/kg orally every 4-6 hours as needed. Children being treated for nausea receive the same dosage.
The maximum dosage a patient can intake in 24 hours varies with age; for adults 2000 mg/day. However, the pediatric maximum dosage for children is much less and it is split into two age groups. From the ages of 6 months to 5 years (or 22.7 kg= 50 lbs) are recommended to take no more than 40 mg/day. Children from the age of 5 to 12 (or 45.5 kg = 100 lbs) must not take more than 75 mg/day. However, children incoming to a hospital with severe behavior disorders are treated with much higher dosages ranging from 100 mg/day to 200 mg/day to control the behavior and induce cooperativeness, via Intramuscular injections for immediate response.
Chlorpromazine poisoning or overdose can be detected with the occurrence of cardiac arrhythmias and extrapyramidal symptoms. The latter refers to symptoms such as excessive tremors, dystonia (continuous spasms and muscle contractions), rigidity, amongst others; caused by damage to the extrapyramidal motor system due to excessive chlorpromazine consumption.
IMPORTANT PROPERTIES
The biological half-life of Chlorpromazine is not very long, lasting only a few hours. However, once metabolized, the excretion through urine or feces may be prolonged. Specially under the effects of other depressants conjoined with chlorpromazine. Once drug use is discontinued, the substance can be found in urine for up to 18 days. Research shows that there is a possibility of minute concentrations of the drug to either be slowly reversible or irreversibly attached to dopamine receptor active sites. Another reason is the possible accumulation of minute amounts of the drug in adipose tissues that is slowly released (Lacoursiere, 1976). After chronic use of this medicine, high levels of resulting metabolites are found in the lungs and liver.