In a 2013 comparison of fifteen antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. It was 13% more effective than
lurasidone and
iloperidone, approximately as effective as
ziprasidone and
asenapine, and 12–16% less effective than
haloperidol,
quetiapine, and
aripiprazole.[13]
A 2014 systematic review carried out by Cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. Compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. No difference was found between the two groups beyond two years of follow-up. Patients under chlorpromazine showed a global improvement in symptoms and functioning. The systematic review also highlighted the fact that the side effects of the drug were 'severe and debilitating', including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of
acute movement disorders. They also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. They called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide.[14]
Chlorpromazine has also been used in
porphyria and as part of
tetanus treatment. It still is recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe
hiccups, severe
nausea/
emesis, and
preanesthetic conditioning are other uses.[15][16] Symptoms of
delirium in hospitalized
AIDS patients have been effectively treated with low doses of chlorpromazine.[17]
Other
Chlorpromazine is occasionally used off-label for treatment of severe
migraine.[18][19] It is often, particularly as
palliation, used in small doses to reduce nausea by
opioid-treated cancer patients and to intensify and prolong the analgesia of the opioids as well.[18][20] Efficacy has been shown in treatment of symptomatic
hypertensive emergency.
In Germany, chlorpromazine still carries label indications for
insomnia, severe
pruritus, and preanesthesia.[21]
Chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases. For example, Miki et al. 1992 trialed daily doses of chlorpromazine, reversing
chloroquine resistance in Plasmodium chabaudi isolates in
mice.[22] Weeks et al., 2018 find that it also possesses a wide spectrum
anthelmintic effect.[23]
There appears to be a dose-dependent risk for seizures with chlorpromazine treatment.[26]Tardive dyskinesia (involuntary, repetitive body movements) and
akathisia (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as
haloperidol[27] or
trifluoperazine, and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as
risperidone or
olanzapine.[28]
Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.
5 times more likely to have considerable weight gain, around 40% with chlorpromazine gaining weight
RR 4.9 CI 2.3 to 10.4
Very low (estimate of effect uncertain)
Sedation
3 times more likely to cause sedation, around 30% with chlorpromazine
RR 2.8 CI 2.3 to 3.5
Acute movement disorder
3.5 times more likely to cause easily reversible but unpleasant severe stiffening of muscles, around 6% with chlorpromazine
RR 3.5 CI 1.5 to 8.0
Parkinsonism
2 times more likely to cause parkinsonism (symptoms such as tremor, hesitancy of movement, decreased facial expression), around 17% with chlorpromazine
RR 2.1 CI 1.6 to 2.8
Decreased blood pressure with dizziness
3 times more likely to cause decreased blood pressure and dizziness, around 15% with chlorpromazine
Previous
hypersensitivity (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.
Consuming food prior to taking chlorpromazine orally limits its absorption; likewise, cotreatment with
benztropine can also reduce chlorpromazine absorption.[5]Alcohol can also reduce chlorpromazine absorption.[5] Antacids slow chlorpromazine absorption.[5]Lithium and chronic treatment with
barbiturates can increase chlorpromazine clearance significantly.[5]Tricyclic antidepressants (TCAs) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure.[5] Cotreatment with
CYP1A2 inhibitors like
ciprofloxacin,
fluvoxamine or
vemurafenib can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects.[5] Chlorpromazine can also potentiate the CNS depressant effects of drugs like
barbiturates,
benzodiazepines,
opioids, lithium and anesthetics and hence increase the potential for adverse effects such as
respiratory depression and
sedation.[5]
Chlorprozamine is also a moderate inhibitor of
CYP2D6 and a substrate for
CYP2D6, and hence can inhibit its own metabolism.[15] It can also inhibit the clearance of
CYP2D6 substrates such as
dextromethorphan, potentiating their effects.[15] Other drugs like
codeine and
tamoxifen, which require
CYP2D6-mediated activation into their respective active metabolites, may have their therapeutic effects attenuated.[15] Likewise,
CYP2D6 inhibitors such as
paroxetine or
fluoxetine can reduce chlorpromazine clearance, increasing serum levels of chlorpromazine and potentially its adverse effects.[5] Chlorpromazine also reduces
phenytoin levels and increases
valproic acid levels.[5] It also reduces
propranolol clearance and antagonizes the therapeutic effects of
antidiabetic agents,
levodopa (a
Parkinson's medication. This is likely due to the fact that chlorpromazine antagonizes the D2 receptor which is one of the receptors dopamine, a levodopa metabolite, activates),
amphetamines and
anticoagulants.[5] It may also interact with anticholinergic drugs such as
orphenadrine to produce
hypoglycaemia (low blood sugar).[5]
Chlorpromazine may also interact with
epinephrine (adrenaline) to produce a paradoxical fall in blood pressure.[5]Monoamine oxidase inhibitors (MAOIs) and
thiazide diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment.[5] Quinidine may interact with chlorpromazine to increase
myocardial depression.[5] Likewise, it may also antagonize the effects of
clonidine and
guanethidine.[5] It also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered.[5]Prochlorperazine and
desferrioxamine may also interact with chlorpromazine to produce transient metabolic
encephalopathy.[5]
The
British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[30] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[31] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[31] Less commonly, there may be a feeling of the world spinning, numbness, or muscle pains.[31] Symptoms generally resolve after a short period of time.[31]
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[32] It may also result in reoccurrence of the condition that is being treated.[33] Rarely, tardive dyskinesia can occur when the medication is stopped.[31]
Pharmacology
Chlorpromazine is classified as a low-potency
typical antipsychotic. Low-potency antipsychotics have more
anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of
extrapyramidal side effects, while high-potency antipsychotics (such as
haloperidol) have the reverse profile.[15]
Chlorpromazine is a very effective antagonist of
D2dopamine receptors and similar receptors, such as
D3 and
D5. Unlike most other drugs of this genre, it also has a high affinity for
D1 receptors. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects.
Dopamine, unable to bind with a receptor, causes a feedback loop that causes dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the
synaptic cleft. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.[15]
Chlorpromazine acts as an
antagonist (blocking agent) on different postsynaptic and presynaptic receptors:
Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
Serotonin receptors (5-HT2, 5-HT6 and 5-HT7), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of
extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor as well as with
intraoperative floppy iris syndrome due to its effect on the iris dilator muscle.[40]
The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.[41]
Chlorpromazine and other typical
antipsychotics are primarily blockers of
D2 receptors. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the D2 receptor. Therefore, a larger dose is required if the drug's affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for
dopamine receptors.[42]
Chlorpromazine tends to have greater effect at
serotonin receptors than at
D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics.[42]
Chlorpromazine and other antipsychotics with
sedative properties such as
promazine and
thioridazine are among the most potent agents at
α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at
histamineH1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other
phenothiazine antipsychotics are as potent at these sites as the most potent classical
antihistamines.[43]
In addition to influencing the neurotransmitters dopamine, serotonin,
epinephrine,
norepinephrine, and
acetylcholine it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves direct effects on antipsychotic drugs on
glutamate receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on
NMDA receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in glutamate and
glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.[44]
Because it acts on so many receptors, chlorpromazine is often referred to as a "
dirty drug".[46]
Pharmacokinetics
Pharmacokinetic parameters of chlorpromazine[5][15][47]
Bioavailability
tmax
CSS
Protein bound
Vd
t1/2
Details of metabolism
Excretion
Notes
10–80%
1–4 hours (Oral); 6–24 hours (IM)
100–300 ng/mL
90–99%
10–35 L/kg (mean: 22 L/kg)
30±7 hours
CYP2D6,
CYP1A2—mediated into over 10 major metabolites.[15] The major routes of metabolism include hydroxylation, N-oxidation, sulfoxidation, demethylation, deamination and conjugation. There is little evidence supporting the development of metabolic tolerance or an increase in the metabolism of chlorpromazine due to microsomal liver enzymes following multiple doses of the drug.[48]
Urine (43–65% after 24 hours)
Its high degree of
lipophilicity (fat solubility) allows it to be detected in the urine for up to 18 months.[5][49] Less than 1% of the unchanged drug is excreted via the kidneys in the urine, in which 20–70% is excreted as conjugated or unconjugated metabolites, whereas 5–6% is excreted in feces.[49]
History
In 1933, the French pharmaceutical company
Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized
promethazine, a
phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.[51]: 77 A year later, the French surgeon Pierre Huguenard used promethazine together with
pethidine as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon,
Henri Laborit, believed the compound stabilized the central nervous system by causing "artificial hibernation", and described this state as "sedation without
narcosis". He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties.[52] In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine.[7]
Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the
Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time. Known colloquially as "Laborit's drug", chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large "broad" and acti* "activity".[7]
Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns,
Raynaud's phenomenon, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelia Quarti who was acting as a volunteer. Quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued (
orthostatic hypotension is a known side effect of chlorpromazine). Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on 19 January 1952, it was administered (alongside pethidine,
pentothal and ECT) to Jacques Lh. a 24-year-old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.[7]
Pierre Deniker had heard about Laborit's work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the
Sainte-Anne Hospital Center in Paris where he was Men's Service Chief.[7] Together with the Director of the hospital,
Jean Delay, they published their first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents.[53] The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour.[54] They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily.[7]
Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the
Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis.[55] By 1954, chlorpromazine was being used in the United States to treat
schizophrenia,
mania, psychomotor excitement, and other
psychotic disorders.[15][56][57]
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's
GlaxoSmithKline) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying
psychiatric hospitals has been compared to that of
penicillin and infectious diseases.[53] But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotics were developed. It also led to the discovery of
antidepressants.[58]
The veterinary use of chlorpromazine has generally been superseded by use of
acepromazine.[64]
Chlorpromazine may be used as an
antiemetic in dogs and cats, or, less often, as sedative before anesthesia.[65] In horses, it often causes
ataxia and lethargy, and is therefore seldom used.[64][65]
It is commonly used to decrease nausea in animals that are too young for other common anti-emetics.[citation needed] It is also sometimes used as a
preanesthetic and
muscle relaxant in cattle, swine, sheep, and goats.[citation needed]
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