Chlorpromazine

From Wikipedia, the free encyclopedia

Not to be confused with Chlorpropamide.
Chlorpromazine

Clinical data
Trade names Largactil, Thorazine, others
AHFS/Drugs.com Monograph
MedlinePlus a682040
 US FDA: Chlorpromazine
License data

 AU: C
Pregnancy
 US: C (Risk not ruled out)
category

Routes of Oral (tablets and syrup available),

administration rectal, IM, IV infusion
 N05AA01 (WHO)
ATC code

Legal status
  AU: S4 (Prescription only)
 CA: ℞-only
Legal status  UK: POM (Prescription only)
 US: ℞-only

Pharmacokinetic data
10–80% (Oral; large interindividual
Bioavailability
variation)[1]
Protein binding 90–99%[1]
Metabolism Liver, mostly CYP2D6-mediated[1]
Biological half-
30 hours[2]
life
Excretion Urine (43–65% in 24 hrs)[1]
Identifiers
IUPAC name[show]
 50-53-3 (free base)
CAS Number 69-09-0 (hydrochloride)

 2726
PubChem CID

 83
IUPHAR/BPS

 DB00477
DrugBank

 2625
ChemSpider

 U42B7VYA4P
UNII

 D00270
KEGG

 CHEBI:3647
ChEBI

 CHEMBL71
ChEMBL

ECHA InfoCard 100.000.042

Chemical and physical data
Formula C17H19ClN2S
318.86 g/mol (free base)
Molar mass
355.33 g/mol (hydrochloride)
 3D model  Interactive image
(JSmol)
SMILES[show]
InChI[show]
(verify)

Chlorpromazine (CPZ), marketed under the trade names Thorazine and Largactil among
others, is an antipsychotic medication.[2] It is primarily used to treat psychotic disorders such
as schizophrenia.[2] Other uses include the treatment of bipolar disorder, attention deficit
hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not
improve following other measures.[2] It can be given by mouth, by injection into a muscle, or
into a vein.[2]

Common side effects include movement problems, sleepiness, dry mouth, low blood pressure
upon standing, and increased weight.[2] Serious side effects may include the potentially
permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, and low
white blood cell levels.[2] In older people with psychosis as a result of dementia it may
increase the risk of death.[2] It is unclear if it is safe for use in pregnancy.[2] Chlorpromazine is
in the typical antipsychotic class.[2] Its mechanism of action is not entirely clear but believed
to be related to its ability as a dopamine antagonist.[2] It also has anti-serotonergic and
antihistaminergic properties.[2]

Chlorpromazine was discovered in 1950 and was the first antipsychotic.[3][4] It is on the
World Health Organization's List of Essential Medicines, the most effective and safe
medicines needed in a health system.[5] Its introduction has been labeled as one of the great
advances in the history of psychiatry.[6][7] It is available as a generic medication.[2] The
wholesale cost in the developing world is between US$0.02 and US$0.12 per day.[8] In the
United States it costs about US$2 per day.[2]

Contents
 1 Medical uses
o 1.1 Other
 2 Adverse effects
o 2.1 Contraindications
o 2.2 Interactions
o 2.3 Tolerance and withdrawal
 3 Pharmacology
o 3.1 Pharmacokinetics
o 3.2 Pharmacodynamics
o 3.3 Peripheral effects
 4 History
 5 Brand names
 6 Veterinary use
 7 Research
o 7.1 Amebocidal ability
 8 References
 9 External links
Medical uses
Chlorpromazine is classified as a low-potency typical antipsychotic and in the past was used
in the treatment of both acute and chronic psychoses, including schizophrenia and the manic
phase of bipolar disorder, as well as amphetamine-induced psychoses. 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.[9]

In a 2013 comparison of 15 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.[10]

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.[9][11] Symptoms of delirium in medically-hospitalized AIDS patients have been
effectively treated with low doses of chlorpromazine.[12]

Other

Chlorpromazine is occasionally used off-label for treatment of severe migraine.[13][14] It is

often, particularly as palliation, used in small doses to reduce nausea suffered by opioid-
treated cancer patients and to intensify and prolong the analgesia of the opioids as well.[13][15]

In Germany, chlorpromazine still carries label indications for insomnia, severe pruritus, and
preanesthesia.[16]

Comparison of chlorpromazine to placebo[17]

Findings in Quality of
Measured outcome Findings in words
numbers evidence
Global effects
30% less risk of having no
Not any improvement RR 0.7 CI
improvement in mental state, Very low
(9 weeks – 6 months) 0.6 to 0.9
behaviour and functioning (estimate of effect
Relapse (6 months – 2 RR 0.7 CI uncertain)
35% less risk of relapse
years) 0.5 to 0.9

Adverse effects
See also: List of adverse effects for chlorpromazine
"Thorazine shuffle" redirects here. For the Gov't Mule song, see Dose (album).

There appears to be a dose-dependent risk for seizures with chlorpromazine treatment.[18]

Tardive dyskinesia and akathisia are less commonly seen with chlorpromazine than they are
with high potency typical antipsychotics such as haloperidol[19] 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.[20]

Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of
time.

Comparison of chlorpromazine to placebo[17]

Measured Findings in Quality of
Findings in words
outcome numbers evidence
Adverse effects
5 times more likely to have considerable
RR 4.9 CI
Weight gain weight gain, around 40% with
2.3 to 10.4
chlorpromazine gaining weight
3 times more likely to cause sedation, around RR 2.8 CI
Sedation
30% with chlorpromazine 2.3 to 3.5
3.5 times more likely to cause easily
Acute movement RR 3.5 CI
reversible but unpleasant severe stiffening of Very low
disorder 1.5 to 8.0
muscles, around 6% with chlorpromazine (estimate of
2 times more likely to cause parkinsonism effect uncertain)
(symptoms such as tremor, hesitancy of RR 2.1 CI
Parkinsonism
movement, decreased facial expression), 1.6 to 2.8
around 17% with chlorpromazine
Decreased blood 3 times more likely to cause decreased blood
RR 2.4 CI
pressure with pressure and dizziness, around 15% with
1.7 to 3.3
dizziness chlorpromazine

Contraindications

Absolute contraindications include:[1]

 Circulatory
 CNS depression
 Coma
 Drug intoxication
 Bone marrow suppression
 Phaeochromocytoma
 Hepatic failure
 Active liver disease

 Previous hypersensitivity (including jaundice, agranulocytosis, etc.) to

phenothiazines, especially chlorpromazine, or any of the excipients in the formulation
being used.

Relative contraindications include:[1]

 Epilepsy
 Parkinson's disease
 Myasthenia gravis
  Hypoparathyroidism
 Prostatic hypertrophy

Very rarely, elongation of the QT interval may occur, increasing the risk of potentially fatal
arrhythmias.[21]

Interactions

Consuming food prior to taking chlorpromazine orally limits its absorption, likewise
cotreatment with benztropine can also reduce chlorpromazine absorption.[1] Alcohol can also
reduce chlorpromazine absorption.[1] Antacids slow chlorpromazine absorption.[1] Lithium
and chronic treatment with barbiturates can increase chlorpromazine clearance
significantly.[1] Tricyclic antidepressants (TCAs) can decrease chlorpromazine clearance and
hence increase chlorpromazine exposure.[1] Cotreatment with CYP1A2 inhibitors like
ciprofloxacin, fluvoxamine or vemurafenib can reduce chlorpromazine clearance and hence
increase exposure and potentially also adverse effects.[1] 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.[1]

It is also a moderate inhibitor of CYP2D6 and also a substrate for CYP2D6 and hence can
inhibit its own metabolism.[9] It can also inhibit the clearance of CYP2D6 substrates such as
dextromethorphan and hence also potentiate their effects.[9] Other drugs like codeine and
tamoxifen which require CYP2D6-mediated activation into their respective active
metabolites may have their therapeutic effects attenuated.[9] Likewise CYP2D6 inhibitors
such as paroxetine or fluoxetine can reduce chlorpromazine clearance and hence increase
serum levels of chlorpromazine and hence potentially also its adverse effects.[1]
Chlorpromazine also reduces phenytoin levels and increases valproic acid levels.[1] 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.[1] It may also interact with anticholinergic drugs
such as orphenadrine to produce hypoglycaemia (low blood sugar).[1]

Chlorpromazine may also interact with epinephrine (adrenaline) to produce a paradoxical fall
in blood pressure.[1] Monoamine oxidase inhibitors (MAOIs) and thiazide diuretics may also
accentuate the orthostatic hypotension experienced by those receiving chlorpromazine
treatment.[1] Quinidine may interact with chlorpromazine to increase myocardialdepression.[1]
Likewise it may also antagonize the effects of clonidine and guanethidine.[1] It also may
reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments
should be considered.[1] Prochlorperazine and desferrioxamine may also interact with
chlorpromazine to produce transient metabolic encephalopathy.[1]

Other drugs that prolong the QT interval such as quinidine, verapamil, amiodarone, sotalol
and methadone may also interact with chlorpromazine to produce additive QT interval
prolongation.[1]

Tolerance and withdrawal

The British National Formulary recommends a gradual withdrawal when discontinuing
antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[22] While
withdrawal symptoms can occur, there is no evidence that tolerance develops to the drug's
antipsychotic effects. A patient can be maintained for years on a therapeutically effective
dose without any decrease in effectiveness being reported. Tolerance appears to develop to
the sedating effects of chlorpromazine when it is first administered. Tolerance also appears to
develop to the extrapyramidal, parkinsonian and other neuroleptic effects, although this is
debatable.[23]

A failure to notice withdrawal symptoms may be due to the relatively long half life of the
drug resulting in the extremely slow excretion from the body. However, there are reports of
muscular discomfort, exaggeration of psychotic symptoms and movement disorders, and
difficulty sleeping when the antipsychotic drug is suddenly withdrawn, but after years of
normal doses these effects are not normally seen.[23]

Pharmacology
Pharmacokinetics

Pharmacokinetic parameters of chlorpromazine[1][9][24]

Protei
Bioavailabilit Details of Excretio
tmax CSS n Vd t1/2 Notes
y metabolism n
bound
CYP2D6, Its high
CYP1A2— degree of
mediated into lipophilicity
over 10 major (fat
metabolites.[9] solubility)
The major allows it to
routes of be detected
metabolism in the urine
include for up to 18
hydroxylation, months.[1][26]
1–4 N-oxidation, Less than
10–35
hours sulphoxidation Urine 1% of the
100– L/kg 30±7
(Oral) 90– , (43–65% unchanged
10–80% 300 ng/m (mean hour
; 6–24 99% demethylation, after 24 drug is
L : 22 s
hours deamination hours) excreted via
L/kg)
(IM) and the kidneys
conjugation. in the urine,
There is little in which
evidence 20–70% is
supporting the excreted as
development conjugated
of metabolic or
tolerance or an unconjugate
increase in the d
metabolism of metabolites,
chlorpromazin whereas 5–
 e due to 6% is
microsomal excreted in
liver enzymes feces.[26]
following
multiple doses
of the drug.[25]

Three common metabolites of chlorpromazine

Pharmacodynamics

Chlorpromazine is a very effective antagonist of D2 dopamine 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.[9]

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-HT1 and 5-HT2), with anxiolytic, and antiaggressive properties
as well as an attenuation of extrapyramidal side effects, but also leading to weight
gain and ejaculation difficulties.
 Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo,
and weight gain)
  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)
 M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic symptoms
such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus
tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic
action may attenuate extrapyramidal side effects).

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.[27]

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.[23]
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.[23]

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 histamine H1 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.[28]

In addition to influencing the neurotransmitters dopamine, serotonin, epinephrine,

norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve
glutamanergic 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.[29]

Chlorpromazine does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[30]

Peripheral effects
Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors
(reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming
of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug".[31]

History

Advertisement for Thorazine (chlorpromazine) from the early 1960s[32]

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.[33] 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.[34] In December 1950, the chemist Paul Charpentier produced a series of
compounds that included RP4560 or chlorpromazine.[3] Simone Courvoisier conducted
behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats.
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.[3]
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 possible side effect of chlorpromazine). Despite this, Laborit continued to
push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant
initially, but on January 19, 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.[3]

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.[3] Together with the Director of the hospital, Professor
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.[35]
The response was dramatic; treatment with chlorpromazine went beyond simple sedation
with patients showing improvements in thinking and emotional behaviour.[36] They also
found that doses higher than those used by Laborit were required, giving patients 75–100 mg
daily.[3]

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.[citation needed] By 1954, chlorpromazine was being used in the United States to treat
schizophrenia, mania, psychomotor excitement, and other psychotic disorders.[9][37][38] 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.[35] 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.[39]

Chlorpromazine largely replaced electroconvulsive therapy, hydrotherapy,[40] psychosurgery,

and insulin shock therapy.[36] By 1964, about 50 million people worldwide had taken it.[41]
Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the
treatment of schizophrenia, an effective drug although not a perfect one.[17] The relative
strengths or potencies of other antipsychotics are often ranked or measured against
chlorpromazine in aliquots of 100 mg, termed chlorpromazine equivalents or CPZE.[42]

Brand names
Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by Bayer in West-
Germany since July 1953[43]).

Veterinary use
The veterinary use of chlorpromazine has generally been superseded by use of
acepromazine.[44]

Chlorpromazine may be used as an antiemetic in dogs and cats, or, less often, as sedative
prior to anesthesia.[45] In horses, it often causes ataxia and lethargy, and is therefore seldom
used.[44][45]

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]

The use of chlorpromazine in food-producing animals is not permitted in the EU, as a

maximum residue limit could not be determined following assessment by the European
Medicines Agency.[46]

Research
Amebocidal ability

Chlorpromazine has tentative benefit in animals infected with Naegleria fowleri.[47]

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