Chlorpromazine: being synthesized in 1951. The drug

Chlorpromazine:
how an ingenious change to an initial idea led to its prominent position in
clinical psychiatry

Introduction

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Chlorpromazine is a drug which has
become an indisputably important development within the pharmaceutical industry,
having consistently proven to be an effective medication, since first being
synthesized in 1951. The drug is used in treating numerous patients with mental
illnesses, such as schizophrenia and bipolar. This is because of its ability to
help re-establish a balance of the naturally occurring substances in the brain,
an interaction which will be further discussed later in the report.

The intended aim of this report is to research and then write about
how Chlorpromazine, one of pharmaceuticals more vital developments, came to be,
including: the chemical process to synthesize this drug; the mechanism, clearly
highlighting each step of the interaction of Chlorpromazine with body, and
finally an analysis of the side effects. From this, I will be able to make conclusions
about the drug itself and how the benefits outweigh any possible negatives,
hence its continuous use and prescription.

Through
writing this report on Chlorpromazine, I hope to not only expand my knowledge
of the medication’s use and development, but also gain a greater understanding
of the ways it has helped several people throughout the decades. However, despite my research and aims,
this drug report might not include as much thorough detail regarding the
biological aspects, because that requires a greater background knowledge in
that area.

 

History

Chlorpromazine is a significant drug
and the first of its kind, being an antipsychotic drug, which is a medicine
that is mainly used to treat mental illnesses like schizophrenia and bipolar
disorder. Since its initial synthesis in 1951, there is yet to be another
antipsychotic drug that can prove to treat schizophrenia with significantly more
effect; this is therefore one of the reasons why Chlorpromazine remains on the
World Health Organization’s ‘List of Essential Medicines’ 2.

 

This
medicine was synthesized in December of 1951 by Paul Charpentier, who worked within the
pharmaceutical company Rhône-Poulenc, however the use of this drug nowadays
differs to Charpentier’s original intention.2 When Chlorpromazine
was sent out for a clinical review months later, it was initially designed to
act in place of a “possible
potentiator of general anesthesia” 3. The research and
synthesis presented by Paul Charpentier thus caused colleagues and fellow
researchers within the industry to encourage the use of this medicine prior to
surgery, as CPZ proved to calm and sedate the patients, because it was found to
treat the central nervous system. 2

As a result
of the success this drug proved to be, Henri Laborit, who practised within the French
army as a surgeon and physiologist, had the idea that this medicine may be of
use in psychiatry. In collaboration with Hamon, Paraire and Velluz, this “landmark drug” 4 helped
to revolutionise the psychiatric treatments when it was first prescribed to a
young man, Jacques Lh., who was suffering from agitations and mania.  This
treatment supported Laborit’s proposition since Jacques was released only 20
days later, due to a recovery from his previous psychotic state.4

Despite
having to occasionally swap the CPZ medication for other traditional
antipsychotic methods, due to irritation from the intravenous process, this overall demonstration exhibited its
potential to have success in sedating patients and general psychiatry; because
of this the first paper on CPZ in psychiatry was published in March of 1952
with many compelling arguments for the use of Chlorpromazine.3

Later that same year, CPZ was prescribed throughout France as
an antipsychotic, going by the name of Largactil. Within the following three
years, Chlorpromazine entered the psychiatric clinical practice as a medication
and soon found itself in use worldwide.3 The prescription and use of
this drug in psychiatry seems like a sudden and abrupt decision, especially in comparison
to the usual protocol of drug developments followed today, which averages at 12
years 5; therefore, there is a clear reflection of how systems and processes have differed
within 60 years.2

 

Synthesis

The diagram
shown above represents the reaction between 2-chlorophenothiazine and 3-(Dimethylamino)propyl
chloride, in the presence of: sodium hydroxide; potassium
carbonate; tetra(n-butyl)ammonium
hydrogensulfate and toluene. 6

The conditions
for optimum yield are: to have the laboratory at room temperature; reflux the
mixture in toluene, to aid this reaction, and finally react these compounds
using PTC (phase-transfer catalysis). 7

To
synthesise this drug, an N-alkylation reaction needs to occur between the amine
functional group in the central ring of 2-chlorophenothiazine and the 3-(Dimethylamino)propyl
chloride in order to form the desired product, Chlorpromazine. For mechanisms
like this, it’s standard to use a base such as sodium amide or other alkylmetal
derivatives; however, when used in a liquid-liquid state, this reaction is
deemed unsuccessful since the second reactant isn’t just a simple alkyl halide.
Even with large amounts of aqueous NaOH, this reaction still had mixed results
and an undesirable yield of product.

Because of
this, a change to the conditions must be considered and from multiple tests, it’s
found to be beneficial for alkylation reactions to take place under
phase-transfer catalysis. By using a solid base and organic liquid there is a
high efficiency of alkylation, especially due to the limited water supply in
the system, which enhances the efficiency of the PTC.

In terms of
the actual synthesis, it starts with the formation of a sodium salt after
reacting NaOH with the amine group at room temperature, An addition of
potassium carbonate and tetra(n-butyl)ammonium hydrogensulfate is then required
to produce a hydrochloride salt. Finally the whole mixture is refluxed for 18
hours in toluene, which is when the alkylations start occurring at an efficient
enough rate.7

 

Mechanism process with body

Subsequent research into the mode of action of
chlorpromazine and later agents has shown that their primary antipsychotic
activity is through blockade of dopamine (D2) receptors in the mesolimbic
pathway of the brain, overactivity of which is understood to be responsible for
the positive symptoms of schizophrenia (eg, delusions, hallucinations and
disorganised speech).

However, there is little or no effect on the negative
symptoms of schizophrenia (eg, lack of emotion and apathy). The
dopamine-blocking effects of antipsychotic agents on other neurological
pathways, such as the nigrostriatal pathway, and their effects on other
neurotransmitter systems, such as serotonin, acetylcholine and histamine,
impact on the nature and severity of their side effects.8 

 

2 Chlorpromazine acts as a blocking agent, the
technical term being “antagonist”, with various postsynaptic and
presynaptic receptors, the main one being D2 (dopamine) receptors. 3 Dopamine is a neurotransmitter that is known to be
involved in affecting mood and behaviour, amongst other things.

2 The effectiveness of this antipsychotic drug is due
to its ability to block dopamine receptors. This conclusion came from the
hypothesis that mental illnesses, such as schizophrenia and bipolar disorder,
arise as a result of excessive dopamine activity. In addition, substances like
cocaine are found to be psychomotor, which also increase the dopamine levels in
the body and can consequently cause psychotic problems.

The various dopamine
receptors (subtypes D1, D2, D3 and D4) account for its different
antipsychotic properties on productive and unproductive symptoms. Thus an
almost perfect correlation occurs between the therapeutic dose of a typical
antipsychotic, like Chlorpromazine, and the drug’s attraction for the D2
receptor.

 

Side effects

4 Despite being one of the most
effective antipsychotic drugs in the industry, Chlorpromazine does entail some
negative side effects. These may include drowsiness, dehydration, blurred vision, weight gain
and possibly insomnia. Another odd effect from this drug is that constant
hiccups often occur, which can cause inconvenience. It has also proved to
effect the nervous system, including previously a severe reaction with a few
patients. However many doctors still continue to prescribe Chlorpromazine
because its positives and effective treatment outweigh the negative side
effects.

 

Conclusions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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