Phenothiazines

At Phenothiazines it is a subgroup of the thiazines. They are primarily used as neuroleptics.

What are phenothiazines?

Phenothiazines are derivatives of phenothiazine that are of pharmacological relevance. In medicine they are used as neuroleptics. There they are also as tricyclic neuroleptics known.

The history of phenothiazines can be traced back to the beginning of organic chemistry.In 1865, the German chemist August Kekule (1829-1896) presented the thesis that carbon atoms are located in ring systems within organic substances. This was initially important for the paint industry, which produced the dyes thionine and methylene blue from 1876 onwards. Both had a phenothiazine structure. Medicine later attempted to treat illnesses such as depression, headache and malaria with methylene blue, but this was ultimately unsuccessful.

At the beginning of the 20th century, the phenothiazines seemed to be forgotten and were mainly used in veterinary medicine for the treatment of worm diseases. In humans, on the other hand, therapies were refrained from due to excessive toxicity. From the 1940s, however, medical research began to focus again on phenothiazines. The French pharmaceutical company Rhone-Poulenc finally discovered phenothiazines that had antihistamine properties. This led to the synthesis of neuroleptics in 1950.

Pharmacological effect

Phenothiazine is used as the starting compound for numerous neuroleptics. What is meant is a tricyclic connection. Its middle ring has a sulfur atom and a nitrogen atom as a heterocycle. Phenothiazines have an affinity for the dopamine receptors. So they are able to block them. But other neurotransmitters such as noradrenaline, histamine and serotonin are also inhibited by them.

The basic structure of the phenothiazines consists of three rings. Depending on the substitution of the basic structure, a distinction is made between three phenothiazine groups. There are phenothiazines with an aliphatic series chain, piperidyl side chain and piperazinyl side chain. The alipathic phenothiazines have strong sedative effects, while they can cause side effects in the vegetative area.

The aliphatic phenothiazines include promazine, levomepromazine, chlorpromazine, triflupromazine, promethazine and profenamine. Piperidyl-phenothiazines such as thioridazine, mesoridazine and periciazine have a moderate calming effect.

In contrast, piperazinyl phenothiazines have only weak sedative and antihistaminic effects. In return, however, they develop a pronounced antiemetic and antipsychotic effect. Its representatives include perphenazine, fluphenazine, prochlorperazine and trifluoperazine.

Furthermore, phenothiazines can have a local anesthetic, anti-adrenergic and ganglion-blocking effect, which means they have a broader spectrum than other neuroleptics.

The breakdown of the phenothiazines takes place in the liver. The pharmacological effectiveness of the metabolites has not yet been clarified. The drug is slowly excreted from the body through the kidneys.

Medical application & use

In medicine, the phenothiazines can be used in different areas. They serve as neuroleptics for the treatment of psychoses and thereby influence the psyche of the patient. They are particularly suitable for the therapy of schizophrenia to combat hallucinations and delusions.

In addition, the phenothiazines can be administered as sedatives. As antiemetics, they fight dizziness and vomiting, while as antihistamines they treat allergic reactions.

A particularly tried and tested phenothiazine is the low-potency promethazine. It has been used successfully against agitation and anxiety for decades.

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Risks & side effects

As dopamine antagonists, phenothiazines can cause numerous side effects, some of which are serious. These include extrapyramidal motor effects such as dystonia, early dyskinesia, late dyskinesia, restlessness and Parkinson's symptoms such as tremors, rigidity and pathological immobility.

These undesirable effects can be traced back to the blocking of the highly effective substances on the dopamine receptors. Phenothiazines of the chlorpromazine type can also disturb the body's heat regulation. Other active ingredients of this type in turn trigger a long QT syndrome, which causes severe cardiac arrhythmias that can be fatal.

The phenothiazines also cause psychological side effects such as drive disorders, impoverishment of emotional life and restlessness in the realm of the possible. Some patients develop psychological dependence on the drug.

In the case of organic side effects, there is a risk that the kidneys and liver will be affected. An overdose of phenothiazines is also considered a health hazard. This can trigger symptoms such as visual disturbances, tremors, too low blood pressure, racing heart, drowsiness, disorders of movement coordination, cramps, psychomotor excitement and hallucinations. Some people have even fallen into a coma.