Phenothiazines are a subgroup of thiazines. They are used primarily as neuroleptics.
What are phenothiazines?
Phenothiazines are derivatives of phenothiazine that are of pharmacologic relevance. In medicine, they are used as neuroleptics. There they are also known as tricyclic neuroleptics. 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 within organic substances are located in ring systems. This was initially of importance to the dye industry, which began producing the dyes thionine and methylene blue in 1876. Both had a phenothiazine structure. Later, medicine attempted to treat diseases such as depression, headaches and malaria with methylene blue, but this was ultimately unsuccessful. At the beginning of the 20th century, phenothiazines seemed to be forgotten and were mainly used in veterinary medicine to treat worm diseases. In humans, on the other hand, therapies were abandoned due to excessive toxicity. From the 1940s, however, medical research began to take a closer look at phenothiazines again. The French pharmaceutical company Rhone-Poulenc finally discovered phenothiazines that had antihistaminic properties. This led to the synthesis of neuroleptics in 1950.
Pharmacological action
Phenothiazine serves as the parent compound for numerous neuroleptics. This refers to a tricyclic compound. Its middle ring has a sulfur atom as well as a nitrogen atom as a heterocycle. Phenothiazines have an affinity for dopamine receptors. Thus, they are able to block them. However, they also inhibit other neurotransmitters such as norepinephrine, histamine and serotonin. The basic structure of phenothiazines consists of three rings. Depending on the substitution of the basic skeleton, three phenothiazine groups are differentiated. Thus, there are phenothiazines with alipathic series chain, piperidyl side chain and piperazinyl side chain. The alipathic phenothiazines exhibit strong sedative effects, while they may cause side effects in the autonomic area. Alipathic phenothiazines include promazine, levomepromazine, chlorpromazine, triflupromazine, promethazine, and profenamine. Piperidyl phenothiazines such as thioridazine, mesoridazine, and periciazine exert a moderately strong sedative effect. In contrast, piperazinyl phenothiazines have only weak sedative and antihistaminic effects. However, they have pronounced antiemetic and antipsychotic effects. Their representatives include perphenazine, fluphenazine, prochlorperazine, and trifluoperazine. Furthermore, phenothiazines can have local anesthetic, anti-adrenergic, and ganglion blocking effects, giving them a broader spectrum than other neuroleptics. The breakdown of phenothiazines occurs in the liver. The pharmacological efficacy of the metabolites has not yet been clarified. Slow excretion of the drug from the body occurs via the kidneys.
Medical application and use
In medicine, phenothiazines can be used in various fields. For example, they serve as neuroleptics for the treatment of psychosis, affecting the psyche of patients. They are particularly suitable for the treatment of schizophrenia to combat hallucinations and delusions. In addition, phenothiazines can be administered as tranquilizers (sedatives). As antiemetics, they address dizziness and vomiting, while as antihistamines they treat allergic reactions. A particularly proven phenothiazine is the low-potency promethazine. Thus, it has been successfully administered for decades to treat states of agitation and anxiety.
Risks and side effects
As dopamine antagonists, phenothiazines can cause numerous side effects, some of which are severe. These include extrapyramidal motor effects such as dystonia, early dyskinesia, tardive dyskinesia, agitation, and Parkinsonian symptoms such as tremor, rigidity, and pathologic immobility. These adverse effects are due to the blockade of the highly potent substances on the dopamine receptors. Phenothiazines of the chlorpromazine type may also disrupt the body’s thermoregulation.Other active substances of this type in turn trigger a long-QT syndrome, resulting in severe cardiac arrhythmias that can take a fatal course. Phenothiazines can also cause psychological side effects such as impulsive disorders, impoverishment of emotional life and restlessness. In some patients, a psychological dependence on the drug develops. 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 risk. This can cause symptoms such as visual disturbances, tremors, low blood pressure, palpitations, drowsiness, disturbances in movement coordination, convulsions, psychomotor agitation and hallucinations. Some affected individuals have even fallen into comas.
