Phenothiazine derivatives: classification, use, side effects

Phenothiazine derivatives are one of the most important groups of drugs in modern pharmacology, used in the treatment of mental disorders and other pathologies. The discovery of antipsychotic and antipsychotic effects was made by chance, in the development of antiallergic drugs. In addition to the basic properties, they are characterized by a wide range of effects on the human body, which is more dependent on the chemical structure of the compounds.

general description

Phenothiazine derivatives are the main representatives of modern antipsychotics. Phenothiazine, from which the substances of this pharmacological group are synthesized, used to be used in medicine as an anthelmintic and antiseptic drug, but now it has lost its significance. Now it is used in agriculture as an insecticidal and anthelmintic agent. This substance has neither psychotic nor neurotropic properties.

In 1945, French researchers found that when N-dialkylaminoalkyl radicals were introduced into its formula, compounds with antipsychotic activity could be obtained.

The chemical structure of antipsychotic derivatives can be summarized as follows:

Pharmacological action

Among the phenothiazine-derived drugs, drugs have been obtained that have the following effect:

• antihistamine;
• antispasmodic;
• antipsychotic;
• sedative;
• antidepressant;
• hypothermic (decrease in body temperature);
• antiarrhythmic;
• vasodilator;
• antiemetic;
• increased activity of other drugs: painkillers, anticonvulsants and sleeping pills.

Due to the mild nature of sedation, such drugs are called tranquilizers (from lat. Tran-quillns - quiet, calm). With the development of the means of this group, doctors have the opportunity to intervene in the human mental processes. The main mechanism of their action is to block the effect of adrenaline on the reticular formation of the brain. In this process, the pituitary gland - adrenal cortex system is involved.

The first drug to be widely used was Aminazin. 10 years after its receipt, it was already used by about 50 million people. In total, about 5,000 phenothiazine derivatives were synthesized. Of these, about forty are actively used in therapeutic practice.

The scope of antipsychotics - phenothiazine derivatives

Antipsychotic drugs are used for the following diseases:

• Mental disorders: schizophrenia; neurasthenia; delusions, hallucinations; neurosis; insomnia; anxiety and fear; emotional tension; increased irritability; delirium tremens and others.
• Violations of the vestibular apparatus.
• Surgery: in the form of combined general anesthesia.

Some drugs have a more pronounced antipsychotic property, while others are active antipsychotics. Aliphatic and piperazine derivatives of phenothiazine combine antipsychotic activity (elimination of delirium, automatisms) and a sedative effect.

Physiochemical properties

The main properties of these compounds are:

• Appearance - crystalline white powders (some with a creamy tint), odorless.
• Hygroscopicity (absorb moisture from the air).
• Good solubility in water, alcohols, chloroform. The compounds are insoluble in ether and benzene.
• Fast oxidizability. In this case, the radical can be cleaved off, sulfoxides, nitric acid and other substances are formed. The process is accelerated by the action of light. In chemistry, sulfuric acid, potassium bromate or iodate, bromine water, hydrogen peroxide, chloramine and other reagents are used to oxidize these compounds.
• The products of oxidation of derivatives dissolve well in organic solvents. They are painted in bright colors (red-pink, yellow-pink, lilac). This property is used to detect and quantify phenothiazine preparations, as well as their metabolites, in various biological fluids.
• The manifestation of the basic properties. Upon reaction with acids, they form salts that have the same solubility properties.
• In the light, these substances and their solutions can acquire a pinkish color.

Phenothiazine derivatives are not found in nature. They are obtained synthetically by extraction with organic solvents from alkaline aqueous solutions. Medicines are stored in a dry, dark place tightly sealed (to protect against oxidation).

Pharmacokinetics

Antipsychotics, derivatives of phenothiazine, are absorbed into the bloodstream mainly in the intestines. Since they have a hydrophobic character, this contributes to their interaction with proteins. Mostly they are localized in the brain, liver and kidneys.

Excretion of phenothiazine-derived drugs occurs with urine and partially with feces. In urine, they are detected mainly in the form of metabolites, which can be several dozen species when taking the medicine. The biological transformation of these substances in the human body occurs according to the following main reactions:

• oxidation, the formation of sulfoxides, sulfones;
• demethylation;
• aromatic hydroxylation.

Toxicology

As with other psychotropic drugs, side and toxic effects are also manifested in phenothiazine derivatives. In toxicological chemistry, a large number of poisonings are described, which often occur when combined with other drugs (antibiotics, insulin, barbiturates and others). Taking these drugs in high doses can be fatal.

These substances are able to accumulate in the human body. Therapeutic doses are withdrawn slowly (for example, "Aminazine" at a dosage of 50 mg / day. It is excreted within 3 weeks). The nature of poisoning with drugs with phenothiazine derivatives depends on age, gender, dose and does not have specific symptoms. After death, these compounds and their metabolites are able to persist in the human body for 3 months. Diagnosis of poisoned patients is carried out using a study of urine and blood.

Quantitative determination of derivatives is carried out by several methods:

• acid-base titration;
• cerimetry (redox titration with cerium);
• spectrophotometric method (used to analyze factory-made drugs);
• Kjeldahl method;
• iodometry;
• photocolorimetric method;
• gravimetry;
• indirect complexometric titration.

Classification

By the nature of the expressed pharmacological action, 2 main groups of these drugs are distinguished:

• 10-alkyl derivatives (antipsychotic, sedative and anti-allergic effect);
• 10-acyl derivatives (used in the treatment of cardiovascular diseases).

The phenothiazine alkyl derivatives include Promazin, Promethazine, Chlorpromazine, Levomepromazin, Trifluoperazin. They have a lipophilic group with tertiary nitrogen at position 10 (see the structural diagram above). Morazizin, Etatsizin, which contain a carboxyl group in the structure of active molecules, are classified as acyl derivatives.

There is also another classification - by the nature of the radicals of nitrogen atoms. Comparative characteristics of the action of phenothiazine derivatives and their distribution according to this attribute are shown in the table below.

Among the new generation of drugs, the following can be distinguished:

• antidepressants (“fluoroacisin”);
• funds that expand the coronary vessels ("Nonahlazin");
• antiarrhythmic drugs ("Etatsizin", "Etmozin");
• antiemetics (Thiethylperazine).

Aliphatic derivatives

Aliphatic phenothiazine derivatives include drugs such as:

• Chlorpromazine hydrochloride (trade names - "Largactil", "Aminazine", "Plegomazin").
• Levomepromazine ("Metotrimeprazine", "Tizercin", "Nozinan").
• Alimemazine ("Theralen", "Theraligen").
• Piportil (Pipothiazine).
• Propazine ("Promazin").

One of the most widely used drugs in this group is Chlorpromazine. It has the following effect:

• antipsychotic (reduces delirium, hallucinations in patients with schizophrenia, reduces aggressiveness);
• sedative (elimination of affect, decrease in motor activity, removal of acute psychoses);
• sleeping pills (in large doses);
• anxiolytic (decrease in fear, anxiety, tension);
• antiemetic (sometimes used to eliminate severe vomiting);
• antiallergic (blocking histamine receptors);
• muscle relaxant (muscle relaxation);
• hypothermic (decrease in body temperature due to suppression of the center of thermoregulation in the hypothalamus);
• increased anesthesia, sleeping pills and other drugs that depress the central nervous system.

Piperazine derivatives

Piperazine derivatives of phenothiazine include:

• Meterazine.
• Prochlorperazine.
• Fluphenazine hydrochloride ("Fluorophenazine", "Fluphenazine", "Moditen").
• Etalerazine.
• Thioproperazine.
• Fluphenazine Decanoate ("Moditen Depot").
• Majeptil.
• Trifluoperazine hydrochloride ("Triftazin", "Stelazin").
• Perphenazine.
• Metophenazate ("Frenolon").

These drugs are more active as antipsychotic drugs, but also cause more pronounced side effects (extrapyramidal disorders). The smallest number of such complications is Frenolon.

A typical antipsychotic from the phenothiazine derivative group is Trifluoperazin. It has a more active effect in the treatment of psychosis than chlorpromazine. Sedative and adrenergic blocking effects are reduced. Perphenazine and Trifluoperazin are often used as an effective antiemetic in diseases caused by radiation exposure. Moditen-depot is characterized by a longer action than other drugs of this group (the therapeutic effect lasts for 1-2 weeks).

Piperedine derivatives

The group of piperidine derivatives of phenothiazine includes the following drugs:

• Thioridazine (Sonapax).
• Periciazine ("Neuleptil").
• Pipothiazine ("Piportil").
• Melleril.
• Thiodazine.

These medicines are less active and have fewer side effects. They have a good sedative effect without drowsiness. Due to their greater safety, they are often prescribed for patients in old age. However, when taken in large doses, they may cause cardiotoxic effects and destruction of the retina. Pipothiazine has a long-lasting effect for a month, so it is used in the treatment of severe mental disorders on an outpatient basis.

Contraindications and overdose

Contraindications regarding the use of typical antipsychotics of each of the three groups indicated above are given in the table:

Side effects

Most phenothiazine-based antipsychotics are “typical” in the nature of the side effects, that is, they cause extrapyramidal disorders (signs of parkinsonism):

• increased muscle tone;
• tremor;
• motor inhibition (slowing down of active movements);
• masked face, rare blinking;
• solidification in one position and other symptoms that increase gradually.

Taking antipsychotics from the phenothiazine derivative group leads to the following most common side effects:

• disorientation in space;
• allergic reactions to the skin and mucous membranes, pigmentation, sensitivity to sunlight;
• menstrual irregularities;
• galactorrhea (pathological discharge of milk from the mammary glands, not associated with breastfeeding);
• spastic contractions of the muscles of the face and neck;
• impotence;
• breast enlargement;
• hyperthermia;
• decrease in blood pressure and its fluctuations;
• motor anxiety, restlessness;
• tachycardia;
• drowsiness;
• decreased production of salivary and digestive glands, a feeling of dry mouth;
• deterioration of the motility of the digestive tract;
• hemolytic anemia;
• urinary retention.

Many of these medications are addictive with prolonged use.

Interaction with other drugs

Limitations on the combined use of phenothiazine derivatives are associated with the effects of overdose and side effects. It is not recommended to combine them with the following substances:

• alcohol (increased sedative properties);
• drugs that lower blood pressure in hypertension, beta-blockers (development of orthostatic hypotension);
• "Bromocriptine" (an increase in the concentration of prolactin in the blood, leading to hormonal disorders);
• drugs that depress the central nervous system (anticonvulsants, narcotic painkillers, barbiturates, sleeping pills) - the occurrence of severe depressive states and other mental disorders;
• drugs for the treatment of hyperthyroidism (increased secretion of the thyroid gland) and preparations containing lithium, as this increases the likelihood of extrapyramidal disorders and increases their severity;
• anticoagulants (the development of agranulocytosis, clinically manifested in the form of frequent infectious diseases, ulcerative lesions of the mucous membranes; its complications are toxic hepatitis, pneumonia, necrotic enteropathy).

For more information on the indications, contraindications and side effects, see the instructions for these drugs.