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 neuroleptic and antipsychotic effects was made by chance, during 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 largely depends on the chemical structure of the compounds.
General Description
Phenotiazine derivatives are the main representatives of modern antipsychotics. Phenothiazine, from which the substances of this pharmacological group are synthesized, was previously used in medicine as an anthelmintic and antiseptic drug, but at present 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 are introduced into its formulayou can get compounds with antipsychotic activity.
Generally, the chemical structure of neuroleptic derivatives can be represented as follows:
Pharmacological action
Among phenothiazine derivatives, drugs have been obtained that have the following effect:
- antihistamine;
- antispasmodic;
- antipsychotic;
- sedative;
- antidepressive;
- hypothermic (decrease in body temperature);
- antiarrhythmic;
- vasodilating;
- antiemetic;
- increasing the activity of other drugs: painkillers, anticonvulsants and sleeping pills.
Due to the mild nature of the sedative effect, such drugs are called tranquilizers (from Latin tran-quillns - quiet, calm). With the development of the means of this group, doctors have the opportunity to intervene in the mental processes of a person. The main mechanism of their action is to block the effect of adrenaline on the reticular formation of the brain. The pituitary-adrenal cortex system is involved in this process.
The first widely used drug was Aminazine. 10 years after its receipt, it was already used by about 50 million people. In total, about 5000 phenothiazine derivatives have been synthesized. Of these, about forty are actively used in therapeutic practice.
Field of application of neuroleptics – phenothiazine derivatives
Antipsychotic drugs are used for the following diseases:
- Mental disorders: schizophrenia; neurasthenia; delirium, hallucinations; neuroses; insomnia; anxiety and fear; emotional tension; increased excitability; delirium tremens and others.
- Vestibular disorders.
- Surgery: as combined general anesthesia.
Some drugs have a more pronounced antipsychotic property, while others are active antipsychotics. Phenothiazine derivatives of the aliphatic and piperazine series combine antipsychotic activity (elimination of delirium, automatisms) and a sedative effect.
Physical and chemical properties
The main properties of these compounds are:
- Appearance - White crystalline powders (some creamy), odorless.
- Hygroscopicity (absorb moisture from the air).
- Good solubility in water, alcohols, chloroform. The compounds are insoluble in ether and benzene.
- Fast oxidation. In this case, a radical can be split 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.
- Oxidation products of derivatives dissolve well inorganic solvents. They are painted in bright colors (red-pink, yellow-pink, lilac). This property is used to detect and quantify phenothiazine drugs as well as their metabolites in various body fluids.
- Manifestation of basic properties. When reacted with acids, they form s alts that have the same solubility properties.
- In the light, these substances and their solutions may acquire a pinkish color.
Phenothiazine derivatives do not occur in nature. They are obtained synthetically by extraction with organic solvents from alkaline aqueous solutions. Medicines are stored in a dry, dark place, tightly closed (to protect against oxidation).
Pharmacokinetics
Neuroleptics, phenothiazine derivatives, are absorbed into the blood mainly in the intestines. Since they are hydrophobic in nature, this facilitates their interaction with proteins. They are mainly localized in the brain, liver and kidneys.
The excretion of phenothiazine derivatives occurs in the urine and partly in the feces. In the urine, they are detected mainly in the form of metabolites, which can be several dozen types when taking the medicine. The biological transformation of these substances in the human body occurs according to the following main reactions:
- oxidation, 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 large doses can be fatal.
These substances can accumulate in the human body. Therapeutic doses are excreted slowly (for example, "Aminazin" at a dosage of 50 mg / day is excreted within 3 weeks). The nature of poisoning with drugs with phenothiazine derivatives depends on age, sex, 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 the 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 pronounced pharmacological action, 2 main groups of these drugs are distinguished:
- 10-alkyl derivatives (neuroleptic, sedative and antiallergiceffect);
- 10-acyl derivatives (used in the treatment of cardiovascular diseases).
The phenothiazine alkyl derivatives include "Promazin", "Promethazine", "Chlorpromazine", "Levomepromazine", "Trifluoperazine". They have a lipophilic group with a tertiary nitrogen in position 10 (see the structural diagram above). The acyl-derivatives include "Moracizin", "Etacizin", which contain a carboxyl group in the structure of active molecules.
There is also another classification - according to the nature of the radicals at the nitrogen atoms. Comparative characteristics of the action of phenothiazine derivatives and their distribution on this basis is given in the table below.
| Group of derivatives | Main pharmacological effect | Typical representative | Frequency of side effects |
| Aliphatic | Mild antipsychotic and sedative | Chlorpromazine | Moderate |
| Piperazines | Strong antipsychotic, antiemetic, moderate antidepressant, activating | Trifluoperazine | High |
| Piperidine | Mild antipsychotic, sedative, anti-anxiety, corrective behavior | Thioridazine | Low |
Among the new generation drugs are the following:
- antidepressants ("Ftorocyzine");
- means that expand the coronary vessels ("Nonachlazine");
- antiarrhythmic drugs ("Etacizin", "Etmozin");
- antiemetic ("Thiethylperazine").
Aliphatic derivatives
Aliphatic phenothiazine derivatives include drugs such as:
- Chlorpromazine hydrochloride (trade names are Largactyl, Aminazine, Plegomazine).
- Levomepromazine ("Methotrimeprazine", "Tisercin", "Nozinan").
- Alimemazine ("Teralen", "Teraligen").
- Piportil ("Pipothiazine").
- Propazin ("Promazin").
One of the most widely used drugs in this group is Chlorpromazine. It has the following effect:
- antipsychotic (reduces delusions, hallucinations in patients with schizophrenia, reduces aggressiveness);
- sedative (elimination of affect, reduction of physical activity, removal of acute psychosis);
- sleeping pills (in high doses);
- anxiolytic (reducing fear, anxiety, tension);
- antiemetic (sometimes used to control severe vomiting);
- antiallergic (blocking histamine receptors);
- muscle relaxant (relaxationmuscles);
- hypothermic (decrease in body temperature due to suppression of the thermoregulatory center in the hypothalamus);
- increased anesthesia, sleeping pills and other drugs that depress the central nervous system.
Piperazine derivatives
Piperazine phenothiazine derivatives include:
- Meterazine.
- Prochlorperazine.
- Fluphenazine hydrochloride ("Fluphenazine", "Fluphenazine", "Moditen").
- Etalerazine.
- Thioproperazine.
- Fluphenazine-decanoate ("Moditen-depot").
- Majeptil.
- Trifluoperazine hydrochloride ("Triftazine", "Stelazine").
- Perphenazine.
- Methophenazate ("Frenolon").
These drugs are more active as antipsychotics, but they also cause more pronounced side effects (extrapyramidal disorders). Frenolon has the least number of such complications.
Trifluoperazine is a typical antipsychotic from the group of phenothiazine derivatives. It has a more active effect in the treatment of psychosis than Chlorpromazine. Sedative and adrenoblocking action is reduced. Perphenazine and trifluoperazine are often used as effective antiemetics 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).
Pipedine derivatives
Piperidine groupphenothiazine derivatives include the following drugs:
- Thioridazine (Sonapax).
- Pericyazine ("Neuleptil").
- Pipothiazine ("Piportil").
- Melleril.
- Thiodazine.
These drugs 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 to patients in old age. However, when taken in high doses, they can cause cardiotoxic effects and destruction of the retina. Pipothiazine has a long-term effect for a month, so it is used in the treatment of severe mental disorders in outpatient settings.
Contraindications and overdose
Contraindications regarding the use of typical antipsychotics of each of the three groups indicated above are shown in the table:
| Drug name | Restrictions | Overdose |
| "Chlorpromazine" |
1. Pregnancy and breastfeeding period. 2. Individual intolerance to the components. 3. Coma, CNS depression. 4. Severe liver or kidney failure. 5. Cholelithiasis and urolithiasis. 6. Acute cerebrovascular accident and brain injury in the acute period. 7. Decreased production of thyroid hormones. 8. Heart failure at the stage of decompensation, severe cardiac pathologiesvascular system. 9. Thromboembolism, blood diseases. 10. Ulcerative lesions of the gastrointestinal tract (in the acute period). 11. Angle-closure glaucoma. 12. Children's age up to 1 year. |
Neuroleptic syndrome (high muscle tone, mental disorders, fever), hypotension, toxic liver damage, hypothermia |
| "Trifluoperazine" |
1. Pp. 1-4, 8, 9 of the previous remedy. 2. Children under 3 years old. |
Hypotension, arrhythmia, tachycardia, disturbances in visual perception and reflexes, shock, convulsions, disorientation, respiratory depression, restlessness, hypothermia, pupillary dilation. |
| "Thioridazine" |
1. Pp. 1-4, 6, 8, 12 (see "Chlorpromazine"). 2. Porphyrin disease. 3. Depression. 4. With caution, appoint patients with pathologies according to paragraphs. 4, 7, 10, 11 (see "Chlorpromazine"), as well as alcohol abuse, breast cancer, prostatic hyperplasia, epilepsy, impaired respiratory function, Reye's syndrome and in old age. |
Drowsiness, urinary disturbance, coma, confusion, dry mouth, hypotension, convulsions, respiratory depression. |
Side effects
Most phenothiazine-based neuroleptics are "typical" in terms of side effects, that is, they cause extrapyramidal disorders (signsparkinsonism):
- increased muscle tone;
- tremor;
- motor retardation (slowdown of active movements);
- mask face, rare blinking;
- freezing in one position and other symptoms that gradually increase.
Phenothiazine antipsychotics cause the following most common side effects:
- disorientation in space;
- allergic reactions on the skin and mucous membranes, pigmentation, sensitivity to sunlight;
- menstrual irregularity;
- galactorrhea (abnormal secretion of milk from the mammary glands, not associated with breastfeeding);
- spastic contractions of the muscles of the face and neck;
- impotence;
- breast augmentation;
- hyperthermia;
- decrease in blood pressure and its fluctuations;
- motor restlessness, restlessness;
- tachycardia;
- drowsy;
- decreased production of salivary and digestive glands, feeling of dry mouth;
- impaired gastrointestinal motility;
- hemolytic anemia;
- urinary retention.
Many of these drugs are addictive when taken long term.
Interaction with other drugs
Restrictions on the co-administration of phenothiazine derivatives are associated with the phenomena that lead to overdose, andside effects. It is not recommended to combine them with the following substances:
- alcohol (increased sedative properties);
- drugs that reduce 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 conditions and other mental disorders;
- drugs for treating hyperthyroidism (overactive thyroid gland) and products containing lithium, as this increases the likelihood of extrapyramidal disorders and increases their severity;
- anticoagulants (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 about indications, contraindications and side effects, see the instructions for these drugs.
