Phenothiazine derivatives: classification, use, side effects. Antipsychotics - phenothiazine derivatives

The phenothiazine ring is a condensed system of three rings - thiazine and benzene rings associated with it, therefore phenothiazine can be called as a dibenz derivative of thiazine.

Although phenothiazine exhibits physiological activity (antihelminthic effect and local antiseptic), at present it has lost its value as a drug.

Phenothiazine derivatives having a substituent (R) at positions 2 and 10 of the ring are of much greater importance. More often R 10 is a 3-dialkylaminopropanol residue

Such phenothiazine derivatives combine a large group of psychotropic drugs (neuroleptics).

In appearance, all these drugs are similar to each other. These are mostly white or white crystalline powders with a creamy shade, some have a greenish-yellowish color (triftazine, mepazin). It is very easily soluble in water, easily in 95% alcohol, chloroform; practically insoluble in ether and benzene.

Of the chemical properties of phenothiazine derivatives, the most characteristic is their ability to oxidize. Depending on the nature of the oxidizing agent (bromic water, nitric and sulfuric acids, ferric chloride, etc.), oxidation products of various colors are formed. Therefore, these reactions are used to identify drugs of the phenothiazine series.

The place of the greatest reactivity in the phenothiazine molecule and its derivatives is the sulfur atom, which can be oxidized to $ 4+ and S 6 "h

Oxidation of phenothiazine or its derivatives with bromine in acetic acid or another oxidizing agent, for example hydrogen peroxide, leads to the formation of S-oxide (I) and sulfone dioxide (II).

Due to the tertiary nitrogen in the molecule, phenothiazine derivatives can react with general alkaloid reagents (see "Alkaloids").

All drugs of the phenothiazine series are used in the form of hydrochlorides, therefore, after isolation of the base with alkali, chlorine ion with a solution of silver nitrate is found in the filtrate.

Of the possible impurities in the preparations, GF X admits sulfates, heavy metals and phenothiazine within the standards. The acidity limit is also determined.

Methods for the quantitative determination of drugs of the phenothiazine series are diverse and are based on the properties of the compounds. The pharmacopoeial method is the method of acid-base titration in non-aqueous media. The drug is dissolved in glacial acetic acid or acetone, mercury oxide acetate is added and titrated with perchloric acid for a crystal violet or methyl orange indicator.

The pharmacopoeial method is also the usual method of neutralization with differentiating solvents. This method is recommended by GF X for solution and tablets of diprazine. Determination of nitrogen by the Kjeldahl method is recommended by the GFC for the quantitative determination of aminazine in solution. , tightly closed with paraffin-embedded stoppers, in a dry place.

When working with phenothiazine derivatives, precautions should be taken to exclude the possibility of powder and solutions getting on the skin and mucous membranes, since "they cause severe irritation, swelling of the eyelid skin, and a decrease in blood pressure.

The drugs belong to the list B.

Pharmacopoeial drugs of the phenothiazine series are chlorpromazine, digaraein, trnftazine, chloracizin.

Phenothiazines- a group of chemical compounds that are derivatives of phenothiazine, many of which are widely used as medicines.

Phenothiazine is a heterocyclic compound; C 12 H 9 NS:

Pale yellow crystalline powder. We will slightly dissolve in water and ether, we will easily dissolve in hot alcohol, melting point 182 °; molecular weight (weight) 199.26. Synthesized in 1883 by A. Bernthsen. It is used in veterinary practice as an insecticidal and antihelminthic agent.

Phenothiazine derivatives were proposed as medicines in the middle of the 20th century. The first phenothiazines introduced into medical practice were the antihistamines etizine and diprazine (see), as well as the anticholinergic blocker dinesin (see). Of particular importance was the synthesis and study of the pharmacological properties of chlorpromazine (see. Aminazine), which was the ancestor of a new class of medicinal substances - neuroleptics (see. Neuroleptic drugs).

The widest range of pharmacol. alkylaminoalkyl derivatives of phenothiazine are active. They affect the central nervous system, causing sedative, antiemetic and some other effects, have antihistamine, antispasmodic, adreno- and anticholinergic action, potentiate the action of anesthetics, hypnotics and analgesics.

Of fundamental importance for the manifestation of certain pharmacological properties in phenothiazines are the structure of the side chain attached to the nitrogen atom in the 10th position of the phenothiazine molecule and the structure of the chain in the 2nd position. Thus, phenothiazines belonging to antipsychotics, in the 10th position have a side chain of the -CH2-CH2-CH2-NR type, that is, the factor determining the presence of neuroleptic properties is the intramolecular side chain distance equal to the length of three methylene groups between nitrogen atoms in 10th position of phenothiazine and side chain. Branching of the side chain usually leads to a decrease in neuroleptic activity. The substituents in the 2-position of the phenothiazine molecule in neuroleptics from among the phenothiazine derivatives can be halogen or the following radicals: -CH3, -OCH3, -CF3, -SO2N (CH3) 2 -CN. It is believed that such substituents should have electron-acceptor properties. According to the structure of the alkyl side chain, antipsychotics from among phenothiazine derivatives are usually divided into three groups: aliphatic, piperidine and piperazine.

The most active antipsychotics among phenothiazines are drugs of the piperazine group, for example, triftazine (see), ethaperazine (see), fluorophenazine (see), the chemical structure of which is characterized by an optimal combination of side chain elements and a radical (usually group - CF 3) in Position 2 of the phenothiazine molecule. It is believed that compounds of this structure have conformational similarities with the dopamine molecule. This gives them high complementarity with respect to central dopamine receptors and the ability to easily bind to them. Meanwhile, it is known that the degree of neuroleptic activity is proportional to the ability of substances to block dopaminergic transmission in some parts of the brain. In addition to antipsychotics, among phenothiazines, there are other drugs that affect the central nervous system, for example, the antidepressant fluoroacizine (see), the antiemetic agent thiethylperazine, etc.

When the alkyl side chain in the 10th position is replaced by an acyl side chain (-CO-CH2-CH2-NR, R 1), that is, when 10-acyl derivatives of phenothiazine are obtained, the spectrum of their pharmacological activity changes significantly. In such phenothiazines, the central neurotropic activity and some types of peripheral action (for example, adrenergic blocking, antihistamine) almost completely disappear, but at the same time the antispasmodic activity increases, antianginal and antiarrhythmic properties appear.

Nonachlazine (see) and chloracizine (see) belong to 10-acyl derivatives of phenothiazine with pronounced antianginal activity. They improve blood supply and energy balance of the myocardium, have an antispasmodic effect. There is an adrenergic component in the mechanism of their action. The antiarrhythmic agent etmozin also belongs to 10-acyl derivatives of phenothiazine (see). In terms of chemical structure and properties, it is similar to nonachlazine and chloracizine, but it has a predominantly antiarrhythmic effect. It is used for extrasystoles, attacks of atrial fibrillation, atrial arrhythmias, paroxysmal tachycardia, for arrhythmias associated with an overdose of cardiac glycosides.

In addition to the drugs noted above, methylene blue (see) belongs to phenothiazines, which is used in medical practice mainly as an antiseptic and as an antidote for some poisoning.

Bibliography: Medicines Used in Psychiatry, ed. G. Ya. Avrutskiy, p. 18, M., 1980; Loved in BI and Raevsky KS Pharmacological and clinical characteristics of neuroleptics-10-alkylpiperazinylpropyl derivatives of phenothiazine, in the book: Usp. in the creation of new drugs, ed. D.A. Kharkevich, p. 33, M., 1973; R and e all to and y KS Pharmacology of neuroleptics, p. 32, M., 1976; Psychopharmacolo-gical agents, ed. by M. Gordon, v. 2, p. 2, N. Y-L, 1967.

K. S. Raevsky.

Phenothiazine derivatives

Phenothiazine, or thiodiphenylamine, has been used in the past in medical practice as an anthelmintic drug for enterobiasis and as an antiseptic for inflammatory diseases of the urinary tract. Currently, due to the introduction into practice of more effective and less toxic drugs, it is no longer used in medicine. In veterinary medicine, phenothiazine is used for helminthic invasions in cattle, pigs, and horses. Technical (crude) phenothiazine is used to kill mosquito larvae. Phenothiazine derivatives include methylene blue. In 1945, it was found that when the hydrogen at the nitrogen atom of the phenothiazine nucleus is replaced by alkylaminoalkyl radicals, polyene compounds with strong antihistaminic activity, cholinolytic and other important pharmacological properties can be produced. The first in a series of alkylamino derivatives of phenothiazine that found application as antihistamines was 10- (2-diethylaminoethyl) -phenothiazine hydrochloride, which was used under the name ethyin. The diethyl analogue of etizine, called dinesin, turned out to be a substance with n-anticholinergic activity and found application as a remedy for the treatment of parkinsonism. Further studies have shown that 10- (2-dimethylaminopropyl) -phenothiazine hydrochloride, or diprain, has a very strong antihistaminic activity. In a more detailed study of these and other similar phenothiazine derivatives, it was found that they have a multifaceted effect on the central and peripheral nervous system. Diprazine, along with antihistamine activity, has sedative properties, enhances the effect of drugs, hypnotics, analgesics and local non-anesthetic substances, causes a decrease in body temperature, has an antiemetic effect, and has adrenolytic activity. In the search for substances that have a more active and more selective effect on the functions of the central nervous system, phenothiazine derivatives were synthesized, when substituted in the C2 position, the nucleus with a chlorine atom or other substituents. One of the most active was 2-chloro-103-dimethyl-aminopropyl) -phenothiazine hydrochloride, or aminazine. Subsequently, various other phenothiazine derivatives were synthesized. Many phenothiazine derivatives are antipsychotics. However, in a series of phenothiazines, new antidepressants have also been obtained (see Fluoroacizine), coronary-dilating drugs (see Nonahlazin), antirhythmic (see Etmozin, Etacizin), antiemetic (see Thietylperazine) drugs. Antipsychotics of the phenothiazine series, depending on the characteristics of their chemical structure, are usually divided into three groups: 1) compounds containing a dialkylaminoalkyl chain at the phenothiazine nucleus atom; these are the so-called aliphatic derivatives (chlorpromazine, propazine, levomepromazine, etc.); 2) compounds containing a piperazine nucleus in the side chain; these are the so-called piperazine derivatives (meterazine, ethaperazine, triftazine, fluorophenazine, etc.); 3) compounds containing a piperiine nucleus in the side chain (thioridazine, pericyazine, etc.). The drugs included in each of these groups, along with the properties characteristic of each individual drug, have some common features. Thus, the drugs of the first group (aliphatic derivatives), along with a pronounced antipsychotic effect, are distinguished by the presence of an inhibitory component, the ability to cause lethargy, intellectual and motor inhibition, passivity, and apathy (hypnosedative action). By the strength of the sedative effect, these drugs are superior to other phenoiazine antipsychotics. In the picture of the extrapyamidal disorders caused by them, lethargy, hypokinesia (up to akinetic syndrome) also prevail. Drugs of the second group (piperazine derivatives), along with antipsychotic action, are characterized by the presence of a stimulating, activating component, and in the picture of extrapyramidal disorders, hyperkinetic and dyskinetic phenomena predominate. Drugs of the third group (piperidine derivatives) have less strong antisychotic activity, do not have a hypnosedative effect, and rarely produce extrapyramidal disorders.

Phenothiazine derivatives are antipsychotics. The structure of this group of compounds is based on the phenothiazine ring.

Physicochemical properties

When interacting with acids, phenothiazines form salts that are readily soluble in water, alcohol, chloroform, but practically insoluble in ether and benzene.

The bases are a syrupy mass, insoluble in water, but soluble in alcohol, ether, chloroform, ethyl acetate.

Absorption of phenothiazine derivatives in the UV region of the spectrum, the presence of 2 maxima:

l max. 1.250-260 nm (e 35000) 2.300-315 nm (e 4500)

UV spectra reflect only the electronic structure of the phenothiazine moiety.

The exceptions are those derivatives that contain radicals with free n-electrons in the 2nd position (thioridazine, levomepromazine).

Sulfoxides of phenothiazines have, in contrast to native (basic) compounds, 4 maxima in the UV region: 230,265,285 and 400 nm.

Behavior in the body

Phenothiazines are absorbed as basic substances mainly from the intestines. The hydrophobic nature of phenothiazine bases promotes their interaction with proteins. The apparent volume, distribution (Vр) approaches 100%, therefore, phenothiazines are localized in the tissues of organs (brain, liver, kidneys). Excreted by the kidneys, in urine it is found mainly in the form of metabolites.

• 1 way - transformation in radicals R 1 and R 2
• a) N-O-S-demethylation, which leads to an increase in the polarity of the compounds;
• b) oxidation of the N 10 side chain.
• 2 way - sulfooxidation

Sulfoxidation - the formation of sulfoxides with oxidation states of 4 and 6.

3 way - aromatic hydroxylation at positions 3, 6, followed by conjugation with glucuronic acid.

Analysis of phenothiazines

The detection is carried out according to the general scheme for the identification of medicinal compounds:

GC analysis

Separation of phenothiazine derivatives is carried out in the phase of medium polarity OV-225 (3-5% on chromatone), in glass microcolumns 1-2 m long at 200-250 ° C. Injector temperature 250-300 ° C. Nitrogen-phosphorus detector (sensitivity 0.006 μg / μl), and for chlorine-containing ones - by electron capture (sensitivity - 0.001). The internal standard is imizine.

Visible photometry

These methods are based on the measurement of the absorption of colored reaction products of pr. Phenothiazine:

from the end. H 2 SO 4 - this technique has found the most widespread use. The disadvantage of this method is the possibility of charring in the presence of coextractive substances, especially when using putrefactively decomposed biological material (chlorpromazine, diprazine);

with Mandelin's reagent and conc. H 2 SO 4. The technique is used for phenothiazine derivatives, which with conc. H 2 SO 4 give unstable staining with non-reproducible optical density values ​​(thioridazine, levomepromazine);

with 18% solution of hydrochloric acid and 1 solution of arsenic to - you. The reaction is not inferior in sensitivity to the first two methods, however, mild oxidation conditions exclude the possibility of carbonization of coextractive substances (thioridazine, frenolone).

UV photometry

This method requires a high degree of purification recovery and is usually combined with TLC. The measurement is carried out at l max 250-255 nm in a solution of 0.5 N. H 2 SO 4.

Isolation from biological material (Solomatin method)

basic compounds

Biomaterial + 100% ethanol + oxalic acid to pH = 2-3 formation of water-soluble oxalates of phenothiazines, insist 3 times for 2 hours, extraction, evaporation + 100% alcohol, solution purified from proteins, evaporation + water, filtration, purified solution + ether, organic phase, study for phenothiazines.

Isolation from urine and blood

Separately, 5-10 ml of urine and 2 ml of blood + 50% NaOH to pH 13 10 minutes in a water bath, the hydrolyzate is cooled to room temperature and twice extracted with n-heptane containing 3% isoamyl alcohol, washed with water saturated with heptane and divided into two equal parts in one part, phenothiazine derivatives are detected by thin layer chromatography, and in the other - quantitative determination.

The blood extract is completely consumed for quantitative determination, because contains fewer coextractive substances.

Chromatographic purification and detection in thin layers

The organic solvent is removed from the aliquot of the organic extract in a stream of warm air. Dry residue + chloroform

NF: Silufol

PP: benzene: dioxane: ammonia OR ethyl acetate: acetone: ammonia

As taps, chlorpromazine (required) and those phenothiazine derivatives that were found during the preliminary study are applied.

D: one plate is sprayed with a solution of conc. H 2 SO 4 in ethanol (1: 9) and with a positive result on the second plate, the detection is carried out by dripping with Mark's reagent.

TLC screening

General system

NF: silica gel KSK

PP: acetone: chloroform: ammonia: dioxane

Private system

NF: silica gel KSK

PF: acetone: chloroform

D: 57% HClO4 solution + 0.5% NaNO2 pink-violet

Quality detection.

With solutions of bismuth iodide in potassium iodide and phosphoric-molybdic acid, amorphous precipitates are obtained.

With concentrated sulfuric acid, a persistent purple-red color is produced.

With formalin sulfuric acid, chlorpromazine gives a purple-red coloration, which intensifies upon standing.

With concentrated nitric acid, a rapidly disappearing purple-red color occurs.

With a 5% solution of chloroauric acid (after 3-4 times treatment of the residual aminazine base with 0.1 N HC1 solution), a dark red amorphous precipitate is formed, which turns into a characteristic crystalline precipitate after 20-50 minutes.

Detection of phenothiazines.

Phenothiazines are often detected by thin layer chromatography of alkaline urine extracts, but when ingested orally, specific identification of this compound may not be possible if only urine is available for analysis. Phenothiazines taken in low doses, such as fluphenazine, cannot be detected in urine by any known method.

Qualitative analysis

a) Precipitation reactions

General alkaloid precipitating reagents (often Dragendorff reagent) + Reinecke salt, Bi, Au

b) Microcrystalline reactions

5% gold chloride solution gives characteristic crystalline precipitates + Reinecke's salt gives characteristic crystalline precipitates

oxidation with metal salts with the highest oxidation state (FeCl 3 and HPtCl 4). The test is based on the reaction of many of these compounds with ferric ions in an acidic environment. It is undertaken to examine urine, stomach contents and residues of substances from the scene.

• a) Reagent FPN (FeCl 3 + HClO 4 + HNO 3), Colors ranging from pink, red or orange to purple or blue may indicate the presence of phenothiazines or their metabolites. The urine of patients who regularly take traditional phenothiazines for medicinal purposes, such as chlorpromazine, usually gives a positive reaction. Sensitivity Chlorpromazine, 25 mg / l.
• b) Elenium + HPtCl 4> purple precipitate; Thioridazine - gray-pink precipitate; Levomepromazin - bright green coloration.

quantitation

The quantitative determination of phenothiazine derivatives is carried out without preliminary chromatographic purification and separation only if the absence of other basic substances in the biological object is established. If available, for the quantitative determination of phenothiazine derivatives, chromatographic purification is carried out by TLC. For this, the entire aliquot of the extract for quantitative determination is applied in the form of a continuous strip 1 cm wide on a chromatographic plate on the starting line and chromatographed. At the end of chromatography in UV light, mark the connection zone with the corresponding Rf, parallel to the taps, remove the sorbent layer containing the compound with a scalpel into a test tube. Elution is carried out with 10 ml of a solution of 25% ammonia in ethanol (1: 1), the eluate is separated by filtration through a glass filter No. 4, evaporated to dryness in a stream of cold air. The dry residue is dissolved in 5 ml of 0.1 N HCl solution, then 4 ml of 0.01 N HCl are added.

In the absence of other basic substances, the second part of the heptane extract (blood, urine) is reextracted with 5 ml of 0.1 N. HCl, and then 4 ml of 0.01 N HCl. Hydrochloric acid solutions are combined.

To the combined hydrochloric acid solution, 12 ml of an acetate buffer solution (pH 3.5), 2 ml of a saturated solution of methyl orange and 5 ml of chloroform are added. The resulting mixture is shaken in a separating funnel - in the presence of phenothiazine derivatives, the chloroform layer turns yellow (heliantates of phenothiazine derivatives extracted with chloroform). The chloroform layer is separated and the optical density of the colored solution is determined (photoelectrocolorimeter FEK-56, etc., cuvette 10 mm, blue light filter with a maximum transmission at 400 nm).

To construct a calibration curve, standard solutions are prepared in 0.01 n HCl of phenothiazine derivatives with a content of 1, 2-10 μg / ml of phenothiazine derivatives and investigated by the above procedure. Based on the results of determining the optical density, a calibration graph is built. The above method isolates up to 60% of phenothiazine derivatives from blood and up to 80% from urine.

Phenothiazine itself has neither psychotic nor neurotropic properties. It is known as an anthelmintic and insecticidal drug. Psychotropic drugs are obtained by introducing various radicals into its molecule at positions 2 and 10.

All phenothiazine derivatives are hydrochlorides and are similar in appearance. These are white with reddish, some (triftazine, mepazin) with a greenish-yellow tint, crystalline powders. Easily soluble in water, 95% alcohol, chloroform, practically insoluble in ether and benzene. They easily oxidize and darken in the light. Solutions without stabilizers deteriorate. In contact with skin or mucous membranes, they cause severe irritation (weigh or pour from one container to another wearing rubber gloves and a respirator!). With intramuscular injections, painful infiltrates are possible, and with rapid injection into a vein, damage to the epithelium. Therefore, the drugs are diluted in solutions of novocaine, glucose, isotonic sodium chloride solution.

Cause photosensitization in animals; in addition to neuroleptic action - muscle relaxation, reduce body temperature; block the trigger zone of the vomiting center and prevent or remove the development of the emetic effect mediated through this zone (for example, from apomorphine, arecoline, etc.), do not act antiemetic when irritating the vestibular apparatus and gastric mucosa; oppress the cough center, eliminate hiccups.

Aminazine. Fine crystalline powder, white or white with a cream shade, easily soluble in water; possesses bactericidal action, therefore solutions are prepared in boiled distilled water without subsequent sterilization.

Aminazine has a well-pronounced central adrenolytic effect. It more strongly blocks impulses coming from extero- than from interoreceptors: it prevents neurogenic stomach ulcers that occur during immobilization and electro-stimulation of rats, but does not affect their development when the duodenum is traumatized; reduces the time between the end of feed intake and the beginning of the ruminant period and prevents the cessation of ruminant cycles in sheep after severe electrical stimulation of the skin. Horses are more sensitive to chlorpromazine than cattle.

Administered orally and intramuscularly: as an anti-stress agent for various manipulations with animals; for premidication and potentiation of the action of analgesics, anesthetic, hypnotics and anticonvulsants; before manipulations to eliminate blockage of the esophagus in ruminants (in emergency cases, it can be administered intravenously), to reduce joint dislocations; with self-gnawing and hypogalactia in fur-bearing animals; as an antiemetic for deworming dogs with arecoline.

After the application of chlorpromazine to slaughter animals, it is most often found in the lungs, kidneys and liver. Residual amounts in the muscles persist for 12-48 hours.

Levomepromazine (tizercin). It potentiates anesthetics and analgesics stronger than chlorpromazine, but acts weaker than it as an antiemetic. It acts more on norepinephrine rather than dopamine receptors. Side effects are less pronounced.

Eteperazine. Better tolerated and more antiemetic than chlorpromazine, but less suitable for premedication.

Triftazin. The most active antipsychotic. According to the sedative effect, chlorpromazine is stronger, and according to the adrenolytic effect, it is weaker. Does not possess antihistamine, anticonvulsant and antispasmodic effects. It inhibits the peristalsis of the gastrointestinal tract in ruminants more than in animals of other species. Less liver damage.

Fluorophenazine decanoate. The drug with a moderately pronounced sedative effect, blocks more dopamine than norepinephrine receptors. Its antipsychotic effect is combined with an activating one. It is of interest for animal testing as a long-acting antipsychotic (a single injection lasts for 1-2 weeks or more).

Derivatives of butyrophenone.

The peculiarity of the pharmacodynamics of drugs in this group is that they have strongly pronounced antipsychotic and stimulating properties, while sedative and hypothermic ones are weaker. More specifically than other antipsychotics, they act on the cerebral cortex, enhancing the inhibition processes in it. This is apparently due to the great affinity of their chemical structure to GABA, an inhibitory mediator of the cerebral cortex. The main disadvantage is the possibility of extrapyramidal disorders. However, these disorders arise from high doses. Studies have shown that butyrophenones (haloperidol) are promising for use in veterinary medicine as anti-stress and promoting the growth of young animals. The latter, apparently, is associated with the well-pronounced energizing properties of butyrophenones.

Haloperidol. One of the most active antipsychotics (even stronger than triftazine), which is characterized by sedative and central adrenolytic effects (especially on dopamine receptors) in the absence of central and peripheral effects on cholinergic receptors, low toxicity.

Approximate doses (mg / kg weight): 0.07-0.1 orally and 0.045-0.08 intramuscularly to prevent transport stress in calves.

Of other butyrophenones, of interest trifluperidol(psychotic effect is more active than haloperidol), droperidol(strong, fast, but short-lived).

Rauwolfia alkaloids.

Extracts from the roots and leaves of the rauwolfia plant have long been used as sedatives and antihypertensive agents in Indian folk medicine. Rauwolfia is a perennial shrub of the kutrov family that grows in South and Southeast Asia (India, Sri Lanka). The plant, especially in the roots, contains a large amount of alkaloids (reserpine, aymalicin, serpin, etc.), which act as a sedative, hypotensive (reserpine) or adrenolytic (aymalicin, etc.).

Under the influence of rauwolfia alkaloids, especially reserpine, animals calm down and physiological sleep deepens, interoreceptive reflexes are inhibited. The hypotensive effect is manifested quite strongly, in connection with which the drugs are widely used in medicine for hypertension. The hypotensive effect develops gradually, as much as possible - after a few days.

Unlike chlorpromazine, reserpine (one of the main Rauwolfia alkaloids) does not have an adrenolytic effect and

along with this, it causes a number of cholinomimetic effects: a slowdown in cardiac activity, an increase in the motility of the gastrointestinal tract, etc. It does not have a ganglion-blocking effect.

Of the mechanisms of action, a violation of the process of deposition of norepinephrine is important, its release from the presynaptic endings of the adrenergic nerves is accelerated. In this case, the mediator is rapidly inactivated by monoamine oxidase and its effect on peripheral organs weakens. Reserpine does not seem to affect the reuptake of norepinephrine. Reserpine reduces the content of norepinephrine, dopamine and serotonin in the central nervous system, since the transport of these substances from the cell plasma is blocked and they are deaminated. As a result, reserpine has a depressing effect on the central nervous system. Animals become less active and less responsive to exogenous stimuli. The effect of sleeping pills and narcotic substances is enhanced.

Under the influence of reserpine, the content of catecholamines in the heart, blood vessels and other organs decreases. As a result, cardiac output, total peripheral vascular resistance, and arterial blood pressure decrease. Most authors deny the effect of reserpine on the vasomotor center. Along with lowering blood pressure, kidney function improves: blood flow increases and glomerular filtration increases.

The secretion and motility of the gastrointestinal tract are increased. This is due to the predominance of the influence of the vagus nerve and the local irritant effect, which manifests itself with prolonged use of the drug.

Reserpine lowers body temperature, which is apparently explained by a decrease in the serotonin content in the hypothalamus. In dogs and cats, causes constriction of the pupils and relaxation of the blinker membrane. There is also some information about the depressing effect on the gonads in animals.

The drugs of this group are used as sedatives and hypotensives for stress and other neuropsychiatric disorders, hypertension, mild heart failure, thyrotoxicosis.

Side effects usually occur with prolonged use of drugs and are manifested by drowsiness, diarrhea, increased blood clotting, bradycardia, fluid retention in the body. These phenomena are removed by atropine.

Reserpine. An ester that breaks down in the body into reserpic acid, which is a derivative of indole, and other compounds. White or yellowish fine-crystalline powder, very slightly soluble in water and alcohol, well in chloroform. The most active drug has a more pronounced local irritant effect.

Cattle are very sensitive to it, therefore, when administered intravenously, the dose should not exceed 7 mg per animal. Horses are also sensitive to reserpine, 5 mg parenterally causes severe colic. Dogs and cats tolerate higher doses of reserpine - 0.03-0.035 mg / kg body weight.

Used for prevention, treatment of stress, with neuroses, hypertension, thyrotoxicosis. Contraindicated in severe cardiovascular diseases, insufficient renal function, gastric ulcer and duodenal ulcer,

Carbidine. Indole derivative. White crystalline powder, easily soluble in water, very little in alcohol; pH of solutions is 2.0-2.5. Possesses neuroleptic, antipsychotic activity and moderate antidepressant effect. Side effects are possible: stiffness, tremor, hyperkinesis, which can be removed with cyclodol.

It is used for nervous disorders, it is possible for the prevention of stress, in medicine for schizophrenia and alcoholic psychosis. Contraindicated in case of impaired liver function, drug and analgesic poisoning.

Lithium salts.

Lithium is an element from the group of alkali metals, widespread in nature, in small amounts found in the blood, organs and muscles of animals. Lithium salts have long been used in medicine to treat gout and dissolve kidney stones. In the early 1950s, it was found that lithium preparations have a sedative effect on mental patients and prevent attacks of schizophrenia. In this regard, lithium preparations belong to a new group of sedative substances - normotimics. They are able to normalize the functions of the central nervous system and are active in both depression and excitement.

Pharmacodynamics of drugs is simple. They are rapidly absorbed after oral administration, distributed depending on the blood supply to organs and tissues. In the body, they dissociate into ions, which can be found in various organs and tissues 2-3 hours after the administration of the drug. Lithium is excreted mainly by the kidneys, and the excretion depends on the content of sodium and potassium ions in the blood. With a lack of sodium chloride, lithium is delayed, and with increased administration, the excretion of lithium increases. Lithium can cross the placenta and be excreted in milk.

The mechanism of the psychotropic action of lithium is explained by two theories: electrolyte and neurotransmitter. According to the first, lithium ions affect the transport of sodium and potassium ions in the nervous and

muscle cells, and lithium is a sodium antagonist. In the second, lithium increases the intracellular deamination of norepinephrine, decreasing its content in the brain tissues. In large doses, it lowers the amount of serotonin. In addition, the sensitivity of the brain to neurotransmitters changes. The effect of lithium on healthy and sick people is not the same; therefore, there are conflicting data in the literature.

The pharmacodynamics of lithium has been studied in laboratory animals and in humans.

In comparison with chlorpromazine, lithium has a milder and longer effect on the nervous system, but weaker. Lithium does not raise the threshold of sensitivity and does not suppress the defensive reflex, it reduces motor activity and research activity. Lithium oxybutyrate inhibits the transmission of excitation from the afferent pathways of the brain, while blocking the flow of pain impulses from the periphery to the central nervous system. The drugs prevent the manifestation of the stimulant effect on the central nervous system of various stimulants and at the same time weaken depression.

[Lithium potentiates the action of haloperidol, benzodiazepines and analgesics.

The drugs suppress the function of the thyroid gland, inhibiting the stimulating effect of thyrotropin, that is, they inhibit the pituitary gland, but increase the content of luteinizing, parathyroid hormones and insulin. The latter changes the metabolism of carbohydrates and fats. Lithium also affects nitric acid metabolism, improves the absorption of amino acids, reduces the amount of ammonia in the body and increases the amount of urea in the urine. Lithium salts increase urination by inhibiting the secretion of antidiuretic hormone.

The main drug is lithium carbonate. It is used for the prevention and treatment of psychosis and depression in medicine, in veterinary medicine for the prevention of stress in poultry farming and when transporting calves, as well as before vaccination of animals, including poultry.

Side effects - thirst, drowsiness, depression, heart failure.

Contraindicated in case of impaired renal function and cardiovascular system.

Lithium carbonate. White light powder, hardly soluble in water, solutions of alkaline reaction, insoluble in alcohol.

Reduces the aggressiveness of poultry and other animals, but the rank struggle remains in piglets. Reduces physical activity, improves adaptation to new conditions, improves animal resistance and body weight gain.

It is used for stresses before and after transportation, animal transplantation and vaccination of poultry.

Lithium oxybutyrate. White crystalline powder, easily soluble in water, difficult - in alcohol. It is a lithium analogue of sodium oxybutyrate. The action is associated with the presence of a lithium ion, and the sedative effect characteristic of sodium oxybutyrate is expressed. The drug is more active and less toxic. Assign with the same indications inside and intramuscularly in the same doses.

TRANQUILIZERS

The name of the group comes from the Latin tranquillare - to make calm, serene. These are substances that have a calming effect on the central nervous system. Unlike neuroleptics, tranquilizers do not have a pronounced antipsychotic effect, they reduce emotional tension, anxiety and fear, mainly of neurotic origin. Therefore, tranquilizers affect only with minor dysfunctions of the nervous system. Most drugs, along with a sedative effect, have a weak muscle relaxation and anticonvulsant effect, which is associated with their effect on the central nervous system. The tranquilizing effect of certain drugs is accompanied by an activating or sedative effect.

According to their chemical structure, tranquilizers are divided into several groups:

1) benzodiazepine derivatives (chlosepide, sibazone, phenazepam, nozepam);

2) derivatives of propanediol (meprotan);

3) derivatives of diphenylmethane (amisyl).

Most drugs when taken orally are absorbed quickly, the highest concentration in blood plasma is observed after 2-4 hours. A decrease in concentration by 50% occurs after 8-10 hours. Substances undergo biotransformation in the body. In the form of metabolites, conjugates and partially unchanged, they are excreted mainly by the kidneys, less - by the gastrointestinal tract.

Under the influence of tranquilizers, the excitability of the subcortical regions of the brain (limbic system, thalamus, hypothalamus) decreases and interactions between them and the cerebral cortex are inhibited. In addition, these substances inhibit spinal polysynaptic reflexes. As a result, a sedative effect develops and skeletal muscle tone decreases. Thanks to this, an anticonvulsant effect is possible. They potentiate the depressing effect on the central nervous system of drugs, hypnotics and analgesics. They practically do not affect autonomic innervation, although certain drugs (amisil) block the cholinergic systems of the brain. A decrease in heart rate and breathing is associated with a decrease in fear and muscle tension.

With prolonged use of drugs, addiction develops, side effects are possible (drowsiness, nausea, etc.).

Tranquilizers are used in medicine in psychiatric practice, in veterinary medicine for neuroses, stress for premedication before surgery, for skin diseases accompanied by itching.

Benzodiazepine derivatives. The drug molecule is based on a benzodiazepine core. When hydrogen atoms are replaced in it with halogens or oxygen, compounds with a pronounced tranquilizing effect are obtained.

All preparations are white with a yellowish tinge crystalline powders, insoluble in water, hardly soluble in alcohol. Under the influence of light, they quickly collapse.

In the mechanism of action, the main link is a weakening of the formation and action of dopamine and norepinephrine in the brain and an increase, like bromides, of inhibition processes, where the neurotransmitter is gamma-aminobutyric acid (GABA). Benzodiazepines also interact with their specific receptors. The main action for this group is sedation. Anticonvulsant activity, potentiation of the action of hypnotics and analgesics are also expressed. A hypnotic effect is possible from high doses.

Chlosepide (Chlordiazepoxide, Elenium). This is the first representative of benzodiazepine derivatives. Pharmacodynamics is typical for this group. Has a calming effect on the nervous system, relaxes muscles, stops cramps, can induce sleep. It is rapidly absorbed, acts for 8-10 hours. It is used for neuroses, excitement of the nervous system, for spastic conditions, for myositis, arthritis and skin diseases, accompanied by muscle tension. Introduce inside after feeding. Treatment begins with a small dose.

Contraindicated in pregnancy, as it crosses the placental barrier, acute liver and kidney disease.

Sibazon (diazepam, seduxen). In terms of chemical structure and pharmacological action, it is close to chlorsepide, but more active than it. The tranquilizing effect is more pronounced, reduces the feeling of fear, anxiety, tension, and normalizes sleep. Anticonvulsant activity is expressed and has an antiarrhythmic effect.

Applied for the same indications, as well as for convulsions in combination with other anticonvulsants and gastric ulcer. Contraindications, as for chlosepide.

Phenazepam. It has the most powerful tranquilizing effect, in terms of activity it is close to antipsychotics. It also causes pronounced anticonvulsant, muscle relaxant and hypnotic effects. Enhances the effect of sleeping pills and drugs.

It is indicated for neuroses, psychosomatic stress, accompanied by anxiety, fear, increased irritability, as an anticonvulsant and hypnotic; to prevent stress and improve adaptation. Complications and contraindications are the same as for chlosepide.

Nozepam (tazepam, oxazepam). Compared to previous drugs, the effect is weaker, but less toxic and better tolerated. Less pronounced muscle relaxant and anticonvulsant effect.

It is used for mild disorders of the nervous system (neuroses and neurosis-like conditions). Contraindications are the same, allergic and dyspeptic phenomena are possible.

Derivatives of propanediol.

Propanediol derivatives have similar pharmacological properties to benzodiazepines. They inhibit the transmission of excitation in the area of ​​the interneurons of the spinal cord, inhibit the thalamus and hypothalamus, resulting in a calming effect. The drugs relax muscles and have an anticonvulsant effect, enhance the effect of substances that depress the nervous system. The vegetative system is not affected.

Meprotan (meprobamate, andaksin). White crystalline powder, slightly soluble in water, well in alcohol. Easily absorbed from the gastrointestinal tract, slowly decomposes, excreted mainly by the kidneys. It has a pronounced sedative and anticonvulsant effect, slightly lowers body temperature. Induction of microsomal liver enzymes. Acts weaker than benzodiazepines and less toxic.

It is used for neuroses arising from fear, anxiety, increased muscle tone, in surgery - in preparation for operations. Assign inside after feeding. Addiction may develop, drowsiness and muscle weakness may occur.

Diphenylmethane derivatives.

Substances of this group, along with the general in the action of tranquilizers, have a strong blocking effect on the cholinergic systems of the brain, therefore they are called central anticholinergics. In addition, the peripheral anticholinergic action is also expressed.

Amisil (benactnzii). White crystalline powder, soluble in water, difficult - in alcohol. It has a central and peripheral anticholinergic effect, has a sedative and anticonvulsant effect, suppresses the cough reflex. It has a moderate antispasmodic, antihistamine, antiserotonin and local anesthetic effect. Weakens the influence of the vagus nerve, as a result of which the pupils dilate, the secretion of glands decreases, and the tone of smooth muscles decreases.

It is used for neurotic conditions, extrapyramidal disorders, preparation for anesthesia and in the postoperative period, with spasms of smooth muscles, for dilating the pupil for diagnostic purposes, as an antitussive agent. Assign inside 1-3 times a day. To dilate the pupil, 1-3 drops of a 1-2% solution are injected into the conjunctival sac.

Side effects: dry mouth, tachycardia, dilated pupils. Contraindicated in glaucoma.

Nootropic drugs.

The first information about nootropic substances appeared in the 70s. The name of the group comes from the Greek. noos - thinking, reason and tropos - striving, affinity. In the 80s, they occupied a prominent place among psychotropic drugs, as they activate the integrative mechanisms of the brain, improve memory and mental activity, and increase the brain's resistance to harmful influences. The first and main drug in this group is piracetam.

Nootropics, unlike other psychotropic drugs, do not significantly affect motor reactions, the activity of these substances does not have a hypnotic and analgesic effect, and does not change the functions of the peripheral nervous system. At the same time, they characteristically affect a number of functions of the central nervous system: they facilitate communication between the cerebral hemispheres, and increase its resistance to hypoxia.

The mechanism of action has not been studied accurately enough, but it was found that nootropics increase ATP synthesis, glucose utilization, and activate phospholipase. In terms of chemical structure, piracetam is similar to gamma-aminobutyric acid (GABA) and has many similarities in action. GABAergic substances (aminalon, sodium oxybutyrate, etc.) are combined into one group with nootropics, since they have much in common in their action on the central nervous system. They improve metabolic processes in the brain, stimulate learning, correct disorders in stress, hypoxia, intoxication, aging. Nootropic drugs are considered as a means of metabolic therapy, because they are based on substances of biogenic origin and affect metabolic processes.

Nootropics improve redox reactions, other metabolic processes and blood circulation in the brain. Increase tissue resistance to hypoxia, various toxic effects, restore blood flow and impaired brain functions, relieve lethargy and lethargy.

The drugs are used in medicine for depression, lethargy, treatment of poisoning, memory and cerebral circulation disorders, hypoxia, in gerontology and in the complex therapy of various mental illnesses.

Due to the positive and versatile effect on the functions of the brain and blood circulation in it, nootropics are a promising group of substances. It is necessary to study their action on animals for use in veterinary medicine.

Piracetam (Nootropil). List B. White crystalline powder, well soluble in water and alcohol. Easily absorbed, penetrates the blood-brain barrier, excreted by the kidneys without changes.

Increases the activity of adenylate cyclase and energy potential, inhibits nucleotide phosphatase, improves memory, learning, resistance to hypoxia. Reduces lethargy, eliminates autonomic and neurotic disorders. It is indicated for hypoxia, cerebrovascular accidents, depression, etc. Applied orally and intramuscularly, the course of treatment is 2-3 weeks. Indicative doses for dogs 0.1-0.4 g.

Contraindicated in pregnancy and acute renal failure.

Aminalon (gammalon, ganevrin). Gamma Aminobutyric Acid (GABA). List B. White powder, easily soluble in water, slightly - in alcohol.

GABA is contained in the central nervous system and is involved in inhibition processes by interacting with specific receptors. Improves blood circulation in the brain, breathing, thinking, restores movement, and weakens vestibular disorders. It is prescribed for vascular diseases of the brain, after brain injuries, with polyneuritis, developmental delay. Administered orally before feeding 3 times a day. An indicative dose for dogs is 0.25 g.

Phenibut. Gamma-amino-beta-phenylbutyric acid hydrochloride. White powder, easily soluble in water, less in alcohol.

Reduces tension, fear, anxiety, lengthens and enhances the effect of substances that depress the central nervous system; the action is similar to tranquilizers. Does not eliminate convulsions. It is indicated for neuroses and before surgery. Administered orally before feeding 3 times a day in the same doses as Aminalon.

ANTI-CARBON DRUGS

In some diseases of animals, the tone of skeletal muscles increases and their fibrillar contractions appear, sometimes seizures develop later. Anticonvulsants are used to relieve this tension and to prevent or reduce seizures. For this purpose, you can use all substances that depress the central nervous system, but they also affect other organs and systems. Therefore, as anticonvulsant substances, it is advisable to use drugs that selectively suppress convulsive reactions and do not have a general inhibitory effect on the central nervous system. The most effective are diphenine, hexamidine, benzonal and trimethine. In terms of chemical structure, these compounds are classified into different groups. Some derivatives of barbituric acid (phenobarbital, benzonal) also have anticonvulsant activity.

The mechanism of action of anticonvulsants is different, but they all inhibit the transmission of excitation in the synapses of certain areas of the brain, increase the threshold of excitability of these areas of the brain and slow down the time of the motor reaction. Some drugs affect electrolyte metabolism and increase the content of GABA in brain cells, which is involved in central inhibition processes.

The preparations are white crystalline powders, very little or insoluble in water, hardly soluble in alcohol; destroyed by light. Well absorbed from the gastrointestinal tract. Biotransformation occurs mainly in the liver, metabolites and some of the substances are excreted unchanged by the kidneys. Since the substances are persistent, slight accumulation (diphenin) is possible. With prolonged use, addiction (barbiturates) is possible.

Diphenin. A mixture of diphenylhydantoin and sodium bicarbonate (85:15). Promotes the release of sodium ions from nerve cells, which reduces the excitability of neurons and the transmission of excitation in the central nervous system. Relieves all types of cramps and skeletal muscle tension.

Prescribed for seizures of various origins, some forms of cardiac arrhythmias and vestibular disorders. Administered orally after feeding.

Side effects: nausea, vomiting, difficulty breathing, ataxia. Contraindicated in diseases of the liver, kidneys, heart, cachexia.

Hexamidine. A pyrimidine derivative, chemically similar to phenobarbital, but less active and toxic. It has a longer effect than diphenin and is used for the same purposes as a therapeutic and prophylactic agent. The side effects and contraindications are the same.

Beizonal. A derivative of barbituric acid, therefore, it acts similarly to phenobarbital, exerting an anticonvulsant effect, but not causing drowsiness, lethargy, lethargy. Prescribed for the treatment of seizures of various origins, used orally after feeding. Treatment begins with a small dose, gradually increasing it to the optimum. Cancellation of the drug and replacement of the previously used one are also made gradually (3-5 days).

The contraindications are the same.

Trimetin. Derivative of oxazolidinedione. It acts weaker than the previous remedies, therefore it is active in small seizures of seizures, in mental and vascular-vegetative disorders. The combined use in small doses with other anticonvulsants is advisable.

Assign inside after feeding 2-3 times a day.