Traditional medicine

Non-steroidal anti-inflammatory drugs pharmacology briefly. Characteristics of individual drugs

Inflammation is a pathological process that occurs in response to the action of damaging factors that stimulate the formation and release of inflammatory mediators - eicosanoids (prostaglandins, leukotrienes, thromboxanes), bradykinin, histamine, serotonin. Anti-inflammatory drugs are divided into 2 groups:

Steroid anti-inflammatory drugs - GCS;

Nonsteroidal anti-inflammatory drugs (NSAIDs) are non-narcotic analgesics.

Steroid anti-inflammatory drugs - adrenal hormones, GCS. They have a pronounced anti-inflammatory effect. GCS include cortisone, hydrocortisone, prednisolone, triamcinolone, dexa target zones (see Chapter 12).

The mechanism of the anti-inflammatory action of GCS:

Suppression of the enzyme phospholipase A2, which at a certain stage takes part in the formation of prostaglandins - mediators of inflammation;

Inhibition of the formation of other mediator substances - bradykinin, leukotrienes, histamine, serotonin;

Reduced sensitivity of tissue receptors to inflammatory mediators;

Weakening the productive and alternative phases of inflammation. Indications for use: severe forms of rheumatism, rheumatoid arthritis, polyarthritis, etc.

The mechanism of anti-inflammatory action of non-steroidal anti-inflammatory drugs:

Suppression of the enzyme cyclooxygenase and disruption of prostaglandin synthesis;

Suppression of the activity of other inflammatory mediators (histamine, serotonin, etc.);

Reduced energy supply in the area of inflammation;

Inhibition of subcortical pain centers.

Classification of NSAIDs

Indole derivatives	Acid derivatives		Oxidizing agents		Pyrazolone derivatives
Indomethacin (methindol)	Diclofenac sodium (voltaren, ortofen, veral, Naklofen, Diclak, Dikloberl, Olfen, raptev) Ketorolac (ketanov, Ketolong) Etodolac Ibuprofen (brufen, nurofen, Ibuprom, Ibutard, imet, Irfen, edea) Ketoprofen (ketonal, fastum		Piroxicam (tilcotyl) Meloxicam (speech forest, Meloxicam, Meloxam) Tenoxncam (Revodina,		Analgin (metamizole) Butadione (phenylbutazone)

		Naproxen (nalgesin, PROMAX)		tilcotyl)
		Acetylsalicylic acid
		(aspirin)

Indications for use: myalgia "arthritis, radiculitis, bursitis, rheumatism, pain due to traumatic injuries, etc. (see Chapter 5),

Indomethacin(inteban, metnndol) - NSAIDs, which also have analgesic, antipyretic and antirheumatic effects.

Indications for use: rheumatoid arthritis, rheumatism, arthritis, inflammation and swelling during fractures, dislocations, bruises, after tooth extraction, neuritis, sciatica, spondyloarthritis, gout, bursitis, synovitis, tendonitis and the like.

Side effects: headache, dizziness, hallucinations, digestive disorders, changes in the cornea and retina.

Contraindications: peptic ulcer, mental disorders, epilepsy, parkinsonism, arterial hypertension, age up to 10 years.

Diclofenac(Voltaren, Veral, Ortofen, Naklofen, Feloran) - NSAIDs with a pronounced anti-inflammatory effect, also has a moderate antipyretic and analgesic effect. With long-term treatment, it intensively penetrates into the joint cavity. Reduces pain at rest and movement, morning joint stiffness and swelling. A lasting effect develops after 1-2 weeks. treatment.

Indications for use: osteoarthritis, rheumatoid arthritis and other inflammatory diseases of the joints and spine, bruises and inflammation of soft tissues, and the like.

Side effects: nausea, anorexia, stomach pain, flatulence, constipation, erosive and ulcerative lesions of the mucous membrane of the digestive tract with signs of bleeding, headache, drowsiness, depression, toxic effects on the kidneys and hematopoiesis, allergic reactions.

Ketorolac(ketanov) - NSAIDs with a pronounced analgesic effect. The action occurs after 30 minutes, maximum after 1 hour, duration of action is 4-6 hours.

The drug also has antiplatelet properties (reduces blood viscosity).

Indications for use: pain in the postoperative period, with dislocations, fractures, soft tissue damage, cancer; hepatic and renal colic, toothache and the like.

Side effects: dry mouth, drowsiness, headache, dizziness, tinnitus, swelling, stomatitis, diarrhea, liver dysfunction, weight gain, allergic reactions.

Contraindications: peptic ulcer, bleeding, age up to 16 years, pregnancy and childbirth.

Pharmacosafety: - acetisalicylic acid cannot be combined with other NSAIDs, as this will enhance the thiulcerogenic effect (formation of gastric ulcers)

- Butadione is incompatible with GCS;

- Intramuscular administration of analgin is painful;

- Ketorolac (ketanov) should not be used for a long time (orally - no more than 5 days, parenterally - no more than 2 days) and for pain relief in obstetrics;

- Indomethacin should be taken with milk during meals. If you have a history of allergies, it is better not to use it.

Nonspecific stimulant therapy and anti-inflammatory drugs

Drug name	Release form			Directions for use			Higher doses and storage conditions
Biogenic stimulants
Aloe extract liquid (Extr. Aloes fluidum)	Solution in ampoules of 1 ml			Subcutaneously 1 ml			Under normal conditions
Apilak (Apilacum)	Tablets 0.001 g			Sublingual 1 tablet 3 times a day for 10 days			In a dry, dark place at a temperature not exceeding 20 ° C
PhiBS (FIBS)	Solution in ampoules			Subcutaneously 1 ml 1 time by train for 30 days			In a dark place
Plazmol (Plasmolum)	Solution in ampoules of 1 ml			Subcutaneously 1 ml once a day or every other day, a total of 10 injections
Enzyme preparations
Lidaza (Lydasa)	Ampoules, 5 ml bottles containing 64 UO powder			Dissolve in 1 ml of physiological solution of sodium chloride or novocaine, 1 ml intramuscularly			In a dark place at a temperature not exceeding 15 ° C
crystal (Tgurvipit crystallisa			Ampoules of 0.01 g powder			Dissolve in 1 ml of physiological solution of sodium chloride or novocaine, deep intramuscularly, intrapleurally, inhalation; for outdoor use			In a dry, dark place at a temperature not exceeding 10 ° C
Drugs affecting immune processes
Prodigiosan (Prodihyosapit)			0.005% solution in 1 ml ampoules (0.05 mg/ml)			0.5-0.6 ml intramuscularly 1 time every 4-6 days			In a dark place at a temperature of 4-8 "C
Pyrogenal (Pyrogenalum)			Ampoules of 1 ml containing 0.001, 0.025, 0.05 and 0.1 powder			Intramuscularly 1 time per day at an initial dose of 25-50 MPD			VRD-1 thousand MTD In a dark place at a temperature of 2-10 ° C
Timalin (Thymalinum)						Deep intramuscular injection 0.005-0.02 g per day			In a dry, dark place at a temperature not exceeding 20 ° C
Azathioprine (Asathioprinum)			Tablets 0.05 g			0.005 g/kg 2-3 times a day for 1-2 months.			In a dark place
Antiallergic drugs
Diphenhydramine (Dimedrolum)			Powder, tablets of 0.005, 0.01, 0.02, 0.03 and 0.05 g, suppositories of 0.005 and 0.0 g, 1% solution in ampoules of 1 ml (10 mg/ml)			Orally 0.03-0.05 g 1-3 times a day; rectally 1-2 times a day after a cleansing enema; intramuscularly 1-5 ml intravenously drip 1 ml in 100 ml of physiological sodium chloride solution			Orally: VRD-0.1, VDC-0.25 g intramuscularly: VRD 0.05 g (5 ml of 1% solution), VDD 0.15 (15 ml) List B In an airtight container in a dark place
Suprastin (Suprastinum)			Tablets of 0.025 g 2% solution in ampoules of 1 ml (20 mg/ml)			Orally, 1 tablet 3 times a day; intramuscularly, intravenously 1-2 ml
Diazolin (Diasolinum)			Powder, dragee i), 05.0.1g			Orally 0.05-0.2 g after meals 1-3 times a day			VRD-0.3 g, VDD-0.6 g list B V dark dry place
Loratadine (Loratadinum)		Tablets 0.01 g syrup 100 ml			Orally 1 tablet or 2 teaspoons of syrup 1 time per day			Under normal conditions
Fexofenadine (Fexofenadi		Tablets of 0.03, 0.12 and 0.18 g			Orally 0.12-0.18 g 1 time per day			Under normal conditions
Cromolyn sodium (Sgotoiupit Sodium)		Capsules 0.02 g			Inhalation: 1 capsule 3-8 times a day			Under normal conditions
Nonsteroidal anti-inflammatory drugs
Indomethacin (Jndometaci-pit)		Capsules of 0.025 and 0.05 g suppositories of ED g 10% ointment 40 g			Orally 0.025 g 2-3 times a day while eating with milk rectally, 1 suppository before bedtime; on affected areas of skin
Diclofenac (Diclofenac)		Tablets 0.025 and 0.05 g capsules 0.025 g 2.5% solution in ampoules 3 ml (25 mg/ml); suppositories 0.05 and 0.1 g, 1% gel 30, 50 and 100 g, 2% ointment 30 g			Orally 0.025-0.05 g 2-3 times a day during or after meals intramuscularly, intravenously 3 ml rectally 0.1-0.05 g topically to affected areas of the skin			VDD-1.5 g List B
Ketorolac (Ketorolac)		Tablets 0.01 g, 3% solution in ampoules and disposable syringe 1 ml (30 mg/ml)			Orally, 1 tablet 3 times a day; deep in slowly 0.01-0.06 g			List B In a dry, dark place at room temperature

The release forms of other drugs are described in the relevant sections.

Nonsteroidal anti-inflammatory drugs (NSAIDs) occupy a leading position in terms of consumption in the world, which is explained, first of all, by their high effectiveness in pain syndrome of inflammatory origin.

The uniqueness of NSAIDs as a class of drugs is due to the combination of anti-inflammatory, analgesic, antipyretic and antithrombotic effects. For pain of moderate and high intensity, the analgesic effect of NSAIDs is stronger than that of simple analgesics (paracetamol), and in some drugs the strength is comparable to opiates.

Due to the large number of NSAIDs on the market, therapists and neurologists often face the question of rational choice of a specific drug for conditions accompanied by pain, especially in pathologies of the joints and the musculoskeletal system in general.

The choice of drug should be made taking into account the risk of complications of pharmacotherapy and should be made in favor of drugs with the most favorable tolerability.

Classification and mechanism of action of NSAIDs

There are several classifications of NSAIDs, the most complex of which is the classification by chemical structure, reflecting the heterogeneity in the structure of the molecule of different NSAIDs.

In clinical practice, it is of fundamental importance to divide NSAIDs according to the selectivity of their effect on cyclooxygenase (COX), which catalyzes one of the stages of prostaglandin synthesis and is thereby responsible for the development of the inflammatory reaction.

Suppression of COX leads to increased utilization of arachidonic acid through the lipoxygenase pathway, i.e., to increased formation of leukotrienes, which constrict blood vessels and limit exudation.

There are two subtypes (isoenzymes) of COX in the human body: COX-1 and COX-2.

COX-1 is present in almost all organs and is the isoenzyme that works not only in conditions of inflammation, but also in the absence of it, and ensures normal physiological processes (synthesis of protective stomach mucus, some stages of hematopoiesis, filtration and reabsorption in the kidneys). Under pathological conditions, COX-1 is involved in the development of inflammation.

COX-2 is found in high concentrations in the brain, bones, organs of the female reproductive system, and kidneys; its synthesis is strongly activated under conditions of inflammation. It is believed that it is COX-2 that takes part in the synthesis of pro-inflammatory prostaglandins, which potentiate the activity of inflammatory mediators (histamine, serotonin, bradykinin), irritate pain receptors at the site of inflammation, participate in controlling the activity of the thermal regulation center, promoting cell proliferation, mutagenesis and destruction.

High activity of COX-2 is found in epithelial cancer cells and atherosclerotic plaques, where the enzyme accordingly inhibits the natural processes of apoptosis and promotes atherogenesis.

Inhibition of COX-1 and COX-2 under the influence of non-selective NSAIDs contributes to the development of side effects associated with inhibition of the physiological role of COX, primarily gastropathy (erosions and gastric ulcers), which is especially important if regular and long-term use of NSAIDs is necessary (usually , for rheumatic diseases). That is why selective COX-2 inhibitors were developed - nimesulide, celecoxib and others, which significantly reduced the risk of such complications.

So, suppression of COX activity produces anti-inflammatory, analgesic and antipyretic effects. The antiplatelet effect is explained by the ability of NSAIDs to inhibit COX-1 in platelets, disrupting the formation of thromboxane A2. Only acetylsalicylic acid is used as an antiplatelet agent in medical practice.

Some COX-2 inhibitors (nimesulide, meloxicam, celecoxib) in clinical studies have shown an antitumor effect against colon polyps, some anti-atherosclerotic effect, as well as a beneficial therapeutic effect in Alzheimer's disease, but these properties require further study.

The vast majority of NSAIDs are weak organic acids and are therefore absorbed in the acidic environment of the stomach. Table 3 shows the pharmacokinetic parameters of the most popular NSAIDs.

Most NSAIDs have a small volume of distribution and half-life, but the duration of the effect does not always depend on these parameters, since the ability to penetrate and accumulate at the site of inflammation is key.

The short half-life reduces the risk of drug complications. The speed of onset of the effect generally depends on the tropism of certain drugs to organs and tissues.

Due to the unique combination of pharmacological effects, NSAIDs have found wide use in medicine; the main indications for use are summarized in Table. 4.

Adverse Adverse Reactions

Due to the significant popularity of NSAIDs in clinical practice, as well as the high level of self-medication with this group of drugs, the clinician needs to be aware of the most common complications of NSAID therapy.

The most common adverse reactions include damage to the mucous membrane of the gastrointestinal tract (erosion, ulcers), which occurs as a result of inhibition of the synthesis of protective mucus. In this regard, the risk of damage to the mucous membrane by digestive juices, especially gastric juices, increases.

NSAIDs can lead to the development of so-called "silent" ulcers, i.e. ulcers that occur without a typical pain syndrome due to the presence of analgesic activity in the drugs. Such ulcers, after a long asymptomatic existence, can manifest as gastrointestinal bleeding.

The risk of developing “silent” ulcers is high in elderly patients, therefore, in this group of patients, with long-term use of NSAIDs, regular endoscopic monitoring is necessary.

The next complication is "aspirin asthma"(Vidal syndrome) - a combination of asthma attacks with urticaria, rhinitis and polyposis of the nasal mucosa. Since COX is inhibited under the influence of NSAIDs, arachidonic acid is utilized through the formation of leukotrienes, which cause this complication.

It should be noted that many NSAIDs (most often non-selective COX inhibitors) can cause partial bronchoconstriction or bronchospasm, so patients with bronchial asthma or a history of bronchospasm on NSAIDs are prescribed these drugs with great caution or do not use them at all.

Non-selective NSAIDs block COX-1 in the kidneys, which leads to impaired filtration and reabsorption, provokes water and electrolyte retention in the body and provokes edema. Fluid retention is dangerous in patients with arterial hypertension and chronic heart failure, therefore, when using NSAIDs, they need more careful monitoring of hemodynamic parameters, and sometimes dose adjustment of cardiac medications. Some NSAIDs (for example, diclofenac) have severe nephrotoxicity.

Hemorrhagic syndrome most often observed with the use of acetylsalicylic acid, since the drug irreversibly inhibits platelet aggregation and has anticoagulant properties. However, it must be remembered that when NSAIDs and antithrombotic drugs are co-administered, the risk of bleeding increases.

Hepatotoxic reactions(from a slight increase in liver enzyme levels to more severe forms) can be observed when using drugs that are metabolized in the liver. Risk factors include alcohol abuse, liver disease and concurrent use of hepatotoxic drugs.

A serious complication is Reye's syndrome, which is an acute toxic encephalopathy with cerebral edema and fatty degeneration of internal organs, primarily the liver. In this case, there are no signs of inflammatory disease of the brain.

An adverse reaction occurs when acetylsalicylic acid is prescribed against the background of a viral infection (influenza, chicken pox, measles). Symptoms can develop at any age, but the vast majority of cases affect children under 15 years of age. The disease can stop at the initial stage, but most often it worsens to a precomatous or comatose state.

The number of cases of Reye's syndrome in developed countries is very low due to the ban on the use of acetylsalicylic acid in children with fever caused by influenza.

NSAIDs can reduce fertility and have a negative effect on the fetus, so their use in pregnant women and women planning pregnancy is undesirable.

Conclusion

NSAIDs have a unique combination of anti-inflammatory, analgesic, antipyretic and antithrombotic effects, which makes it possible to control the course of many diseases.

The success of pharmacotherapy largely depends on knowledge of the characteristics of the action of individual NSAIDs, which provides an individual approach when selecting a drug for a particular patient. These features primarily include the degree of penetration into the tissues that need to be affected pharmacologically, as well as the tolerability profile, taking into account which is important for preventing the development of complications of therapy, especially from the gastrointestinal tract during long-term treatment.

N.V. Sturov, V.I. Kuznetsov

Currently, nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for a number of diseases. It should be noted that the NSAID group includes several dozen drugs that differ in chemical structure, pharmacokinetics, pharmacodynamics, tolerability and safety. Due to the fact that many NSAIDs have comparable clinical efficacy, it is the safety profile of the drug and its tolerability that today comes to the forefront among the most significant characteristics of NSAIDs. This paper presents the results of the largest clinical studies and meta-analyses that examined the negative effects of NSAIDs on the digestive, cardiovascular and kidney systems. Particular attention is paid to the mechanism of development of the identified adverse drug reactions.

Key words: non-steroidal anti-inflammatory drugs, safety, cyclooxygenase, microsomal PGE2 synthetase, gastrotoxicity, cardiotoxicity, oxicams, coxibs.

For quotation: Dovgan E.V. Clinical pharmacology of non-steroidal anti-inflammatory drugs: course towards safety // Breast Cancer. 2017. No. 13. pp. 979-985

Clinical pharmacology of non-steroidal anti-inflammatory drugs: focus on safety
Dovgan E.V.

Smolensk Regional Clinical Hospital

Currently the non-steroidal anti-inflammatory drugs (NSAIDs) are the basis of therapy for a number of diseases. It should be noted that the NSAID group includes lots of drugs with different chemical structure, pharmacokinetics, pharmacodynamics, tolerance and safety. Due to the fact that many NSAIDs have comparable clinical efficacy, it is the drug safety profile and its tolerability that comes first among the most significant characteristics of NSAIDs. This paper presents the results of the largest clinical trials and meta-analyzes, in which the negative effect of NSAIDs on the digestive, cardiovascular and kidney systems was studied. Also special attention is paid to the mechanism of development of adverse drug effects.

Key words: nonsteroidal anti-inflammatory drugs, safety, cyclooxygenase, microsomal PGE 2 synthetase, gastrotoxicity, cardiotoxicity, oxicam, coxibes.
For citation: Dovgan E.V. Clinical pharmacology of non-steroidal anti-inflammatory drugs: focus on safety // RMJ. 2017. No. 13. P. 979–985.

The article is devoted to the clinical pharmacology of non-steroidal anti-inflammatory drugs

Despite the fact that more than 100 years have passed since the beginning of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in clinical practice, representatives of this group of drugs are still widely in demand by doctors of various specialties and are the basis for the treatment of a wide range of diseases and pathological conditions, such as acute and chronic musculoskeletal pain, mild to moderate traumatic pain, renal colic, headache and dysmenorrhea.

Mechanism of action of NSAIDs

NSAIDs are a rather heterogeneous group of drugs that differ in chemical structure, anti-inflammatory and analgesic activity, safety profile and a number of other characteristics. However, despite a number of significant differences, all NSAIDs have a similar mechanism of action, discovered more than 40 years ago. NSAIDs have been found to inhibit cyclooxygenases (COX), which regulate the formation of various prostanoids. As is known, COX is represented by two isoforms - COX-1 and COX-2. COX-1 is constitutional, constantly present in tissues and regulates the synthesis of prostanoids such as prostaglandins (PG) (PGE2, PGF2α, PGD2, 15d-PGJ2), prostacyclin PGI2 and thromboxane A2, which regulate local homeostasis in the body. It should be noted that the effects of prostanoids are realized through their action on specific receptors, while exposure to the same receptor located in different cells leads to different effects. For example, the effect of PGE2 on the EP3 receptor of gastric epithelial cells is accompanied by increased production of mucus and bicarbonates, while at the same time, activation of this receptor located on the parietal cells of the stomach leads to a decrease in the production of hydrochloric acid, which is accompanied by a gastroprotective effect. In this regard, it is believed that a significant part of the adverse drug reactions (ADRs) characteristic of NSAIDs are caused precisely by the inhibition of COX-1.
Until recently, COX-2 was considered an inducible enzyme, which is normally absent and appears only in response to inflammation, but work in recent years indicates that constitutional COX-2 is also present in the body in small quantities, which plays an important role in the development and functioning of the brain, thymus, kidneys and gastrointestinal tract (GIT). Therefore, the inhibition of constitutional COX-2 observed with the prescription of selective COX-2 inhibitors (for example, coxibs) may be accompanied by the development of a number of serious ADRs from the cardiovascular system (CVS) and kidneys.
In addition to a number of physiological functions, COX-2 plays an important role in the development and maintenance of inflammation, pain and fever. It is under the influence of COX-2 that the active formation of PGE2 and a number of other prostanoids, which are the main mediators of inflammation, occur. Excessive formation of PGE2, observed during inflammation, is accompanied by a number of pathological reactions. For example, signs of inflammation such as swelling and redness are caused by local vasodilation and increased vascular permeability when PGE2 interacts with EP2 and EP4 receptors; Along with this, the effect of this PG on peripheral sensory neurons leads to hyperalgesia. As is known, PGE2 is synthesized from PGN2 using microsomal PGE2 synthetase 1 (m-PGE2S 1), cytosolic PGE2 synthetase (c-PGE2S) and microsomal PGE2 synthetase 2 (m-PGE2S 2). It has been established that c-PGE2S works in concert with COX-1 and, under the influence of this enzyme (but not under the influence of COX-2), converts PGN2 into PGE2, i.e. this synthetase regulates the production of PGE2 normally. In contrast, m-PGE2C 1 is inducible and works in concert with COX-2 (but not COX-1) and converts PGN2 to PGE2 in the presence of inflammation. Thus, it is m-PGE2S 1 that is one of the key enzymes that regulates the synthesis of such a significant inflammatory mediator as PGE2.
It has been established that the activity of m-PGE2S 1 increases under the influence of pro-inflammatory cytokines (for example, interleukin-1b and tumor necrosis factor alpha), while at the same time, studies in recent years indicate that representatives of the oxicam group (for example, meloxicam) are able to inhibit m- PGE2C 1 and thereby reduce the production of PGE2 during inflammation. The data obtained indicate the presence of at least two mechanisms of action for oxicams: the first mechanism, also characteristic of other NSAIDs, is the effect on COX, and the second is associated with inhibition of m-PGE2C 1, leading to the prevention of excessive formation of PGE2. Perhaps it is the presence of two mechanisms of action in oxicams that explains their favorable safety profile and, above all, the low incidence of ADRs from the cardiovascular system and kidneys while maintaining high anti-inflammatory effectiveness.
Next, we present the results of meta-analyses and large clinical trials that examined the safety of NSAIDs.

Negative effects of NSAIDs on the gastrointestinal tract

ADRs from the gastrointestinal tract are the most common and well-studied complications that develop during NSAID therapy. Two main mechanisms for the negative effects of NSAIDs on the gastric mucosa have been described: firstly, local effects due to the fact that some NSAIDs are acids and, when they enter the stomach, can have a direct damaging effect on the gastric epithelium; secondly, systemic effects through inhibition of PG synthesis through inhibition of COX.
As is known, PGs play a very important role in protecting the gastric mucosa from the effects of hydrochloric acid, with the most significant PGs being PGE2 and PGI2, the formation of which is normally regulated by COX-1 and COX-2. It was found that these PGs regulate the production of hydrochloric acid in the stomach, the secretion of bicarbonates and mucus, which protect the gastric mucosa from the negative effects of hydrochloric acid (Table 1).
At the same time, the negative effect of NSAIDs (primarily non-selective) on the stomach is associated with a disruption in the production of PGE2 due to inhibition of COX-1, which is accompanied by increased production of hydrochloric acid and a decrease in the production of substances that have a gastroprotective effect (bicarbonates and mucus) (Fig. 1).

It should be noted that COX-2 is involved in maintaining normal gastric function, plays an important role in the healing of gastric ulcers (by regulating the production of PGE2, which interacts with EP4 receptors), and the use of superselective COX-2 inhibitors may slow down the healing of gastric ulcers, which in some cases it ends with complications such as bleeding or perforation. Some studies suggest that 1 in 600–2400 patients taking NSAIDs are hospitalized with gastrointestinal bleeding or perforation, and 1 in 10 hospitalized patients die.
Data from a large-scale study conducted by Spanish scientists indicate a higher incidence of gastric ADRs when using non-COX-2 selective NSAIDs. Compared with no NSAIDs, non-selective COX-2 inhibitors were found to significantly increase the risk of serious upper gastrointestinal complications (adjusted relative risk (RR) 3.7; 95% confidence interval (CI): 3.1–4 ,3). Along with this, selective COX-2 inhibitors were less likely to cause the development of such complications (RR 2.6; 95% CI: 1.9–3.6). It should be noted that the highest risk of serious complications was identified when prescribing the selective COX-2 inhibitor etoricoxib (RR 12), followed by naproxen (RR 8.1) and indomethacin (RR 7.2), on the contrary, the safest NSAIDs were ibuprofen (RR 2), rofecoxib (RR 2.3) and meloxicam (RR 2.7) (Figure 2). The higher risk of serious upper gastrointestinal injury with etoricoxib therapy is likely due to the drug interfering with the healing process of gastric ulcers by interfering with the production of PGE2 (associated with COX-2), which binds to EP4 to promote ulcer healing.

In a study by Melero et al. It has been demonstrated that non-selective NSAIDs are significantly more likely than selective COX-2 inhibitors to cause severe gastrointestinal lesions. Thus, the RR of gastrointestinal bleeding was minimal during treatment with aceclofenac (comparator drug, RR 1) and meloxicam (RR 1.3). In contrast, ketorolac had the greatest risk of bleeding (RR 14.9).
Of interest are the results of a network meta-analysis by Yang M. et al., which assessed the effect on the gastrointestinal tract of moderately selective COX-2 inhibitors (nabumetone, etodolac and meloxicam) and coxibs (celecoxib, etoricoxib, parecoxib and lumiracoxib). The meta-analysis included results from 36 studies with a total of 112,351 participants, aged 36 to 72 years (median 61.4 years), and study duration ranging from 4 to 156 weeks. (median 12 weeks). It was found that the probability of developing a complicated gastric ulcer in the coxibs group was 0.15% (95% CI: 0.05–0.34), and in the group of moderately selective COX-2 inhibitors was 0.13% (95% CI: 0.04–0.32), the difference is statistically insignificant. It was also shown that the odds of symptomatic gastric ulcers in the coxibs group were 0.18% (95% CI: 0.01–0.74) versus 0.21% (95% CI: 0.04–0.62). ) in the group of moderately selective inhibitors, the difference is statistically insignificant. There were also no statistically significant differences between the two NSAID groups in the likelihood of gastric ulcers detected by gastroscopy. It should be noted that the frequency of adverse events (AEs) was comparable in both groups (Table 2).

In summary, the results of this meta-analysis demonstrate comparable tolerability and GI safety of moderately selective NSAIDs and coxibs.
In addition to damage to the stomach and intestines, hepatotoxic reactions may develop with the use of NSAIDs. According to various studies, the incidence of liver damage caused by NSAIDs is relatively low and ranges from 1 to 9 cases per 100 thousand people. Various types of liver damage have been described for almost all NSAIDs, with most reactions being asymptomatic or mild. Hepatotoxic reactions caused by NSAIDs can manifest themselves in different ways, for example: ibuprofen can cause the development of acute hepatitis and ductopenia (disappearing bile ducts); During treatment with nimesulide, acute hepatitis and cholestasis may occur; oxicams can lead to acute hepatitis, hepatonecrosis, cholestasis and ductopenia.
For some NSAIDs, a direct relationship has been established between the duration of prescription and the dose and the risk of liver damage. Thus, in the work of Donati M. et al. The risk of developing acute serious liver damage was analyzed during the use of various NSAIDs. It was found that when the duration of therapy was less than 15 days, the highest risk of liver damage was caused by nimesulide and paracetamol (adjusted odds ratio (OR) 1.89 and 2.66, respectively). The risk of developing hepatotoxic reactions in the case of long-term administration of NSAIDs (more than 30 days) increased for a number of drugs by more than 8 times (Table 3).

Negative effects of NSAIDs on the cardiovascular system

As is known, acetylsalicylic acid (ASA) in low doses has a cardioprotective effect, reducing the incidence of ischemic complications from the cardiovascular system and nervous system, and therefore is widely used for the prevention of myocardial infarction, stroke and cardiovascular death. Unlike ASA, many NSAIDs can have a negative effect on the cardiovascular system, which is manifested by worsening the course of heart failure, destabilization of blood pressure and thromboembolic complications.
These negative effects are due to the effect of NSAIDs on platelet and endothelial function. Normally, the ratio between prostacyclin (PGI2) and thromboxane A2 plays an important role in the regulation of platelet aggregation, while PGI2 is a natural antiplatelet agent, and thromboxane A2, on the contrary, stimulates platelet aggregation. When selective COX-2 inhibitors are prescribed, prostacyclin synthesis decreases, while at the same time thromboxane A2 continues to be synthesized (the process is controlled by COX-1), which ultimately leads to activation and increased platelet aggregation (Fig. 3).

It should be emphasized that the clinical significance of this phenomenon has been confirmed in a number of studies and meta-analyses. Thus, in a systematic review and meta-analysis of 42 observational studies, it was found that selective COX-2 inhibitors, such as etodolac and etoricoxib, most significantly increased the risk of myocardial infarction (RR 1.55 and 1.97, respectively). On the contrary, naproxen, celecoxib, ibuprofen and meloxicam practically did not increase the risk of developing thrombotic complications from the cardiovascular system.
Similar data were obtained in a meta-analysis of 19 studies published in 2015. In their work, Asghar et al. found that the risk of developing thrombotic complications from the heart (disease codes I20-25, I46-52 according to ICD-10) practically did not increase during treatment with ibuprofen (OR 1.03; 95% CI: 0.95–1.11) , naproxen (RR 1.10; 95% CI: 0.98–1.23) and meloxicam (RR 1.13; 95% CI: 0.98–1.32) compared with no NSAID therapy. At the same time, rofecoxib (RR 1.46; 95% CI: 1.10–1.93) and indomethacin (RR 1.47; 95% CI: 0.90–2.4) increased the risk of developing such complications. This study examined the effect of drug dosage on the combined relative risk of complications (cRR), which was calculated as the sum of the risks of thrombotic complications from the heart, blood vessels and kidneys. It turned out that the CR did not increase only when high doses of meloxicam (15 mg/day) and indomethacin (100–200 mg/day) were prescribed compared with low doses. On the contrary, when high doses of rofecoxib were prescribed (more than 25 mg/day), the RR increased more than 4 times (from 1.63 to 6.63). To a lesser extent, an increase in dosage contributed to the increase in RR with the use of ibuprofen (1.03 [≤1200 mg/day] versus 1.72) and diclofenac (1.17 versus 1.83). Summarizing the results of this meta-analysis, we can conclude that among selective COX-2 inhibitors, meloxicam is one of the safest drugs.
Along with the development of myocardial infarction, NSAIDs can lead to the development or worsen the course of chronic heart failure (CHF). Thus, data from a large-scale meta-analysis showed that the prescription of selective COX-2 inhibitors and high doses of “traditional” NSAIDs (such as diclofenac, ibuprofen and naproxen) increased the likelihood of hospitalization due to deterioration by 1.9–2.5 times compared with placebo CHF.
The results of a large case-control study published in 2016 in the British Medical Journal are noteworthy. It was found that the use of NSAIDs during the previous 14 days increased the likelihood of hospitalization due to progression of CHF by 19%. The highest risk of hospitalization was observed during treatment with ketorolac (RR 1.83), etoricoxib (RR 1.51), indomethacin (RR 1.51), while during the use of etodolac, celecoxib, meloxicam and aceclofenac the risk of CHF progression was almost didn't increase.
It should be noted that the negative effect of NSAIDs on the course of CHF is due to an increase in peripheral vascular resistance (due to vasoconstriction), sodium and water retention (which leads to an increase in circulating blood volume and an increase in blood pressure).
The use of a number of NSAIDs, especially highly selective ones, is accompanied by an increased risk of stroke. Thus, a systematic review and meta-analysis of observational studies published in 2011 demonstrated an increased risk of stroke during treatment with rofecoxib (RR 1.64; 95% CI: 1.15–2.33) and diclofenac (RR 1.27; 95 % CI: 1.08–1.48) . However, treatment with naproxen, ibuprofen and celecoxib had virtually no effect on the risk of stroke.
In a prospective population-based study, Haag et al. 7636 patients (mean age 70.2 years) took part, who had no indications of cerebral ischemia at the time of inclusion in the study. Over a 10-year follow-up period, 807 patients experienced stroke (460 ischemic, 74 hemorrhagic and 273 unspecified), with a higher risk of stroke in those receiving non-selective NSAIDs and selective COX-2 inhibitors (RR 1.72 and 2. 75, respectively) compared with patients who received selective COX-1 inhibitors (indomethacin, piroxicam, ketoprofen, flubiprofen and apazone). It should be emphasized that the highest risk of stroke among non-selective NSAIDs was found in naproxen (RR 2.63; 95% CI: 1.47–4.72), and among selective COX-2 inhibitors, rofecoxib was the most unsafe with respect to stroke ( RR 3.38; 95% CI: 1.48–7.74). Thus, this study found that the use of selective COX-2 inhibitors in elderly patients is significantly more likely than the use of other NSAIDs to lead to the development of stroke.

Negative effects of NSAIDs on kidney function

Nephrotoxicity is one of the most common ADRs associated with the use of NSAIDs, with 2.5 million people in the United States annually experiencing renal impairment while being treated with drugs in this group.
The renal toxicity of NSAIDs may include prerenal azotemia, hyporenin hypoaldosteronism, sodium retention, hypertension, acute interstitial nephritis, and nephrotic syndrome. The main cause of renal dysfunction is the effect of NSAIDs on the synthesis of a number of PGs. One of the main PGs that regulate kidney function is PGE2, which, interacting with the EP1 receptor, inhibits the reabsorption of Na+ and water in the collecting duct, i.e., has a natriuretic effect. It has been established that the EP3 receptor is involved in the delay in the absorption of water and sodium chloride in the kidneys, and EP4 regulates hemodynamics in the renal glomeruli. It should be noted that prostacyclin dilates the arterioles of the kidneys, and thromboxane A2, on the contrary, has a pronounced vasoconstrictor effect on the glomerular capillaries, which leads to a decrease in the glomerular filtration rate. Thus, the decrease in the production of PGE2 and prostacyclin caused by the use of NSAIDs is accompanied by a decrease in blood flow to the kidneys, leading to sodium and water retention.
A number of studies have found that both selective and non-selective NSAIDs can cause acute renal dysfunction; in addition, the use of non-selective NSAIDs is considered as one of the causes of the development of chronic renal failure (CRF). The results of 2 epidemiological studies suggest that the RR of chronic renal failure during treatment with NSAIDs ranges from 2 to 8.
A large-scale retrospective study conducted in the United States involving more than 350 thousand patients examined the effect of various NSAIDs on the development of acute renal failure (defined as an increase in creatinine levels by more than 50%). It was found that the use of NSAIDs was associated with an increased risk of acute kidney injury (adjusted RR 1.82; 95% CI: 1.68–1.98) compared with non-use of drugs of this group. The risk of kidney damage varied significantly among NSAIDs, with drug toxicity increasing as its selectivity for COX-2 decreased. For example, rofecoxib (RR 0.95), celecoxib (RR 0.96) and meloxicam (RR 1.13) had virtually no negative effect on kidney function, while indomethacin (RR 1.94), ketorolac (RR 2 .07), ibuprofen (RR 2.25) and high doses of ASA (RR 3.64) significantly increased the risk of renal dysfunction. Thus, this study demonstrated the lack of effect of selective COX-2 inhibitors on the development of acute renal dysfunction.
In this regard, patients at high risk of renal impairment should avoid prescribing both non-selective NSAIDs in high doses and superselective COX-2 inhibitors, which can also cause renal impairment.

Conclusion

Currently, a doctor has a large number of different NSAIDs in his or her arsenal, which differ both in effectiveness and in the spectrum of ADRs. Speaking about the safety of NSAIDs, it is necessary to emphasize that the selectivity of the drug with respect to COX isoforms largely determines from which organs and systems ADRs occur. For example, non-selective NSAIDs have gastrotoxic effects and can worsen kidney function; on the contrary, more modern highly selective COX-2 inhibitors (primarily coxibs) more often cause thrombotic complications - heart attacks and strokes. How can a doctor choose the optimal drug among so many NSAIDs? How to maintain a balance of effectiveness and safety? Data from numerous clinical studies and meta-analyses show that NSAIDs with a moderate index of selectivity for COX-2 (for example, meloxicam) are largely free of the ADRs associated with both non-selective and superselective drugs.

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CLINICAL PHARMACOLOGY OF NON-STEROID ANTI-INFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a large and chemically diverse group of drugs that are widely used in clinical practice. Historically, this is the oldest group of anti-inflammatory (antiphlogistic) drugs. Its study began in the first half of the last century. In 1827, the glycoside salicin was isolated from willow bark, the antipyretic effect of which had been known for a long time. In 1838, salicylic acid was obtained from it, and in 1860, the complete synthesis of this acid and its sodium salt was carried out. In 1869, acetylsalicylic acid was synthesized. Currently, there is a large arsenal of NSAIDs (more than 25 types), and in practical medicine they are used to treat more than 1000 drugs created on their basis. The great “popularity” of NSAIDs is explained by the fact that they have anti-inflammatory, analgesic and antipyretic effects and bring relief to patients with corresponding symptoms (inflammation, pain, fever), which are observed in many diseases. A feature of modern NSAIDs is the variety of dosage forms, including those for topical use in the form of ointments, gels, sprays, as well as suppositories and preparations for parenteral administration. Most drugs in the NSAID group belong, according to modern terminology, to “acid” anti-inflammatory drugs, so named because they are derivatives of organic acids and are themselves weak acids with a pH of 4.0. Some authors attach great importance to the indicated pH value, believing that this contributes to the accumulation of these compounds at the site of inflammation.

Over the past 30 years, the number of NSAIDs has increased significantly and currently this group includes a large number of drugs that differ in chemical structure, features of action and application.

^ CLASSIFICATION OF NSAIDs (by chemical structure and activity).

I group - NSAIDs with pronounced anti-inflammatory activity .

Salicylates	a) acetylated: Acetylsalicylic acid (ASA) - (aspirin); Lysine monoacetylsalicylate (aspizole, laspal); b) non-acetylated: Sodium salicylate; - choline salicylate (sachol); - salicylamide; - dolobid (diflunisal); - disalcide; - trilisate.
Pyrazolidines	- azapropazone (Raimox); - clofezone; - phenylbutazone (butadione); Oxyphenylbutazone.
^ Indoleacetic acid derivatives	- indomethacin (methindol); - sulindac (clinoril); Etodalak (lodin);
Phenylacetic acid derivatives	- diclofenac sodium (ortofen, voltaren); Diclofenac potassium (Voltaren - Rapid); Fentiazac (donorest); - lonasalac calcium (irritene).
Oxycams	- piroxicam (roxicam); - tenoxicam (tenoctin); Meloxicam (movalis); - lornoxicam (xefocam).
Alcanons	- nabumetone (relifix).
^ Propionic acid derivatives	- ibuprofen (brufen, nurofen, solpaflex); Naproxen (naprosyn); - sodium salt of naproxen (apranax); - ketoprofen (knavon, profenid, oruvel); Flurbiprofen (flugalin); - fenoprofen (fenopron); Fenbufen (Lederlene); - tiaprofenic acid (surgam).

Group II - NSAIDs with weak anti-inflammatory activity.

^ Anthranilic acid derivatives (fenamates)	- mefenamic acid (pomstal); Meclofenamic acid (Meclomet); Niflumic acid (donalgin, nifluril); Morniflumate (nifluril); Tolfenamic acid (clotam).
Pyrazolones	- metamizole (analgin); - aminophenazone (amidopyrine); Propyphenazone.
^ Para-aminophenol derivatives	- phenacetin; Paracetamol.
Heteroarylacetic acid derivatives	- ketorolac; Tolmetin (tolectin).
Different	- proquazon (biarizon); - benzydamine (tantum); Nimesulide (mesulide); - Celebrex (celecoxib).

^ CLASSIFICATION OF NSAIDs

(by duration of action)

1. Short-acting (T1/2 = 2-8 hours):

Ibuprofen; - ketoprofen; - indomethacin; - fenoprofen;

Voltaren; - fenamates. - tolmetin;

2. Average duration of action (T1/2 = 10-20 hours):

Naproxen; - sulindac; - diflunisal.

3. Long-term action (T1/2 = 24 hours or more):

Oxycams; - phenylbutazone.
^ Classification by degree of selectivity

COX-1 selective low doses of acetylsalicylic acid

COX-2 non-selective most NSAIDs

COX-2 selective coxibs (rofecoxib, celecoxib, valdecoxib, etoricoxib, lumiracoxib), nimesulide, meloxicam, etodolac

COX-3 selective paracetamol
^ PHARMACODYNAMICS OF NSAIDs

From a clinical point of view, all NSAIDs have a number of common features:

1. Non-specific anti-inflammatory effect, i.e. inhibitory effect on any inflammatory process, regardless of its etiological and nosological characteristics.

2. A combination of anti-inflammatory, analgesic and antipyretic effects.

3. Relatively well tolerated, which is apparently due to rapid elimination from the body.

4. Inhibitory effect on platelet aggregation.

5. Binding to serum albumin, and there is competition between different drugs for binding sites. This is significant because, on the one hand, unbound drugs are quickly eliminated from the body and have no additional effect, and on the other hand, drugs freed from albumin can create an unusually high concentration and cause side effects.

The main key mechanisms are universal for most drugs, although their different chemical structures suggest a predominant effect on certain specific processes. In addition, most of the mechanisms listed below are multi-component, i.e. within each of them, the same type of effect of different groups of drugs can be realized in different ways.

^ The action of NSAIDs consists of the following key links:

1. Prevention of damage to cellular structures, reducing capillary permeability, which most clearly limits the exudative manifestations of the inflammatory process (inhibition of lipid peroxidation, stabilization of lysosomal membranes, preventing the release of lysosomal hydrolases into the cytoplasm and extracellular space, capable of destroying proteoglycans, collagen, cartilage tissue).

2. Reduced intensity of biological oxidation, phosphorylation and glycolysis, which leads to inhibition of the production of macroergs necessary for the biosynthesis of substances, transport of liquid and metal ions across the cell membrane, and for many other processes that play an important role in the pathogenesis of inflammation (reduced energy supply to the inflammatory reaction) . In addition, the effect on tissue respiration and glycolysis changes plastic metabolism, because intermediate products of oxidation and glycolytic transformations of substrates serve as building materials for various synthetic reactions (for example, the biosynthesis of kinins, mucopolysaccharides, immunoglobulins).

3. Inhibition of synthesis or inactivation of inflammatory mediators (histamine, serotonin, bradykinin, lymphokines, prostaglandins, complement factors and other nonspecific endogenous damaging factors).

4. Modification of the inflammatory substrate, i.e. some change in the molecular configuration of tissue components, preventing them from reacting with damaging factors.

5. Cytostatic effect, leading to inhibition of the proliferative phase of inflammation and a decrease in the post-inflammatory phase of the sclerotic process.

6. Inhibition of rheumatoid factor production in patients with rheumatoid arthritis.

7. Disturbance in the conduction of pain impulses in the spinal cord (metamizole).

8. The inhibitory effect on hemocoagulation (primarily on the inhibition of platelet aggregation) turns out to be an additional, secondary factor in the anti-inflammatory effect: a decrease in the intensity of coagulation in the capillaries of inflamed areas prevents disruption of microcirculation.
^ MECHANISMS OF ACTION OF NSAIDs

Undoubtedly, the most important mechanism of action of NSAIDs is the ability to inhibit COX, an enzyme that catalyzes the conversion of free polyunsaturated fatty acids (for example, arachidonic acid) into prostaglandins (PGs), as well as other eicosanoids - thromboxanes (TrA2) and prostacyclin (PG-I2) (Fig. 1). It has been proven that prostaglandins have diverse biological activities:

a) are mediators of the inflammatory response: they accumulate at the site of inflammation and cause local vasodilation, edema, exudation, migration of leukocytes and other effects (mainly PG-E2 and PG-I2);

b) sensitize receptors to pain mediators (histamine, bradykinin) and mechanical effects, lowering the sensitivity threshold;

V) increase the sensitivity of hypothalamic thermoregulation centers to the action of endogenous pyrogens (interleukin-1, etc.) formed in the body under the influence of microbes, viruses, toxins (mainly PG-E2);

G) play an important physiological role in protecting the mucous membrane of the gastrointestinal tract(increased secretion of mucus and alkali; preservation of the integrity of endothelial cells inside the microvessels of the mucosa, helping to maintain blood flow in the mucosa; preservation of the integrity of granulocytes and thus maintaining the structural integrity of the mucosa);

d) affect kidney function: cause vasodilation, maintain renal blood flow and glomerular filtration rate, increase renin release, sodium and water excretion, and participate in potassium homeostasis.

In recent years, it has been established that there are at least two cyclooxygenase isoenzymes that are inhibited by NSAIDs. The first isoenzyme - COX-1 - controls the production of PGs, which regulate the integrity of the mucous membrane of the gastrointestinal tract, platelet function and renal blood flow, and the second isoenzyme - COX-2 - is involved in the synthesis of PGs during inflammation. Moreover, COX-2 is absent under normal conditions, but is formed under the influence of certain tissue factors that initiate the inflammatory response (cytokines and others). In this regard, it is assumed that the anti-inflammatory effect of NSAIDs is due to inhibition of COX-2, and their undesirable reactions are due to inhibition of COX-1. The ratio of the activity of NSAIDs in terms of blocking COX-1/COX-2 allows us to judge their potential toxicity. The lower this value, the more selective the drug is for COX-2 and, thus, the less toxic. For example, for meloxicam it is 0.33, diclofenac - 2.2, tenoxicam - 15, piroxicam - 33, indomethacin - 107.

The latest data indicate that NSAIDs not only inhibit cyclooxygenase metabolism, but also actively influence the synthesis of PG associated with the mobilization of Ca in smooth muscles. Thus, butadione inhibits the transformation of cyclic endoperoxides into prostaglandins E2 and F2, and fenamates can also block the reception of these substances in tissues.

An important role in the anti-inflammatory effect of NSAIDs is played by their effect on the metabolism and bioeffects of kinins. In therapeutic doses, indomethacin, ortofen, naproxen, ibuprofen, and acetylsalicylic acid (ASA) reduce the formation of bradykinin by 70-80%. This effect is based on the ability of NSAIDs to provide nonspecific inhibition of the interaction of kallikrein with high molecular weight kininogen. NSAIDs cause a chemical modification of the components of the kininogenesis reaction, as a result of which, due to steric hindrances, the complementary interaction of protein molecules is disrupted and effective hydrolysis of high molecular weight kininogen by kallikrein does not occur. A decrease in the formation of bradykinin leads to inhibition of the activation of α-phosphorylase, which leads to a decrease in the synthesis of arachidonic acid and, as a consequence, the manifestation of the effects of its metabolic products shown in Fig. 1.

No less important is the ability of NSAIDs to block the interaction of bradykinin with tissue receptors, which leads to the restoration of impaired microcirculation, a decrease in capillary overextension, a decrease in the output of the liquid part of the plasma, its proteins, pro-inflammatory factors and formed elements, which indirectly affects the development of other phases of the inflammatory process. Since the kallikrein-kinin system plays the most important role in the development of acute inflammatory reactions, the greatest effectiveness of NSAIDs is observed in the early stages of inflammation in the presence of a pronounced exudative component.

Of particular importance in the mechanism of anti-inflammatory action of NSAIDs are inhibition of the release of histamine and serotonin, blockade of tissue reactions to these biogenic amines, which play a significant role in the inflammatory process. The intramolecular distance between the reaction centers in the molecule of antiphlogistics (compounds such as butadione) approaches those in the molecule of inflammatory mediators (histamine, serotonin). This gives reason to assume the possibility of competitive interaction of the mentioned NSAIDs with receptors or enzyme systems involved in the processes of synthesis, release and transformation of these substances.

As mentioned above, NSAIDs have a membrane-stabilizing effect. By binding to the G-protein in the cell membrane, antiphlogistics affect the transmission of membrane signals through it, suppress the transport of anions, and influence biological processes dependent on the general mobility of membrane lipids. They realize their membrane-stabilizing effect by increasing the microviscosity of membranes. Penetrating through the cytoplasmic membrane into the cell, NSAIDs also affect the functional state of the membranes of cellular structures, in particular lysosomes, and prevent the proinflammatory effect of hydrolases. Data were obtained on the quantitative and qualitative characteristics of the affinity of individual drugs for the protein and lipid components of biological membranes, which can explain their membrane effect.

One of the mechanisms of damage to cell membranes is free radical oxidation. Free radicals generated during lipid peroxidation play an important role in the development of inflammation. Therefore, the inhibition of peroxidation in membranes by NSAIDs can be considered as a manifestation of their anti-inflammatory effect. It must be taken into account that one of the main sources of generation of free radicals is the metabolic reactions of arachidonic acid. Individual metabolites of its cascade cause the accumulation of polymorphonuclear neutrophils and macrophages at the site of inflammation, the activation of which is also accompanied by the formation of free radicals. NSAIDs, by functioning as scavengers of these compounds, offer the possibility of a new approach to the prevention and treatment of tissue damage caused by free radicals.

In recent years, research into the effect of NSAIDs on the cellular mechanisms of the inflammatory response has received significant development. NSAIDs reduce the migration of cells to the site of inflammation and reduce their phlogogenic activity, and the effect on polymorphonuclear neutrophils correlates with inhibition of the lipoxygenase pathway of arachidonic acid oxidation. This alternative pathway for the conversion of arachidonic acid leads to the formation of leukotrienes (LT) (Fig. 1), which meet all the criteria for inflammatory mediators. Benoxaprofen has the ability to influence 5-LOG and block the synthesis of LT.

Less studied is the effect of NSAIDs on the cellular elements of the late stage of inflammation - mononuclear cells. Some NSAIDs reduce the migration of monocytes, which produce free radicals and cause tissue destruction. Although the important role of cellular elements in the development of the inflammatory response and the therapeutic effect of anti-inflammatory drugs is undoubted, the mechanism of action of NSAIDs on the migration and function of these cells awaits clarification.

There is an assumption about the release of natural anti-inflammatory substances by NSAIDs from the complex with plasma proteins, which comes from the ability of these drugs to displace lysine from its connection with albumin.

Department of Clinical Pharmacology, Volgograd Medical Academy

Table 1.

Classification of NSAIDs (according to chemical structure and activity).

I group - NSAIDs with pronounced anti-inflammatory activity .

Salicylates	a) acetylated: Acetylsalicylic acid (ASA) - (aspirin); Lysine monoacetylsalicylate (aspizole, laspal); b) non-acetylated: Sodium salicylate; Choline salicylate (sachol); Salicylamide; Dolobid (diflunisal); Disalcide; Trilisat.
Pyrazolidines	Azapropazone (Ramox); Clofezone; Phenylbutazone (butadione); Oxyphenylbutazone.
Indoleacetic acid derivatives	Indomethacin (metindole); Sulindac (clinoril); Etodalak (lodin);
Phenylacetic acid derivatives	Diclofenac sodium (ortofen, voltaren); Diclofenac potassium (Voltaren - Rapid); Fentiazac (donorest); Lonazalac calcium (irritene).
Oxycams	Piroxicam (Roxicam); Tenoxicam (Tenoctin); Meloxicam (movalis); Lornoxicam (xefocam).
Alcanons	Nabumetone (relifix).
Propionic acid derivatives	Ibuprofen (brufen, nurofen, solpaflex); Naproxen (naprosyn); Naproxen sodium salt (apranax); Ketoprofen (knavon, profenid, oruvel); Flurbiprofen (flugalin); Fenoprofen (fenopron); Fenbufen (Lederlene); Tiaprofenic acid (surgam).