Clinical pharmacology of non-steroidal anti-inflammatory drugs. Mechanisms of action of NSAIDs. Negative effects of NSAIDs on the gastrointestinal tract

Department of Clinical Pharmacology, Volgograd Medical Academy

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 the 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 (Table 1).

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 (methindol); 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).

For quotation: Nasonov E.L. NON-STEROID ANTI-INFLAMMATORY DRUGS // Breast cancer. 1999. No. 8. P. 9

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of pharmacological agents whose therapeutic activity is associated with preventing the development or reducing the intensity of inflammation. Currently, there are more than 50 dosage forms differing in chemical structure, classified as NSAIDs, which in turn are divided into several main subclasses (Table 1).

N Steroidal anti-inflammatory drugs (NSAIDs) are a class of pharmacological agents whose therapeutic activity is associated with preventing the development or reducing the intensity of inflammation. Currently, there are more than 50 dosage forms differing in chemical structure, classified as NSAIDs, which in turn are divided into several main subclasses ( ).
Table 1. Classification of NSAIDs

I. Acid derivatives
1. Arylcarboxylic acids
Salicylic acid: . aspirin . diflunisal . trisalicylate . benorylate . sodium salicylate		Anthranilic acid (fenamates) . flufenamic acid . mefenamic acid . meclofenamic acid
2. Arylalkanoic acids
Arylacetic acid . diclofenac . fenclofenac . alclofenac .fentiazak Heteroarylacetic acid . tolmetin . zomepirac . cloperac . ketorolac trimethamine Indole/indene acetic acids . indomethacin . sulindak . etodolac . acemetacin		Arylpropionic acid . ibuprofen . flurbiprofen . ketoprofen . naproxen . oxaprozin . fenoprofen . fenbufen . suprofen . indoprofen . tiaprofenic acid . benoxaprofen . pirprofen
3. Enolic acid
Pyrazolidinediones . phenylbutazone . oxyphenylbutazone . azapropazone . feprazone		Oxycams . piroxicam . isoxicam . sudoxicam . meloxicam
II. Non-acid derivatives
. proquazon . thiaramide . bufexamak . epirazole . nabumethon		. flurproquazon . flufizone . tinoridine . colchicine
III. Combination drugs
. arthrotek (diclofenac + misoprostol)

NSAIDs are one of the most commonly used drugs in clinical practice. They are prescribed to approximately 20% of inpatients suffering from various diseases of the internal organs.

Mechanism of action

With the exception of nabumetone (a pro-drug in base form), NSAIDs are organic acids with a relatively low pH. Due to this, they actively bind to plasma proteins and accumulate in the site of inflammation, in which, unlike non-inflamed tissue, an increase in vascular permeability and a relatively low pH are observed. NSAIDs are similar in pharmacological properties, biological activity and mechanisms of action.
In 1971, J. Vane first discovered that acetylsalicylic acid and indomethacin in low concentrations exhibit their anti-inflammatory analgesic and antipyretic effects due to suppression of COX enzyme activity, taking part in the biosynthesis of PG. Since then, the view that the anti-inflammatory and other effects of NSAIDs are primarily due to suppression of PG synthesis, is generally accepted. Indeed, almost all currently synthesized NSAIDs block COX in vitro as part of the PG-endoperoxide synthetase complex, without affecting to a lesser extent the activity of other enzymes involved in the metabolism of arachidonic acid (phospholipase A 2 , lipoxygenase, isomerase). It is also assumed that suppression of PG synthesis, in turn, can lead to a variety of secondary pharmacological effects detected in patients treated with NSAIDs, including those associated with changes in the function of neutrophils, T- and B-lymphocytes, synthesis of LT, etc. In addition, antiprostaglandin The activity of NSAIDs explains some of their vascular effects (reducing the intensity of PG-induced edema and erythema), analgesic effect and the causes of the development of major adverse reactions (peptic ulcer, platelet dysfunction, bronchospasm, hypertension, impaired glomerular filtration).
Possible points of application of pharmacological activity of NVPs
.PG synthesis
.LT synthesis
.Formation of superoxide radiacles
.Release of lysosomal enzymes
.Activation of cell membranes:
-enzymes
-NAPDH oxidation
-phospholipases
-transmembrane transport of anions
-capture of GHG precursors
Aggregation and adhesion of neutrophils
.Lymphocyte function
.RF synthesis
Cytokine synthesis
.Metabolism of cartilage

However, in recent years, ideas about the points of application of NSAIDs in the regulation of PG synthesis have significantly expanded and been refined. Previously, it was believed that COX is the only enzyme whose inhibition reduces the synthesis of PGs involved in the development of inflammation and “normal” PGs that regulate the function of the stomach, kidneys and other organs. But recently, two isoforms of COX (COX-1 and COX-2) were discovered, which play different roles in the regulation of PG synthesis. As already noted, it is COX-2 that regulates the synthesis of PGs induced by various proinflammatory stimuli, while the activity of COX-1 determines the production of PGs that participate in normal physiological cellular reactions not associated with the development of inflammation. Preliminary results, obtained so far only from in vitro experiments, showed that some NSAIDs inhibit COX-1 and COX-2 equally, while others were 10 to 30 times more potent at inhibiting COX-1 than COX-2.
These results, although preliminary, are very important, as they help explain the characteristics of the pharmacological activity of NSAIDs and the reasons for the development of some side effects that are most characteristic of strong COX inhibitors. Indeed, it is well known that PGE 2 and PGI 2 have a protective effect on the gastric mucosa, which is associated with their ability to reduce gastric secretion of hydrochloric acid and increase the synthesis of cytoprotective substances. It is assumed that the gastrointestinal complications of NSAIDs are associated with the suppression of COX-1. Another cyclooxygenase product is thromboxane A 2 , inhibition of the synthesis of which by NSAIDs disrupts platelet aggregation and promotes bleeding. In addition, PGs play an important role in the regulation of glomerular filtration, renin secretion and maintaining water and electrolyte balance. It is obvious that PG inhibition can lead to a variety of renal dysfunction, especially in patients with concomitant renal pathology. It is believed that it is the ability of GCs to selectively inhibit COX-2 that determines the significantly lower incidence of gastric ulcers during treatment with these drugs compared to NSAIDs, and the lack of effect on blood clotting and kidney function. Finally, inhibition of cyclooxygenase activity may potentially promote a switch in arachidonic acid metabolism. acids on the lipoxygenase pathway, causing hyperproduction of LT. This explains the development of bronchospasm and other immediate hypersensitivity reactions in some patients receiving NSAIDs. It is believed that overproduction of LTV4 in the stomach may be one of the reasons for the development of the vascular inflammatory component of ulcerative lesions of the gastrointestinal tract. LTV4 is known to cause activation and hypersecretion of the leukocyte adhesion molecule CD11b/CD18. At the same time, antibodies to CD11b/CD18 are able to prevent the development of NSAID-induced gastric ulceration. From these positions, we can well explain the powerful preventive effect of synthetic PGs of the E1 series for NSAID-induced gastropathy. It is known that PGE1 have the ability to suppress the activation of neutrophils, prevent the adhesion of neutrophils to ECs stimulated by NSAIDs, and inhibit the synthesis of LTV4 by neutrophils.
In general, all these results create a theoretical basis for the targeted development of new chemical compounds capable of selectively inhibiting COX-2, which will allow us to approach the creation of drugs with higher anti-inflammatory activity and low toxicity.
Table 2. Recommended doses of NSAIDs for rheumatic diseases

A drug	Dose range (mg/day)	Frequency of administration during the day
Acetylsalicylic acid:
aspirin	1000 - 6000	2 - 4
Choline magnesium salicylate	1500 - 4000	2 - 4
salsalat	1500 - 5000	2 - 4
diflunisal	500 - 1500
meclofenamate sodium	200 - 400
Arylalkanoic acid:
ibuprofen	1200 - 3200	3 - 6
fenoprofen	1200 - 3200	3 - 4
ketoprofen	100 - 400	3 - 4
diclofenac	75 - 150	2 - 3
flurbiprofen	100 - 300	2 - 3
naproxen	250 - 1500
Indole/indenacetic acid:
indomethacin	50 - 200	2 - 4
sulindak	300 - 400
etodolac	600 - 120	3 - 4
Heteroarylacetic acid:
tolmetin	800 - 1600	4 - 6
ketorolac	15 - 150
Enolic acid:
phenylbutazone	200 - 800	1 - 4
piroxicam	20 - 40
Naphthylalkanones:
nabumethon	1000 - 2000	1 - 2
Oxazolepropionic acid:
oxaprozin	600 - 1200

One of the first NSAIDs that has higher selectivity for COX-2 is nimesulide (mesulide). Almost all new selective COX-2 inhibitors currently being developed (NS-398, CGP-28238 or flusulide, FK-3311, L-745337, MK-966 and T-614) are chemical analogues of nimesulide. Nimesulide has approximately 1.3 - 2.512 times higher activity against COX-2 than COX-1. This drug has the ability to inhibit COX-2 activity in a time-dependent manner to form a secondary, slowly dissociating, stable ("secondary") enzyme-inhibitor complex, while for COX-1 it exhibits competitive, reversible COX inhibitor activity. This unique feature of nimesulide is ultimately an important factor determining the higher selectivity of the drug for COX-2 than COX-1.
The optimal dose of the drug in patients with osteoarthritis, as well as soft tissue damage, is 100 mg 2 times a day, as effective as piroxicam (20 mg/day), naproxen (500 - 10 00 mg/day), diclofenac (150 mg/day), etodolac (600 mg/day).
The incidence of side effects of nimesulide is 8.87%, while in patients receiving other NSAIDs it reaches 16.7%.
Thus, in an analysis of 22,939 patients with osteoarthritis treated with nimesulide at a dose of 100 - 400 mg / day for 5 - 21 days (average 12 days), the overall incidence of side effects, mainly from the gastrointestinal tract, was observed in only 8.2 % of cases. At the same time, the development of side effects was the basis for interrupting treatment in only 0.2%, and no serious anaphylactic reactions or complications from the gastrointestinal tract (ulcers, bleeding) were registered. It is noteworthy that the frequency of side effects in patients over 60 years of age did not differ from that in the general patient population. In an analysis of the results of 151 clinical trials of nimesulide, the incidence of side effects was 7.1% and did not differ from that in the placebo group. The drug extremely rarely causes increased bronchospasm in patients receiving antiasmatic drugs. In general, nimesulide is very well tolerated by patients with bronchial asthma and hypersensitivity to aspirin or other NSAIDs.
Table 3. Average half-life of various NSAIDs

A drug	Half-life, h
Short-lived:
aspirin	0,25 (0,03)
diclofenac	1,1 (0,2)
etodolac	3,0; 6,5 (0,3)*
fenoprofen	2,5 (0,5)
flufenamic acid	1,4; 9,0
flurbiprofen	3,8 (1,2)
ibuprofen	2,1 (0,3)
indomethacin	4,6 (0,7)
ketoprofen	1,8 (0,4)
pirprofen	3,8; 6,8
tiaprofenic acid	3,0 (0,2)
tolmetin	1,0 (0,3); 5,8 (1,5)*
Long-lived:
Azapropazone	15 (4)
Diflunisal	13 (2)
Fenbufen	11,0
Nabumethon	26 (5)
Naproxen	14 (2)
Oxaprozin	58 (10)
Phenylbutazone	68 (25)
Piroxicam	57 (22)
Sulindak	14 (8)
Tenoxicam	60 (11)
Salicylates	2 - 15**
*Note.* The standard deviation is given in parentheses; one asterisk - two-phase elimination; two stars - elimination is dose-dependent.

In recent years, it has become obvious that the prostaglandin hypothesis satisfactorily fits the therapeutic effects of only low doses of NSAIDs, but it cannot fully explain the mechanisms of action of high doses of drugs. It turned out that the anti-inflammatory and analgesic activity of NSAIDs often does not correlate with their ability to suppress PG synthesis. For example, the “anti-inflammatory” dose of aspirin is much higher than that required to suppress PG synthesis, and sodium salicylate and other non-acetylated salicylates, which very weakly suppress COX activity, are not inferior in anti-inflammatory activity to NSAIDs, which are strong inhibitors of PG synthesis (Multicencer salicilateaspirin comparison study group, 1989). It is believed that it is these features that determine the lower toxicity of non-acetylated salicylates in relation to the gastrointestinal tract, the lack of effect on platelets and the good tolerability of these drugs even in patients with hypersensitivity to aspirin. Some toxic reactions, such as hepatitis, neurological disorders (tinnitus, depression, meningitis, confusion), interstitial nephritis, are also probably not associated with PG-dependent mechanisms of action of NSAIDs.
Effects of NSAIDs that are not believed to be directly related to their antiprostaglandin activity include the following:
1) suppression of prosteoglycan synthesis by articular cartilage cells;
2) suppression of peripheral inflammation due to central mechanisms;
3) increased T-cell proliferation and IL-2 synthesis by lymphocytes;
4) suppression of neutrophil activation;
5) impairment of the adhesive properties of neutrophils mediated by CD11b/CD 18.
In particular, it has been shown that acetylsalicylic acid and salicylic sodium (but not indomethacin) suppress the development of inflammatory edema of the extremities when the drugs are administered into the lateral ventricle of the brain. This is not due to systemic antiprostaglandin effects, since similar doses of salicylates and indomethacin in the bloodstream did not have an anti-inflammatory effect. These data suggest that salicylates may suppress neurogenic (central) mechanisms of development of peripheral inflammation. According to K.K. Wu et al. (1991), salicylates suppress IL-1-induced COX gene expression in EC culture. In addition, under certain experimental conditions, some NSAIDs have the ability to enhance the proliferative activity of T-lymphocytes and the synthesis of IL-2, which is combined with an increase in the level of intracellular calcium, and also suppress the chemotaxis and aggregation of neutrophils, the formation of hypochlorous acid and superoxide radicals by leukocytes, and suppress the activity of phospholipase C and IL-1 synthesis by monocytes. At the same time, the stable PGE1 analog misoprostol enhances the inhibitory effect of NSAIDs on neutrophil activation.
The molecular mechanisms underlying these pharmacological effects of NSAIDs are not completely clear. It is assumed that, being anionic lipophilic molecules, NSAIDs can penetrate the phospholipid bilayer and change the viscosity of biomembranes. This in turn disrupts normal interactions between membrane proteins and phospholipids and prevents cellular activation of leukocytes in the early stages of inflammation. This effect can be realized due to interruption of the transmission of activation signals at the level of guanosine triphosphate binding protein(G protein). It is known that G protein plays an important role in regulating the activation of leukocytes under the influence of anaphylotoxin (C5a) and the chemotactic peptide formyl-methionine-leucine-phenylalanine (FMLP). The binding of these ligands to specific membrane receptors of leukocytes leads to a change in their conformation. The conformational rearrangement is transmitted through the membrane to the G protein, as a result of which it acquires the ability to bind intracellular guanosine triphosphate. This leads to changes in the conformation of the G protein that induce activation of phospholipase A 2 and C and the generation of secondary messengers (diacylglycerol, arachidonic acid, inositol triphosphate) necessary for the implementation of the functional activity of leukocytes. Experimental studies have shown that NSAIDs are able to block the binding of guanosine triphosphate to G protein, which leads to the abolition of the chemotactic effects of C5a and FMLP and the suppression of cellular activation. In turn, arachidonic acid, released from membrane phospholipids during cellular activation, enhances the binding of guanosine triphosphate to G protein, that is, it gives an effect opposite to the action of NSAIDs.
Thus, taking into account the data presented above, it can be assumed that the anti-inflammatory effect of NSAIDs is mediated by two independent mechanisms: low concentrations of NSAIDs, interacting with the arachidonate-COX complex, prevent the formation of stable PGs, and at high (anti-inflammatory) concentrations they block the association of arachidonate with G-protein and, thus, suppress cellular activation.
More recently, E. Kopp and S. Ghosh (1994) discovered a new molecular mechanism of action of NSAIDs, which may be most important in the implementation of the anti-inflammatory and immunomodulatory activity of these drugs. It turned out that salicylic acid and aspirin in therapeutic concentrations suppress transcription factor activation(NF-kB) in T lymphocytes. It is known that NF-kB is an inducible transcription factor present in the cytoplasm of eukaryotic cells, which is activated under the influence of various pro-inflammatory stimuli (bacterial lipopolysaccharide, IL-1, TNF, etc.). These activation signals lead to the translocation of NF-kB from the cytoplasm to the nucleus, where NF-kB binds to DNA and regulates the transcription of several genes, most of which encode the synthesis of molecules involved in the development of inflammation and immune responses; cytokines (IL-1, IL-6, IL-8, IF-b, TNF-a) and cell adhesion molecules (intercellular adhesion molecule 1 (ICAM-1), endothelial-leukocyte adhesion molecule-1, vascular adhesion molecule-1 (VCAM-1) It is noteworthy that GC and CsA have similar mechanisms of action, which allows us to re-evaluate the therapeutic possibilities of using NSAIDs.
Almost all NSAIDs have the ability to reduce pain in concentrations less than necessary to suppress inflammation. Previously it was believed,that since PGs enhance the pain response induced by bradykinin, inhibition of their synthesis is one of the main mechanisms of the analgesic effects of NSAIDs. On the other hand, there is evidence of the effect of NSAIDs on central mechanisms of pain not associated with inhibition of PG synthesis. For example, acetomenophen has very high analgesic activity, despite the lack of ability to inhibit COX activity.
NSAIDs effectively suppress fever in humans and experimental animals. It is known that many cytokines, including IL-1 a/b, TNF- a/b , IL-6, macrophage inflammatory protein 1 and IF- a have endogenous pyrogen activity, and IL-2 and IF-g can induce fever by increasing the synthesis of one or more of the above cytokines. Since the development of fever is associated with PG synthesis induced by proinflammatory cytokines, it is assumed that the antipyretic effect of NSAIDs is due to their anticytokine and antiprostaglandin activity.
Under the influence of aspirin and, to a much lesser extent, other NSAIDs, the platelet aggregation response to various thrombogenic stimuli, including collagen, norepinephrine, ADP and arachidonate, is weakened. This is due to the fact that in platelets aspirin blocks the synthesis of thromboxane A 2 , which has vasoconstrictor activity and promotes platelet aggregation. The mechanism of action of aspirin on the synthesis of thromboxane A 2 determined by irreversible acetylation of serine residues (Ser 529) and suppression of the activity of COX and hydroperoxide, necessary for the synthesis of thromboxane A 2 . It is believed that, in addition to the antiaggregation effect, aspirin may have other points of application in the blood coagulation mechanisms: suppression of the synthesis of vitamin K-dependent coagulation factors, stimulation of fibrinolysis and suppression of the lipoxygenase pathway of arachidonic metabolism in platelets and leukocytes. It has been established that platelets are especially sensitive to aspirin: a single dose of 100 mg of aspirin leads to a decrease in the serum concentration of thromboxane B2 (a hydrolysis product of thromboxane A 2)by 98% within 1 hour, and only 30 mg per day effectively inhibits thromboxane synthesis. At the same time, the antithrombogenic effect of aspirin is limited by the ability to suppress the production of prostacyclin (PGI2), which has an effect on vascular tone and platelet condition that is opposite to that of thromboxane A 2 . However, unlike platelets, the synthesis of EC prostacyclin after taking aspirin is very quickly restored. All this taken together created the prerequisites for the use of aspirin for the prevention of thrombotic disorders in various diseases.

Clinical Application

In rheumatology, NSAIDs are most often used for the following reasons: indications:

In addition, NSAIDs are often used to reduce the severity of menstrual cramping; they contribute to faster closure of the ductus arteriosus; NSAIDs have found use in inflammatory ophthalmological diseases, shock, periodontitis, sports injuries and the treatment of complications of chemotherapy for malignant neoplasms. There are reports of the antiproliferative effect of aspirin and NSAIDs on the intestinal mucosa, which made it possible to discuss the potential possibility of their use in patients with malignant neoplasms of the colon. According to F.M. Giardello et al. (1993), sulindac suppresses the development of adenomatous intestinal polyposis. Recently, the clinical effectiveness of indomethacin in Alzheimer's disease has been discovered. NSAIDs are especially widely used in the treatment of migraine. They are believed to be the treatment of choice in patients with moderate or severe migraine attacks. For example, in a double-blind, controlled study, naproxen was shown to significantly reduce the severity and duration of headaches and photophobia and that it was more effective in this regard than ergotamine. Aspirin and other NSAIDs have a similar effect. To achieve a more pronounced effect against nausea and vomiting, it is recommended to combine NSAIDs with metoclopramide, which accelerates the absorption of drugs. To quickly relieve migraine attacks, it is recommended to use ketorolac, which can be administered parenterally. It is assumed that the effectiveness of NSAIDs for migraine is associated with their ability, by suppressing the synthesis of PG, to reduce the intensity of neurogenic inflammation or, by interfering with serotonin, to reduce the severity of vascular spasm.
Despite the similarity in the chemical properties and basic pharmacological effects of various NSAIDs, significant variations in the “response” to a particular drug are observed in individual patients with the same disease (for example, RA) or with different rheumatic diseases. Indeed, at the population level, no significant differences were found between aspirin and other NSAIDs in RA, but they become obvious when analyzing the effectiveness of various NSAIDs in individual patients. This dictates the need individual selection NSAIDs for every patient.
The choice of NSAID is usually empirical and is largely based on the personal experience of the physician and the past experience of the patient. There is a point of view on the advisability of using the least toxic drugs at the beginning of treatment, which primarily include propionic acid derivatives. It is necessary gradually titrate dose NSAIDs until effective, but not exceeding the maximum allowable, for 1 - 2 weeks and if there is no effect, try using another or other drugs. Prescribing simple analgesics (paracetamol) can reduce the need for NSAIDs. Recommended doses of the most widely used NSAIDs in clinical practice are presented in .
The differences between NSAIDs are especially clear when comparing their clinical effectiveness in patients with different rheumatic diseases. For example, for gout, all NSAIDs are more effective than tolmetin, and for ankylosing spondylitis, indomethacin and other NSAIDs are more effective than aspriin.
Possible reasons for the varying clinical effectiveness of NSAIDs and the spectrum of toxic reactions in individual patients with various rheumatic diseases, as well as practical recommendations for the use of NSAIDs, have recently been summarized in reviews by D.E. Furst (1994) and P.M. Brooks (1993).
An important characteristic of NSAIDs is plasma half-life ( ).
Depending on their half-life, NSAIDs are divided into two main categories: short-lived, with a half-life of no more than 4 hours, and long-lived, with a half-life of 12 hours or more. However, it must be borne in mind that the kinetic parameters of NSAIDs in synovial fluid and tissue may differ significantly from those in serum, in which case the differences between NSAIDs in half-life in the synovium become less significant than in the bloodstream. In this case, the synovial concentration of long-lived drugs correlates with the serum level, and when taking short-lived drugs it is initially low, but then increases significantly and can exceed the serum concentration. This helps explain the long-lasting clinical effectiveness of short-lived drugs. For example, there is evidence that in RA, ibuprofen twice daily is as effective as ibuprofen 4 times daily, despite the very short half-life of ibuprofen in plasma.
Data received about different pharmacological properties of levorotatory (S) and dextrorotary (R) isomers of NSAIDs. For example, ibuprofen is a recemic mixture of left- and right-handed isomers, with the R-isomer mainly determining the analgesic potential of the drug. The S-form of flurbiprofen exhibits strong analgesic activity, but weakly suppresses PG synthesis, and the R-isomer, on the contrary, has higher anti-inflammatory activity. These data may stimulate the development of more potent and selective NSAIDs in the future, but at present the clinical significance of the existence of different enantiomeric forms of NSAIDs is unclear.
It matters more protein binding capacity NSAIDs. It is known that all NSAIDs (except piroxicam and salicylates) are more than 98% bound to albumin. The clinical significance of this property of NSAIDs is that the development of hypoalbuminemia, liver or renal failure dictates the need to prescribe smaller doses of drugs.
During the treatment process it is necessary to take into account daily fluctuations severity of clinical symptoms and inflammatory activity of the disease. For example, with RA, the maximum intensity of stiffness, joint pain and decreased hand grip strength are observed in the morning, while with osteoarthritis, symptoms intensify in the evening. There is evidence that in RA, taking flurbiprofen at night gives a stronger analgesic effect than in the morning, afternoon, or afternoon and evening. For patients with osteoarthritis, in whom the severity of pain is maximum in the evening and early morning, it is preferable to prescribe long-acting indomethacin at bedtime. It is noteworthy that this rhythm of administration led to a significant reduction in the incidence of side effects. Thus, synchronizing the prescription of NSAIDs with the rhythm of clinical activity can increase the effectiveness of treatment, especially with drugs with a short half-life.

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.

Keywords: 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 // RMZh. 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 non-steroidal 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-PGE2C 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 studies 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 developing 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, increasing the 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 with 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 during treatment 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 (determined by 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.

Literature

1. Conaghan P.G. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity // Rheumatology international. 2011. Vol. 32(6). P. 1491–1502.
2. Karateev A.E., Uspensky Yu.P., Pakhomova I.G., Nasonov E.L. A short course on the history of NSAIDs // Scientific and practical rheumatology. 2012. No. 52(3). pp. 101–116.
3. Karateev A.E., Aleynikova T.L. Eicosanoids and inflammation // Modern rheumatology. 2016. No. 10(4). pp. 73–86.
4. Ricciotti E., FitzGerald G.A. Prostaglandins and Inflammation // Arterioscler Thromb Vasc Biol. 2011. Vol. 31(5). P. 986–1000.
5. Kirkby N.S., Chan M.V., Zaiss A.K. et al. Systematic study of constitutive cyclooxygenase-2 expression: role of NF-κB and NFAT transcriptional pathways // Proc Natl Acad Sci USA. 2016. Vol. 113(2). P. 434–439.
6. Xu S., Rouzer C.A., Marnett L.J. Oxicams, a class of nonsteroidal anti-inflammatory drugs and beyond // IUBMB Life. 2014. Vol. 66(12). P. 803–811.
7. Asghar W., Jamali F. The effect of COX-2-selective meloxicam on the myocardial, vascular and renal risks: a systematic review // Inflammopharmacology. 2015. Vol. 23. P. 1–16.
8. Karateev A.E., Nasonov E.L., Yakhno N.N. and others. Clinical recommendations “Rational use of non-steroidal anti-inflammatory drugs (NSAIDs) in clinical practice” // Modern rheumatology. 2015. No. 1(9). pp. 4–23.
9. Wallace J.L. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? // Physiol Rev. 2008. Vol. 88(4). P. 1547–1565.
10. Llorente Melero M.J., Tenias Burillo J.M., Zaragoza Marcet A. Comparative incidence of upper gastrointestinal bleeding with associated individual non-steroidal anti-inflammatory drugs // Rev Esp Enferm Dig. 2002. Vol. 94(1). P. 13–18.
11. Garcia Rodriguez L.A., Barreales Tolosa L. Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population // Gastroenterology. 2007. Vol. 132. P. 498–506.
12. Yang M., Wang H. T., Zhao M. et al. Network Meta-Analysis Comparing Relatively Selective COX-2 Inhibitors Versus Coxibs for the Prevention of NSAID-Induced Gastrointestinal Injury // Medicine (Baltimore). 2015. Vol. 94(40). P. e1592.
13. Rostom A., Goldkind L., Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients // Clin Gastroenterol Hepatol. 2005. Vol. 3. P. 489–498.
14. Traversa G., Bianchi C., Da Cas R. et al. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs // BMJ. 2003. Vol. 327. P. 18–22.
15. Sanchez-Matienzo D., Arana A., Castellsague J., Perez-Gutthann S. Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: a case/noncase analysis of spontaneous reports. Clin Ther. 2006. Vol. 28(8). P. 1123–1132.
16. Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? // World J Gastroenterol. 2010. Vol. 16(45). P. 5651–5661.
17. Donati M., Conforti A., Lenti M.C. et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy // Br J Clin Pharmacol. 2016. Vol. 82(1). P. 238–248.
18. Recommendations for the use of selective and nonselective nonsteroidal antiinflammatory drugs: an American College of Rheumatology white paper // Arthritis Rheum. 2008. Vol. 59(8). P. 1058–1073.
19. Varas-Lorenzo C., Riera-Guardia N., Calingaert B. et al. Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies // Pharmacoepidemiol Drug Saf. 2013. Vol. 22(6). P. 559–570.
20. Bhala N., Emberson J., Merhi A. et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials // Lancet. 2013. Vol. 382(9894). P. 769–779.
21. Arfè A., Scotti L., Varas-Lorenzo C. et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study // BMJ. 2016. Vol. 354. P. i4857.
22. Varas-Lorenzo C., Riera-Guardia N., Calingaert B. et al. Stroke risk and NSAIDs: a systematic review of observational studies // Pharmacoepidemiol Drug Saf. 2011. Vol. 20(12). P. 1225–1236.
23. Haag M.D., Bos M.J., Hofman A. et al. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke // Arch Intern Med. 2008. Vol. 168(11). P. 1219–1224.
24. Whelton A., Hamilton C.W. Nonsteroidal anti-inflammatory drugs: effects on kidney function // J Clin Pharmacol. 1991. Vol. 31(7). P. 588–598.
25. Fisenko V. Different isoforms of cyclooxygenase, prostaglandins and kidney activity // Doctor. 2008. No. 12. pp. 8–11.
26. Swan S.K., Rudy D.W., Lasseter K.C. et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial // Ann Intern Med. 2000. Vol. 133. P. 1–9.
27. Griffin M.R., Yared A., Ray W.A. Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons // Am J Epidemiol. 2000. Vol. 151(5). P. 488–496.
28. Rossat J., Maillard M., Nussberger J. et al. Renal effects of selective cyclooxygenase 2 inhibition in normotensive salt-depleted subjects // Clin Pharmacol Ther. 1999. Vol. 66. P. 76–84.
29. Perneger T.V., Whelton P.K., Klag M.J. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs // N Engl J Med. 1994. Vol. 331(25). P. 1675–1679.
30. Sandler D.P., Burr F.R., Weinberg C.R. Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease // Ann Intern Med. 1991. Vol. 115(3). P. 165–172.
31. Lafrance J.P., Miller D.R. Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury // Pharmacoepidemiol Drug Saf. 2009. Vol. 18(10). P. 923–931.

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.

Fig.1. "Cascade" of arachidonic acid metabolic products and their main effects.

Note: * – LT-S 4, D 4, E 4 are the main biological components of the slow-reacting substance of anaphylaxis MRS-A (SRS-A).

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 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, presented in Fig. 1.

Equally 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 yield 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 should 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.

The effect of NSAIDs on cellular elements of the late stage of inflammation - mononuclear cells - has been less studied. 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.

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

Fig.1. "Cascade" of arachidonic acid metabolic products and their main effects.

Note: * – LT-S 4, D 4, E 4 are the main biological components of the slow-reacting substance of anaphylaxis MRS-A (SRS-A).