Rational use of non-steroidal anti-inflammatory drugs: balance of efficacy and safety. Characteristics of individual drugs B) Classification by mechanism of action

18.08.2020

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Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs that are widely used in clinical practice, and many of them can be bought without a prescription. More than thirty million people worldwide take NSAIDs daily, with 40% of these patients being over 60 years of age (1). About 20% of inpatients receive NSAIDs.

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 noted in many diseases.

Over the past 30 years, the number of NSAIDs has increased significantly, and now this group includes a large number of drugs that differ in the characteristics of their action and use.

NSAIDs are classified according to the severity of anti-inflammatory activity and chemical structure. The first group includes drugs with a pronounced anti-inflammatory effect. NSAIDs of the second group, which have a weak anti-inflammatory effect, are often referred to as "non-narcotic analgesics" or "analgesics-antipyretics".

From a practical point of view, it is important that drugs belonging to the same group and even close in chemical structure differ somewhat both in the strength of the effect and in the frequency of development and the nature of undesirable reactions. So, among the NSAIDs of the first group, indomethacin and diclofenac have the most powerful anti-inflammatory activity, and ibuprofen has the least. Indomethacin, which is a derivative of indoleacetic acid, is more gastrotoxic than etodolac, which also belongs to this chemical group. The clinical efficacy of the drug may depend on the type and characteristics of the course of the disease in a particular patient, as well as on his individual response.

The use of NSAIDs for human treatment dates back several millennia.

Celsus (1st century BC) described 4 classic signs of inflammation:

hyperemia, fever, pain, edema

and used willow bark extract to relieve these symptoms.

In 1827, the glycoside salicin was isolated from willow bark.

In 1869 a company employee « Bayer » (Germany) Felix Hofmann synthesized acetylsalicylic acid (at the request of a father suffering from severe rheumatism) with a more palatable taste than the extremely bitter willow bark extract.

In 1899 the company “ Bayer» began commercial production of aspirin.

There are currently over 80 non-steroidal anti-inflammatory drugs

The drugs were given a common name non-steroidal anti-inflammatory,since they differ from steroidal anti-inflammatory glucocorticoids in chemical properties and mechanism of action.

More than 300 million people worldwide take NSAIDs annually, of which 200 million purchase drugs without a doctor's prescription.

30 million people are forced to take them constantly.

1 . Classification

AND)Classification of NSAIDs by activity and chemical structure:

NSAIDs with pronounced anti-inflammatory activity

Acids

Salicylates

Acetylsalicylic acid (aspirin)

Diflunisal

Lysine monoacetylsalicylate

Pyrazolidines

Phenylbutazone

Indoleacetic acid derivatives

Indomethacin

Sulindak

Etodolac

Phenylacetic acid derivatives

Diclofenac

Oxycams

Piroxicam

Tenoxicam

Lornoxicam

Meloxicam

Propionic acid derivatives

Ibuprofen

Naproxen

Flurbiprofen

Ketoprofen

Tiaprofenic acid

Non-acid derivatives

Alkanones

Nabumeton

Sulfonamide derivatives

Nimesulide

Celecoxib

Rofecoxib

NSAIDs with weak anti-inflammatory activity

Anthranilic acid derivatives

Mefenamic acid

Etofenamat

Pyrazolones

Metamizole

Aminophenazone

Propyphenazone

Paraaminophenol derivatives

Phenacetin

Paracetamol

Heteroarylacetic acid derivatives

Ketorolac

B) Classification by mechanism of action:

I. Selective COX-1 inhibitors

Acetylsalicylic acid in low doses (0.1-0.2 per day)

II. Non-selective inhibitors of COX-1 and COX-2

Acetylsalicylic acid in high doses (1.0-3.0 per day or more)

Phenylbutazone

Ibuprofen

Ketoprofen

Naproxen

Niflumic acid

Piroxicam

Lornoxicam

Diclofenac

Indomethacin and a number of other NSAIDs

III. Selective COX-2 inhibitors

Meloxicam

Nimesulide

Nabumeton

IV. Highly Selective COX-2 Inhibitors

Celecoxib

Parecoxib

V. Selective COX-3 inhibitors

Acetaminophen

Metamizole

Non-selective inhibitors of COX-1 and COX-2, acting primarily in the central nervous system

Paracetamol

2. Pharmacodynamics

Mechanism of action

The main and common element in the mechanism of action of NSAIDs is inhibition of the synthesis of prostaglandins (PG) from arachidonic acid by inhibiting the enzyme cyclooxygenase (PG-synthetase) (Fig. 1).

Figure: 1. Metabolism of arachidonic acid

PGs have a versatile biological activity:

a) are inflammatory response mediators: cause local vasodilation, edema, exudation, migration of leukocytes and other effects (mainly PG-E 2 and PG-I 2);

6) sensitize receptors to pain mediators (histamine, bradykinin) and mechanical influences, lowering the pain threshold;

in) increase the sensitivity of the hypothalamic centers of thermoregulation to the action of endogenous pyrogens (interleukin-1 and others), formed in the body under the influence of microbes, viruses, toxins (mainly PG-E 2).

In recent years, it has been found that there are at least two cyclooxygenase isoenzymes that are inhibited by NSAIDs. The first isoenzyme, COX-1 (COX-1), controls the production of prostaglandins, which regulates the integrity of the gastrointestinal mucosa, platelet function and renal blood flow, and the second isozyme, COX-2, is involved in the synthesis of prostaglandins during inflammation. Moreover, COX-2 is absent under normal conditions, but is formed under the influence of some tissue factors that initiate an inflammatory reaction (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, the classification of NSAIDs in terms of selectivity for various forms of cyclooxygenase is presented in Table 2. The ratio of NSAID activity in terms of blocking COX-1 / COX- 2 makes it possible to judge their potential toxicity. The lower this value, the more selective the drug is in relation to COX-2 and, thus, less toxic. For example, for meloxicam it is 0.33, diclofenac - 2.2, tenoxicam - 15, piroxicam - 33, indomethacin - 107.

Classification of NSAIDs by selectivity for various forms of cyclooxygenase ( Drugs Therapy Perspectives, 2000, with additions)

Other mechanisms of action of NSAIDs

The anti-inflammatory effect can be associated with inhibition of lipid peroxidation, stabilization of lysosomal membranes (both of these mechanisms prevent damage to cellular structures), a decrease in the formation of ATP (energy supply of the inflammatory reaction decreases), inhibition of neutrophil aggregation (the release of inflammatory mediators from them is disturbed), inhibition of the production of rheumatoid factor in patients with rheumatoid arthritis. The analgesic effect is to a certain extent associated with a violation of the conduction of pain impulses in the spinal cord (metamizole).

The main mechanism of action of NSAIDs decoded in 1971 r . Wayne, Smith.

At the heart of - a depressing effect on the biosynthesis of prostaglandins.

NSAIDs cause

Block or

Inhibition of the transition of cyclooxygenase to an active enzyme.

As a result education decreases sharply proinflammatory PG types E andF.

Inflammation.

1) The main components of inflammation

Alteration,

Hyperemia,

Exudation

Proliferation.

The combination of these phenomena underlies local signs inflammation:

Redness,

Temperature increase,

Functional impairment.

As a result of the generalization of the process, along with local changes, develop andgeneral

Intoxication,

Fever,

Leukocytosis,

Immune system response.

2) By the nature of the course, inflammation can besharp and chronic .

Acute inflammation lasts from several days to several weeks.

It is characterized by:

Pronounced signs of inflammation and

The predominance of either alteration or vascular-exudative phenomena.

Chronic inflammation - this is a more sluggish, long-term ongoing process.

Dominated by:

Dystrophic and

Proliferative phenomena.

In the process of inflammation under the influence of various damaging factors

(microbes, their toxins, lysosomal enzymes, hormones)

turns on Arachidonic acid cascade

(with inflammation, arachidonic acid is released from membrane phospholipids).

1) phospholipase A is activated 2 ,

which from the phospholipids of cell membranes releases arachidonic acid.

Arachidonic acid is a precursor of prostaglandins (PG) - inflammatory mediators.

2 ) Pgrowthaglandins

in the focus of inflammation take part in the development

Vasodilation,

Hyperemia

Fevers.

3 ) ANDrachidonic acid is involved in the metabolic process:

cyclooxygenase and lipoxygenase.

With the participation of cyclooxygenase arachidonic acid is converted to inflammatory mediators

Cyclic endoperoxides 1

Prostaglandins 2

Prostacyclins

Thromboxanes 3

With the participation of lipoxygenase

Arachidonic acid is converted to leukotrienes - mediators of immediate allergic reactions and mediators of inflammation.

Cyclooxygenase (COX) is a key enzyme in the metabolism of arachidonic acid.

This enzyme catalyzes two independent reactions:

1) cyclooxygenase attachment of an oxygen molecule to arachidonic acid molecule to form PGG2

2) peroxidase - leads to the conversion of PGG2 into a more stable PGN2

The synthesis of endoperoxides, prostaglandins and leukotrienes is accompanied by

the appearance of free oxygen radicalspromoting

The development of the inflammatory process,

Cell damage

Damage to subcellular structures

The occurrence of pain reactions

The prostaglandins themselves (E 1, I 2) the most active mediators of inflammation:

Increase the activity of inflammatory and pain mediators (histamine, serotonin, bradykinin)

Dilate arterioles

Increase capillary permeability

Participate in the development of edema and hyperemia

Participate in microcirculation disorders

Participate in the formation of pain

ProstaglandinsF 2 and thromboxane A 2

Cause narrowing of venules

Thromboxane A 2

Promotes the formation of blood clots, aggravating microcirculation disorders

Prostaglandin receptors located

- non cell membranes in peripheral tissues

- nat the endings of the sensory nerves

- in CNS

Most prostaglandin receptors have an activating function.

Strengthening the formation of prostaglandins in the central nervous system (local) facilitates the conduction of pain impulses, leads to hyperalgesisai, increased body temperature.

3. Pharmacokinetics

All NSAIDs are well absorbed in the gastrointestinal tract. They almost completely bind to plasma albumin, displacing some other drugs (see the chapter "Drug Interactions"), and in newborns - bilirubin, which can lead to the development of bilirubin encephalopathy. The most dangerous in this respect are salicylates and phenylbutazone. Most NSAIDs penetrate well into the synovial fluid of the joints. NSAIDs are metabolized in the liver, excreted through the kidneys.

The pharmacokinetics of NSAIDs is a very important characteristic, since it also affects the pharmacodynamics of drugs. Drugs in this group can be administered in various ways and are available in a variety of dosage forms. Many drugs are used rectally (in suppositories) or topically (in gels and ointments). Not all NSAIDs can be injected, however, a large number of them are available in the form of solutions for intramuscular administration, and a number of drugs are available for intravenous administration (acetylsalicylic acid, paracetamol, ketorolac, ketoprofen, lornoxicam). But the most frequent and simple route of administration, usually acceptable to the patient, is oral administration. All NSAIDs can be administered enterally - in capsules, dragees or tablets. When taken orally, all drugs in this group are well (up to 80-90% or more) absorbed in the upper intestines, however, the rate of absorption and the time to reach the maximum plasma concentration can differ significantly for individual drugs. Most NSAIDs are derived from weak organic acids. Due to their acidic properties, these drugs (and / or their metabolites) have a high affinity for proteins (they bind to plasma proteins by more than 90%), more actively accumulate in the inflamed tissue, in the gastric mucosa and in its lumen, in the liver, cortical layer kidneys, blood and bone marrow, but create low concentrations in the central nervous system (Brune K, Glatt M, Graf P, 1976; Rainsford KD, Schweitzer A, Brune K. 1981). This character of pharmacokinetics plays an important role in the manifestation of not only anti-inflammatory, but also unwanted side effects of NSAIDs. High affinity for plasma proteins is the reason for the competitive displacement of drugs from other groups from the association with albumin (see the section "Interaction of NSAIDs with other drugs"). With a decrease in the level of albumin in the blood, the free (unbound) fraction of NSAIDs increases, which can lead to an increase in the effects of NSAIDs, up to toxic. Non-acidic derivatives, neutral (paracetamol, celecoxib) or weakly alkaline (pyrazolones - metamizole) drugs are distributed fairly evenly in the body, with the exception of the lumen of the gastrointestinal tract, kidneys and liver, where they can accumulate; unlike acids, they do not accumulate in the inflamed tissue, but create a sufficiently high concentration in the central nervous system, while side effects on the gastrointestinal tract do not or very rarely cause (Brune K, Rainsford KD, Schweitzer A., \u200b\u200b1980; Hinz B, Renner B , Brune K, 2007). Pyrazolones create relatively high concentrations in the bone marrow, skin and oral mucosa. The time to achieve a stable concentration of NSAIDs in plasma with continuous administration is usually 3-5 half-lives.

NSAIDs are actively metabolized in the body, only small amounts of drugs are excreted unchanged. NSAID metabolism occurs mainly in the liver by glucuronidation. A number of drugs - diclofenac, aceclofenac, ibuprofen, piroxicam, celecoxib - are pre-hydroxylated with the participation of cytochrome P-450 (mainly isoenzymes of the CYP 2C family). Metabolites and residual amounts of the drug in unchanged form are excreted by the kidneys with urine and, to a lesser extent, the liver with bile (Vengerovsky A.I., 2006). The duration of the half-life (T 50) for different NSAIDs can vary significantly, from 1-2 hours for ibuprofen to 35-45 hours for piroxicam. The indicators of the half-life of the drug in plasma and in the focus of inflammation (for example, in the joint cavity) can also be different, in particular, for diclofenac they are 2-3 hours and 8 hours, respectively. Therefore, the duration of the anti-inflammatory effect does not always correlate with the clearance of the drug from plasma.

A number of NSAIDs are non-prescription drugs not only in Russia, but also abroad. Free dispensing of such funds is based on the features of pharmacodynamics (preferential, but not selective inhibition of COX-2) and, more importantly, the features of the pharmacokinetic characteristics that make them the safest drugs if they are used in low doses and a limited (several days) course of administration ... NSAIDs such as diclofenac and ibuprofen are very active, but relatively safe drugs due to the peculiarities of their distribution and metabolism. These features are the accumulation and long-term presence of drugs in the inflamed tissue (effective compartment) and, at the same time, their rapid clearance from the central compartment, including the blood, vascular wall, heart and kidneys, that is, from the compartment of possible side effects. Therefore, such drugs are better suited for OTC dispensing than other NSAIDs (Brune K., 2007).

To reduce the risk of systemic side effects, many NSAIDs are available in the form of gels or ointments for external use (indomethacin, diclofenac, ketoprofen, ibuprofen, etc.). The bioavailability and concentration of NSAIDs in plasma when applied externally are from 5 to 15% of the values \u200b\u200bachieved with systemic administration (Heyneman CA, Lawless-Liday C, Wall GC, 2000), but a rather high concentration. A number of studies confirm the high efficacy of NSAIDs for external use both in experimental models of pain in humans and in clinical settings (McCormack K, Kidd BL, Morris V., 2000; Steen KH, Wegner H, Meller ST. 2001; Moore RA, et al., 1998; Heyneman CA, Lawless-Liday C, Wall GC, 2000). However, with external use of NSAIDs, relatively high concentrations of drugs are created in the dermis, while in muscles these concentrations are equivalent to the level achieved with systemic administration (Heyneman CA, Lawless-Liday C, Wall GC, 2000). Applied to the skin in the area of \u200b\u200bthe joints, NSAIDs reach the synovial fluid, but it remains unclear whether this is the effect of local drug penetration or a consequence of its entry into the systemic circulation. (Vaile JH, Davis P, 1998) In osteoarthritis and rheumatoid arthritis, topical application of NSAIDs gives a very variable (fluctuations in effectiveness from 18 to 92%, Heyneman CA, Lawless-Liday C, Wall GC, 2000), but in general a fairly moderate effect. This variation can be explained by large fluctuations in the level of skin absorption, as well as the pronounced placebo effect of drugs in rheumatic diseases.

Indications for use

1. Rheumatic diseases

Rheumatism (rheumatic fever), rheumatoid arthritis, gouty and psoriatic arthritis, ankylosing spondylitis (ankylosing spondylitis), Reiter's syndrome.

It should be borne in mind that in rheumatoid arthritis, NSAIDs provide only symptomatic effectwithout affecting the course of the disease. They are not able to stop the progression of the process, cause remission and prevent the development of joint deformities. At the same time, the relief that NSAIDs bring to patients with rheumatoid arthritis is so significant that none of them can do without these drugs. With large collagenoses (systemic lupus erythematosus, scleroderma, and others) NSAIDs are often ineffective.

2. Non-rheumatic diseases of the musculoskeletal system

Osteoarthritis, myositis, tendovaginitis, trauma (household, sports). Often, in these conditions, the use of local dosage forms of NSAIDs (ointments, creams, gels) is effective.

3. Neurological diseases. Neuralgia, sciatica, sciatica, lumbago.

4. Renal, hepatic colic.

5. Pain syndrome various etiologies, including headache and toothache, postoperative pain.

6. Fever (as a rule, at a body temperature above 38.5 ° C).

7. Prevention of arterial thrombosis.

8. Dysmenorrhea.

NSAIDs are used in primary dysmenorrhea to relieve pain associated with increased uterine tone due to hyperproduction of PG-F 2a. In addition to the analgesic effect, NSAIDs reduce the amount of blood loss.

A good clinical effect was noted when applied naproxen, and especially its sodium salt, diclofenac, ibuprofen, ketoprofen... NSAIDs are prescribed at the first appearance of pain in a 3-day course or on the eve of menstruation. Adverse reactions, given the short-term use, are rare.

4.2. CONTRAINDICATIONS

NSAIDs are contraindicated in erosive and ulcerative lesions of the gastrointestinal tract, especially in the acute stage, severe impaired liver and kidney function, cytopenias, individual intolerance, pregnancy. If necessary, small doses of aspirin are safest (but not before delivery!) (3).

Indomethacin and phenylbutazone should not be prescribed on an outpatient basis to persons whose professions require increased attention.

4.3. WARNINGS

NSAIDs should be prescribed with caution to patients with bronchial asthma, as well as to persons who have previously had adverse reactions when taking any other NSAIDs.

For patients with hypertension or heart failure, those NSAIDs should be chosen that have the least effect on renal blood flow.

In the elderly, it is necessary to strive for the appointment of the minimum effective doses and short courses of NSAIDs.

4. Adverse reactions

Gastrointestinal tract:

The main negative property of all NSAIDs is the high risk of developing adverse reactions from the gastrointestinal tract. In 30-40% of patients receiving NSAIDs, dyspeptic disorders are noted, in 10-20% - erosion and ulcers of the stomach and duodenum, in 2-5% - bleeding and perforation (4).

Currently, a specific syndrome has been identified - NSAID gastroduodenopathy (five). It is only partially associated with the local damaging effect of NSAIDs (most of them are organic acids) on the mucous membrane and is mainly due to the inhibition of the COX-1 isoenzyme as a result of the systemic action of drugs. Therefore, gastrotoxicity can occur with any route of administration of NSAIDs.

The defeat of the gastric mucosa occurs in 3 stages:

1) inhibition of the synthesis of prostaglandins in the mucous membrane;

2) a decrease in prostaglandin-mediated production of protective mucus and bicarbonates;

3) the appearance of erosions and ulcers, which can be complicated by bleeding or perforation.

Damage is more often localized in the stomach, mainly in the antrum or prepyloric region. Clinical symptoms in NSAID gastroduodenopathy are absent in almost 60% of patients, especially the elderly, therefore, the diagnosis in many cases is established with fibrogastroduodenoscopy. At the same time, in many patients with dyspeptic complaints, mucosal damage is not detected. The absence of clinical symptoms in NSAID gastroduodenopathy is associated with the analgesic effect of drugs. Therefore, patients, especially elderly patients, who do not experience adverse events from the gastrointestinal tract with prolonged use of NSAIDs, are considered as a group at increased risk of developing serious complications of NSAID gastroduodenopathy (bleeding, severe anemia) and require particularly careful monitoring, including endoscopic research (1).

Risk factors for gastrotoxicity: women over 60 years of age, smoking, alcohol abuse, family history of ulcers, concomitant severe cardiovascular disease, concomitant use of glucocorticoids, immunosuppressants, anticoagulants, long-term NSAID therapy, large doses or the simultaneous use of two or more NSAIDs. Aspirin, indomethacin and piroxicam have the highest gastrotoxicity (1).

Methods for improving the tolerance of NSAIDs.

I. Simultaneous administration of drugsprotecting the mucous membrane of the gastrointestinal tract.

According to controlled clinical trials, a synthetic analogue of PG-E 2, misoprostol, is highly effective, the use of which allows to prevent the development of ulcers both in the stomach and in the duodenum (Table 3). Combination drugs are available that include NSAIDs and misoprostol (see below).

The protective effect of various drugs against NSAID-induced ulcers of the gastrointestinal tract (By Champion G.D. et al., 1997 ( 1 ) with additions)

+ preventive effect

0 lack of preventive effect

Effect not specified

* according to the latest data, famotidine is effective at a high dose

The proton pump inhibitor omeprazole has about the same efficacy as misoprostol, but is better tolerated, faster eliminating reflux, pain, and digestive disorders.

H 2 blockers can prevent the formation of duodenal ulcers, but are usually ineffective for stomach ulcers. However, there is evidence that high doses of famotidine (40 mg twice daily) reduce the incidence of both gastric and duodenal ulcers.

Algorithm for the prevention and treatment of NSAID gastroduodenopathy.

By Loeb D.S. et al., 1992 (5) with additions.

The cytoprotective drug sucralfate does not reduce the risk of gastric ulcers, and its effect on duodenal ulcers is not fully understood.

II. Changing the tactics of using NSAIDswhich involves (a) dose reduction; (b) switching to parenteral, rectal or local administration; (c) taking enteric-soluble dosage forms; (d) the use of prodrugs (eg, sulindac). However, due to the fact that NSAID-gastroduodenopathy is not so much a local reaction as a systemic reaction, these approaches do not solve the problem.

III. The use of selective NSAIDs.

As noted above, there are two cyclooxygenase isoenzymes that are blocked by NSAIDs: COX-2, which is responsible for the production of prostaglandins during inflammation, and COX-1, which controls the production of prostaglandins, which maintain the integrity of the gastrointestinal mucosa, renal blood flow, and platelet function. Therefore, selective COX-2 inhibitors should cause fewer adverse reactions. The first such drugs are meloxicam and nabumetone... Controlled studies conducted in patients with rheumatoid arthritis and osteoarthritis have shown that they are better tolerated than diclofenac, piroxicam, ibuprofen and naproxen, and are not inferior to them in terms of effectiveness (6).

The development of a stomach ulcer in a patient requires the abolition of NSAIDs and the use of antiulcer drugs. Continued use of NSAIDs, for example, in rheumatoid arthritis, is possible only against the background of concurrent administration of misoprostol and regular endoscopic monitoring.

In fig. 2 shows an algorithm for the prevention and treatment of NSAID gastroduodenopathy.

Kidney

Nephrotoxicity is the second most important group of NSAID adverse reactions. Two main mechanisms of the negative effect of NSAIDs on the kidneys have been identified.

I... By blocking the synthesis of PG-E 2 and prostacyclin in the kidneys, NSAIDs cause vasoconstriction and impairment of renal blood flow. This leads to the development of ischemic changes in the kidneys, a decrease in glomerular filtration and diuresis volume. As a result, disturbances in water and electrolyte metabolism may occur: water retention, edema, hypernatremia, hyperkalemia, an increase in serum creatinine levels, and an increase in blood pressure.

Indomethacin and phenylbutazone have the most pronounced effects on renal blood flow.

II... NSAIDs can have a direct effect on the renal parenchyma, causing interstitial nephritis (called "analgesic nephropathy"). The most dangerous in this regard is phenacetin. Serious kidney damage is possible up to the development of severe renal failure. The development of acute renal failure with the use of NSAIDs as a consequence of acute allergic interstitial nephritis is described.

Risk factors for nephrotoxicity: age over 65 years, liver cirrhosis, previous renal pathology, decreased circulating blood volume, long-term use of NSAIDs, concomitant use of diuretics.

Hematotoxicity

Most typical for pyrazolidines and pyrazolones. The most formidable complications of their use are aplastic anemia and agranulocytosis.

Coagulopathy

NSAIDs inhibit platelet aggregation and have a moderate anticoagulant effect by inhibiting the formation of prothrombin in the liver. As a result, bleeding may develop, more often from the gastrointestinal tract.

Hepatotoxicity

Changes in the activity of transaminases and other enzymes may be noted. In severe cases, jaundice, hepatitis.

Hypersensitivity reactions (allergies)

Rashes, Quincke's edema, anaphylactic shock, Lyell and Stevens-Johnson syndromes, allergic interstitial nephritis. Cutaneous manifestations are more often observed with the use of pyrazolones and pyrazolidines.

Bronchospasm

As a rule, it develops in patients with bronchial asthma and, more often, when taking aspirin. Its causes may be allergic mechanisms, as well as inhibition of the synthesis of PG-E 2, which is an endogenous bronchodilator.

Prolongation of pregnancy and delay in labor

This effect is due to the fact that prostaglandins (PG-E 2 and PG-F 2a) stimulate the myometrium.

5 ... Pdosage and administration rules

Individualization of drug choice.

For each patient, the most effective drug with the best tolerance should be selected. Moreover, it may be any NSAID, but as an anti-inflammatory it is necessary to prescribe a drug from group I. The sensitivity of patients to NSAIDs of even one chemical group can vary widely, so the ineffectiveness of one of the drugs does not yet indicate the ineffectiveness of the group as a whole.

When using NSAIDs in rheumatology, especially when replacing one drug with another, it should be borne in mind that the development of the anti-inflammatory effect lags behind in time from the analgesic... The latter is noted in the first hours, while the anti-inflammatory - after 10-14 days of regular intake, and when naproxen or oxicam is prescribed, even later - at 2-4 weeks.

Dosage.

Any new drug for this patient must be prescribed first. in the smallest dose... With good tolerance, after 2-3 days, the daily dose is increased. Therapeutic doses of NSAIDs are in a wide range, and in recent years there has been a tendency towards an increase in single and daily doses of drugs characterized by the best tolerance (naproxen, ibuprofen), while maintaining restrictions on the maximum doses of aspirin, indomethacin, phenylbutazone, piroxicam. In some patients, the therapeutic effect is achieved only when using very high doses of NSAIDs.

Time of receipt.

With a long course appointment (for example, in rheumatology), NSAIDs are taken after meals. But to obtain a quick analgesic or antipyretic effect, it is preferable to prescribe them 30 minutes before or 2 hours after a meal, washed down with 1/2-1 glass of water. After taking it for 15 minutes, it is advisable not to go to bed in order to prevent the development of esophagitis.

The time of taking NSAIDs can also be determined by the time of maximum severity of the symptoms of the disease (pain, stiffness in the joints), that is, taking into account the chronopharmacology of the drugs. In this case, you can deviate from the generally accepted schemes (2-3 times a day) and prescribe NSAIDs at any time of the day, which often allows you to achieve a greater therapeutic effect with a lower daily dose.

With severe morning stiffness, it is advisable to take rapidly absorbed NSAIDs as early as possible (immediately after waking up) or prescribe long-acting drugs at night. The highest rate of absorption in the gastrointestinal tract and, therefore, a more rapid onset of the effect are possessed by naproxen sodium, diclofenac potassium, water-soluble (“effervescent”) aspirin, ketoprofen.

Monotherapy.

The simultaneous use of two or more NSAIDs is not advisable for the following reasons:

The effectiveness of such combinations has not been objectively proven;

In a number of such cases, there is a decrease in the concentration of drugs in the blood (for example, aspirin reduces the concentration of indomethacin, diclofenac, ibuprofen, naproxen, piroxicam), which leads to a weakening of the effect;

The risk of developing unwanted reactions increases. An exception is the possibility of using paracetamol in combination with any other NSAIDs to enhance the analgesic effect.

In some patients, two NSAIDs may be prescribed at different times of the day, for example, rapidly absorbing in the morning and afternoon, and long-acting in the evening.

Conclusion

Anti-inflammatory drugs drugs are called that prevent the development of pathophysiological mechanisms of inflammation and eliminate its signs, but do not affect the cause of the inflammatory reaction. They are represented by non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal anti-inflammatory drugs. The most commonly used NSAIDs. In Russia, 3.5 million people take NSAIDs for a long time.

NSAIDs have both a wide range of indications and no less side effects and contraindications that the doctor should remember when prescribing them and the nurse when observing the patient. And also a big role in the conduct of pharmacotherapy with non-steroidal anti-inflammatory drugs is assigned to the nurse, who should:

1 Strictly follow the doctor's prescriptions.

2 Clarify the allergic history in patients, because allergic reactions to NSAIDs are not uncommon.

3 In young women, clarify the possibility of pregnancy, because NSAIDs can adversely affect the fetus.

4 Educate the patient on the rules for taking NSAIDs (take after meals with plenty of water), monitor the implementation.

5 If the patient is in the hospital daily, monitor the patient's well-being, mood, skin and mucous membranes, the presence of edema, blood pressure, urine color, stool character and immediately inform the doctor if changes appear!

6 On an outpatient basis, the nurse should train the patient to control possible side effects.

7. Timely refer the patient to the studies prescribed by the doctor.

8. Explain to the patient the danger of self-medication.

List of references

non-steroidal anti-inflammatory drug dosing

2) http://www.antibiotic.ru

3) Kharkevich D.A. "Pharmacology" 2005

Posted on Allbest.ru

...

Non-steroidal anti-inflammatory drugs (NSAIDs)

This is a group of drugs, the effects of which are anti-inflammatory, antipyretic and analgesic. The severity of each of them is different for different drugs. These drugs are called non-steroidal because they differ in structure from hormonal drugs, glucocorticoids. The latter also have a powerful anti-inflammatory effect, but at the same time they have the negative properties of steroid hormones.

The mechanism of action of NSAIDs

The mechanism of action of NSAIDs is their indiscriminate or selective inhibition (inhibition) of the varieties of the COX enzyme - cyclooxygenase. COX is found in many tissues of our body and is responsible for the production of various biologically active substances: prostaglandins, prostacyclins, thromboxane and others. Prostaglandins, in turn, are mediators of inflammation, and the more there are, the more pronounced the inflammatory process. NSAIDs, inhibiting COX, reduce the level of prostaglandins in tissues, and the inflammatory process regresses.

Scheme for the appointment of NSAIDs

Some NSAIDs have a number of rather serious side effects, while other drugs in this group are not characterized as such. This is due to the peculiarities of the mechanism of action: the influence of drugs on various types of cyclooxygenase - COX-1, COX-2 and COX-3.

COX-1 in a healthy person is found in almost all organs and tissues, in particular, in the digestive tract and kidneys, where it performs its most important functions. For example, prostaglandins synthesized by COX are actively involved in maintaining the integrity of the gastric and intestinal mucosa, maintaining adequate blood flow in it, reducing the secretion of hydrochloric acid, increasing pH, secretion of phospholipids and mucus, stimulating cell proliferation (reproduction). Drugs that inhibit COX-1 cause a decrease in the level of prostaglandins not only in the focus of inflammation, but throughout the body, which may entail negative consequences, which will be discussed below.

COX-2, as a rule, is absent in healthy tissues or is found, but in insignificant amounts. Its level rises directly during inflammation and in its very focus. The drugs that selectively inhibit COX-2, although they are often taken systemically, act precisely on the focus, reducing the inflammatory process in it.

COX-3 is also involved in the development of pain and fever, but it has nothing to do with inflammation. Certain NSAIDs affect precisely this type of enzyme and have little effect on COX-1 and 2. Some authors, however, believe that COX-3, as an independent isoform of the enzyme, does not exist, and it is a variant of COX-1: these questions need conducting additional research.

NSAID classification

There is a chemical classification of non-steroidal anti-inflammatory drugs, based on the structural features of the molecule of the active substance. However, biochemical and pharmacological terms are probably of little interest to a wide range of readers, so we offer you another classification, which is based on the selectivity of COX inhibition. According to her, all NSAIDs are divided into:
1. Non-selective (affect all types of COX, but mainly COX-1):

Indomethacin;
Ketoprofen;
Piroxicam;
Aspirin;
Diclofenac;
Acyclofenac;
Naproxen;
Ibuprofen.

2. Non-selective, affecting equally on COX-1 and COX-2:

Lornoxicam.

3. Selective (inhibit COX-2):

Meloxicam;
Nimesulide;
Etodolac;
Rofecoxib;
Celecoxib.

Some of the drugs listed above have practically no anti-inflammatory effect, but rather have an analgesic (Ketorolac) or antipyretic effect (Aspirin, Ibuprofen), so we will not talk about these drugs in this article. Let's talk about those NSAIDs, the anti-inflammatory effect of which is most pronounced.

Briefly about pharmacokinetics

Non-steroidal anti-inflammatory drugs are administered orally or intramuscularly.
When taken orally, they are well absorbed in the digestive tract, their bioavailability is about 70-100%. They are better absorbed in an acidic environment, and a shift in the pH of the stomach to the alkaline side slows down absorption. The maximum concentration of the active substance in the blood is determined 1-2 hours after taking the drug.

When administered intramuscularly, the drug binds to blood proteins by 90-99%, forming functionally active complexes.

They penetrate well into organs and tissues, especially into the focus of inflammation and synovial fluid (located in the joint cavity). NSAIDs are excreted in the urine. The half-life varies widely depending on the drug.

Contraindications to the use of NSAIDs

It is undesirable to use drugs in this group under the following conditions:

individual hypersensitivity to components;
as well as other ulcerative lesions of the digestive tract;
leuko- and thrombopenia;
heavy and;
pregnancy.

The main side effects of NSAIDs

These are:

ulcerogenic effect (the ability of drugs in this group to provoke the development of the gastrointestinal tract);
dyspeptic disorders (discomfort in the stomach, and others);
bronchospasm;
toxic effects on the kidneys (impaired function, increased blood pressure, nephropathy);
toxic effects on the liver (increased activity in the blood of hepatic transaminases);
toxic effects on the blood (a decrease in the number of formed elements up to aplastic anemia, which manifests itself);
prolongation of pregnancy;
(skin rash, anaphylaxis).

Number of reports of adverse reactions of NSAID drugs received in 2011-2013

Features of NSAID therapy

Since the drugs of this group, to a greater or lesser extent, have a damaging effect on the gastrointestinal mucosa, most of them must be taken after meals, drinking plenty of water, and, preferably, with the parallel use of drugs to maintain the gastrointestinal tract. As a rule, this role is played by proton pump inhibitors: Omeprazole, Rabeprazole and others.

Treatment with NSAIDs should be carried out for the shortest possible time and with the lowest effective doses.

Persons with impaired renal function, as well as elderly patients, are usually prescribed a dose below the average therapeutic dose, since the processes in these categories of patients are slowed down: the active substance has an effect and is excreted for a longer period.
Let's consider individual drugs of the NSAID group in more detail.

Indomethacin (Indomethacin, Metindol)

Release form - tablets, capsules.

It has a pronounced anti-inflammatory, analgesic and antipyretic effect. It inhibits the aggregation (sticking to each other) of platelets. The maximum concentration in the blood is determined 2 hours after ingestion, the half-life is 4-11 hours.

Assign, as a rule, by mouth, 25-50 mg 2-3 times a day.

The side effects listed above are quite pronounced for this drug, therefore, it is currently used relatively rarely, yielding primacy to other, safer in this regard, drugs.

Diclofenac (Almiral, Voltaren, Diklak, Dikloberl, Naklofen, Olfen and others)

Release form - tablets, capsules, injection, suppositories, gel.

It has a pronounced anti-inflammatory, analgesic and antipyretic effect. It is rapidly and completely absorbed in the gastrointestinal tract. The maximum concentration of the active substance in the blood is reached after 20-60 minutes. Almost 100% absorbed with blood proteins and transported throughout the body. The maximum concentration of the drug in the synovial fluid is determined after 3-4 hours, the half-life of it from it is 3-6 hours, from blood plasma - 1-2 hours. It is excreted in urine, bile and feces.

As a rule, the recommended dose of diclofenac for adults is 50-75 mg 2-3 times a day by mouth. The maximum daily dose is 300 mg. The retard form, equal to 100 g of the drug in one tablet (capsule), is taken once a day. When administered intramuscularly, a single dose is 75 mg, the frequency of administration is 1-2 times a day. The preparation in the form of a gel is applied with a thin layer on the skin in the area of \u200b\u200bthe inflammation, the frequency of application is 2-3 times a day.

Etodolak (Aetol Fort)

Release form - capsules of 400 mg.

The anti-inflammatory, antipyretic and analgesic properties of this drug are also quite pronounced. It has moderate selectivity - it acts mainly on COX-2 in the inflammation focus.

It is rapidly absorbed from the gastrointestinal tract when taken orally. Bioavailability is independent of food intake and antacids. The maximum concentration of the active substance in the blood is determined after 60 minutes. 95% bound to blood proteins. Plasma half-life is 7 hours. It is excreted from the body mainly in the urine.

It is used for urgent or long-term therapy of rheumatological pathology: as well as in the case of pain syndrome of any etiology.
It is recommended to take the drug 400 mg 1-3 times a day after meals. If long-term therapy is necessary, the dose of the drug should be adjusted once every 2-3 weeks.

Contraindications are standard. Side effects are similar to those of other NSAIDs, however, due to the relative selectivity of the drug, they appear less often and are less pronounced.
Reduces the effect of some antihypertensive drugs, in particular, ACE inhibitors.

Aceclofenac (Aertal, Diclotol, Zerodol)

Available in 100 mg tablet form.

A worthy analogue of diclofenac with a similar anti-inflammatory and analgesic effect.
After oral administration, it is rapidly and almost 100% absorbed by the gastric mucosa. With the simultaneous intake of food, the rate of absorption slows down, but its degree remains the same. It binds to plasma proteins almost completely, in this form spreading throughout the body. The concentration of the drug in the synovial fluid is quite high: it reaches 60% of its concentration in the blood. The average elimination half-life is 4-4.5 hours. It is excreted mainly by the kidneys.

Side effects should be noted dyspepsia, increased activity of hepatic transaminases, dizziness: these symptoms are quite common, in 1-10 cases out of 100. Other adverse reactions are much less common, in particular, less than one patient in 10,000.

It is possible to reduce the likelihood of developing side effects by prescribing the patient the minimum effective dose as soon as possible.

It is not recommended to take aceclofenac during pregnancy and lactation.
Reduces the antihypertensive effect of antihypertensive drugs.

Piroxicam (Piroxicam, Fedin-20)

Release form - tablets of 10 mg.

In addition to anti-inflammatory, analgesic and antipyretic effects, it also has an antiplatelet effect.

Well absorbed in the gastrointestinal tract. Simultaneous food intake slows down the rate of absorption, but does not affect the degree of its effect. The maximum concentration in the blood is observed after 3-5 hours. The concentration in the blood is much higher with the intramuscular injection of the drug than after taking it orally. It penetrates 40-50% into synovial fluid and is found in breast milk. Undergoes a number of changes in the liver. It is excreted in the urine and feces. The half-life is 24-50 hours.

The analgesic effect appears within half an hour after taking the pill and lasts for a day.

Dosages of the drug vary depending on the disease and range from 10 to 40 mg per day in one or more doses.

Contraindications and side effects are standard.

Tenoxicam (Texamen-L)

Release form - powder for preparation of solution for injection.

Apply intramuscularly to 2 ml (20 mg of the drug) per day. In acute - 40 mg once a day for 5 consecutive days at the same time.

Enhances the effects of indirect anticoagulants.

Lornoxicam (Xefokam, Larfix, Lorakam)

Release form - tablets of 4 and 8 mg, powder for preparation of solution for injection, containing 8 mg of the drug.

The recommended oral dose is 8-16 mg per day 2-3 times. The tablet should be taken before meals with plenty of water.

Intramuscularly or intravenously, 8 mg is administered at a time. Frequency rate of injections per day: 1-2 times. The solution for injection must be prepared immediately before use. The maximum daily dose is 16 mg.
Elderly patients do not need to reduce the dosage of lornoxicam, however, due to the likelihood of adverse reactions from the gastrointestinal tract, persons with any gastroenterological pathology should take it with caution.

Meloxicam (Movalis, Melbek, Revmoxicam, Rekoksa, Melox and others)

Release form - tablets of 7.5 and 15 mg, solution for injection of 2 ml in an ampoule containing 15 mg of active ingredient, rectal suppositories, also containing 7.5 and 15 mg of Meloxicam.

Selective COX-2 inhibitor. Less often than other drugs of the NSAID group, it causes side effects in the form of kidney damage and gastropathy.

As a rule, in the first few days of treatment, the drug is used parenterally. 1-2 ml of solution is injected deep into the muscle. When the acute inflammatory process subsides a little, the patient is transferred to the tablet form of meloxicam. Inside, it is used regardless of food intake at 7.5 mg 1-2 times a day.

Celecoxib (Celebrex, Revmoxib, Zitsel, Phlogoxib)

Release form - capsules of 100 and 200 mg of the drug.

A specific inhibitor of COX-2 with a pronounced anti-inflammatory and analgesic effect. When used in therapeutic doses, it practically does not have a negative effect on the mucous membrane of the gastrointestinal tract, since it has a very low degree of affinity for COX-1, therefore, it does not cause disruption of the synthesis of constitutional prostaglandins.

As a rule, celecoxib is taken at a dosage of 100-200 mg per day in 1-2 doses. The maximum daily dose is 400 mg.

Side effects are rare. In the case of long-term use of the drug in a high dosage, ulceration of the mucous membrane of the digestive tract, gastrointestinal bleeding, agranulocytosis, etc.

Rofecoxib (Denebol)

Release form - solution for injection in 1 ml ampoules, containing 25 mg of active ingredient, tablets.

Highly selective inhibitor of COX-2 with pronounced anti-inflammatory, analgesic and antipyretic properties. Virtually no effect on the mucous membrane of the gastrointestinal tract and kidney tissue.

It is prescribed with caution in women in the 1st and 2nd trimesters of pregnancy, during lactation, for persons suffering or severe.

The risk of developing side effects from the gastrointestinal tract increases with taking high dosages of the drug for a long time, as well as in elderly patients.

Etoricoxib (Arcoxia, Exineph)

Release form - tablets of 60 mg, 90 mg and 120 mg.

Selective COX-2 inhibitor. It does not affect the synthesis of prostaglandins in the stomach, it does not affect the function of platelets.

The drug is taken orally, regardless of food intake. The recommended dose directly depends on the severity of the disease and varies between 30-120 mg per day in 1 dose. Elderly patients do not need to adjust the dosage.

Side effects are extremely rare. As a rule, they are noted by patients taking etoricoxib for 1 year or more (for serious rheumatic diseases). The spectrum of undesirable reactions arising in this case is extremely wide.

Nimesulide (Nimegesic, Nimesil, Nimid, Aponil, Nimesin, Remesulid and others)

Release form - tablets of 100 mg, granules for the preparation of a suspension for oral administration in a sachet containing 1 dose of the drug - 100 mg each, gel in a tube.

Highly selective inhibitor of COX-2 with pronounced anti-inflammatory, analgesic and antipyretic effects.

The drug is taken orally, 100 mg twice a day, after meals. The duration of treatment is determined individually. The gel is applied to the affected area, rubbing lightly into the skin. Frequency rate of application - 3-4 times a day.

When Nimesulide is prescribed to elderly patients, dose adjustment of the drug is not required. The dose should be reduced in case of severe impairment in the patient's liver and kidney function. May have hepatotoxic effects by inhibiting liver function.

During pregnancy, especially in the 3rd trimester, nimesulide is strongly discouraged. During breastfeeding, the drug is also contraindicated.

Nabumeton (Sinmeton)

Release form - tablets of 500 and 750 mg.

Non-selective COX inhibitor.

A single dose for an adult patient is 500-750-1000 mg during or after a meal. In severe cases, the dose may be increased to 2 grams per day.

Side effects and contraindications are similar to those of other non-selective NSAIDs.
Not recommended for use during pregnancy and lactation.

Combined non-steroidal anti-inflammatory drugs

There are drugs containing two or more active substances from the NSAID group, or NSAIDs in combination with vitamins or other drugs. The main ones are listed below.

Dolaren. Contains 50 mg of diclofenac sodium and 500 mg of paracetamol. In this drug, the pronounced anti-inflammatory effect of diclofenac is combined with the bright analgesic effect of paracetamol. Take the drug by mouth, 1 tablet 2-3 times a day after meals. The maximum daily dose is 3 tablets.
Neurodiclovitis. Capsules containing 50 mg of diclofenac, vitamin B1 and B6, as well as 0.25 mg of vitamin B12. Here, the analgesic and anti-inflammatory effect of diclofenac is enhanced by the B vitamins, which improve the metabolism in the nervous tissue. The recommended dose of the drug is 1-3 capsules per day in 1-3 doses. Take the drug after meals with plenty of fluids.
Olfen-75, produced in the form of a solution for injection, in addition to diclofenac in the amount of 75 mg also contains 20 mg of lidocaine: due to the presence of the latter in the solution, injections of the drug become less painful for the patient.
Fanigan. Its composition is similar to that of Dolaren: 50 mg of sodium diclofenac and 500 mg of paracetamol. It is recommended to take 1 tablet 2-3 times a day.
Flamidez. A very interesting drug that is different from others. In addition to 50 mg of diclofenac and 500 mg of paracetamol, it also contains 15 mg of serratiopeptidase, which is a proteolytic enzyme and has a fibrinolytic, anti-inflammatory and anti-edema effect. Available in the form of tablets and gel for topical use. The tablet is taken orally, after a meal, with a glass of water. As a rule, 1 tablet is prescribed 1-2 times a day. The maximum daily dose is 3 tablets. The gel is used externally, applying it to the affected skin area 3-4 times a day.
Maxigezik. A drug similar in composition and action to Flamidez described above. The difference lies in the manufacturing company.
Diplo-P-Pharmex. The composition of these tablets is similar to that of Dolaren. The dosages are the same.
Dolar. Same.
Dolex. Same.
Oxalgin-DP. Same.
Tsinepar. Same.
Diclokain. Like Olfen-75, it contains diclofenac sodium and lidocaine, but both active ingredients are in half the dosage. Accordingly, it is weaker in action.
Dolaren gel. Contains diclofenac sodium, menthol, linseed oil and methyl salicylate. All these components, to one degree or another, have an anti-inflammatory effect and potentiate the effects of each other. The gel is applied to the affected skin 3-4 times during the day.
Nimid forte. Tablets containing 100 mg of nimesulide and 2 mg of tizanidine. This drug successfully combines the anti-inflammatory and analgesic effects of nimesulide with the muscle relaxant (muscle relaxing) action of tizanidine. It is used for acute pain caused by spasm of skeletal muscles (in the popular way - with pinching of the roots). The drug is taken orally after a meal with plenty of fluids. The recommended dose is 2 tablets per day in 2 divided doses. The maximum duration of treatment is 2 weeks.
Nizalid. Like nimid forte, it contains nimesulide and tizanidine in similar dosages. The recommended doses are the same.
Alit. Dissolving tablets containing 100 mg of nimesulide and 20 mg of dicycloverine, which is a muscle relaxant. It is taken orally after meals with a glass of liquid. It is recommended to take 1 tablet 2 times a day for no longer than 5 days.
Nanogan. The composition of this drug and the recommended dosages are similar to those of the drug Alit, described above.
Oksigan. Same.

Currently, non-steroidal 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 currently come to the fore among the most significant characteristics of NSAIDs. This paper presents the results of the largest clinical trials and meta-analyzes in which the negative effects of NSAIDs on the digestive, cardiovascular systems and kidneys were studied. 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 citation:Dovgan E.V. Clinical pharmacology of non-steroidal anti-inflammatory drugs: a course towards safety // BC. 2017. No. 13. S. 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, tolerability and safety. Due to the fact that many NSAIDs have comparable clinical efficacy, it is the drug safety profile and its tolerability that come 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, gastro-toxicity, 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 demanded 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, traumatic pain of mild to moderate intensity, renal colic, headache, and dysmenorrhea.

The 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. It has been established that NSAIDs inhibit cyclooxygenases (COX), which regulate the formation of various prostanoids. As you know, COX is represented by two isoforms - COX-1 and COX-2. COX-1 is constitutional, constantly present in tissues and regulates the synthesis of such prostanoids as prostaglandins (PGs) (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 the action on 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 an increase in the production of mucus and bicarbonates; at the same time, the 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 due precisely to 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 recent studies indicate that constitutional COX-2 is also present in the body in small amounts, which plays an important role in the development and the functioning of the brain, thymus, kidneys and gastrointestinal tract (GIT). Therefore, inhibition of constitutional COX-2, observed with the administration of selective COX-2 inhibitors (for example, coxibs), may be accompanied by the development of a number of serious ADRs in the cardiovascular system (CVS) and kidneys.
Besides 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 PGE2 and a number of other prostanoids, which are the main mediators of inflammation, are actively formed. Excessive formation of PGE2, observed during inflammation, is accompanied by a number of pathological reactions. For example, signs of inflammation such as edema and erythema 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 PGE2 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 PHN2 into PGE2, i.e., this synthetase regulates the production of PGE2 in normal conditions. In contrast, m-PGE2C 1 is inducible and works in concert with COX-2 (but not COX-1) and converts PHN2 to PGE2 in the presence of inflammation. Thus, it is m-PGE2C 1 that is one of the key enzymes regulating the synthesis of such an important inflammatory mediator as PGE2.
It was found that the activity of m-PGE2C 1 increases under the influence of proinflammatory cytokines (for example, interleukin-1b and tumor necrosis factor alpha), at the same time, recent studies indicate that representatives of the oxicam group (for example, meloxicam) are able to inhibit m- PGE2S 1 and thereby reduce the production of PGE2 during inflammation. The data obtained indicate the presence of at least two mechanisms of action in oxicams: the first mechanism, characteristic of other NSAIDs, is the effect on COX, and the second is associated with the inhibition of m-PGE2C 1, leading to the prevention of excessive formation of PGE2. It is possible that it is the presence of two mechanisms of action in oxicams that explains their favorable safety profile and, above all, the low incidence of ADR from the CVS and kidneys, while maintaining a high anti-inflammatory efficacy.
Next, we present the results of meta-analyzes and large clinical trials that investigated the safety of NSAIDs.

The negative effect of NSAIDs on the digestive tract

Gastrointestinal ADRs are the most common and well-studied complications associated with NSAID therapy. Two main mechanisms of the negative effect of NSAIDs on the gastric mucosa are described: first, local effects due to the fact that some NSAIDs are acids and, when ingested into the stomach, can have a direct damaging effect on the epithelium of the stomach; secondly, systemic exposure through inhibition of PG synthesis through inhibition of COX.
As you know, 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 impaired production of PGE2 due to inhibition of COX-1, which is accompanied by an increase in the 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 the maintenance of normal gastric function, plays an important role in the healing of gastric ulcers (by regulating the production of PGE2 that interacts with EP4 receptors), and the use of superselective COX-2 inhibitors can slow down the healing of gastric ulcers, which in some cases, it ends with complications such as bleeding or perforation. Some studies show that 1 in 600-2400 patients taking NSAIDs are admitted to the hospital with gastrointestinal bleeding or perforation, and every 10th hospitalized patient dies.
Data from a large-scale study conducted by Spanish scientists indicate a higher incidence of gastric ADR when using non-COX-2 selective NSAIDs. It was found that, compared with the use of NSAIDs, the use of non-selective COX-2 inhibitors significantly increased the risk of serious complications from the upper gastrointestinal tract (adjusted relative risk (RR) 3.7; 95% confidence interval (CI): 3.1-4 , 3). Along with this, selective COX-2 inhibitors caused the development of such complications to a lesser extent (RR 2.6; 95% CI: 1.9–3.6). It should be noted that the highest risk of developing serious complications was revealed when prescribing a selective COX-2 inhibitor, etoricoxib (RR 12), followed by naproxen (RR 8.1) and indomethacin (RR 7.2), on the contrary, ibuprofen was the safest NSAID. (RR 2), rofecoxib (RR 2.3), and meloxicam (RR 2.7) (Fig. 2). The higher risk of serious damage to the upper gastrointestinal tract during therapy with etoricoxib is probably due to the fact that this drug disrupts the healing process of gastric ulcers by disrupting the production of PGE2 (associated with COX-2), which, by binding to EP4, promotes the healing of the ulcer.

In a study by Melero et al. it has been demonstrated that non-selective NSAIDs are much more likely than selective COX-2 inhibitors to cause severe gastrointestinal lesions. Thus, the RR of gastrointestinal bleeding was minimal against the background of treatment with aceclofenac (reference drug, RR 1) and meloxicam (RR 1.3). In contrast, ketorolac was at the highest risk of bleeding (RR 14.9).
Of interest are the results of a network meta-analysis by Yang M. et al., Which evaluated 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 the results of 36 studies with a total of 112,351 participants, aged 36 to 72 years (median 61.4 years), with study durations ranging from 4 to 156 weeks. (median 12 weeks). It was found that the probability of developing a complicated gastric ulcer in the coxib group was 0.15% (95% CI: 0.05-0.34), and in the group of moderately selective COX-2 inhibitors - 0.13% (95% CI: 0.04–0.32), the difference is statistically insignificant. In addition, it was shown that the likelihood of symptomatic gastric ulcer in the coxib group was 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 not statistically significant. Also, there were no statistically significant differences between the two groups of NSAIDs in the likelihood of gastric ulcers detected by gastroscopy. A comparable frequency of adverse events (AEs) in both groups should be noted (Table 2).

Thus, the results of this meta-analysis demonstrate comparable gastrointestinal tolerability and safety of moderately selective NSAIDs and coxibs.
In addition to damage to the stomach and intestines, against the background of the use of NSAIDs, the development of hepatotoxic reactions is possible. 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); against the background of treatment with nimesulide, acute hepatitis, cholestasis may occur; oxicams can cause acute hepatitis, hepatonecrosis, cholestasis and ductopenia.
For some NSAIDs, a direct relationship has been established between the duration of administration and the dose and the risk of liver damage. Thus, in the work of Donati M. et al. analyzed the risk of developing acute serious liver damage against the background of the use of various NSAIDs. It was found that with a duration of therapy 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 in a number of drugs by more than 8 times (Table 3).

The negative effect of NSAIDs on CVS

As you know, acetylsalicylic acid (ASA) in low doses has a cardioprotective effect, reducing the incidence of ischemic complications from the cardiovascular system and the nervous system, and therefore is widely used to prevent myocardial infarction, stroke and cardiovascular death. Unlike ASA, many NSAIDs can have a negative effect on the CVS, which is manifested by a worsening of the course of heart failure, destabilization of blood pressure and thromboembolic complications.
These negative effects are due to the influence 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 prescribing selective COX-2 inhibitors, prostacyclin synthesis decreases, while thromboxane A2 continues to be synthesized (the process controls 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-analyzes. 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, increased the risk of developing myocardial infarction to the greatest extent (RR 1.55 and 1.97, respectively). On the contrary, naproxen, celecoxib, ibuprofen, and meloxicam practically did not increase the risk of thrombotic complications from CVS.
Similar findings came from 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 (RR 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 such complications. In the framework of this study, the effect of drug dosage on the combined relative risk of complications (ROR) was studied, which was calculated as the sum of the risks of thrombotic complications from the heart, blood vessels and kidneys. It turned out that the ROR did not increase only when high doses of meloxicam (15 mg / day) and indomethacin (100-200 mg / day) were prescribed as compared to low doses. On the contrary, with the appointment of high doses of rofecoxib (more than 25 mg / day), the ORR increased more than 4 times (from 1.63 to 6.63). To a lesser extent, an increase in dosage contributed to an increase in the ORR in the presence 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 the 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 prescribing selective COX-2 inhibitors and high doses of "traditional" NSAIDs (such as diclofenac, ibuprofen and naproxen) 1.9-2.5 times higher than placebo increased the likelihood of hospitalization due to worsening of the course CHF.
Noteworthy is the results of a large case-control study published in 2016 in the British Medical Journal. It was found that the use of NSAIDs within the previous 14 days increased the likelihood of hospitalization due to the 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 practically did not 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 the volume of circulating blood and an increase in blood pressure).
The use of a number of NSAIDs, primarily highly selective, is accompanied by an increase in the risk of stroke. Thus, a systematic review and meta-analysis of observational studies published in 2011 demonstrated an increased risk of stroke with 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 little or no effect on the risk of stroke.
In a prospective population-based study, Haag et al. 7,636 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 suffered stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified), while those who received non-selective NSAIDs and selective COX-2 inhibitors had a higher risk of stroke (RR 1.72 and 2, 75, respectively) compared with patients who received selective COX-1 inhibitors (indomethacin, piroxicam, ketoprofen, flubiprofen and apazon). It should be emphasized that the highest risk of stroke among nonselective NSAIDs was found in naproxen (RR 2.63; 95% CI: 1.47-4.72), and among the selective COX-2 inhibitors, rofecoxib was the most unsafe for stroke ( RR 3.38; 95% CI 1.48-7.74). Thus, in this study, it was found that the use of selective COX-2 inhibitors in elderly patients significantly more often than the use of other NSAIDs leads to the development of stroke.

The negative effects of NSAIDs on kidney function

Nephrotoxicity is one of the most common ADRs that occur with the use of NSAIDs, while in the United States every year 2.5 million people experience renal dysfunction during treatment with this group of drugs.
The toxic effect of NSAIDs on the kidneys can manifest itself in the form of prerenal azotemia, hyporenin hypoaldosteronism, sodium retention in the body, 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 regulating renal 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 was found that the EP3 receptor is involved in delaying the absorption of water and sodium chloride in the kidneys, and EP4 regulates hemodynamics in the glomeruli. It should be noted that prostacyclin dilates renal arterioles, while 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 chronic renal failure (CRF). The results of 2 epidemiological studies indicate that the RR of the onset of chronic renal failure during treatment with NSAIDs ranges from 2 to 8.
In a large-scale retrospective study conducted in the USA with the participation of more than 350 thousand patients, the effect of various NSAIDs on the development of acute renal dysfunction was studied (determined by an increase in creatinine levels by more than 50%). It was found that the use of NSAIDs was accompanied by an increased risk of acute renal dysfunction (adjusted RR 1.82; 95% CI: 1.68–1.98) compared with the non-use of drugs in this group. The risk of kidney damage varied significantly with NSAIDs, with drug toxicity increasing with decreasing COX-2 selectivity. For example, rofecoxib (RR 0.95), celecoxib (RR 0.96), and meloxicam (RR 1.13) had virtually no negative effect on renal 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 impairment. Thus, this study demonstrated no effect of selective COX-2 inhibitors on the development of acute renal dysfunction.
In this regard, patients with a high risk of impaired renal function should avoid prescribing both nonselective NSAIDs in high doses and superselective COX-2 inhibitors, which can also cause impaired renal function.

Conclusion

Currently, a doctor has a large number of various NSAIDs in his arsenal, which differ both in effectiveness and in the spectrum of NLR. Speaking about the safety of NSAIDs, it should be emphasized that the selectivity of the drug in relation to COX isoforms largely determines from which organs and systems ADRs arise. For example, non-selective NSAIDs have gastrotoxic effects and can impair 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 best drug among so many NSAIDs? How to strike a balance between efficiency and safety? Data from numerous clinical studies and meta-analyzes show that NSAIDs with an average selectivity index for COX-2 (for example, meloxicam) are largely devoid of ADRs inherent in both non-selective drugs and superselective drugs.

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For citation:E.L. Nasonov Non-steroidal anti-inflammatory drugs // BC. 1999. No. 8. P. 9

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

H steroidal anti-inflammatory drugs (NSAIDs) are a class of pharmacological agents whose therapeutic activity is associated with preventing the development or decreasing the intensity of inflammation. Currently, there are more than 50 dosage forms that differ in chemical structure, classified as NSAIDs, which in turn are subdivided 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 ... alklofenac .fentiazac 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
... proquazone ... tiaramide ... buffet ... epirazole ... nabumetone		... fluorproquazone ... flufizone ... tinoridine ... colchicine
III. Combined drugs
... arthrotec (diclofenac + misoprostol)

NSAIDs are among the most commonly used drugs in clinical practice. They are prescribed by approximately 20% of inpatients suffering from various diseases of 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 focus of inflammation, in which, in contrast to 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 exert their anti-inflammatory analgesic and antipyretic effects due to suppressing the activity of the enzyme COXparticipating in the biosynthesis of PG. Since then, the point of view according to which the anti-inflammatory and other effects of NSAIDs are primarily associated with suppression of GHG synthesisis generally accepted. Indeed, almost all currently synthesized NSAIDs in vitro block COX as part of the PG-endoperoxide synthetase complex, to a lesser extent without affecting the activity of other enzymes involved in the metabolism of arachidonic acid (phospholipase A 2 , lipoxygenase, isomerase). It is also assumed that the 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, the synthesis of RT, etc. In addition, antiprostaglandin the activity of NSAIDs explains some of their vascular effects (a decrease in the intensity of PG-induced edema and erythema), the analgesic effect and the reasons for the development of the main side reactions (peptic ulcer, impaired platelet function, bronchospasm, hypertension, glomerular filtration disorder).
Possible points of application of the pharmacological activity of NVP
.GHG synthesis
.LT synthesis
.Superoxide Radiakl Formation
.Release of lysosomal enzymes
.Activation of cell membranes:
-enzymes
-NAPDH oxidation
-phospholipase
-transmembrane transport of anions
-capture of predecessors of GHG
.Aggregation and adhesion of neutrophils
.Function of lymphocytes
.RF synthesis
.Cytokine synthesis
.Cartilage metabolism

However, in recent years, ideas about the points of application of NSAIDs in the regulation of PG synthesis have significantly expanded and refined. Previously, it was believed that COX is the only enzyme, the inhibition of which reduces the synthesis of PGs involved in the development of inflammation, and "normal" PGs, which regulate the function of the stomach, kidneys and other organs. But recently, two COX isoforms (COX-1 and COX-2) have been discovered that play different roles in the regulation of PG synthesis. As already noted, it is COX-2 that regulates the synthesis of GHGs induced by various pro-inflammatory stimuli, while the activity of COX-1 determines the production of GHGs involved in normal physiological cellular reactions not associated with the development of inflammation. Preliminary results, obtained so far only in in vitro experiments, showed that some NSAIDs equally inhibit COX-1 and COX-2, while others suppressed COX-1 by 10-30 times more than COX-2.
These results, although preliminary, are very important, since they allow explaining the features of the pharmacological activity of NSAIDs and the reasons for the development of some of the side effects that are most inherent in 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 , the inhibition of the synthesis of which NSAIDs disrupt platelet aggregation and promote bleeding. In addition, PGs play an important role in the regulation of glomerular filtration, renin secretion and maintenance of water and electrolyte balance. It is obvious that inhibition of PG can lead to a variety of renal dysfunctions, especially in patients with concomitant renal pathology. It is believed that it is the ability of HA to selectively inhibit COX-2 that causes a significantly lower incidence of gastric ulcers during treatment with these drugs in comparison with NSAIDs, no effect on blood clotting and renal function. Finally, suppression of cyclooxygenase activity can potentially facilitate the switching of the metabolism of arachidonic acids on the lipoxygenase pathway, causing overproduction of LT. This explains the development in some patients receiving NSAIDs, bronchospasm and other reactions of immediate hypersensitivity. It is believed that the 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. LTB4 is known to induce 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 explain well the powerful preventive effect of synthetic PGs of the E1 series in NSAID-induced gastropathies. It is known that PGE1 have the ability to suppress the activation of neutrophils, prevent adhesion of neutrophils to EC, 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 a higher anti-inflammatory activity and low toxicity.
Table 2. Recommended doses of NSAIDs for rheumatic diseases

A drug	Dose range (mg / day)	Frequency rate of admission 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
sodium meclofenamate	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:
nabumetone	1000 - 2000	1 - 2
Oxazole propionic acid:
oxaprozin	600 - 1200

One of the first NSAIDs with a 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 the activity of COX-2 in a time-dependent manner with the formation of a secondary slowly dissociating stable ("secondary") enzyme-inhibitor complex, while against COX-1 it exhibits the activity of a competitive reversible COX inhibitor. Ultimately, this unique feature of nimesulide is 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 lesions 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%.
So, when analyzing 22,939 patients with osteoarthritis treated with nimesulide at a dose of 100-400 mg / day for 5-21 days (on average 12 days), the total frequency of side effects, mainly from the gastrointestinal tract, was observed only in 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 recorded. It is noteworthy that the incidence of side effects in patients over 60 years old did not differ from that in the general population of patients. When analyzing 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 rarely causes an increase in 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
Nabumeton	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 asterisks - 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 the synthesis of PG. For example, the "anti-inflammatory" dose of aspirin is significantly higher than that required to suppress GHG synthesis, and salicylic sodium and other non-acetylated salicylates, which very weakly suppress COX activity, are not inferior in anti-inflammatory activity to NSAIDs, which are potent inhibitors of GHG 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 action on platelets and the good tolerance of these drugs even in patients with hypersensitivity to aspirin. Some toxic reactions, such as hepatitis, neurological disorders (tinnitus, depression, meningitis, disorientation), interstitial nephritis, are also probably not associated with the PG-dependent mechanisms of action of NSAIDs.
The effects of NSAIDs, which are not believed to be directly related to their antiprostaglandin activity, include the following:
1) suppression of prostateoglycan synthesis by cells of the articular cartilage;
2) suppression of peripheral inflammation due to central mechanisms;
3) enhancement of T-cell proliferation and synthesis of IL-2 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 drugs are injected into the lateral ventricle of the brain. This is not associated with 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 can 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 chemotaxis and aggregation of neutrophils, the formation of hypochloric acid and superoxide radicals by leukocytes, inhibit the activity phospholipase C and the synthesis of IL-1 by monocytes. At the same time, the stable analogue of PGE1 misoprostol enhances the inhibitory effect of NSAIDs on the activation of neutrophils.
The molecular mechanisms behind these pharmacological effects of NSAIDs are not fully understood. It is assumed that, being anionic lipophilic molecules, NSAIDs can penetrate the phospholipid bilayer and change the viscosity of biomembranes. This, in turn, leads to the disruption of 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 the G-protein plays an important role in the regulation of the process of activation of leukocytes under the influence of anaphylotoxin (C5a) and the chemotactic peptide formyl-methionine-leucine-phenylalanine (FMLF). The binding of these ligands to specific membrane receptors of leukocytes leads to a change in their conformation. Conformational rearrangement is transferred across the membrane to the G-protein, as a result of which it acquires the ability to bind intracellular guanosine triphosphate. This leads to such changes in the conformation of the G-protein that induce the 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 the G-protein, which leads to the cancellation of the chemotactic effects of C5a and FMLF and suppression of cellular activation. In turn, arachidonic acid, released from membrane phospholipids during cellular activation, enhances the binding of guanosine triphosphate to the G-protein, that is, it gives an effect opposite to that 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 PG, and in high (anti-inflammatory) concentrations - block the association of arachidonate with the 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 is probably the 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 inhibit 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 molecules 1 (ICAM-1), endothelial-leukocyte adhesion molecule-1, vascular adhesion molecule-1 (VCAM-1) It is noteworthy that HA and CsA have similar mechanisms of action, which allows us to re-evaluate the therapeutic possibilities of using NSAIDs.
Virtually all NSAIDs have the ability to reduce pain at concentrations less than necessary to suppress inflammation. Previously believed, that, since PHs enhance the pain response induced by bradykinin, suppression 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 pain mechanisms that are not associated with with inhibition of the synthesis of GHG. For example, acetomenophen has very high analgesic activity, despite the lack of ability to inhibit the activity of COX.
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 the activity of endogenous pyrogens, 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 proinflammatory cytokine-induced PG synthesis, 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 aggregation response of platelets 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 required for the synthesis of thromboxane A 2 ... It is believed that, in addition to the antiaggregatory effect, aspirin may have other points of application in the mechanisms of blood coagulation: 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 (the hydrolysis product of thromboxane A 2) by 98% within 1 hour, and only 30 mg per day effectively inhibit 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 state, opposite to that of thromboxane A 2 ... However, unlike platelets, the synthesis of prostacyclin EC 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 commonly used for the following testimony:

In addition, NSAIDs are often used to reduce the severity of menstrual spasticity; they promote faster closure of the ductus arteriosus; NSAIDs have found application in inflammatory ophthalmic 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 for their use in patients with malignant neoplasms of the colon. According to F.M. Giardello et al. (1993), sulindac inhibits the development of adenomatous intestinal polyposis. Clinical efficacy of indomethacin in Alzheimer's disease was recently discovered. NSAIDs are especially widely used in the treatment of migraines. They are believed to be the treatment of choice in patients with moderate to 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 than ergotamine in this regard. Aspirin and other NSAIDs have a similar effect. To achieve a more pronounced effect on nausea and vomiting, it is recommended to combine NSAIDs with metoclopramide, which accelerates the absorption of drugs. For quick relief of migraine attacks, it is recommended to use ketorolac, which can be administered parenterally. It is assumed that the effectiveness of NSAIDs in migraine is associated with their ability, by suppressing the synthesis of PGs, to reduce the intensity of neurogenic inflammation or, by interfering with serotonin, to reduce the severity of vascular spasm.
Despite the similarity of the chemical properties and main pharmacological effects of various NSAIDs, in some patients with the same disease (for example, RA) or with different rheumatic diseases, there are significant fluctuations in the "response" to one or another drug. Indeed, at the population level, there were no significant differences between aspirin and other NSAIDs in RA, but they become apparent when analyzing the effectiveness of various NSAIDs in individual patients. This dictates the need individual selection NSAIDs for each patient.
The choice of NSAIDs is usually empirical and is largely based on the doctor's personal experience and the patient's past experience. There is a point of view that it is advisable to use the least toxic drugs at the beginning of treatment, which primarily include propionic acid derivatives. It is necessary gradually titrate dose NSAIDs to effective, but not exceeding the maximum allowable, within 1 - 2 weeks and in the absence of effect, try to use another or other drugs. Prescribing simple analgesics (paracetamol) can reduce the need for NSAIDs. The 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 efficacy in patients with different rheumatic diseases. For example, for gout, all NSAIDs are more effective than tolmetin, and for ankylosing spondyloarthritis, indomethacin and other NSAIDs are more effective than aspriin.
Possible reasons for the different clinical efficacy of NSAIDs and the spectrum of toxic reactions in individual patients with different 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 the half-life, NSAIDs are divided into two main categories: short-lived, with a half-life of no more than 4 hours, and long-lived, in which this indicator is 12 hours or more. However, it should be borne in mind that the kinetic parameters of NSAIDs in synovial fluid and tissue can differ significantly from serum, and in this case, the differences between NSAIDs in the half-life in the synovium become less significant than in the bloodstream. At the same time, 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 explains the long-term clinical efficacy of short-lived drugs. For example, there is evidence that in RA, taking ibuprofen 2 times a day is as effective as taking it 4 times, despite the very short half-life of ibuprofen in plasma.
Data on various pharmacological properties of levorotatory (S) and dextrorotatory (R) isomers of NSAIDs... For example, ibuprofen is a recemic mixture of levorotatory and dextrorotatory isomers, with the R isomer mainly determining the analgesic potential of the drug. The S-form of flurbiprofen exhibits strong analgesic activity, but weakly inhibits the synthesis of PG, while the R-isomer, on the contrary, has a higher anti-inflammatory activity. These data in the future may be a stimulus for the creation of more powerful and selective NSAIDs, however, at present, the clinical significance of the existence of various enantiomeric forms of NSAIDs is unclear.
More important is protein binding capacity NSAIDs. It is known that all NSAIDs (except for piroxicam and salicylates) bind to albumin by more than 98%. The clinical significance of this property of NSAIDs is that the development of hypoalbuminemia, hepatic or renal failure dictates the need to prescribe smaller doses of drugs.
In the process of treatment it is necessary to consider daily fluctuations severity of clinical symptoms and inflammatory activity of the disease. For example, in RA, the maximum intensity of stiffness, joint pain and a decrease in the grip force of the hand are observed in the morning hours, while in osteoarthritis the 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. Patients with osteoarthritis, in whom the severity of pain is maximal in the evening and early morning, it is preferable to prescribe prolonged-release indomethacin at bedtime. It is noteworthy that this rhythm of intake led to a significant decrease in the frequency of side effects. Thus, the synchronization of NSAID prescription with the rhythm of clinical activity makes it possible to increase the effectiveness of treatment, especially with drugs with a short half-life.

Mechanism of action

Figure: 1.

PGs have a versatile biological activity:

1. are mediators of the inflammatory reaction: they cause local vasodilation, edema, exudation, migration of leukocytes and other effects (mainly PG-E 2 and PG-I 2);
2. sensitize receptors to pain mediators (histamine, bradykinin) and mechanical influences, lowering the pain threshold;
3. increase the sensitivity of the hypothalamic centers of thermoregulation to the action of endogenous pyrogens (interleukin-1 and others) formed in the body under the influence of microbes, viruses, toxins (mainly PG-E 2).

In recent years, it has been found that there are at least two cyclooxygenase isoenzymes that are inhibited by NSAIDs. The first isoenzyme, COX-1 (COX-1), controls the production of prostaglandins, which regulates the integrity of the gastrointestinal mucosa, platelet function and renal blood flow, and the second isozyme, COX-2, is involved in the synthesis of prostaglandins during inflammation. Moreover, COX-2 is absent under normal conditions, but is formed under the influence of some tissue factors that initiate an inflammatory reaction (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. The ratio of the activity of NSAIDs in terms of blocking COX-1 / COX-2 allows one to judge their potential toxicity. The lower this value, the more selective the drug is in relation to COX-2 and, thus, less toxic. For example, for meloxicam it is 0.33, diclofenac - 2.2, tenoxicam - 15, piroxicam - 33, indomethacin - 107:

1. Expressed selectivity for COX-1
o Aspirin
o Indomethacin
o Ketoprofen
o Piroxicam
o Sulindak
2. Moderate selectivity for COX-1
o Diclofenac
o Ibuprofen
o Naproxen
3. Approximately equivalent inhibition of COX-1 and COX-2
o Lornoxicam
4. Moderate selectivity for COX-2
o Etodolac
o Meloxicam
o Nimesulide
o Nabumeton
5. Expressed selectivity for COX-2
o Celecoxib
o Rofecoxib

Other mechanisms of action of NSAIDs

Main effects

Anti-inflammatory effect

NSAIDs predominantly suppress the exudation phase. The most powerful drugs - indomethacin, diclofenac, phenylbutazone - also act on the proliferation phase (decreasing collagen synthesis and associated tissue hardening), but weaker than on the exudative phase. NSAIDs practically do not affect the alteration phase. In terms of anti-inflammatory activity, all NSAIDs are inferior to glucocorticoids, which, by inhibiting the enzyme phospholipase A 2, inhibit the metabolism of phospholipids and disrupt the formation of both prostaglandins and leukotrienes, which are also the most important mediators of inflammation.

Analgesic effect

It manifests itself to a greater extent with pain of weak and moderate intensity, which are localized in muscles, joints, tendons, nerve trunks, as well as with headache or toothache. With severe visceral pain, most NSAIDs are less effective and are inferior in strength to the analgesic effect of drugs of the morphine group (narcotic analgesics). At the same time, a number of controlled studies have shown a fairly high analgesic activity of diclofenac, ketorolac, ketoprofen, metamizole for colic and postoperative pain. The effectiveness of NSAIDs in renal colic that occurs in patients with urolithiasis is largely associated with the inhibition of PG-E 2 production in the kidneys, a decrease in renal blood flow and urine formation. This leads to a decrease in pressure in the renal pelvis and ureters above the site of obstruction and provides a long-lasting analgesic effect. The advantage of NSAIDs over narcotic analgesics is that they do not depress the respiratory center, do not cause euphoria and drug dependence, and in colic it is also important that they do not have a spasmogenic effect.

Antipyretic effect

NSAIDs work only for fever. The normal body temperature is not affected, which differs from "hypothermic" drugs (chlorpromazine and others).

Antiaggregatory effect

As a result of inhibition of COX-1 in platelets, the synthesis of the endogenous proaggregant thromboxane is suppressed. The strongest and most prolonged antiaggregatory activity is possessed by aspirin, which irreversibly suppresses the ability of a platelet to aggregate for its entire life span (7 days). The antiaggregatory effect of other NSAIDs is weaker and reversible. Selective COX-2 inhibitors do not affect platelet aggregation.

Immunosuppressive effect

It is moderately expressed, manifests itself with prolonged use and has a "secondary" character: by reducing capillary permeability, NSAIDs make it difficult for immunocompetent cells to contact the antigen and the contact of antibodies with the substrate.

Pharmacokinetics

All NSAIDs are well absorbed in the gastrointestinal tract. They almost completely bind to plasma albumin, displacing some other drugs, and in newborns - bilirubin, which can lead to the development of bilirubin encephalopathy. The most dangerous in this respect are salicylates and phenylbutazone. Most NSAIDs penetrate well into the synovial fluid of the joints. NSAIDs are metabolized in the liver, excreted through the kidneys.

Drug interactions

Quite often, patients who receive NSAIDs are prescribed other drugs. In this case, it is imperative to take into account the possibility of their interaction with each other. Thus, NSAIDs can enhance the effect of indirect anticoagulants and oral hypoglycemic agents. At the same time, they weaken the effect of antihypertensive drugs, increase the toxicity of antibiotics-aminoglycosides, digoxin and some other drugs, which is of significant clinical significance and entails a number of practical recommendations.

The simultaneous administration of NSAIDs and diuretics should, if possible, be avoided, in view of, on the one hand, the weakening of the diuretic effect and, on the other, the risk of developing renal failure. The most dangerous is the combination of indomethacin with triamterene.

Many drugs administered simultaneously with NSAIDs, in turn, can affect their pharmacokinetics and pharmacodynamics:

Sodium bicarbonate enhances the absorption of NSAIDs in the gastrointestinal tract;

The anti-inflammatory effect of NSAIDs is enhanced by glucocorticoids and "slow-acting" (basic) anti-inflammatory drugs (gold preparations, aminoquinolines);

The analgesic effect of NSAIDs is enhanced by narcotic analgesics and sedatives.

Rational use of non-steroidal anti-inflammatory drugs: balance of efficacy and safety. Characteristics of individual drugs B) Classification by mechanism of action

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B) Classification by mechanism of action:

I. Selective COX-1 inhibitors

II. Non-selective inhibitors of COX-1 and COX-2

III. Selective COX-2 inhibitors

IV. Highly Selective COX-2 Inhibitors

V. Selective COX-3 inhibitors

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Etodolak (Aetol Fort)

Aceclofenac (Aertal, Diclotol, Zerodol)

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Celecoxib (Celebrex, Revmoxib, Zitsel, Phlogoxib)

Rofecoxib (Denebol)

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The negative effect of NSAIDs on CVS

The negative effects of NSAIDs on kidney function

Conclusion

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