home Auditorium 8 Characteristics of individual drugs. Clinical pharmacology of non-steroidal anti-inflammatory drugs General characteristics of non-steroidal anti-inflammatory drugs

Characteristics of individual drugs. Clinical pharmacology of non-steroidal anti-inflammatory drugs General characteristics of non-steroidal anti-inflammatory drugs

Department of Clinical Pharmacology, Volgograd Medical Academy

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

Over the past 30 years, the number of NSAIDs has increased significantly and currently this group includes a large number of drugs that differ in chemical structure, features of action and application (Table 1).

Table 1.

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

I group - NSAIDs with pronounced anti-inflammatory activity .

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

Mechanism of action

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

Rice. 1.

PGs have 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 threshold of pain sensitivity;
3. increase the sensitivity of the hypothalamic thermoregulation centers 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 established that there are at least two cyclooxygenase isoenzymes that are inhibited by NSAIDs. The first isoenzyme - COX-1 (COX-1 - English) - controls the production of prostaglandins, regulating the integrity of the mucous membrane of the gastrointestinal tract, platelet function and renal blood flow, and the second isoenzyme - COX-2 - is involved in the synthesis of prostaglandins during inflammation. Moreover, COX-2 is absent under normal conditions, but is formed under the influence of certain 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 adverse reactions are due to inhibition of COX. The ratio of the activity of NSAIDs in terms of blocking COX-1/COX-2 allows us to judge their potential toxicity. The lower this value, the more selective the drug is for COX-2 and, thus, the less toxic. For example, for meloxicam it is 0.33, diclofenac - 2.2, tenoxicam - 15, piroxicam - 33, indomethacin - 107:

1. Pronounced 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 Nabumethon
5. Pronounced selectivity for COX-2
o Celecoxib
o Rofecoxib

Other mechanisms of action of NSAIDs

The anti-inflammatory effect may 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 (the energy supply of the inflammatory reaction is reduced), inhibition of neutrophil aggregation (the release of inflammatory mediators from them is impaired), inhibition of the production of rheumatoid factor in patients with rheumatoid arthritis. The analgesic effect is to a certain extent associated with disruption of the conduction of pain impulses in the spinal cord (metamizole).

Main effects

Anti-inflammatory effect

NSAIDs primarily suppress the exudation phase. The most powerful drugs - indomethacin, diclofenac, phenylbutazone - also act on the proliferation phase (reducing collagen synthesis and associated tissue sclerosis), but weaker than on the exudative phase. NSAIDs have virtually no effect on the alteration phase. In terms of anti-inflammatory activity, all NSAIDs are inferior to glucocorticoids, which, by inhibiting the enzyme phospholipase A2, 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 in pain of mild to moderate intensity, which is localized in the muscles, joints, tendons, nerve trunks, as well as in headaches or toothaches. For severe visceral pain, most NSAIDs are less effective and inferior in the analgesic effect to 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 for renal colic that occurs in patients with urolithiasis is largely due to 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-term 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 case of colic, it is also important that they do not have a spasmogenic effect.

Antipyretic effect

NSAIDs only work for fever. They do not affect normal body temperature, which is different from “hypothermic” drugs (chlorpromazine and others).

Anti-aggregation effect

As a result of inhibition of COX-1 in platelets, the synthesis of the endogenous proaggregant thromboxane is suppressed. Aspirin has the strongest and longest-lasting antiaggregation activity, which irreversibly suppresses the platelet’s ability to aggregate for the entire duration of its life (7 days). The antiaggregation effect of other NSAIDs is weaker and reversible. Selective COX-2 inhibitors do not affect platelet aggregation.

Immunosuppressive effect

It is expressed moderately, manifests itself with long-term use and has a “secondary” character: by reducing capillary permeability, NSAIDs impede the contact of immunocompetent cells with the antigen and the contact of antibodies with the substrate.

Pharmacokinetics

All NSAIDs are well absorbed from the gastrointestinal tract. 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 regard are salicylates and phenylbutazone. Most NSAIDs penetrate well into the synovial fluid of joints. NSAIDs are metabolized in the liver and excreted through the kidneys.

Drug interactions

Quite often, patients who receive NSAIDs are also prescribed other medications. In this case, it is necessary 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 aminoglycoside antibiotics, digoxin and some other drugs, which has significant clinical significance and entails a number of practical recommendations.

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

Many drugs prescribed concomitantly 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.

There is a large group of diseases, an important pathogenetic link of which is the effect of acidic gastric contents on the mucous membrane of the upper gastrointestinal tract (GIT). These are gastric ulcer and duodenal ulcer (DU); gastroesophageal reflux disease (GERD); ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs); chronic gastritis with non-ulcer dyspepsia; symptomatic ulcers in Zollinger-Ellison syndrome; peptic ulcers of gastroenteroanastomosis, etc. An imbalance between the factors of aggression of the gastric contents and the protective factors of the mucous membrane of the stomach and duodenum is a classic idea of the pathogenesis of peptic ulcer disease. The issues of rational pharmacotherapy of acid-dependent diseases of the upper gastrointestinal tract are among the most pressing due to their widespread prevalence, complex etiopathogenesis, and a large arsenal of drugs. Mostly people of working age suffer from this gastrointestinal pathology, which puts them in the category of not only medical, but also socially significant problems. However, the mechanisms of protection of the gastric mucosa prevent its damage. The most important protective factors are: protective mucous barrier; bicarbonate synthesis; synthesis of protective prostaglandins; state of regional blood flow; antroduodenal acid brake; epithelial regeneration.

Prostaglandins (PG) are of great importance in maintaining the basal level of bicarbonate secretion, and the participation of Helicobacter pylori has been shown in the mechanism of reducing their secretion. Aggressive factors that damage the mucous membrane include: hyperproduction of hydrochloric acid and pepsin; infection of the mucous membrane with H. pylori; the damaging effects of bile and pancreatic juice associated with impaired motility of these organs and the development of duodenogastric reflux. Long-term use of a number of medications is an important damaging factor for the mucous membrane of the stomach and duodenum. Thus, NSAIDs (acetylsalicylic acid, indomethacin, ketorolac, diclofenac, etc.) and glucocorticosteroids (GCS) contribute to the inhibition of protective factors: the former by suppressing the synthesis of prostaglandins, the latter by influencing the processes of microcirculation, regeneration and stimulation of the secretion of hydrochloric acid and pepsin. Thus, an urgent task of rational pharmacotherapy for patients suffering from gastrointestinal diseases is the possibility of stratifying the risk of developing complications when using drugs of the NSAID class together.

Non-steroidal anti-inflammatory drugs are among the most popular drugs and are of great importance for practical healthcare, as they are often used in everyday medical practice; many of these drugs are available without a prescription, that is, they are widely available to the population.

More than 30 million people in the world take NSAIDs daily, 40% of them are over 60 years of age. It is predicted that the number of such patients will increase as the population of developed countries ages and, accordingly, the prevalence of diseases for which NSAIDs are used increases. First of all, these are degenerative diseases of the musculoskeletal system and rheumatic lesions of soft tissues, which have not only medical, but also social significance, as it leads to long-term loss of ability to work and disability.

Pharmacodynamics of non-steroidal anti-inflammatory drugs

The widespread use of NSAIDs is explained by the universal spectrum of action of these drugs. They have anti-inflammatory, analgesic and antipyretic effects and bring relief to patients with the corresponding symptoms that are observed in many diseases. Due to their analgesic activity, NSAIDs constitute a group of non-narcotic (non-opiate) analgesics. Having started treatment with NSAIDs, patients with rheumatic diseases very rarely (no more than 10% of cases) switch to taking simple analgesics. In clinical medicine, a frequently occurring phenomenon is identified - pain, which can be varied in its manifestations and causes. It can occur as a protective biological reaction of the body. However, severe, intolerable or long-term pain forms foci of pathological excitation, enhancing functional and morphological changes in organs and musculoskeletal formations. Acute pain is a symptom, but chronic pain can essentially become a disease in its own right. Experts from different countries are unanimous in their opinion that the differences in the effectiveness of NSAIDs when used as painkillers and anti-inflammatory drugs are relatively small. Reviews of several dozen clinical studies of various drugs in this group for osteoarthritis, rheumatoid arthritis, and dorsopathy do not provide grounds to rank these drugs according to their degree of effectiveness.

The action of analgesics is aimed at preventing and reducing the activation of primary afferents and suppressing the transmission of pain impulses at the segmental and suprasegmental levels. A preventive approach to protecting the patient from the effects of surgical trauma is possible by prescribing NSAIDs before surgery. The mechanism of this effect is associated with the prevention of central hypersensitization of neurons in the dorsal horns of the spinal cord, the effect of NSAIDs on the peripheral and central mechanisms of the appearance and development of acute pain, thereby preventing pathological neuroplastic changes in the spinal cord. This eliminates the possibility of physiological pain turning into pathological (neuropathic). At the same time, NSAIDs can be considered as pathogenetic agents, which significantly expands and transforms the idea of drugs in this group not only as means of symptomatic therapy.

The areas of application of NSAIDs are varied. The main diseases for the treatment of which drugs in this group are used include the following:

rheumatic diseases: rheumatism (rheumatic fever), rheumatoid arthritis, gouty and psoriatic arthritis, ankylosing spondylitis (ankylosing spondylitis), Reiter's syndrome;
non-rheumatic diseases of the musculoskeletal system: osteoarthritis, myositis, tendo-vaginitis, trauma (domestic, sports);
neurological diseases (neuralgia, radiculitis, sciatica, lumbago);
renal, hepatic colic;
prevention of arterial thrombosis;
dysmenorrhea;
fever;
pain syndrome of various etiologies.

Currently, the arsenal of NSAIDs is quite wide. Drugs in this group are traditionally divided according to their chemical structure, but this classification does not reflect the properties of the various groups of NSAIDs. For their correct use in clinical practice, it is important to know the differences in the mechanism of action of certain NSAIDs and, accordingly, classify them according to this criterion.

Mechanism of action of non-steroidal anti-inflammatory drugs

In recent decades, significant progress has been made in studying the mechanism of action of NSAIDs. So, in the early 1970s. J.R. Wayne and a group of researchers showed that the analgesic, antipyretic and anti-inflammatory effects of acetylsalicylic acid are due to the suppression of PG synthesis. It has also been shown that the mechanism of action of NSAIDs is inhibition of cyclooxygenase (COX), due to which the production of PG is reduced. The complex set of reactions that make up the inflammatory process involves numerous biologically active substances that are mediators of inflammation. These include proteins and polypeptides (kinins and kallikreins), leukocyte factors (chemotaxis factors, interleukins, anti-keylons, etc.), proteins of the complement system; biogenic amines (histamine and serotonin) and products of arachidonic acid metabolism - eicosanoids (PG, prostacyclin, thromboxanes) and leukotrienes.

NSAIDs have a depressing effect on the formation and manifestation of the effects of many of the listed factors. However, the effect of drugs on the activity of proteins and biogenic amines is mainly attributed to secondary effects. According to modern concepts, the key and most general mechanism of the anti-inflammatory action of NSAIDs is the inhibition of PG biosynthesis from arachidonic acid. Back in the 1970s. a version was expressed about the existence of different types of COX. The synthesis of COX-1 is constitutive, that is, the enzyme is constantly expressed and functions in tissues and organs and is involved primarily in the regulation of physiological processes. The expression of COX-2 (the level of its activity under physiological conditions is very low) is induced by cytokines during tissue damage or inflammation, and the synthesis of phlogogenic PGs is associated with its activity.

The ability of NSAIDs to inhibit the synthesis of PGs involved in the development of the pathological process determines their anti-inflammatory, analgesic and antipyretic effects. Undesirable side effects of NSAIDs, such as erosions and ulcerative lesions of the gastrointestinal tract, gastric bleeding and renal dysfunction, also develop due to inhibition of the formation of eicosanoids - prostacyclin (PG I2), PG E2 and thromboxane A2. Thus, the ulcerogenic activity of NSAIDs is caused by a violation of the physiological functions of PG E2 and prostacyclin in the gastric mucosa. Both hormones perform a protective, gastroprotective function: they stimulate mucus production, inhibit the secretion of hydrochloric acid and improve tissue nutrition by dilating blood vessels and improving microcirculation. Thus, when taking NSAIDs, suppression of PG synthesis leads to the development of erosions of the mucous membrane and its ulcerative lesions.

At present, it is advisable to classify NSAIDs by their inhibitory activity against COX isoforms, or by their mechanism of action. According to a number of studies, most NSAIDs inhibit COX-1 and COX-2 equally. According to the selectivity of action in relation to the inhibition of both COX isoforms, selective and non-selective NSAIDs are distinguished. Non-selective ones suppress both isoenzymes to the same extent, selective ones - predominantly COX-2. A number of authors note that selective COX-2 inhibitors are less effective for pain associated with inflammatory lesions of the joints and spine than non-selective NSAIDs.

Inhibition of COX-2 is considered as one of the mechanisms of anti-inflammatory and analgesic activity of NSAIDs, and inhibition of COX-1 is considered as a mechanism for the development of adverse drug reactions.

It is obvious that non-selective COX inhibitors, such as ketorolac, have the highest analgesic activity. Selective COX-2 inhibitors provide comparable analgesia to that caused by traditional NSAIDs, but do not exceed them in analgesic activity. The ratio of the activity of NSAIDs according to the degree of blocking COX-1/COX-2 allows us to judge their potential toxicity: the lower this value, the more selective the drug is for COX-2 and, accordingly, the less toxic. For example, for nimesulide it is 0.22; for meloxicam - 0.33; diclofenac - 2.2; piroxicam - 33; indomethacin - 107. Studies have shown that after taking 100 mg of aceclofenac, COX-2 activity in human neutrophils is blocked by more than 97%, and COX-1 activity by 46%; when taking 75 mg of diclofenac, this ratio was 97 and 82%, respectively.

Classification of non-steroidal anti-inflammatory drugs

The classification of NSAIDs according to their mechanism of action is generally accepted.

Selective COX-1 inhibitors:
- acetylsalicylic acid in low doses (0.1-0.2 g per day).
- Non-selective inhibitors of COX-1 and COX-2:
acetylsalicylic acid in high doses (1.0-3.0 g per day or more); phenylbutazone; ibuprofen; ketoprofen; naproxen; niflumic acid; piroxicam; lornoxicam; diclofenac; aceclofenac; indomethacin and a number of other NSAIDs.
- Selective COX-2 inhibitors:
meloxicam; nimesulide.
- Highly selective COX-2 inhibitors:
celecoxib; etoricoxib.

acetaminophen; Metamizole sodium.

Currently, research into the selectivity of NSAIDs is ongoing.

Pharmacokinetics of non-steroidal anti-inflammatory drugs

An important characteristic that also affects the pharmacodynamics of drugs is the pharmacokinetics of NSAIDs.

When taken orally, all drugs in this group are well absorbed (up to 80-90% or more) in the upper intestines, but for individual drugs the rate of absorption and the time to reach maximum plasma concentrations may vary significantly.

Most NSAIDs are derivatives of 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%. High affinity for plasma proteins is the reason for the competitive displacement of drugs from other groups from their association with albumin. Metabolism of NSAIDs occurs mainly in the liver through glucuronidation. A number of drugs (diclofenac, aceclofenac, ibuprofen, piroxicam, celecoxib) are pre-hydroxylated with the participation of cytochrome P-450 (mainly CYP2C9 isoenzymes). Metabolites and residual amounts of the drug in unchanged form are excreted by the kidneys with urine and, to a lesser extent, by the liver with bile.

The T½ of the drug in plasma and at the site of inflammation (for example, in the joint cavity) is also different, in particular, for diclofenac they are 2-3 hours and 8 hours, respectively. That is why the duration of the anti-inflammatory effect does not always correlate with drug clearance from plasma.

Most NSAIDs, both selective and non-selective, are very active but relatively safe drugs due to their distribution and metabolism. They easily penetrate and accumulate in inflamed tissue, but are quickly cleared from the central compartment, including the blood, vascular wall, heart and kidneys, which reduces the possibility of developing adverse drug reactions (ADRs).

Side effects when using non-steroidal anti-inflammatory drugs

Despite the undoubted clinical effectiveness, the use of NSAIDs has its limitations. This is because even short-term use of these drugs in small doses can lead to the development of ADRs, which occur in approximately 25% of cases, and in 5% of patients can be seriously life-threatening. The risk of ADRs is especially high in elderly and senile people, who make up more than 60% of NSAID users.

A significant proportion of these patients have one, or more often several, concomitant diseases (arterial hypertension, diabetes mellitus, angina pectoris, etc.), which significantly increases the risk of complications.

It has now been shown that up to 50% of all atypical pharmacological responses - drug ineffectiveness or adverse drug reactions - can be associated with the genetic characteristics of patients, namely, with polymorphic regions of genes for proteins involved in the pharmacokinetics or pharmacodynamics of drugs, the so-called polymorphic markers or allelic variants. For NSAIDs, such a candidate gene is CYP2C9, which encodes the main enzyme for the biotransformation of NSAIDs in the liver. In this regard, in recent years, special attention has been drawn to the problem of the safe use of NSAIDs, while the main negative property of all drugs in this group is the high risk of developing adverse reactions from the gastrointestinal tract (Table).

30-40% of patients receiving NSAIDs experience dyspeptic disorders, 10-20% have erosions and ulcers of the stomach and duodenum, and 2-5% have bleeding and perforation.

Despite the identification of new contraindications and risks, traditional NSAIDs and selective COX-2 inhibitors remain the mainstays of treatment for pain, inflammation and fever. When assessing the safety of NSAIDs, it should be remembered that risk factors such as arterial hypertension, dyslipidemia, diabetes mellitus, smoking, and excess weight are more dangerous in terms of the development of complications than the use of drugs.

Nimesulide: safety of use

One of the most commonly used drugs from the NSAID group is nimesulide.

Nimesulide (Nise ®) is a selective inhibitor of COX-2, which determines the active anti-inflammatory and analgesic effect of the drug and, at the same time, its high safety.

Since the drug only slightly inhibits the activity of COX-1 and has little effect on the formation of PG under physiological conditions, the risk of side effects is reduced. Unlike most COX-2-selective agents, nimesulide has a powerful antipyretic effect. Antihistamine, antibradykinin and chondroprotective effects of nimesulide are also noted.

The drug is completely and fairly quickly absorbed from the gastrointestinal tract, the maximum concentration in the blood plasma is achieved 1.5-2.5 hours after administration. Subject to first pass effect through the liver. Plasma protein binding is 95-99%. Penetrates well into the acidic environment of the inflammation site (the concentration is 40% of the plasma concentration), synovial fluid (43%). Easily penetrates histohematic barriers. Nimesulide is actively metabolized in the liver, the main metabolite - 4-hydroxynimesulide (25% of the dose taken) - has similar pharmacological activity, is excreted by the kidneys (65%) and the liver with bile (35%). T½ is 1.5-5 hours.

Indications for the use of nimesulide are: rheumatoid arthritis, arthritis with rheumatism and exacerbation of gout, psoriatic arthritis, ankylosing spondylitis, osteochondrosis with radicular syndrome, radiculitis, sciatic nerve neuritis, lumbago, osteoarthritis, tendovaginitis, bursitis, post-traumatic inflammation of soft tissues and the musculoskeletal system (damage and rupture of ligaments, bruises).

Table. Side effects observed when taking non-steroidal anti-inflammatory drugs

Organ or organ system	Side effects	Frequency of occurrence, %
Gastrointestinal tract	Nausea, vomiting, diarrhea, constipation; erosions and peptic ulcers of the stomach and duodenum; esophagitis; strictures	10–50
Gastrointestinal tract	Gastrointestinal bleeding; small intestinal erosions	1–5
Liver	Toxic liver damage, hepatitis, liver failure	1–5
The cardiovascular system	Increased blood pressure, fluid retention and increased circulating blood volume	1–5
Kidneys	Nephropathy, impaired glomerular filtration and tubular function, fluid retention in the body, edema, decreased sodium excretion under the influence of diuretics, interstitial nephritis	1–5
Blood	Anemia; inhibition of hematopoiesis in the bone marrow - leukopenia and agranulocytosis; platelet aggregation disorder	<1
Respiratory system	Exacerbation of bronchial asthma in patients with rhinitis, nasal polyps and urticaria (Vidal syndrome)	<1
central nervous system	Headache, confusion, hallucinations, depression, tremor, tinnitus, dizziness, toxic amblyopia	1–5
central nervous system	Aseptic meningitis	0,01
The immune system	Hypersensitivity: urticaria, skin rash, itching, pneumonitis	<1
Other organs	Ototoxicity, stomatitis, vasculitis, infertility, cartilage damage	<1

Nimesulide is effective for osteochondrosis, osteoarthrosis, pain syndrome of various origins, including pain in the postoperative period, injuries, arthralgia, myalgia, algodismenorrhea, toothache and headache; fever of various origins, including infectious and inflammatory diseases.

Nimesulide is prescribed orally for adults at a dose of 0.1 g 2 times a day, the maximum daily dose is 0.2 g. For external use, the drug is produced in the form of a gel, applied in a thin layer, 3-4 times a day.

Of the undesirable effects, nimesulide can cause dyspeptic disorders, rarely - erosive and ulcerative lesions of the gastrointestinal mucosa, increased activity of liver transaminases, headache, dizziness, thrombocytopenia, leukopenia, allergic reactions. An analysis of the risk of developing gastrointestinal bleeding while taking NSAIDs in a large-scale clinical and epidemiological study showed that out of 2813 (the control group included 7193 patients) episodes of this complication, nimesulide was one of the safest. The relative risk of bleeding for nimesulide was 3.2, diclofenac - 3.7, meloxicam - 5.7, rofecoxib - 7.2. Nimesulide has been actively studied in Russia. A review of Russian clinical studies that determined the comparative effectiveness and safety of this drug for the period from 1995 to 2009 included 21 studies (1590 patients) in which nimesulide was prescribed at a dose of 200 to 400 mg / day for a period of 7 days to 12 months.

The drug showed reliably significant safety: no dangerous gastrointestinal complications such as bleeding or ulcer perforation were identified. Gastric and duodenal ulcers were detected in 13.3% of the examined patients, which is approximately 1/3 less than with the use of classical non-selective NSAIDs.

An important issue in the safe use of nimesulide is the assessment of its effect on liver function. On average, serious hepatotoxic complications, manifested by clinically pronounced cholestatic and cytolytic syndromes or acute liver failure, occur during regular use of NSAIDs in approximately 1 in 10 thousand patients. Over the past 5 years, discussion of the problem of hepatotoxicity of nimesulide has been under special control, in particular, by European regulatory authorities. At present, a compromise decision has been made to recommend the use of nimesulide in the European Union with a course prescription for an average period of up to 15 days and at a dose not exceeding 200 mg/day; further use of the drug is determined by the attending physician individually. Overall, the final EMEA (European Medicines Agency) opinion on nimesulide highlights the positive safety profile of nimesulide. It is promising to develop and maintain a pharmacovigilance system in our country for a reliable assessment of all serious ADRs associated with the use of NSAIDs, including the effect of nimesulide on the functional state of the liver. Currently, an analysis of the available literature data on the Russian Federation shows that the hepatotoxicity of nimesulide does not differ from other representatives of the NSAID class. At the same time, nimesulide has a positive pharmacoeconomic profile, which makes it available to all patients in need.

Conclusion

Thus, rational pharmacotherapy of patients with comorbid pathology, suffering from both gastrointestinal diseases and pathology of the musculoskeletal system, symptomatic therapy of pain and inflammatory syndrome should be carried out taking into account a personalized approach to the patient and a rational choice of medications.

This is most clearly manifested when taking NSAIDs, glucocorticosteroids, benzodiazepines, antibiotics (ciprofloxacin, tetracycline, metronidazole, nitrofurantoin), anti-tuberculosis drugs (isoniazid), theophylline, digoxin, quinidine, warfarin, phenytoin, iron sulfate, etc. Study of drugs of the NSAID class, taking into account their main pharmacokinetic, pharmacodynamic properties, clinical effectiveness and safety help to improve the prognosis of the disease, the patient’s quality of life, and increase the patient’s adherence to therapy.

One of the most studied drugs of the NSAID class, which has a positive pharmacoeconomic profile with a fairly high level of effectiveness and safety, is nimesulide (Nise ®). To increase the effectiveness of treatment, it is recommended to use NSAIDs in the lowest effective doses and, if possible, for the shortest course. The use of drugs based on the principles of evidence-based medicine, a comprehensive assessment of drug interactions, as well as a comprehensive assessment of ADR risk factors are the basis for increasing the effectiveness and safety of complex pharmacotherapy using NSAIDs.

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Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of medications that are widely used in clinical practice, many of which can be purchased without a prescription. More than thirty million people worldwide take NSAIDs daily, with 40% of these patients 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 corresponding symptoms (inflammation, pain, fever), which are observed in many diseases.

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

NSAIDs are classified depending on the severity of their 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 similar in chemical structure differ somewhat in both the strength of the effect and the frequency of development and nature of adverse reactions. Thus, among 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 effectiveness of the drug may depend on the type and characteristics of the disease in a particular patient, as well as on his individual reaction.

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

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

hyperemia, fever, pain, swelling

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 his father, who suffered from severe rheumatism) with a more acceptable taste than the extremely bitter extract of willow bark.

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

There are currently more than 80 non-steroidal anti-inflammatory drugs

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

Every year, more than 300 million people worldwide take NSAIDs, of which 200 million purchase the drugs without a prescription.

30 million people are forced to take them constantly.

1 . Classification

A)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

Ibuprufen

Naproxen

Flurbiprofen

Ketoprofen

Tiaprofenic acid

Non-acid derivatives

Alcanons

Nabumethon

Sulfonamide derivatives

Nimesulide

Celecoxib

Rofecoxib

NSAIDs with weak anti-inflammatory activity

Anthranilic acid derivatives

Mefenamic acid

Etofenamate

Pyrazolones

Metamizole

Aminophenazone

Propyphenazone

Para-aminophenol 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

Nabumethon

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 predominantly in the central nervous system

Paracetamol

2. Pharmacodynamics

Mechanism of action

Rice. 1. Metabolism of arachidonic acid

PGs have versatile biological activity:

a) are mediators of the inflammatory response: 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 effects, lowering the threshold of pain sensitivity;

V) increase the sensitivity of hypothalamic thermoregulation centers 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 established that there are at least two cyclooxygenase isoenzymes that are inhibited by NSAIDs. The first isoenzyme - COX-1 (COX-1 - English) - controls the production of prostaglandins, regulating the integrity of the mucous membrane of the gastrointestinal tract, platelet function and renal blood flow, and the second isoenzyme - COX-2 - is involved in the synthesis of prostaglandins during inflammation. Moreover, COX-2 is absent under normal conditions, but is formed under the influence of certain 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 according to selectivity for various forms of cyclooxygenase is presented in Table 2. The ratio of the activity of NSAIDs in terms of blocking COX-1/COX- 2 allows us to judge their potential toxicity. The lower this value, the more selective the drug is for COX-2 and, thus, the less toxic. For example, for meloxicam it is 0.33, diclofenac - 2.2, tenoxicam - 15, piroxicam - 33, indomethacin - 107.

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

Other mechanisms of action of NSAIDs

The main mechanism of action of NSAIDs deciphered in 1971 G . Wayne, Smith.

At the core- inhibitory effect on the biosynthesis of prostaglandins.

NSAIDs cause

Block or

Inhibition of the transition of cyclooxygenase to the active enzyme.

As a resulteducation is sharply decreasing pro-inflammatory PGs types E andF.

Inflammation.

1) Main components of inflammation

Alteration,

Hyperemia,

Exudation

Proliferation.

The combination of these phenomena underlies local signs inflammation:

Redness,

Temperature increase,

Impaired function.

As a result of the generalization of the process, along with local changes,are common

Intoxication,

Fever,

Leukocytosis,

Immune system response.

2) According to the nature of the course, inflammation can besharp And chronic .

Acute inflammation lasts from several days to several weeks.

It is characterized by:

Vivid signs of inflammation and

The predominance of either alteration or vascular-exudative phenomena.

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

Prevail:

Dystrophic and

Proliferative phenomena.

During inflammation under the influence of various damaging factors

(microbes, their toxins, lysosome enzymes, hormones)

turns on "cascade" of arachidonic acid

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

1) phospholipase A is activated 2 ,

which releases arachidonic acid from cell membrane phospholipids.

Arachidonic acid is a precursor of prostaglandins (PGs) - mediators of inflammation.

2 ) Pgrowth glandins

at the site of inflammation take part in the development

Vasodilation,

Hyperemia,

Fevers.

3 ) ARachidonic acid is involved in the metabolic process:

cyclooxygenase and lipoxygenase.

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

Cyclic endoperoxides 1

Prostaglandins 2

Prostacyclins

Thromboxanes 3

With the participation of lipoxygenase

Arachidonic acid is converted into 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 addition of an oxygen molecule to an arachidonic acid molecule to form PGG2

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

The synthesis of endoperoxides, prostaglandins and leukotrienes is accompanied by

the appearance of oxygen free radicals, promoting

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 mediators of inflammation and pain (histamine, serotonin, bradykinin)

Dilate arterioles

Increases capillary permeability

Participate in the development of edema and hyperemia

Participate in microcirculation disorders

Participate in the formation of pain sensations

ProstaglandinsF 2 and thromboxane A 2

Causes narrowing of venules

Thromboxane A 2

Promotes the formation of blood clots, aggravating microcirculation disorders

Prostaglandin receptors located

-nand cell membranes in peripheral tissues

-nand the endings of sensory nerves

-VCNS

Most prostaglandin receptors perform an activating function.

Increased formation of prostaglandins in the central nervous system (local) facilitates the conduction of pain impulses, leads to hyperalgesisand an increase in body temperature.

3. Pharmacokinetics

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

The pharmacokinetics of NSAIDs is a very important characteristic of them, since it also affects the pharmacodynamics of the 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 administered by injection, but a large number of them are available in the form of solutions for intramuscular administration, and a number of drugs are also available for intravenous administration (acetylsalicylic acid, paracetamol, ketorolac, ketoprofen, lornoxicam). But the most common and simplest route of administration, usually acceptable to the patient, is oral administration. All NSAIDs can be used enterally - in capsules, pills or tablets. When taken orally, all drugs in this group are well (up to 80-90% or more) absorbed in the upper intestine, however, the rate of absorption and the time to reach maximum plasma concentrations may vary significantly for individual drugs. Most NSAIDs are derivatives of 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%), accumulate more actively in inflamed tissue, in the gastric mucosa and in its lumen, in the liver, and in the cortex 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 nature of pharmacokinetics plays an important role in the manifestation of not only anti-inflammatory, but also undesirable side effects of NSAIDs. High affinity for plasma proteins is the reason for the competitive displacement of drugs from other groups from binding with albumin (see section “Interaction of NSAIDs with other drugs”). When the level of albumin in the blood decreases, the free (unbound) fraction of NSAIDs increases, which can lead to increased effects of NSAIDs, even toxic ones. 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 inflamed tissue, but create a fairly high concentration in the central nervous system, and they do not cause side effects in the gastrointestinal tract or cause them extremely rarely (Brune K, Rainsford KD, Schweitzer A., 1980; Hinz B, Renner B , Brune K, 2007). Pyrazolones create relatively high concentrations in the bone marrow, skin and oral mucosa. The time to achieve stable plasma concentrations of NSAIDs with chronic use is usually 3-5 half-lives.

NSAIDs are actively metabolized in the body, only small amounts of drugs are excreted unchanged. Metabolism of NSAIDs occurs mainly in the liver through 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, by the liver with bile (Vengerovsky A.I., 2006). The half-life (T 50) of different NSAIDs can vary significantly, from 1-2 hours for ibuprofen to 35-45 hours for piroxicam. The half-life of the drug in plasma and in the site 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 drug clearance from plasma.

A number of NSAIDs are over-the-counter drugs not only in Russia, but also abroad. The free release of such drugs is based on the pharmacodynamics (predominant, but not selective inhibition of COX-2) and, more importantly, 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 at the same time relatively safe drugs due to the characteristics of their distribution and metabolism. These features consist in 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 over-the-counter use 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 plasma concentrations of NSAIDs when applied topically range from 5 to 15% of the values achieved with systemic administration (Heyneman CA, Lawless-Liday C, Wall GC, 2000), but at the site of application (in the area of inflammation) a fairly high concentration. A number of studies confirm the high effectiveness of NSAIDs when used externally 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, when NSAIDs are administered topically, relatively high drug concentrations are created in the dermis, while in muscle these concentrations are equivalent to the levels achieved with systemic administration (Heyneman CA, Lawless-Liday C, Wall GC, 2000). When applied to the skin in the joint area, NSAIDs reach the synovial fluid, but it remains unclear whether this is an effect of local penetration of the drug or a consequence of its entry into the systemic circulation. (Vaile JH, Davis P, 1998) In osteoarthritis and rheumatoid arthritis, topical use of NSAIDs produces a very variable (efficacy ranges from 18 to 92%, Heyneman CA, Lawless-Liday C, Wall GC, 2000), but generally quite moderate effect. This scatter may 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 only provide symptomatic effect without 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 deformation. 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. For large collagenoses (systemic lupus erythematosus, scleroderma and others), NSAIDs are often ineffective.

2. Non-rheumatic diseases of the musculoskeletal system

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

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

4. Renal, hepatic colic.

5. Pain syndrome of various etiologies, including headaches, toothaches, and postoperative pain.

6. Fever(usually at body temperature above 38.5°C).

7. Prevention of arterial thrombosis.

8. Dysmenorrhea.

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

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

4.2. CONTRAINDICATIONS

NSAIDs are contraindicated for erosive and ulcerative lesions of the gastrointestinal tract, especially in the acute stage, severe liver and kidney dysfunction, cytopenias, individual intolerance, and pregnancy. If necessary, the safest (but not before childbirth!) are small doses of aspirin (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 experienced adverse reactions when taking any other NSAIDs.

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

In elderly people, it is necessary to strive to prescribe 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. 30-40% of patients receiving NSAIDs experience dyspeptic disorders, 10-20% have erosions and ulcers of the stomach and duodenum, and 2-5% have bleeding and perforation (4).

Currently, a specific syndrome has been identified - NSAID-gastroduodenopathy(5). It is only partly associated with the local damaging effect of NSAIDs (most of them are organic acids) on the mucous membrane and is mainly due to inhibition of the COX-1 isoenzyme as a result of the systemic action of the drugs. Therefore, gastrotoxicity can occur with any route of administration of NSAIDs.

Damage to the gastric mucosa occurs in 3 stages:

1) inhibition of prostaglandin synthesis in the mucosa;

2) reduction of prostaglandin-mediated production of protective mucus and bicarbonates;

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

The damage is most often localized in the stomach, mainly in the antrum or prepyloric region. Clinical symptoms of NSAID gastroduodenopathy are absent in almost 60% of patients, especially the elderly, so the diagnosis in many cases is made by 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 the drugs. Therefore, patients, especially the elderly, who do not experience adverse events from the gastrointestinal tract with long-term use of NSAIDs, are considered to be at increased risk of developing serious complications of NSAID-gastroduodenopathy (bleeding, severe anemia) and require particularly careful monitoring, including endoscopic study (1).

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

Methods for improving the tolerability of NSAIDs.

I. Simultaneous administration of drugs, protecting the mucous membrane of the gastrointestinal tract.

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

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

+ preventive effect

0 lack of preventive effect

The effect is not specified

* According to the latest data, famotidine is effective in high doses

The proton pump inhibitor omeprazole has approximately the same effectiveness as misoprostol, but is better tolerated and quickly eliminates reflux, pain and digestive disorders.

H 2 blockers can prevent the formation of duodenal ulcers, but are generally ineffective against gastric 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.

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

The cytoprotective drug sucralfate does not reduce the risk of developing gastric ulcers; its effect on duodenal ulcers has not been fully determined.

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

III. 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 that 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 nabumethon. Controlled studies conducted in patients with rheumatoid arthritis and osteoarthritis have shown that they are better tolerated than diclofenac, piroxicam, ibuprofen and naproxen, but are not inferior in effectiveness (6).

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

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

Kidneys

Nephrotoxicity is the second most important group of adverse reactions of NSAIDs. Two main mechanisms for the negative effects 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 deterioration 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, increased serum creatinine levels, increased blood pressure.

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

II. NSAIDs may have a direct effect on the renal parenchyma, causing interstitial nephritis (so-called “analgesic nephropathy”). The most dangerous in this regard is phenacetin. Serious kidney damage may occur, including 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 has been 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 serious complications when using them 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, most often from the gastrointestinal tract.

Hepatotoxicity

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

Hypersensitivity reactions (allergy)

Rash, Quincke's edema, anaphylactic shock, Lyell's and Stevens-Johnson syndromes, allergic interstitial nephritis. Skin manifestations are more common 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.

Prolonging pregnancy and slowing labor

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

5 . Pdosage and prescription rules

Individualization of drug choice.

For each patient, the most effective drug with the best tolerability should be selected. Moreover, this could be any NSAID, but as an anti-inflammatory drug 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 drug does not indicate the ineffectiveness of the group as a whole.

When using NSAIDs in rheumatology, especially when replacing one drug with another, it must be taken into account that the development of the anti-inflammatory effect lags behind the analgesic effect. The latter is noted in the first hours, while the anti-inflammatory effect is observed after 10-14 days of regular use, and when naproxen or oxicams are prescribed even later - at 2-4 weeks.

Dosage.

Any drug new to a given patient must be prescribed first. V lowest dose. If well tolerated, the daily dose is increased after 2-3 days. Therapeutic doses of NSAIDs are in a wide range, and in recent years there has been a tendency to increase 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.

For long-term course prescriptions (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, with 1/2-1 glass of water. After taking it, it is advisable not to lie down for 15 minutes in order to prevent the development of esophagitis.

The moment 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 regimens (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.

In case of 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. Naproxen sodium, diclofenac potassium, water-soluble (“effervescent”) aspirin, and ketoprofen have the greatest absorption rate in the gastrointestinal tract and, therefore, a faster onset of effect.

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 NSAID to enhance the analgesic effect.

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

Conclusion

Anti-inflammatory drugs are drugs 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 nonsteroidal anti-inflammatory drugs (NSAIDs) and steroidal anti-inflammatory drugs. NSAIDs are the most commonly used. 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, which the doctor should remember when prescribing them and the nurse when monitoring the patient. And also a large role in the conduct of pharmacotherapy with non-steroidal anti-inflammatory drugs is given to the nurse, who should:

1 Strictly follow the doctor’s instructions.

2 Check with patients allergy history, because allergic reactions to NSAIDs are not uncommon.

3 For young women, check the possibility of pregnancy, because NSAIDs may adversely affect the fetus.

4 Teach the patient the rules for taking NSAIDs (take after meals with enough water), monitor compliance.

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

6 In an outpatient setting, the nurse should teach the patient to monitor for possible side effects.

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

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

Bibliography

non-steroidal anti-inflammatory drug dosage

2) http://www.antibiotic.ru

3) Kharkevich D.A. "Pharmacology" 2005

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

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

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

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

Mechanism of action

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

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

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

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

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

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

Clinical Application

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

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