What are NSAIDs. Non-steroidal anti-inflammatory drugs for the treatment of joints: classification, list

Inflammation is one of the pathological processes characterizing numerous diseases. From a general biological point of view, this is a protective and adaptive reaction, however, in clinical practice, inflammation is always considered as a pathological symptom complex.

Anti-inflammatory drugs are a group of drugs used to treat diseases that are based on the inflammatory process. Depending on the chemical structure and features of the mechanism of action, anti-inflammatory drugs are divided into the following groups:

Steroid anti-inflammatory drugs - glucocorticoids;

Basic, slow-acting anti-inflammatory drugs.

This chapter will also review the clinical pharmacology of paracetamol. This drug is not classified as an anti-inflammatory drug, but it has analgesic and antipyretic effects.

25.1. NON-STEROID ANTI-INFLAMMATORY DRUGS

According to the chemical structure, NSAIDs are derivatives of weak organic acids. These drugs, respectively, have similar pharmacological effects.

The classification of modern NSAIDs according to the chemical structure is presented in Table. 25-1.

However, the classification of NSAIDs based on their selectivity for COX isoforms, presented in Table 1, is of clinical importance. 25-2.

The main pharmacological effects of NSAIDs include:

Anti-inflammatory effect;

Anesthetic (analgesic) effect;

Antipyretic (antipyretic) effect.

Table 25-1. Classification of non-steroidal anti-inflammatory drugs by chemical structure

Table 25-2. Classification of non-steroidal anti-inflammatory drugs based on selectivity for cyclooxygenase-1 and cyclooxygenase-2

A key element in the mechanism of the pharmacological effects of NSAIDs is the inhibition of prostaglandin synthesis, due to the inhibition of the COX enzyme, the main enzyme in the metabolism of arachidonic acid.

In 1971, a group of researchers from the UK, led by J. Vane, discovered the main mechanism of action of NSAIDs associated with the inhibition of COX, a key enzyme in the metabolism of arachidonic acid, a precursor of prostaglandins. In the same year, they also put forward a hypothesis that it is the antiprostaglandin activity of NSAIDs that underlies their anti-inflammatory, antipyretic and analgesic effects. At the same time, it became obvious that, since prostaglandins play an extremely important role in the physiological regulation of the gastrointestinal tract and renal circulation, the development of the pathology of these organs is a characteristic side effect that occurs during the treatment of NSAIDs.

In the early 90s, new facts appeared that made it possible to consider prostaglandins as central mediators of the most important processes occurring in the human body: embryogenesis, ovulation and pregnancy, bone metabolism, growth and development of cells of the nervous system, tissue repair, kidney and gastrointestinal function, tone blood vessels and blood coagulation, immune response and inflammation, cell apoptosis, etc. The existence of two isoforms of COX was discovered: a structural isoenzyme (COX-1), which regulates the production of prostaglandins involved in the normal (physiological) functional activity of cells, and an inducible isoenzyme (COX -2), whose expression is regulated by immune mediators (cytokines) involved in the development of the immune response and inflammation.

Finally, in 1994, a hypothesis was formulated according to which the anti-inflammatory, analgesic and antipyretic effects of NSAIDs are associated with their ability to inhibit COX-2, while the most common side effects (damage to the gastrointestinal tract, kidneys, impaired platelet aggregation) are associated with suppression of COX-1 activity.

Arachidonic acid, formed from membrane phospholipids under the influence of the enzyme phospholipase A 2, on the one hand, is a source of inflammatory mediators (pro-inflammatory prostaglandins and leukotrienes), and on the other hand, a number of biologically active substances involved in the physiological processes of the body (prostacyclin, thromboxane A) are synthesized from it. 2, gastroprotective and vasodilating prostaglandins, etc.). Thus, the metabolism of arachidonic acid is carried out in two ways (Fig. 25-1):

Cyclooxygenase pathway, as a result of which prostaglandins, including prostacyclin and thromboxane A 2, are formed from arachidonic acid under the influence of cyclooxygenase;

lipoxygenase pathway, as a result of which leukotrienes are formed from arachidonic acid under the influence of lipoxygenase.

Prostaglandins are the main mediators of inflammation. They cause the following biological effects:

Sensitize nociceptors to pain mediators (histamine, bradykinin) and lower the pain threshold;

Increase the sensitivity of the vascular wall to other mediators of inflammation (histamine, serotonin), causing local vasodilation (redness), an increase in vascular permeability (edema);

They increase the sensitivity of the hypothalamic centers of thermoregulation to the action of secondary pyrogens (IL-1, etc.), formed under the influence of microorganisms (bacteria, viruses, fungi, protozoa) and their toxins.

Thus, the generally accepted concept of the mechanism of the analgesic, antipyretic and anti-inflammatory effects of NSAIDs is based on the inhibition of the synthesis of pro-inflammatory prostaglandins by inhibiting cyclooxygenase.

The existence of at least two cyclooxygenase isoenzymes, COX-1 and COX-2, has been established (Table 25-3). COX-1 is an isoform of cyclooxygenase that is expressed under normal conditions and is responsible for the synthesis of prostanoids (prostaglandins, prostacyclin, thromboxane A 2) involved in the regulation of the physiological functions of the body (gastroprotection, platelet aggregation, renal blood flow, uterine tone, spermatogenesis, etc.) . COX-2 is an induced isoform of cyclooxygenase involved in the synthesis of pro-inflammatory prostaglandins. Expression of the COX-2 gene is stimulated in migrating and other cells by inflammatory mediators - cytokines. Analgesic, antipyretic and anti-inflammatory effects of NSAIDs are due to COX-2 inhibition, while adverse drug reactions (ulcerogenicity, hemorrhagic syndrome, bronchospasm, tocolytic effect) are due to COX-1 inhibition.

Table 25-3. Comparative characteristics of cyclooxygenase-1 and cyclooxygenase-2 (according to D. De Witt et al., 1993)

It was found that the three-dimensional structures of COX-1 and COX-2 are similar, but still note "small" differences (Table 25-3). Thus, COX-2 has "hydrophilic" and "hydrophobic" pockets (channels), in contrast to COX-1, which has only a "hydrophobic" pocket in its structure. This fact made it possible to develop a number of drugs that highly selectively inhibit COX-2 (see Table 25-2). The molecules of these drugs have such a structure

the tour that their hydrophilic part they bind to the "hydrophilic" pocket, and the hydrophobic part - to the "hydrophobic" pocket of cyclooxygenase. Thus, they are able to bind only to COX-2, which has both a “hydrophilic” and a “hydrophobic” pocket, while most other NSAIDs, interacting only with a “hydrophobic” pocket, bind both to COX-2 and to COX-1.

It is known about the existence of other mechanisms of anti-inflammatory action of NSAIDs:

It has been established that the anionic properties of NSAIDs allow them to penetrate into the bilayer of phospholipid membranes of immunocompetent cells and directly influence the interaction of proteins, preventing cellular activation in the early stages of inflammation;

NSAIDs increase the level of intracellular calcium in T-lymphocytes, which increases the proliferation and synthesis of IL-2;

NSAIDs interrupt neutrophil activation at the G-protein level. According to the anti-inflammatory activity of NSAIDs, it is possible to arrange

in the following order: indomethacin - flurbiprofen - diclofenac - piroxicam - ketoprofen - naproxen - phenylbutazone - ibuprofen - metamizole - acetylsalicylic acid.

A greater analgesic than anti-inflammatory effect is possessed by those NSAIDs that, due to their chemical structure, are neutral, accumulate less in inflammatory tissue, penetrate the BBB more quickly and suppress COX in the central nervous system, and also affect the thalamic centers of pain sensitivity. Noting the central analgesic effect of NSAIDs, one cannot exclude their peripheral action associated with the anti-exudative effect, which reduces the accumulation of pain mediators and mechanical pressure on pain receptors in tissues.

The antiplatelet effect of NSAIDs is due to blocking the synthesis of thromboxane A 2 . So, acetylsalicylic acid irreversibly inhibits COX-1 in platelets. When taking a single dose of the drug, a clinically significant decrease in platelet aggregation in a patient is observed for 48 hours or more, which significantly exceeds the time of its removal from the body. Restoration of aggregation ability after irreversible inhibition of COX-1 by acetylsalicylic acid occurs, apparently, due to the appearance of new populations of platelets in the bloodstream. However, most NSAIDs reversibly inhibit COX-1, and therefore, as their concentration in the blood decreases, restoration of the aggregation ability of platelets circulating in the vascular bed is observed.

NSAIDs have a moderate desensitizing effect associated with the following mechanisms:

Inhibition of prostaglandins in the focus of inflammation and leukocytes, which leads to a decrease in monocyte chemotaxis;

Decrease in the formation of hydroheptanotrienoic acid (reduces the chemotaxis of T-lymphocytes, eosinophils and polymorphonuclear leukocytes in the focus of inflammation);

Inhibition of blast transformation (division) of lymphocytes due to blockade of the formation of prostaglandins.

The most pronounced desensitizing effect of indomethacin, mefenamic acid, diclofenac and acetylsalicylic acid.

Pharmacokinetics

A common property of NSAIDs is a fairly high absorption and oral bioavailability (Table 25-4). Only acetylsalicylic acid and diclofenac have a bioavailability of 30-70%, despite the high degree of absorption.

The elimination half-life for most NSAIDs is 2-4 hours. However, long-term circulating drugs such as phenylbutazone and piroxicam can be given 1-2 times a day. All NSAIDs, with the exception of acetylsalicylic acid, are characterized by a high degree of binding to plasma proteins (90-99%), which, when interacting with other drugs, can lead to a change in the concentration of their free fractions in blood plasma.

NSAIDs are metabolized, as a rule, in the liver, their metabolites are excreted by the kidneys. Metabolic products of NSAIDs usually do not have pharmacological activity.

The pharmacokinetics of NSAIDs is described as a two-chamber model, where one of the chambers is tissue and synovial fluid. The therapeutic effect of drugs in articular syndromes is to some extent associated with the rate of accumulation and the concentration of NSAIDs in the synovial fluid, which increases gradually and persists much longer than in the blood after discontinuation of the drug. However, there is no direct correlation between their concentration in the blood and synovial fluid.

Some NSAIDs (indomethacin, ibuprofen, naproxen) are eliminated from the body by 10-20% unchanged, and therefore the state of the excretory function of the kidneys can significantly change their concentration and the final clinical effect. The rate of elimination of NSAIDs depends on the size of the administered dose and the pH of the urine. Since many of the drugs in this group are weak organic acids, they are more rapidly excreted in alkaline urine than in acidic urine.

Table 25-4. Pharmacokinetics of some non-steroidal anti-inflammatory drugs

Indications for use

As a pathogenetic therapy, NSAIDs are prescribed for inflammation syndrome (soft tissues, musculoskeletal system, after operations and injuries, rheumatism, non-specific lesions of the myocardium, lungs, parenchymal organs, primary dysmenorrhea, adnexitis, proctitis, etc.). NSAIDs are also widely used in the symptomatic treatment of pain syndrome of various origins, as well as in febrile conditions.

A significant limitation in the choice of NSAIDs is complications from the gastrointestinal tract. In this regard, all side effects of NSAIDs are conventionally divided into several main categories:

Symptomatic (dyspepsia): nausea, vomiting, diarrhea, constipation, heartburn, pain in the epigastric region;

NSAID-gastropathy: subepithelial hemorrhages, erosions and ulcers of the stomach (less often - duodenal ulcers), detected during endoscopic examination, and gastrointestinal bleeding;

NSAID enteropathy.

Symptomatic side effects are noted in 30-40% of patients, more often with long-term use of NSAIDs. In 5-15% of cases, side effects are the reason for discontinuation of treatment within the first 6 months. Meanwhile, dyspepsia, according to endoscopic examination, is not accompanied by erosive and ulcerative changes in the gastrointestinal mucosa. In cases of their appearance (without special clinical manifestations), mainly with a widespread erosive-ulcerative process, the risk of bleeding increases.

According to an analysis by the FDA, NSAID-associated gastrointestinal injury is responsible for 100,000-200,000 hospital admissions and 10,000-20,000 deaths each year.

The basis of the mechanism for the development of NSAID gastropathy is the inhibition of the activity of the COX enzyme, which has two isomers - COX-1 and COX-2. Inhibition of COX-1 activity leads to a decrease in the synthesis of prostaglandins in the gastric mucosa. The experiment showed that exogenously administered prostaglandins increase the resistance of the mucous membrane to such damaging agents as ethanol, bile acids, acid and salt solutions, as well as NSAIDs. Therefore, the function of prostaglandins in relation to the gastroduodenal mucosa is protective, providing:

Stimulation of the secretion of protective bicarbonates and mucus;

Strengthening the local blood flow of the mucous membrane;

Activation of cell proliferation in the processes of normal regeneration.

Erosive and ulcerative lesions of the stomach are observed both with the parenteral use of NSAIDs and with their use in suppositories. This once again confirms the systemic inhibition of prostaglandin production.

Thus, a decrease in the synthesis of prostaglandins, and consequently, the protective reserves of the mucous membrane of the stomach and duodenum, is the main cause of NSAID gastropathy.

Another explanation is based on the fact that already a short time after the administration of NSAIDs, an increase in the permeability of the mucous membrane for hydrogen and sodium ions is observed. It is suggested that NSAIDs (directly or through pro-inflammatory cytokines) can induce apoptosis of epithelial cells. Evidence is provided by enteric-coated NSAIDs, which cause changes in the gastric mucosa much less frequently and less significantly in the first weeks of treatment. However, with their long-term use, it is still likely that the resulting systemic suppression of prostaglandin synthesis contributes to the appearance of gastric erosions and ulcers.

Significance of infection H. pylori as a risk factor for the development of erosive and ulcerative lesions of the stomach and duodenum in most foreign clinical studies is not confirmed. The presence of this infection is associated primarily with a significant increase in the number of duodenal ulcers and only a slight increase in ulcers localized in the stomach.

The frequent occurrence of such erosive and ulcerative lesions depends on the presence of the following risk factors [Nasonov E.L., 1999].

Absolute risk factors:

Age over 65;

Pathology of the gastrointestinal tract in history (especially peptic ulcers and gastric bleeding);

Concomitant diseases (congestive heart failure, arterial hypertension, renal and hepatic insufficiency);

Treatment of concomitant diseases (taking diuretics, ACE inhibitors);

Taking high doses of NSAIDs (relative risk 2.5 in people taking low doses and 8.6 in people taking high doses of NSAIDs; 2.8 when treated with standard doses of NSAIDs and 8.0 when treated with high doses of drugs) ;

Simultaneous use of several NSAIDs (the risk doubles);

Combined use of NSAIDs and glucocorticoids (relative risk 10.6 higher than when taking only NSAIDs);

Combined intake of NSAIDs and anticoagulants;

Treatment with NSAIDs for less than 3 months (relative risk 7.2 for those treated for less than 30 days and 3.9 for those treated for more than 30 days; risk 8.0 for treatment for less than 1 month, 3.3 for treatment from 1 to 3 months and 1 ,9 - more than 3 months);

Taking NSAIDs with a long half-life and non-selective for COX-2.

Possible risk factors:

The presence of rheumatoid arthritis;

Female;

Smoking;

Alcohol intake;

Infection H. pylori(data are inconsistent).

As can be seen from the above data, the role of NSAIDs is extremely important. Among the main features of NSAID-gastropathy, the predominant localization of erosive and ulcerative changes (in the antrum of the stomach) and the absence of subjective symptoms or moderately severe symptoms were identified.

Erosions of the stomach and duodenum associated with the use of NSAIDs often do not manifest any clinical symptoms, or patients have only slightly pronounced, sometimes occurring pain in the epigastric region and / or dyspeptic disorders, which patients often do not attach importance to and therefore do not seek medical help. In some cases, patients get so used to their mild abdominal pain and discomfort that when they go to the clinic about the underlying disease, they do not even report them to the attending physician (the underlying disease worries patients much more). There is an opinion that NSAIDs reduce the intensity of the symptoms of gastrointestinal lesions due to their local and general analgesic effect.

Most often, the first clinical symptoms of erosive and ulcerative lesions of the stomach and duodenum are the appearance of weakness, sweating, pallor of the skin, minor bleeding, and then vomiting and melena. The results of most studies emphasize that the risk of NSAID gastropathy is maximum in the first month of their appointment. Therefore, when prescribing NSAIDs for a long time, each practitioner must evaluate the possible risks and benefits of prescribing it and pay special attention to risk factors for NSAID gastropathy.

In the presence of risk factors and the development of dyspeptic symptoms, an endoscopic examination is indicated. If signs of NSAID gastropathy are detected, it is necessary to decide whether it is possible to refuse to take NSAIDs or choose a method of protection of the gastrointestinal mucosa. Cancellation of drugs, although it does not lead to a cure for NSAID gastropathy, but allows you to stop side effects, increase the effectiveness of antiulcer therapy and reduce the risk of recurrence of the ulcerative erosive process in the gastrointestinal tract. If it is impossible to interrupt treatment, the average daily dose of the drug should be reduced as much as possible and protective therapy of the gastrointestinal mucosa should be carried out, which helps to reduce the gastrotoxicity of NSAIDs.

There are three ways to medically overcome gastrotoxicity: gastrocytoprotectors, drugs that block the synthesis of hydrochloric acid in the stomach, and antacids.

In the mid-80s of the last century, misoprostol was synthesized - a synthetic analogue of prostaglandin E, which is a specific antagonist of the negative effects of NSAIDs on the mucosa.

Conducted in 1987-1988. controlled clinical trials have shown the high efficacy of misoprostol in the treatment of NSAID-induced gastropathy. The famous MUCOSA study (1993-1994), which included more than 8 thousand patients, confirmed that misoprostol is an effective prophylactic agent that, with long-term use of NSAIDs, significantly reduces the risk of developing serious gastroduodenal complications. In the United States and Canada, misoprostol is considered the first-line drug for the treatment and prevention of NSAID-induced gastropathy. On the basis of misoprostol, combined drugs containing NSAIDs were created, for example, artrotek * containing 50 mg of diclofenac sodium and 200 μg of misoprostol.

Unfortunately, misoprostol has a number of significant drawbacks, primarily related to its systemic action (leads to the development of dyspepsia and diarrhea), inconvenient regimen and high cost, which limited its distribution in our country.

Another way to protect the gastrointestinal mucosa is omeprazole (20-40 mg / day). The classic OMNIUM study (omeprazole vs. misoprostol) showed that omeprazole was overall as effective in the treatment and prevention of NSAID-induced gastropathy as misoprostol used at the standard dosage (800 mcg/day for four treatment doses and 400 mcg for two prophylaxis). At the same time, omeprazole better relieves dyspeptic symptoms and causes side effects much less frequently.

However, in recent years, evidence has begun to accumulate that proton pump inhibitors in NSAID-induced gastropathy do not always produce the expected effect. Their therapeutic and prophylactic effect can largely depend on various endo- and exogenous factors, and above all on the infection of the mucosa. H. pylori. In conditions of Helicobacter pylori infection, proton pump inhibitors are much more effective. This is confirmed by the studies of D. Graham et al. (2002), which included 537 patients with a history of endoscopically detected gastric ulcers and long-term use of NSAIDs. The inclusion criterion was the absence H. pylori. The results of the study showed that proton pump inhibitors (as a prophylactic agent) were significantly less effective than the gastroprotective misoprostol.

Monotherapy with non-absorbable antacids (Maalox *) and sucralfate (a drug with film-forming, anti-pepsic and cytoprotective properties), despite its use for the relief of symptoms of dyspepsia, is ineffective in relation to both the treatment and prevention of NSAID gastropathy

[Nasonov E.L., 1999].

According to epidemiological studies in the United States, approximately 12-20 million people take both NSAIDs and antihypertensive drugs, and in general, NSAIDs are prescribed by more than a third of patients suffering from arterial hypertension.

It is known that prostaglandins play an important role in the physiological regulation of vascular tone and kidney function. Prostaglandins, modulating the vasoconstrictor and antinatriuretic effect of angiotensin II, interact with the components of the RAAS, have vasodilating activity in relation to the vessels of the kidneys (PGE 2 and prostacyclin), and have a direct natriuretic effect (PGE 2).

By inhibiting systemic and local (intrarenal) prostaglandin synthesis, NSAIDs can cause an increase in blood pressure not only in patients with arterial hypertension, but also in people with normal blood pressure. It has been established that in patients who regularly take NSAIDs, an increase in blood pressure by an average of 5.0 mm Hg is observed. The risk of NSAID-induced arterial hypertension is especially high in elderly people who take NSAIDs for a long time, with concomitant diseases of the cardiovascular system.

A characteristic property of NSAIDs is interaction with antihypertensive drugs. It has been established that such NSAIDs as indomethacin, pi-

roxicam and naproxen in medium therapeutic doses and ibuprofen (at a high dose) have the ability to reduce the effectiveness of antihypertensive drugs, the basis of the hypotensive effect of which is dominated by prostaglandin-dependent mechanisms, namely β-blockers (propranolol, atenolol), diuretics (furosemide), prazosin, captopril .

In recent years, the point of view that NSAIDs that are more selective for COX-2 than COX-1, not only damage the gastrointestinal tract to a lesser extent, but also exhibit less nephrotoxic activity, has received some confirmation. It has been established that COX-1 is expressed in aterioles, glomeruli of the kidney and collecting ducts, and plays an important role in the regulation of peripheral vascular resistance, renal blood flow, glomerular filtration, sodium excretion, synthesis of antidiuretic hormone and renin. The analysis of the results on the risk of developing arterial hypertension during treatment with the most common NSAIDs in comparison with literature data on the selectivity of drugs for COX-2/COX-1 showed that treatment with drugs that are more selective for COX-2 is associated with a lower risk of arterial hypertension compared with less selective drugs.

According to the cyclooxygenase concept, it is most appropriate to prescribe short-lived, fast-acting and rapidly excreted NSAIDs. These primarily include lornoxicam, ibuprofen, diclofenac, nimesulide.

The antiplatelet effect of NSAIDs also contributes to the occurrence of gastrointestinal bleeding, although other manifestations of the hemorrhagic syndrome may occur with the use of these drugs.

Bronchospasm with the use of NSAIDs most often occurs in patients with the so-called aspirin variant of bronchial asthma. The mechanism of this effect is also associated with the blockade of NSAID COX-1 in the bronchi. At the same time, the main pathway of metabolism of arachidonic acid is lipoxygenase, as a result of which the formation of leukotrienes, which cause bronchospasm, increases.

Despite the fact that the use of selective COX-2 inhibitors is more safe, there are already reports of side effects of these drugs: the development of acute renal failure, delayed healing of gastric ulcers; reversible infertility.

A dangerous side effect of pyrazolone derivatives (metamizole, phenylbutazone) is hematotoxicity. The urgency of this problem is due to the widespread use of metamizole (analgin*) in Russia. In more than 30 countries, the use of metamizole is severely restricted or

generally prohibited. This decision is based on the International Agranulocytosis Study (IAAAS), which showed that metamizole increased the risk of agranulocytosis by 16 times. Agranulocytosis is a prognostically unfavorable side effect of therapy with pyrazolone derivatives, characterized by high mortality (30-40%) as a result of infectious complications associated with agranulocytosis (sepsis, etc.).

We should also mention a rare, but prognostically unfavorable complication of acetylsalicylic acid therapy - Reye's syndrome. Reye's syndrome is an acute disease characterized by severe encephalopathy in combination with fatty degeneration of the liver and kidneys. The development of Reye's syndrome is associated with the use of acetylsalicylic acid, usually after a viral infection (flu, chicken pox, etc.). Most often, Reye's syndrome develops in children with an age peak at 6 years. With Reye's syndrome, a high mortality rate is noted, which can reach 50%.

Impaired renal function is due to the inhibitory effect of NSAIDs on the synthesis of vasodilating prostaglandins in the kidneys, as well as a direct toxic effect on kidney tissue. In some cases, there is an immunoallergic mechanism of the nephrotoxic action of NSAIDs. Risk factors for the development of renal complications are heart failure, arterial hypertension (especially nephrogenic), chronic renal failure, overweight. In the first weeks of taking NSAIDs, it can be aggravated by renal failure associated with a slowdown in glomerular filtration. The degree of impaired renal function varies from a slight increase in blood creatinine to anuria. Also, a number of patients receiving phenylbutazone, metamizole, indomethacin, ibuprofen and naproxen may develop interstitial nephropathy with or without nephrotic syndrome. In contrast to functional renal failure, an organic lesion develops with long-term use of NSAIDs (more than 3-6 months). After discontinuation of the drugs, the pathological symptoms regress, the outcome of the complication is favorable. Fluid and sodium retention is also noted when taking NSAIDs (primarily phenylbutazone, indomethacin, acetylsalicylic acid).

Hepatotoxic action can develop according to an immunoallergic, toxic or mixed mechanism. Immunoallergic hepatitis most often develop at the beginning of NSAID treatment; there is no relationship between the dose of drugs and the severity of clinical symptoms. Toxic hepatitis develops against the background of long-term use of drugs and, as a rule, is accompanied by jaundice. Most often, liver damage is recorded with the use of diclofenac.

Lesions of the skin and mucous membranes are observed in 12-15% of all cases of complications with the use of NSAIDs. Typically, skin lesions occur on the 1-3rd week of use and often have a benign course, manifested by an itchy rash (scarlet fever or morbilliform), photosensitivity (the rash appears only on open areas of the body) or urticaria, which usually develops in parallel with edema. More severe skin complications include polymorphic erythema (may develop while taking any NSAID) and pigmentary fixed erythema (specific for pyrazolone drugs). The use of enolinic acid derivatives (pyrazolones, oxicams) may be complicated by toxicoderma, the development of pemphigus and the exacerbation of psoriasis. Ibuprofen is characterized by the development of alopecia. Local skin complications can develop with parenteral or cutaneous use of NSAIDs, they manifest as hematomas, indurations or erythema-like reactions.

Extremely rarely, when using NSAIDs, anaphylactic shock and Quincke's edema develop (0.01-0.05% of all complications). A risk factor for the development of allergic complications is an atopic predisposition and a history of allergic reactions to drugs of this group.

Damage to the neurosensory sphere when taking NSAIDs is noted in 1-6%, and when using indomethacin - up to 10% of cases. It is mainly manifested by dizziness, headaches, fatigue and sleep disorders. Indomethacin is characterized by the development of retinopathy and keratopathy (deposition of the drug in the retina and cornea). Long-term use of ibuprofen can lead to the development of optic neuritis.

Mental disorders when taking NSAIDs can manifest themselves in the form of hallucinations, confusion (most often while taking indomethacin, up to 1.5-4% of cases, this is due to the high degree of penetration of the drug into the central nervous system). Perhaps a transient decrease in hearing acuity when taking acetylsalicylic acid, indomethacin, ibuprofen and drugs of the pyrazolone group.

NSAIDs are teratogenic. For example, taking acetylsalicylic acid in the first trimester can lead to splitting of the upper palate in the fetus (8-14 cases per 1000 observations). Taking NSAIDs in the last weeks of pregnancy contributes to the inhibition of labor activity (tocolytic effect), which is associated with inhibition of the synthesis of prostaglandin F 2a; it can also lead to premature closure of the ductus arteriosus in the fetus and the development of hyperplasia in the pulmonary vessels.

Contraindications to the appointment of NSAIDs - individual intolerance, peptic ulcer of the stomach and duodenum in the acute stage; gastrointestinal bleeding, leukopenia, severe kidney damage, I trimester of pregnancy, lactation. Acetylsalicylic acid is contraindicated in children under 12 years of age.

In recent years, it has been shown that long-term use of selective COX-2 inhibitors can lead to a significant increase in the risk of cardiovascular complications, and especially chronic heart failure, myocardial infarction. For this reason, rofecoxib® has been deregistered worldwide. And with regard to other selective COX-2 inhibitors, the idea has been formed that these drugs are not recommended for use in patients with a high risk of cardiovascular complications.

When carrying out pharmacotherapy of NSAIDs, it is necessary to take into account the possibility of their interaction with other drugs, especially with indirect anticoagulants, diuretics, antihypertensive and anti-inflammatory drugs of other groups. It should be remembered that NSAIDs can significantly reduce the effectiveness of almost all antihypertensive drugs. In patients with CHF, the use of NSAIDs can increase the frequency of decompensation due to the leveling of the positive effects of ACE inhibitors and diuretics.

Tactics of choosing non-steroidal anti-inflammatory drugs

The anti-inflammatory effect of NSAIDs should be evaluated within 1-2 weeks. If the treatment has led to the expected results, it is continued until the complete disappearance of inflammatory changes.

According to the current strategy of pain management, there are several principles for prescribing NSAIDs.

Individualized: the dose, route of administration, dosage form is determined individually (especially in children), taking into account the intensity of pain and on the basis of regular monitoring.

"Ladder": stepwise anesthesia in compliance with unified diagnostic approaches.

Timeliness of administration: the interval between injections is determined by the severity of pain and the pharmacokinetic features of the action of drugs and its dosage form. It is possible to use long-acting drugs, which, if necessary, can be supplemented with fast-acting drugs.

Adequacy of the route of administration: preference is given to oral administration (the most simple, effective and least painful).

Often occurring acute or chronic pain is a reason for long-term use of NSAIDs. This requires an assessment not only of their effectiveness, but also of safety.

To select the necessary NSAID, it is necessary to take into account the etiology of the disease, the peculiarities of the mechanism of action of the drug, in particular its ability to increase the pain perception threshold and interrupt, at least temporarily, the conduction of a pain impulse at the level of the spinal cord.

When planning pharmacotherapy, the following should be considered.

The anti-inflammatory effect of NSAIDs directly depends on their affinity for COX, as well as on the level of acidity of the solution of the selected drug, which ensures concentration in the area of ​​inflammation. The analgesic and antipyretic action develops the faster, the more neutral pH the NSAID solution has. Such drugs penetrate the central nervous system faster and inhibit the centers of pain sensitivity and thermoregulation.

The shorter the half-life, the less pronounced enterohepatic circulation, the less the risk of cumulation and unwanted drug interactions, and the safer NSAIDs.

The sensitivity of patients to NSAIDs even in one group varies widely. For example, when ibuprofen is ineffective in rheumatoid arthritis, naproxen (also a propionic acid derivative) reduces joint pain. In patients with inflammation syndrome and concomitant diabetes mellitus (in which glucocorticoids are contraindicated), the use of acetylsalicylic acid is rational, the action of which is accompanied by a slight hypoglycemic effect associated with an increase in glucose uptake by tissues.

Pyrazolone derivatives, and in particular phenylbutazone, are especially effective in ankylosing spondylitis (Bekhterev's disease), rheumatoid arthritis, erythema nodosum, etc.

Since many NSAIDs, having a pronounced therapeutic effect, cause a large number of side effects, their choice should be made taking into account the development of the predicted side effect (Table 25-5).

The difficulty of choosing NSAIDs in autoimmune diseases is also due to the fact that they have a symptomatic effect and do not affect the course of rheumatoid arthritis and do not prevent the development of joint deformity.

Table 25-5. Relative risk of complications from the gastrointestinal tract when using non-steroidal anti-inflammatory drugs

Note. For 1, the risk of developing complications from the gastrointestinal tract with the use of placebo was taken.

For an effective analgesic effect, NSAIDs must have high and stable bioavailability, rapid achievement of maximum blood concentration, and a short and stable half-life.

Schematically, NSAIDs can be arranged as follows:

Descending anti-inflammatory action: indomethacin - diclofenac - piroxicam - ketoprofen - ibuprofen - ketorolac - lornoxicam - acetylsalicylic acid;

In descending order of analgesic activity: lornoxicam - ketorolac - diclofenac - indomethacin - ibuprofen - acetylsalicylic acid - ketoprofen;

According to the risk of cumulation and undesirable drug interactions: piroxicam - meloxicam - ketorolac - ibuprofen - diclofenac - lornoxicam.

The antipyretic effect of NSAIDs is well expressed in drugs with both high and low anti-inflammatory activity. Their choice depends on individual tolerance, possible interactions with the drugs used and the predicted adverse reactions.

Meanwhile, in children, paracetamol (acetaminophen *), which is not an NSAID, is the drug of choice as an antipyretic. Ibuprofen can be used as a second-line antipyretic for intolerance or ineffectiveness of paracetamol. Acetylsalicylic acid and metamizole should not be prescribed to children under 12 years of age due to the risk of developing Reye's syndrome and agranulocytosis, respectively.

In patients at high risk of bleeding or perforation due to NSAID-induced ulcers, concomitant administration of NSAIDs and proton pump inhibitors or the synthetic prostaglandin analogue misoprostal* should be considered. Histamine H2 receptor antagonists have been shown to prevent only duodenal ulcers and are therefore not recommended for prophylactic purposes. An alternative to this approach is the appointment of selective inhibitors in such patients.

Evaluation of the effectiveness of non-steroidal anti-inflammatory drugs

The criteria for the effectiveness of NSAIDs are determined by the disease in which these drugs are used.

Monitoring the analgesic activity of NSAIDs. Despite the objectivity of its existence, pain is always subjective. Therefore, if the patient, making complaints about pain, does not make any attempts (explicit or hidden) to get rid of it, it is worth doubting its presence. On the contrary, if the patient suffers from pain, he always demonstrates this either to others, or to himself, or seeks to see a doctor.

There are several ways to assess the intensity of the pain syndrome and the effectiveness of the therapy (Table 25-6).

The most common methods are the use of the Visual Analogue Scale and the Pain Relief Scale.

When using the visual analogue scale, the patient marks the level of pain syndrome severity on a 100-millimeter scale, where "0" - no pain, "100" - maximum pain. When monitoring acute pain, the level of pain is determined before the administration of the drug and 20 minutes after the administration. When monitoring chronic pain, the time interval for studying the intensity of pain is set individually (according to visits to the doctor, it is possible for the patient to keep a diary).

A pain relief scale is used to assess the effectiveness of pain relief. 20 minutes after the administration of the drug, the patient is asked the question: "Did your pain intensity decrease after the administration of the drug compared to the pain before the administration of the drug?". Possible answers are evaluated in points: 0 - the pain did not decrease at all, 1 - slightly decreased, 2 - decreased, 3 - greatly decreased, 4 - completely disappeared. It is also important to evaluate the time of onset of a distinct analgesic effect.

Table 25-6. Methods for grading the intensity of pain syndrome

duration of morning stiffness determined in hours from the moment of awakening.

Articular index- the total severity of pain that occurs in response to standard pressure on the test joint in the area of ​​the joint space. Soreness in joints that are difficult to palpate is determined by the volume of active and passive movements (hip, spine) or compression (foot joints). Soreness is assessed on a four-point system:

0 - no pain;

1 - the patient speaks of soreness at the site of pressure;

2 - the patient talks about soreness and frowns;

3 - the patient tries to stop the impact on the joint. Joint account determined by the number of joints in which

pain on palpation.

Functional index LI determined using a questionnaire, which consists of 17 questions that explain the possibility of performing

a number of elementary household activities involving various groups of joints.

Also, to assess the effectiveness of NSAIDs, the swelling index is used - the total numerical expression of swelling, which is evaluated visually according to the following gradation:

0 - absent;

1 - doubtful or weakly expressed;

2 - explicit;

3 - strong.

Swelling is assessed for the elbow, wrist, metacarpophalangeal, proximal interphalangeal joints of the hands, knee and ankle joints. The circumference of the proximal interphalangeal joints is calculated in total for the left and right hands. The compressive strength of the hand is assessed either using a special device or by squeezing the tonometer cuff filled with air to a pressure of 50 mm Hg. The patient holds his hand for three compressions. Take into account the average value. In case of damage to the joints of the legs, a test is used that evaluates the time it takes to travel a segment of the path. A functional test that assesses the range of motion in the joints is called the Keitel test.

25.2. PARACETAMOL (ACETAMINOPHENE*)

Mechanism of action and main pharmacodynamic effects

The mechanism of analgesic and antipyretic action of paracetamol is somewhat different from the mechanism of action of NSAIDs. There is an assumption that this is primarily due to the fact that paracetamol inhibits the synthesis of prostaglandins by selective blockade of COX-3 (COX-specific isoform for the central nervous system) in the central nervous system, namely directly in the hypothalamic centers of thermoregulation and pain. In addition, paracetamol blocks the conduction of "pain" impulses in the central nervous system. Due to the absence of peripheral action, paracetamol practically does not cause such undesirable drug reactions as ulcers and erosions of the gastric mucosa, antiplatelet action, bronchospasm, and tocolytic action. It is because of the predominantly central action that paracetamol does not have an anti-inflammatory effect.

Pharmacokinetics

The absorption of paracetamol is high: it binds to plasma proteins by 15%; 3% of the drug is excreted by the kidneys in unchanged

form, 80-90% is conjugated with glucuronic and sulfuric acid, resulting in the formation of conjugated metabolites, non-toxic and easily excreted by the kidneys. 10-17% of paracetamol is oxidized by CYP2E1 and CYP1A2 to form N-acetylbenzoquinoneimine, which in turn, by combining with glutathione, is converted into an inactive compound excreted by the kidneys. Therapeutically effective concentration of paracetamol in blood plasma is achieved when it is administered at a dose of 10-15 mg/kg. Less than 1% of the drug passes into breast milk.

Paracetamol is used for the symptomatic treatment of pain syndrome (mild and moderate severity) of various origins and febrile syndrome, often accompanying "colds" and infectious diseases. Paracetamol is the drug of choice for analgesic and antipyretic therapy in children.

For adults and children over 12 years of age, a single dose of paracetamol is 500 mg, the maximum single dose is 1 g, the frequency of administration is 4 times a day. The maximum daily dose is 4 g. In patients with impaired liver and kidney function, the interval between taking paracetamol should be increased. The maximum daily doses of paracetamol in children are presented in Table. 25-7 (multiplicity of appointment - 4 times a day).

Table 25-7. The maximum daily dose of paracetamol in children

Side effects and contraindications to the appointment

Due to the presence of central action in paracetamol, it is practically devoid of such undesirable drug reactions as erosive and ulcerative lesions, hemorrhagic syndrome, bronchospasm, and tocolytic action. When using paracetamol, the development of nephrotoxicity and hematotoxicity (agranulocytosis) is unlikely. In general, paracetamol is well tolerated and is currently considered one of the safest antipyretic analgesics.

The most serious adverse drug reaction of paracetamol is hepatotoxicity. It occurs when an overdose of this drug (taking more than 10 g at a time). The mechanism of hepatotoxic action of paracetamol is associated with the peculiarities of its metabolism. At

an increase in the dose of paracetamol increases the amount of the hepatotoxic metabolite N-acetylbenzoquinone imine, which, due to the resulting deficiency of glutathione, begins to combine with the nucleophilic groups of hepatocyte proteins, which leads to necrosis of the liver tissue (Table 25-8).

Table 25-8. Symptoms of paracetamol intoxication

The search for the mechanism of the hepatotoxic action of paracetamol led to the creation and implementation of an effective method for the treatment of intoxication with this drug - the use of N-acetylcysteine, which replenishes the reserves of glutathione in the liver and in the first 10-12 hours in most cases has a positive effect. The risk of paracetamol hepatotoxicity increases with chronic alcohol abuse. This is due to two mechanisms: on the one hand, ethanol depletes glutathione reserves in the liver, and on the other hand, it causes the induction of the cytochrome P-450 2E1 isoenzyme.

Contraindications to the appointment of paracetamol - hypersensitivity to the drug, liver failure, deficiency of glucose-6-phosphate dehydrogenase.

Interaction with other drugs

Clinically significant interactions of paracetamol with other drugs are presented in the Appendix.

25.3. BASIC, SLOW-ACTING, ANTI-INFLAMMATORY MEDICINES

The group of basic or "modifying" the disease includes drugs that are heterogeneous in chemical structure and mechanism of action and are used for long-term therapy of rheumatoid arthritis and other inflammatory diseases associated with lesions.

eat connective tissue. Conventionally, they can be divided into two subgroups.

Slow-acting drugs with non-specific immunomodulatory effects:

Gold preparations (aurotioprol, myocrysin*, auranofin);

D-pericillamines (penicillamine);

Quinoline derivatives (chloroquine, hydroxychloroquine).

Immunotropic drugs that indirectly stop inflammatory changes in the connective tissue:

Immunosuppressants (cyclophosphamide, azathioprine, methotrexate, cyclosporine);

Sulfa drugs (sulfasalazine, mesalazine). The common pharmacological effects that these drugs have in common are as follows:

The ability to inhibit the development of bone erosion and destruction of cartilage of the joints in non-specific inflammatory reactions;

Predominantly indirect effect of most drugs on the local inflammatory process, mediated through pathogenetic factors of the immune link of inflammation;

Slow onset of therapeutic effect with a latent period for many drugs of at least 10-12 weeks;

Maintaining signs of improvement (remission) for several months after withdrawal.

Mechanism of action and main pharmacodynamic effects

Gold preparations, reducing the phagocytic activity of monocytes, disrupt the uptake of antigen by them and the release of IL-1 from them, which leads to inhibition of T-lymphocyte proliferation, a decrease in the activity of T-helper cells, suppression of the production of immunoglobulins by B-lymphocytes, including rheumatoid factor, and the formation immune complexes.

D-penicillamine, forming a complex compound with copper ions, is able to suppress the activity of T-helpers, stimulate the production of immunoglobulins by B-lymphocytes, including rheumatoid factor, and reduce the formation of immune complexes. The drug affects the synthesis and composition of collagen, increasing the content of aldehyde groups in it that bind the C 1 component of complement, prevents the involvement of the entire complement system in the pathological process; increases the content of the water-soluble fraction and inhibits the synthesis of fibrillar collagen rich in hydroxyproline and disulfide bonds.

The main mechanism of therapeutic action of quinoline derivatives is an immunosuppressive effect associated with impaired nucleic metabolism. This leads to cell death. It is assumed that the drugs disrupt the process of macrophage cleavage and the presentation of autoantigens by CD+ T-lymphocytes.

By inhibiting the release of IL-1 from monocytes, they limit the release of prostaglandins E 2 and collagenase from synovial cells. Reduced release of lymphokines prevents the emergence of a clone of sensitized cells, activation of the complement system and T-killers. It is believed that quinoline preparations stabilize cellular and subcellular membranes, reduce the release of lysosomal enzymes, as a result of which they limit the focus of tissue damage. In therapeutic doses, they have clinically significant anti-inflammatory, immunomodulatory, as well as antimicrobial, lipid-lowering and hypoglycemic effects.

Drugs of the second subgroup (cyclophosphamide, azathioprine and methotrexate) disrupt the synthesis of nucleic acids and proteins in all tissues, their action is noted in tissues with rapidly dividing cells (in the immune system, malignant tumors, hematopoietic tissue, gastrointestinal mucosa, gonads). They inhibit the division of T-lymphocytes, their transformation into helpers, suppressors and cytostatic cells. This leads to a decrease in the cooperation of T- and B-lymphocytes, inhibition of the formation of immunoglobulins, rheumatoid factor, cytotoxins and immune complexes. Cyclophosphamide and azathioprine are more pronounced than methotrexate, inhibit lymphocyte blast transformation, antibody synthesis, inhibition of delayed skin hypersensitivity, and a decrease in the level of gamma and immunoglobulins. Methotrexate in small doses actively affects the indicators of humoral immunity, a number of enzymes that play a role in the development of inflammation, suppressing the release of IL-1 by mononuclear cells. It should be noted that the therapeutic effect of immunosuppressants in the doses used in rheumatoid arthritis and other immunoinflammatory diseases does not correspond to the degree of immunosuppression. Probably, this depends on the inhibitory effect on the cellular phase of the local inflammatory process, and the anti-inflammatory effect itself is also attributed to cyclophosphamide.

Unlike cytostatics, the immunosuppressive effect of cyclosporine is associated with selective and reversible suppression of the production of IL-2 and T-cell growth factor. The drug inhibits the proliferation and differentiation of T-lymphocytes. The main target cells for cyclosporine are CD4+ T (helper lymphocytes). By influence on

laboratory data cyclosporine is comparable to other basic drugs and is especially effective in patients with skin anergy, low ratio of CD4, CD8 and T-lymphocytes in peripheral blood, with an increase in the level of NK-cells (natural killers) and a decrease in the number of cells expressing IL-2- receptors (Table 25-9).

Table 25-9. Most likely targets for anti-inflammatory drugs

Pharmacokinetics

Krizanol (an oily suspension of gold salt, contains 33.6% of metallic gold) is used intramuscularly, the drug is absorbed from the muscles rather slowly. The maximum plasma concentration is usually reached after 4 hours. After a single intramuscular injection of 50 mg (a water-soluble drug containing 50% metallic gold), its level reaches a maximum (4.0-7.0 μg / ml) within 15-30 minutes up to 2 hours. Gold preparations are excreted in urine (70%) and faeces (30%). T 1/2 in plasma is 2 days, and the half-life is 7 days. After a single administration, the level of gold in the blood serum during the first 2 days decreases rapidly (up to 50%), remains at the same level for 7-10 days, and then decreases gradually. After repeated injections (once a week), the level of gold in blood plasma increases, reaching an equilibrium concentration of 2.5-3.0 μg / ml after 6-8 weeks, however, there is no relationship between the concentration of gold in plasma and its therapeutic and side effects, and toxic effect correlates with an increase in its free fraction. The bioavailability of the oral preparation of gold - auranofin (contains 25% of metallic gold) is 25%. With his daily

reception (6 mg / day), the equilibrium concentration is reached after 3 months. Of the dose taken, 95% is lost in the faeces and only 5% in the urine. In the blood plasma, gold salts bind to proteins by 90%, are distributed unevenly in the body: they accumulate most actively in the kidneys, adrenal glands and the reticuloendothelial system. In patients with rheumatoid arthritis, the highest concentrations are found in the bone marrow (26%), liver (24%), skin (19%), bones (18%); in synovial fluid, its level is about 50% of the level in blood plasma. In the joints, gold is predominantly localized in the synovial membrane, and due to a special tropism for monocytes, it accumulates more actively in areas of inflammation. Through the placenta penetrates in small quantities.

D-penicillamine, taken on an empty stomach, is absorbed from the gastrointestinal tract by 40-60%. Dietary proteins contribute to its transformation into sulfide, which is poorly absorbed from the intestine, so food intake significantly reduces the bioavailability of D-penicillamine. The maximum plasma concentration after a single dose is reached after 4 hours. In the blood plasma, the drug is intensely bound to proteins, in the liver it turns into two inactive water-soluble metabolites excreted by the kidneys (sulfide-penicillamine and cysteine-penicillamine-disulfide). T 1/2 in persons with normally functioning kidneys is 2.1 hours, in patients with rheumatoid arthritis it increases by an average of 3.5 times.

Quinoline drugs are well absorbed from the digestive tract. The maximum concentration in the blood is reached on average after 2 hours. With an unchanged daily dose, their level in the blood gradually increases, the time to reach an equilibrium concentration in the blood plasma ranges from 7-10 days to 2-5 weeks. Chloroquine in plasma is 55% bound to albumin. Due to its association with nucleic acids, its concentration in tissues is much higher than in blood plasma. Its content in the liver, kidneys, lungs, leukocytes is 400-700 times higher, in brain tissue 30 times higher than in blood plasma. Most of the drug is excreted in the urine unchanged, a smaller part (about 1/3) is biotransformed in the liver. The half-life of chloroquine ranges from 3.5 to 12 days. With acidification of urine, the rate of excretion of chloroquine increases, with alkalization, it decreases. After stopping the intake, chloroquine slowly disappears from the body, remaining in the places of deposition for 1-2 months, after prolonged use, its content in the urine is detected for several years. The drug easily crosses the placenta, intensively accumulating in the fetal retinal pigment epithelium, and also binding to DNA, inhibits protein synthesis in fetal tissues.

Cyclophosphamide is well absorbed from the gastrointestinal tract, its maximum concentration in the blood is reached after 1 hour, the connection with the protein is minimal. In the absence of impaired liver and kidney function, up to 88% of the drug in the blood and liver is biotransformed into active metabolites, of which aldofosfamide is the most active. It can accumulate in the kidneys, liver, spleen. Cyclophosphamide in unchanged form (20% of the administered dose) and in the form of active and inactive metabolites is excreted from the body with urine. T 1/2 is 7 hours. In case of impaired renal function, an increase in all, including toxic, effects is possible.

Azathioprine is well absorbed from the gastrointestinal tract, turning in the body (in the lymphoid tissue more actively than in others) into the active metabolite 6-mercaptopurine, T 1/2 of which from the blood is 90 minutes. The rapid disappearance of azathioprine from blood plasma is due to its active uptake by tissues and further biotransformation. T 1 / 2 of azathioprine is 24 hours, it does not penetrate through the BBB. It is excreted in the urine both unchanged and as metabolites - S-methylated products and 6-thiouric acid, which is formed under the influence of xanthine oxidase and causes the development of hyperuricemia and hyperuricuria. Blockade of xanthine oxidase with allopurinol slows down the conversion of 6-mercaptopurine, reducing the formation of uric acid and increasing the effectiveness and toxicity of the drug.

Methotrexate is 25-100% absorbed from the gastrointestinal tract (60-70% on average); absorption does not change with increasing dose. Partially, methotrexate is metabolized by the intestinal flora, bioavailability varies widely (28-94%). The maximum concentration is reached after 2-4 hours. Food intake increases the absorption time by more than 30 minutes, without affecting the level of absorption and bioavailability. Methotrexate binds to plasma proteins by 50-90%, practically does not penetrate the BBB, its biotransformation in the liver is 35% when taken orally and does not exceed 6% when administered intravenously. The drug is excreted by glomerular filtration and tubular secretion, about 10% of the methotrexate that has entered the body is excreted in the bile. T 1/2 is 2-6 hours, however, its polyglutamine metabolites are detected intracellularly for at least 7 days after a single dose, and 10% (with normal kidney function) is retained in the body, remaining mainly in the liver (several months) and kidneys ( how many weeks).

In cyclosporine, due to the variability of absorption, bioavailability varies widely, amounting to 10-57%. Maxi-

a small concentration in the blood is reached after 2-4 hours. More than 90% of the drug is associated with blood proteins. It is unevenly distributed between individual cellular elements and plasma: in lymphocytes - 4-9%, in granulocytes - 5-12%, in erythrocytes - 41-58% and in plasma - 33-47%. About 99% of cyclosporine is biotransformed in the liver. It is excreted in the form of metabolites, the main route of elimination is the gastrointestinal tract, no more than 6% is excreted in the urine, and 0.1% is unchanged. The half-life is 10-27 (average 19) hours. The minimum concentration of cyclosporine in the blood, at which a therapeutic effect is observed, is 100 ng / l, the optimal is 200 ng / l, and the nephrotoxic concentration is 250 ng / l.

Indications for use and dosing regimen

Preparations of this group are used in a number of immunopathological inflammatory diseases. Diseases and syndromes in which clinical improvement can be achieved with the help of basic drugs are presented in Table. 25-13.

Doses of drugs and dosing regimen are presented in table. 25-10 and 25-11.

Table 25-10. Doses of basic anti-inflammatory drugs and their dosing regimen

The end of the table. 25-10

Table 25-11. Characteristics of drugs used for immunosuppressive therapy

*Only as intravenous shock therapy.

Treatment with gold preparations is called chryso-, or aurotherapy. The first signs of improvement are sometimes observed after 3-4 months of continuous chrysotherapy. Krizanol is prescribed, starting with one or more trial injections in small doses (0.5-1.0 ml of a 5% suspension) with an interval of 7 days and then switching to a weekly injection of 2 ml of a 5% solution for 7-8 months. Evaluate the result of treatment most often after 6 months from the start of use. Initial signs of improvement may appear after 6-7 weeks, and sometimes only after 3-4 months. When the effect and good tolerance are achieved, then the intervals are increased to 2 weeks, and after 3-4 months, while maintaining signs of remission, up to 3 weeks (maintenance therapy, carried out almost for life). When the first signs of exacerbation appear, it is necessary to return to more frequent injections of the drug. Myocrysin* is used similarly: trial dose - 20 mg, therapeutic dose - 50 mg. If there is no effect within 4 months, it is advisable to increase the dose to 100 mg; if there is no effect in the next few weeks, myocrysin* is canceled. Auranofin is used for the same length of time at 6 mg per day, divided into 2 doses. Some patients need to increase the dose to 9 mg / day (with ineffectiveness for 4 months), others - only at a dose of 3 mg / day, the dose is limited by side effects. Complete medical history of drug allergy, skin and kidney disease, complete blood count, biochemical profile and urinalysis. studied before the start of chrysotherapy, reduce the risk of side effects. In the future, every 1-3 weeks it is necessary to repeat clinical blood tests (with the determination of the number of platelets) and general urine tests. With proteinuria exceeding 0.1 g / l, gold preparations are temporarily canceled, although a higher level of proteinuria sometimes disappears without stopping therapy.

D-penicillamine for the treatment of rheumatoid arthritis is prescribed at an initial dose of 300 mg/day. If there is no effect within 16 weeks, the dose is increased monthly by 150 mg / day, reaching 450-600 mg / day. The drug is prescribed on an empty stomach 1 hour before or 2 hours after a meal and not earlier than 1 hour after taking any other medications. An intermittent scheme (3 times a week) is possible, which allows to reduce the frequency of adverse reactions while maintaining clinical efficacy. Clinical and laboratory improvement occurs after 1.5-3 months, less often at earlier periods of therapy, a distinct therapeutic effect is realized after 5-6 months, and radiographic improvement - not earlier than after 2 years. If there is no effect within 4-5 months, the drug should be discontinued. Often, during treatment, an exacerbation is observed, sometimes ending in spontaneous remission, and in other cases requiring an increase in dose or a transition to a double daily dose. When taking D-penicillamine, a "secondary inefficiency" may develop: the clinical effect obtained at the beginning is replaced by a persistent exacerbation of the rheumatoid process, despite ongoing therapy. In the process of treatment, in addition to careful clinical observation, it is necessary to examine peripheral blood (including platelet count) every 2 weeks for the first 6 months, and then once a month. Liver tests are performed once every 6 months.

The therapeutic effect of quinoline derivatives develops slowly: its first signs are observed no earlier than 6-8 weeks from the start of therapy (for rheumatism earlier - after 10-30 days, and for rheumatoid arthritis, subacute and chronic lupus erythematosus - only after 10-12 weeks ). The maximum effect sometimes develops only after 6-10 months of continuous therapy. The usual daily dose is 250 mg (4 mg/kg) chloroquine and 400 mg (6.5 mg/kg) hydroxychloroquine. In case of poor tolerance or when the effect is achieved, the dose is reduced by 2 times. The recommended low doses (no more than 300 mg of chloroquine and 500 mg of hydroxychloroquine), not inferior in effectiveness to high ones, allow avoiding severe complications. During treatment, it is necessary to re-examine the hemogram, before starting treatment and then every 3 months, ophthalmological control should be carried out with an examination of the fundus and visual fields, a thorough questioning about visual disorders.

Cyclophosphamide is administered orally after meals, in a daily dose of 1-2 to 2.5-3 mg / kg in 2 doses, and large doses are administered intravenously as a bolus according to an intermittent scheme - 5000-1000 mg / m 2 each. Sometimes treatment is started with a half dose. With both schemes, the level of leukocytes should not decrease below 4000 per 1 mm 2. At the beginning of treatment, a complete blood count, determination of platelets and urinary sediment should be carried out

every 7-14 days, and when the clinical effect is achieved and the dose is stabilized, every 2-3 months. Treatment with azathioprine begins with a trial daily dose of 25-50 mg during the first week, then increasing it by 0.5 mg / kg every 4-8 weeks, leading up to the optimal - 1-3 mg / kg in 2-3 doses. The drug is administered orally after meals. Its clinical effect develops no earlier than 5-12 months after the start of therapy. At the beginning of treatment, laboratory control (a clinical blood test with platelet count) is performed every 2 weeks, and when the dose is stabilized, once every 6-8 weeks. Methotrexate can be used orally, intramuscularly and intravenously. As a basic agent, the drug is most often used at a dose of 7.5 mg / week; when used orally, this dose is divided into 3 doses after 12 hours (to improve tolerance). Its action develops very quickly, the initial effect appears after 4-8 weeks, and the maximum - by the 6th month. In the absence of a clinical effect after 4-8 weeks, with good tolerance of the drug, its dose is increased by 2.5 mg / week, but not more than 25 mg (to prevent the development of toxic reactions and deterioration of absorption). In a maintenance dose of 1/3 - 1/2 of the therapeutic dose, methotrexate can be administered with quinoline derivatives and indomethacin. Parenteral methotrexate is administered with the development of toxic reactions from the gastrointestinal tract or with inefficiency (insufficient dose or low absorption from the gastrointestinal tract). Solutions for parenteral administration are prepared immediately before administration. After the abolition of methotrexate, as a rule, an exacerbation develops between the 3rd and 4th week. In the process of treatment, the composition of peripheral blood is monitored every 3-4 weeks and liver tests are performed every 6-8 weeks. The applied doses of cyclosporine vary within a fairly wide range - from 1.5 to 7.5 mg / kg / day, however, exceeding the value of 5.0 mg / kg / day is impractical, since, starting from a level of 5.5 mg / kg / day, the frequency of complications increases. Before starting treatment, a detailed clinical and laboratory examination is carried out (determination of the level of bilirubin and the activity of liver enzymes, the concentration of potassium, magnesium, uric acid in the blood serum, lipid profile, urinalysis). During treatment, blood pressure and serum creatinine levels are monitored: if it increases by 30%, the dose for a month is reduced by 0.5-1.0 mg / kg / day, with normalization of creatinine levels, treatment is continued, and if it is absent, it is stopped.

Side effects and contraindications to the appointment

Basic drugs have many, including severe, side effects. When prescribing them, it is necessary to compare the expected positive changes with possible undesirable ones.

mi reactions. The patient should be informed about the clinical symptoms that need attention and which should be reported to the doctor.

Side effects and complications when prescribing gold preparations are noted in 11-50% of patients. The most common are pruritus, dermatitis, urticaria (sometimes, in combination with stomatitis and conjunctivitis, they require cancellation in combination with the appointment of antihistamines). In severe dermatitis and fever, unithiol* and glucocorticoids are added to the treatment.

Proteinuria is often observed. With a protein loss of more than 1 g / day, the drug is canceled due to the risk of developing nephrotic syndrome, hematuria, and renal failure.

Hematological complications are relatively rare, but they require special vigilance. Thrombocytopenia requires discontinuation of the drug, treatment with glucocorticoids, chelating compounds. Pancytopenia and aplastic anemia are possible; the latter can also be fatal (drug withdrawal is required).

Parenteral administration of myocrysin is complicated by the development of a nitritoid reaction (vasomotor reaction with a drop in blood pressure) - the patient is recommended to lie down for 0.5-1 hour after the injection.

Some side effects are rarely observed: enterocolitis with diarrhea, nausea, fever, vomiting, abdominal pain after discontinuation of the drug (in this case, glucocorticoids are prescribed), cholestatic jaundice, pancreatitis, polyneuropathy, encephalopathy, iritis (corneal ulcers), stomatitis, lung infiltration ( "golden" light). In such cases, discontinuation of the drug is sufficient to provide relief.

Possible taste perversions, nausea, diarrhea, myalgia, megiphonexia, eosinophilia, gold deposits in the cornea and lens. These manifestations require medical supervision.

Side effects when using D-penicillamine are noted in 20-25% of cases. Most often, these are hematopoietic disorders, the most severe of them are leukopenia (<3000/мм 2), тромбоцитопения (<100 000/мм 2), апластическая анемия (необходима отмена препарата). Возможно развитие аутоиммунных синдромов: миастении, пузырчатки, синдрома, напоминающего системную красную волчанку, синдрома Гудпасчера, полимиозита, тиреоидита. После отмены препарата при необходимости назначают глюкокортикоиды, иммунодепрессанты.

Rare complications include fibrosing alveolitis, kidney damage with proteinuria over 2 g/day, and nephrotic syndrome. These conditions require discontinuation of the drug.

It is necessary to pay attention to such complications as a decrease in taste sensitivity, dermatitis, stomatitis, nausea, loss

appetite. The frequency and severity of adverse reactions to D-penicillamine depend both on the drug itself and on the underlying disease.

When prescribing quinoline drugs, side effects rarely develop and practically do not require the abolition of the latter.

The most common side effects are associated with a decrease in gastric secretion (nausea, loss of appetite, diarrhea, flatulence), with the development of dizziness, insomnia, headaches, vestibulopathy, and hearing loss.

Very rarely, myopathy or cardiomyopathy develops (decrease T, ST on the electrocardiogram, conduction and rhythm disturbances), toxic psychosis, convulsions. These side effects disappear after withdrawal and / or symptomatic therapy.

Rare complications include leukopenia, thrombocytopenia, hemolytic anemia, and skin lesions in the form of urticaria, lichenoid and maculopapular rashes, and, extremely rarely, Lyell's syndrome. Most often, this requires discontinuation of the drug.

The most dangerous complication is toxic retinopathy, which is manifested by narrowing of the peripheral visual fields, central scotoma, and later by visual impairment. Cancellation of the drug, as a rule, leads to their regression.

Rare side effects include photosensitivity, pigmentation disorders of the skin, hair, and corneal infiltration. These manifestations are reversible and require observation.

Immunosuppressants have common side effects that are characteristic of any drug in this group (see Tables 25-11), at the same time, each of them has its own characteristics.

The frequency of side effects of cyclophosphamide depends on the duration of use and the individual characteristics of the organism. The most dangerous complication is hemorrhagic cystitis with an outcome in fibrosis, and sometimes in bladder cancer. This complication is observed in 10% of cases. It requires discontinuation of the drug even with symptoms of diarrhea. Alopecia, dystrophic changes in hair and nails (reversible) are noted mainly with the use of cyclophosphamide.

All drugs may develop thrombocytopenia, leukopenia, pancytopenia, which, with the exception of azathioprine, develop slowly and regress after discontinuation.

Possible toxic complications in the form of interstitial pulmonary fibrosis in response to cyclophosphamide and methotrexate. The latter gives such a rare complication as cirrhosis of the liver. They are extremely rare for azathioprine and require discontinuation and symptomatic therapy.

The most common complications for this group are gastrointestinal disorders: nausea, vomiting, anorexia, diarrhea, and abdominal pain. They are

have a dose-dependent effect and most often occur with azathioprine. With it, hyperuricemia is also possible, requiring dose adjustment and the appointment of allopurinol.

Methotrexate is better tolerated than other basic drugs, although the frequency of side effects reaches 50%. In addition to the above side effects, memory loss, stomatitis, dermatitis, malaise, fatigue are possible, which requires dose adjustment or cancellation.

Cyclosporine has fewer immediate and long-term side effects compared to other immunosuppressive agents. Possible development of arterial hypertension, transient azotemia with a dose-dependent effect; hypertrichosis, paresthesia, tremor, moderate hyperbilirubinemia and fermentemia. They most often appear at the beginning of treatment and disappear on their own; only with persistent complications, drug withdrawal is required.

In general, the appearance of undesirable effects can significantly outpace the slowly developing therapeutic effect of immunosuppressants. This must be taken into account when choosing a base drug. Complications common to them are presented in Table. 25-12.

Table 25-12. Side effects of immunosuppressants

"0" - not described, "+" - described, "++" - described relatively often, "?" - no data, "(+)" - clinical interpretation is not known.

All drugs, except quinoline, are contraindicated in acute infectious diseases, and are also not prescribed during pregnancy (except for sulfanilamide drugs). Preparations of gold, D-penicillamine and cytostatics are contraindicated in various disorders of hematopoiesis; levamisole - with a history of drug agranulocytosis, and quinoline - with severe cytopenias,

not related to the underlying disease to be treated with these drugs. Diffuse lesions of the kidneys and chronic renal failure are a contraindication to the appointment of drugs of gold, quinoline, D-penicillamine, methotrexate, cyclosporine; with chronic renal failure, the dose of cyclophosphamide is reduced. With lesions of the liver parenchyma, gold preparations, quinoline, cytostatics are not prescribed, cyclosporine is prescribed with caution. In addition, contraindications to the use of gold preparations are diabetes mellitus, decompensated heart defects, miliary tuberculosis, fibrous-cavernous processes in the lungs, cachexia; relative contraindications - severe allergic reactions in the past (prescribe the drug with caution), seronegativity for rheumatoid factor (in this case, it is almost always poorly tolerated). D-penicillamine is not prescribed for bronchial asthma; use with caution in case of intolerance to penicillin, in the elderly and senile age. Contraindications to the appointment of sulfa drugs - hypersensitivity not only to sulfonamides, but also to salicylates, and sulfonamides and quinoline are not prescribed for porphyria, deficiency of glucose-6-phosphate dehydrogenase. Quinoline derivatives are contraindicated in severe lesions of the heart muscle, especially those combined with conduction disorders, in diseases of the retina, psychosis. Cyclophosphamide is not prescribed for severe heart disease, in the terminal stages of diseases, with cachexia. Gastroduodenal ulcers are a relative contraindication to the appointment of methotrexate. Cyclosporine is contraindicated in uncontrolled arterial hypertension, malignant neoplasms (for psoriasis, it can be used for malignant skin diseases). A history of toxic-allergic reactions to any sulfonamides is a contraindication to the appointment of sulfasalazine.

Choice of medicines

In terms of therapeutic efficacy, gold preparations and immunosuppressants occupy the first place, however, the potential oncogenicity and cytotoxicity of the latter make them, in some cases, be treated as reserve agents; followed by sulfonamides and D-penicillamine, which is less well tolerated. Basic therapy is better tolerated by patients with rheumatoid factor-seropositive rheumatoid arthritis.

Table 25-13. Indications for differentiated prescription of basic anti-inflammatory drugs

D-penicillamine is ineffective in the central form of ankylosing spondylitis and other HLA-B27-negative spondyloarthropathies.

The main indication for the appointment of gold salts is rapidly progressive rheumatoid arthritis with early development of bone erosions,

the articular form of the disease with signs of active synovitis, as well as the articular-visceral form with rheumatoid nodules, Felty and Sjogren's syndromes. The effectiveness of gold salts is manifested by regression of synovitis and visceral manifestations, including rheumatoid nodules.

There is evidence of the effectiveness of gold salts in juvenile rheumatoid arthritis, psoriatic arthritis, separate observations indicate effectiveness in the discoid form of lupus erythematosus (auranofin).

In patients who tolerate it well, the rate of improvement or remission reaches 70%.

D-penicillamine is used mainly in active rheumatoid arthritis, including in patients resistant to treatment with gold preparations; additional indications are the presence of a high titer of rheumatoid factor, rheumatoid nodules, Felty's syndrome, rheumatoid lung disease. In terms of the frequency of development of improvement, its severity and duration, especially remission, D-penicillamine is inferior to gold preparations. The drug is ineffective in 25-30% of patients, in particular, with a haplotype HLA-B27. D-penicillamine is considered the main component in the complex therapy of systemic scleroderma, and its effectiveness in the treatment of biliary cirrhosis, palindromic rheumatism, and juvenile arthritis has been shown.

An indication for the appointment of quinoline drugs is the presence of a chronic immune inflammatory process in a number of rheumatic diseases, especially during remission to prevent relapses. They are effective in discoid lupus erythematosus, eosinophilic fasciitis, juvenile dermatomycitis, palindromic rheumatism, and some forms of seronegative spondyloarthropathies. In rheumatoid arthritis, as a monotherapy, it is used for mild cases, as well as during the period of achieved remission. Quinoline preparations are successfully used in complex therapy with other basic preparations: cytostatics, gold preparations.

Immunosuppressants (cyclophosphamide, azathioprine, methotrexate) are indicated for severe and rapidly progressive forms of rheumatic diseases with high activity, as well as for insufficient effectiveness of previous steroid therapy: for rheumatoid arthritis, Felty and Still's syndrome, systemic connective tissue lesions (systemic lupus erythematosus, dermatopolymyositis, systemic scleroderma, systemic vasculitis: Wegener's granulomatosis, periarteritis nodosa, Takayasu's disease, Cherd's syndrome

zha-Strauss, Harton's disease, hemorrhagic vasculitis with kidney damage, Behcet's disease, Goodpasture's syndrome).

Immunosuppressants have a steroid-sparing effect, which makes it possible to reduce the dose of glucocorticoids and the severity of their side effects.

There are some features in the appointment of drugs in this group: cyclophosphamide is the drug of choice for systemic vasculitis, rheumatoid vasculitis, lupus lesions of the central nervous system and kidneys; methotrexate - for rheumatoid arthritis, seronegative spondyloarthritis, psoriatic arthropathy, ankylosing spondylitis; Azathioprine is most effective in cutaneous manifestations of systemic lupus erythematosus and lupus glomerulonephritis. It is possible to sequentially prescribe cytostatics: cyclophosphamide with subsequent transfer to azathioprine with a decrease in the activity of the process and to achieve stabilization, as well as to reduce the severity of side effects from cyclophosphamide.

A lot of pathological changes occurring in the body accompany the pain syndrome. To combat such symptoms, NSAIDs, or non-steroidal anti-inflammatory drugs, have been developed.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs that are widely used in clinical practice, and many of them 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. About 20% of inpatients receive NSAIDs.

The great "popularity" of non-steroidal anti-inflammatory drugs is due to the fact that they have anti-inflammatory, analgesic and antipyretic effects and bring relief to patients with the corresponding symptoms (inflammation, pain, fever), which are noted in many diseases.

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

About 25 years ago, only 8 groups of NSAIDs were developed. Today, this number has increased to 15. However, even doctors cannot name the exact number. Having appeared on the market, NSAIDs quickly gained wide popularity. Drugs have replaced opioid analgesics. Because they, unlike the latter, did not provoke respiratory depression.

Non-steroidal anti-inflammatory drugs are an extensive and chemically diverse group of drugs. NSAIDs of the old and new generation are divided into non-acid derivatives and acids.

Classification of non-steroidal anti-inflammatory drugs (NSAIDs) by activity and chemical structure

NSAIDs of the latest generation

All NSAIDs are divided into 2 large groups: inhibitors of cyclooxygenase type 1 and type 2, abbreviated as COX-1 and COX-2.

COX-2 inhibitors: NSAIDs of a new generation

This group of NSAIDs has a more selective effect on the body, due to which there are much fewer side effects on the part of the gastrointestinal tract, and the tolerability of these drugs increases. In addition, it is generally accepted that some COX-1 preparations can adversely affect the condition of cartilage tissue. Medicines from the COX-2 group are devoid of this feature, and it is believed that they are good drugs for arthrosis.

However, not everything is so rosy: many of the funds in this group, without affecting the stomach, can adversely affect the cardiovascular system.

The drugs in this group include medicines such as meloxicam, nimesulide, celecoxib, etoricoxib (Arcoxia) and others.

In recent years, new generation drugs have been created and are widely used in medicine. This group of so-called selective drugs NSAIDs. Their very important advantage is that they have a more selective effect on the body, i. they treat what needs to be treated, and at the same time cause less harm to healthy organs. So side effects on the part of the gastrointestinal tract, blood clotting disorders are much less observed, and the tolerance of these drugs increases. In addition, new generation NSAIDs can be actively used in the treatment of joint diseases, in particular, arthritis, since, unlike non-selective NSAIDs, they do not have a negative effect on articular cartilage cells, and therefore are chondroneutral.

Such modern NSAIDs are Nimesulide, Meloxicam, Movalis, Artrozan, Amelotex, Nise and others.

Non-steroidal anti-inflammatory drugs are widely used in clinical practice. Non-steroidal anti-inflammatory drugs for osteochondrosis are very effective in relieving pain. Often they are used as an antipyretic and to relieve pain after surgery.

List of popular and effective non-steroidal anti-inflammatory drugs:

Nimesulide (Nise, Nimesil)

It has been used with great success in the treatment of vertebrogenic back pain, arthritis, etc. Removes inflammation, hyperemia, normalizes temperature. The use of nimesulide quickly leads to a reduction in pain and improved mobility. It is also used as an ointment for application to the problem area. If this causes itching and redness, this is not a contraindication to use. Nimesulide is better not to use in patients during breastfeeding, as well as in the last trimester of pregnancy.

Celecoxib

This drug greatly alleviates the patient's condition with osteochondrosis, arthrosis and other diseases, relieves pain well and effectively fights inflammation. Side effects on the digestive system from celecoxib are minimal or absent at all.

Meloxicam

Also known as movalis. It has an antipyretic, well-marked analgesic and anti-inflammatory effect. The main advantage of this remedy is that, with regular medical supervision, it can be taken for a fairly long period of time.

Meloxicam is available as a solution for intramuscular injection, in tablets, suppositories and ointments. Meloxicam (Movalis) tablets are very convenient in that they are long-acting, and it is enough to take one tablet during the day.

Xefocam

This is a very strong analgesic drug - it can be compared with morphine in terms of the strength of the effect - the effect lasts about 12 hours. At the same time, there was no dependence on the part of the central nervous system and addiction to the drug.

Osteoarthritis, rheumatoid arthritis and other diseases of the joints and spine, occurring with pain and inflammation.

Peculiarities: all drugs in this group act on a similar principle and cause three main effects: analgesic, anti-inflammatory and antipyretic.

In different drugs, these effects are expressed to varying degrees, so some drugs are better suited for the long-term treatment of joint diseases, others are mainly used as painkillers and antipyretics.

The most common side effects: allergic reactions, nausea, abdominal pain, erosion and ulcers of the mucous membrane of the gastrointestinal tract.

Main contraindications: individual intolerance, exacerbation of peptic ulcer of the stomach and duodenum.

Important information for the patient:

Drugs that have a pronounced analgesic effect and a significant number of side effects (diclofenac, ketorolac, nimesulide and others) can only be used as directed by a doctor.

Among non-steroidal anti-inflammatory drugs, a group of so-called "selective" drugs is distinguished, which are less likely to have side effects from the gastrointestinal tract.

Even over-the-counter pain relievers cannot be used long-term. If they are required frequently, several times a week, it is necessary to be examined by a doctor and treated according to the recommendations of a rheumatologist or neurologist.

In some cases, long-term use of this group of drugs requires additional intake of proton pump inhibitors that protect the stomach.

Remember, self-medication is life-threatening, consult a doctor for advice on the use of any medications.

Non-steroidal anti-inflammatory drugs are a large group of pharmacological agents characterized by pronounced anti-inflammatory, analgesic and antipyretic effects.

Note:nonsteroidal anti-inflammatory drugs (NSAIDs) are abbreviated as NSAIDs or NSAIDs.

Important:such a common pain reliever and howParacetamol , does not belong to the group of NSAIDs, because it does not affect the inflammatory process, and is used only to relieve symptoms.

How do non-steroidal anti-inflammatory drugs work?

The action of NSAIDs is aimed at inhibiting the production of the cyclooxygenase (COX) enzyme, which in turn is responsible for the synthesis of biologically active substances - thromboxane, prostaglandins (PG) and prostacyclins, which act as inflammatory mediators. A decrease in the level of PG production contributes to the reduction or complete relief of the inflammatory process.

Different varieties of cyclooxygenase are present in a variety of organs and tissues. The COX-1 enzyme, in particular, is responsible for the normal blood supply to the mucous membrane of the digestive organs and maintaining a stable pH of the stomach by reducing the synthesis of hydrochloric acid.

COX-2 is normally present in tissues in small amounts, or not detected at all. An increase in its level is directly related to the development of inflammation. Drugs that selectively inhibit the activity of this enzyme act directly on the pathological focus. Due to this, there is no indirect negative effect on the organs of the digestive tract.

Note:COX-3 does not affect the dynamics of the inflammatory process, but is responsible for the development of pain and febrile reaction due to hyperthermia (rise in overall body temperature).

Classification of non-steroidal anti-inflammatory drugs for joints

According to the selectivity of the impact, all NSAIDs are divided into:

1. Non-selective, inhibiting all types of COX, but mainly - COX-1.
2. Non-selective, affecting both COX-1 and COX-2.
3. Selective COX-2 inhibitors.

The first group includes:

• Acetylsalicylic acid;
• Piroxicam;
• Indomethacin;
• Naproxen;
• Diclofenac;
• Ketoprofen.

The representative of the second category is Lornoxicam.

The third group includes:

• Nimesulide;
• Rofecoxib;
• Meloxicam;
• Celecoxib;
• Etodolac.

Important:Acetylsalicylic acid and Ibuprofen mainly reduce body temperature, and Ketorolac (Ketorol) reduces the intensity of pain. To reduce inflammation of the joints, they are ineffective, and can only be used for symptomatic therapy.

Pharmacokinetics

Systemic NSAIDs when taken per os are very rapidly absorbed. They are characterized by very high bioavailability (it varies from 70 to 100%). The process of absorption slows down somewhat with an increase in the pH of the stomach. The highest content in the blood serum is reached 1-2 hours after ingestion.

If the drug is administered intramuscularly, it is conjugated (connected) with plasma proteins (the level of binding is up to 99%). The resulting active complexes freely penetrate into the joint tissues and synovial fluid, mainly concentrating in the focus of inflammation.

The active substances of NSAIDs and their metabolites are excreted by the kidneys.

Contraindications

It is highly undesirable for women to use systemic NSAIDs (enteral or parenteral forms) for the treatment of joints during pregnancy. Some drugs in this category may be prescribed by the attending physician if the intended benefit to the mother is higher than the possible risk to the fetus.

Contraindications also include:

• individual hypersensitivity to the drug;
• and erosion of the digestive tract;
• leukopenia;
• thrombopenia;
• and/or liver failure.

Side effects of non-steroidal anti-inflammatory drugs

Drugs that inhibit COX-1 can provoke the development or exacerbation of gastrointestinal diseases, including hyperacid and ulcerative-erosive lesions of the walls of the digestive tract.

Often noted side effects are dyspeptic disorders (, severity "in the pit of the stomach",).

Regular use of NSAIDs or exceeding the recommended dosages often causes a violation of blood clotting, manifested by bleeding. With prolonged use, a decrease in the number of blood cells is possible, up to the development of such a serious disease as aplastic anemia.

Many NSAIDs have a nephrotoxic effect, leading to a decrease in the functional activity of the kidneys, and provoking. With prolonged use, they contribute to the development of nephropathy. Drugs can have a negative effect on liver function.

There is also a possibility of developing bronchospasm while taking non-steroidal anti-inflammatory drugs for the treatment of joints.

The specifics of anti-inflammatory therapy

All means of this group should be used only as directed by a doctor, followed by control of the dynamics of the inflammatory process. The patient should immediately notify the attending physician about all negative changes in the condition. Therapy is carried out at the lowest effective doses for the shortest possible time!

Preparations in the form of capsules or tablets should preferably be taken after meals with plenty of liquid (preferably pure water). So you can reduce the damaging effect of drugs on the mucous membrane of the digestive tract.

With the local use of anti-inflammatory gels and ointments, the likelihood of side effects is almost zero, since the active ingredients almost do not enter the systemic circulation.

Selected NSAIDs for the treatment of joint inflammation

When choosing a drug, the doctor takes into account the nature of the disease, the severity of the pathological process, as well as the individual characteristics of the patient's body (including the presence of chronic diseases and age).

Most often used:

Indomethacin

This medicine is available in the form of capsules and tablets. Standard single dosages are from 25 to 50 mg, and the frequency of administration is 2-3 times a day. Against the background of taking Indomethacin, the side effects characteristic of NSAIDs are especially common, so preference is increasingly given to other, safer means.

diclofenac

Analogues of this drug are Voltaren, Naklofen and Diklak. Diclofenac is produced by pharmacological companies in the form of tablets and capsules, injection solution, gels for application in the area of ​​the diseased joint, and in the form of suppositories. Inside, it is prescribed at a dose of 50-75 mg 2-3 times a day, and the daily dose should not exceed 300 mg. The solution is injected intramuscularly (in the buttock), 3 ml each, observing the time interval between at least 12 hours. Injections are carried out in courses of no more than 5-7 days. The gel should be applied in the projection of the affected joint 2-3 times a day.

Etodolac

The analogue of the drug is Etol Fort. Etodolac is available in 400 mg capsules. It is selective, preferentially inhibiting the activity of COX-2. The drug is prescribed for both emergency care and course therapy, ankylosing spondylitis and osteoarthritis. Single dose - 1 capsule (1-3 times a day after meals). If there is a need for a course, the attending physician adjusts the dosage every 2-3 weeks after assessing the dynamics of the process. Side effects are relatively rare.

Important:Etodolac may reduce the effectiveness of some blood pressure medicines.

Aceclofenac

Analogues of the drug - Zerodol, Diclotol and Aertal. Aceclofenac is a good alternative to Diclofenac in terms of effectiveness. It is produced in tablets of 100 mg, and is used both for urgent relief of symptoms and for course treatment. It is advisable to take tablets 1 pc. 2 times a day with meals. Against the background of admission, pain in the abdominal region is also possible (symptoms are observed in almost 10% of patients), so it is advisable to treat the joints with minimally effective doses and short courses.

Piroxicam

The drug is available in tablets of 10 mg and in the form of a solution for injection; analogue of Piroxicam - Fedin-20. The active substance penetrates into the synovial fluid of the joints, acting directly in the focus of inflammation. Depending on the nosological form and the activity of the process (severity of symptoms), dosages vary from 10 to 40 mg per day (taken simultaneously or divided into several doses). The analgesic effect develops already 30 minutes after taking the tablets and lasts an average of a day.

Tenoxicam

Tenoxicam (Texamen-L) is sold as a powder for the preparation of an injection solution for intramuscular administration. The standard dosage is 2 ml, which corresponds to 20 mg of the active substance (administered 1 time per day). When during the period of exacerbation, a course of treatment is recommended for 5 days (up to 40 mg is administered to the patient daily).

Lornoxicam

The medicine is available in tablets (4 and 8 mg each), as well as in the form of a powder (8 mg) for dilution. Analogues - Lorakam, Ksefokam and Larfiks. The usual dosage of Lornoxicam is 8 to 16 mg 2-3 times a day before meals. Tablets should be taken with a large amount of liquid. The solution is intended for intravenous or intramuscular administration of 8 mg 1-2 times a day. The maximum allowable daily dose for the injection form is 16 mg.

Important:special care in the treatment of Loraxicam should be observed in patients suffering from diseases of the stomach.

Nimesulide

The most common analogues of this drug include Nimesil, Remesulide and Nimegezik. This NSAID is available in the form of granules for suspension, 100 mg tablets and gel for topical external use. The recommended dose is 100 mg 2 times a day after meals. The gel is recommended to be applied to the skin in the projection of the affected joint with light rubbing movements 2-4 times a day.

Important:patients with renal or hepatic insufficiency are assigned smaller doses. The drug has a hepatotoxic effect.

Meloxicam

Other trade names for Meloxicam are Melox, Recoxa, Movalis and Revmoxicam. This remedy for the treatment of inflammation of the joints is produced in the form of tablets of 7.5 or 15 mg, as well as in the form of a solution in ampoules of 2 ml (corresponding to 15 mg of the active ingredient) and suppositories for rectal administration.

The drug selectively inhibits COX-2; it rarely has a negative effect on the stomach and does not lead to nephropathy. At the very beginning of the course of treatment, Meloxicam is prescribed for intramuscular injection (1-2 ml each), and as the activity of the inflammatory process decreases, the patient is prescribed tablets. A single dosage of this NSAID is 7.5 mg, and the frequency of administration is 1-2 times a day.

Rofecoxib

Rofecoxib (another trade name is Denebol) is sold in pharmacies as an injection solution (2 ml ampoules contain 25 mg of the active substance) and in tablets. The degree of negative impact of this NSAID on the kidneys and gastrointestinal tract of this drug is extremely low. The standard therapeutic dose is 12.5-25 mg. The frequency of admission (or intramuscular injection) - 1 time per day. With intense joint pain at the beginning of the course, the patient is prescribed 50 mg of Rofecoxib.

Celecoxib

This selective COX-2 inhibitor is produced in the form of capsules containing 100 or 200 mg of the active substance. Analogues of Celecoxib are Flogoxib, Revmoksib, Celebrex and Zycel. NSAIDs rarely provoke the development or exacerbation of gastrointestinal pathologies if the prescribed treatment regimen is strictly followed. The recommended daily dose is 100-200 mg (at the same time or in 2 doses), and the maximum is 400 mg.

2383 0

Non-steroidal anti-inflammatory drugs (NSAIDs, NSAIDs) are one of the main drugs used to treat inflammatory joint diseases.

They are prescribed in periodic courses for chronic processes, if necessary - for exacerbations of diseases and acute inflammatory processes. NSAIDs exist in various dosage forms - tablets, ointments, injection solutions. The choice of the necessary remedy, dosage and frequency of its use, should be carried out by the doctor.

NSAIDs - what is this group of drugs?

The group of NSAIDs is quite extensive, and includes drugs of various chemical structures. The name "non-steroidal" shows their difference from another large group of anti-inflammatory drugs - corticosteroid hormones.

The common properties of all drugs in this group are their three main effects - anti-inflammatory, analgesic, antipyretic.

This is the reason for another name for this group - non-narcotic analgesics, as well as a huge breadth of their application. These three effects are expressed differently with each drug, so they cannot be completely interchangeable.

Unfortunately, all drugs of the NSAID group have similar side effects. The most famous of them are the provocation of gastric ulcer, liver toxicity and oppression of hematopoiesis. For this reason, you should not exceed the dosage indicated in the instructions, and also take these drugs if you suspect these diseases.

It is impossible to treat abdominal pain with such medicines - there is always a risk of worsening your condition. Various dosage forms of NSAIDs have been invented to improve their effectiveness in each specific situation and reduce potential harm to health.

History of discovery and formation

The use of herbal remedies with anti-inflammatory, antipyretic and analgesic effects is described in the writings of Hippocrates. But the first accurate description of the effect of NSAIDs dates back to the 18th century.

In 1763, the English physician and priest Edward Stone wrote in a letter to the chairman of the Royal Society of London that an infusion of willow bark growing in England has antipyretic properties, described the recipe for its preparation and method of application in feverish conditions.

Almost half a century later, in France, I. Lear isolated a substance from the willow bark that determined its medicinal properties. By analogy with the Latin name for willow is salix, he called this substance salicin. This was the prototype of modern acetylsalicylic acid, which was learned to be obtained chemically in 1839.

The industrial production of NSAIDs was launched in 1888, the first drug that appeared on the pharmacy shelves was acetylsalicylic acid under the trade name Aspirin, produced by Bayer, Germany. She still owns the rights to the Aspirin trademark, so other manufacturers produce acetylsalicylic acid under an international non-proprietary name or create their own (for example, Upsarin).

More recent developments have led to the emergence of a number of new drugs. Research continues to this day, more and more safe and effective means are being created. Oddly enough, but the first hypothesis about the mechanism of action of NSAIDs was formulated only in the 20s of the XX century. Prior to this, drugs were used empirically, their dosages were determined by the patient's well-being, and side effects were not well studied.

Pharmacological properties and mechanism of action

The mechanism of the development of an inflammatory reaction in the body is quite complex, and includes a chain of chemical reactions that trigger each other. One of the groups of substances involved in the development of inflammation is prostaglandins (they were first isolated from prostate tissue, hence the name). These substances have a dual function - they are involved in the formation of protective factors of the gastric mucosa and in the inflammatory process.

The synthesis of prostaglandins is carried out by two types of the cyclooxygenase enzyme. COX-1 synthesizes "gastric" prostaglandins, and COX-2 - "inflammatory", and is normally inactive. It is in the activity of COX that NSAIDs interfere. Their main effect - anti-inflammatory - is due to the inhibition of COX-2, and the side effect - a violation of the protective barrier of the stomach - inhibition of COX-1.

In addition, NSAIDs interfere quite strongly in cellular metabolism, which is the reason for their analgesic effect - they disrupt the conduction of nerve impulses. This is also the cause of lethargy, as a side effect of taking NSAIDs. There is evidence that these drugs stabilize lysosome membranes by slowing down the release of lytic enzymes.

Entering the human body, these drugs are absorbed mostly in the stomach, in small quantities - from the intestines.

Absorption varies, with new drugs bioavailability can reach 96%. Enteric-coated drugs (Aspirin-cardio) are absorbed much worse. The presence of food does not affect the absorption of drugs, but since they increase acidity, it is advisable to take them after meals.

Metabolism of NSAIDs occurs in the liver, which is associated with their toxicity to this organ and the inability to use in various liver diseases. A small part of the received dose of the drug is excreted through the kidneys. Current developments in the field of NSAIDs are aimed at reducing their effect on COX-1 and hepatotoxicity.

Indications for use - scope

Diseases and pathological conditions in which NSAIDs are prescribed are diverse. Tablets are prescribed as an antipyretic for infectious and non-infectious diseases, as well as a remedy for headache, dental, joint, menstrual and other types of pain (except for abdominal pain, if its cause is not clarified). In children, NSAID suppositories are used to relieve fever.

Intramuscular injections of NSAIDs are prescribed as an analgesic and antipyretic agent in a serious condition of the patient. They are necessarily part of the lytic mixture - a combination of drugs that allow you to quickly bring down a dangerous temperature. Intra-articular injections treat severe joint damage caused by inflammatory diseases.

Ointments are used for local effects on inflamed joints, as well as for diseases of the spine, muscle injuries to relieve pain, swelling and inflammation. Ointments can only be applied to healthy skin. In diseases of the joints, all three dosage forms can be combined.

The most famous drugs of the group

The very first NSAID to be marketed was acetylsalicylic acid under the brand name Aspirin. This name, despite being commercial, is strongly associated with the drug. It is prescribed to reduce fever, relieve headaches, in small doses - to improve the rheological properties of blood. In diseases of the joints is rarely used.

Metamizole (Analgin) - no less popular than aspirin. It is used to relieve pain of various origins, including articular. Banned in many European countries, as it has a strong inhibitory effect on hematopoiesis.

- one of the most popular drugs for the treatment of joints. Included in many ointments, available in and. It has a pronounced anti-inflammatory and analgesic effect, with almost no systemic effect.

Side effects

As with any drug, there are numerous side effects associated with taking NSAIDs. The most famous among them is ulcerogenic, i.e. provoking an ulcer. It is caused by inhibition of COX-1 and is almost completely absent in selective NSAIDs.

Acid derivatives have an additional ulcerogenic effect due to an increase in the acidity of gastric juice. Most NSAIDs are contraindicated in gastritis with high acidity, peptic ulcer of the stomach and duodenum, GERD.

Another common effect is hepatotoxicity. It can manifest itself as pain and heaviness in the abdomen, digestive disorders, sometimes - a short-term icteric syndrome, skin itching, and other manifestations of liver damage. For hepatitis, cirrhosis and liver failure NSAIDs are contraindicated.

Inhibition of hematopoiesis, which, when the dosage is constantly exceeded, leads to the development of anemia, in some cases - pancytopenia (lack of all blood cells), impaired immunity, bleeding. NSAIDs are not prescribed for severe diseases of the bone marrow and after its transplantation.

Effects associated with impaired well-being - nausea, weakness, inhibition of reaction, decreased attention, fatigue, allergic reactions up to asthmatic attacks - occur individually.

Classification of NSAIDs

To date, there are many drugs of the NSAID group, and their classification should help the doctor in choosing the most appropriate drug. In this classification, only international non-proprietary names are indicated.

Chemical structure

According to the chemical structure, such non-steroidal anti-inflammatory drugs are distinguished.

Acids (absorbed in the stomach, increase acidity):

• salicylates:
• pyrazolidins:
• indoleacetic acid derivatives:
• derivatives of phenylacetic acid:
• oxicams:
• propionic acid derivatives:

Non-acid derivatives (do not affect the acidity of gastric juice, are absorbed in the intestines):

• alkanones:
• sulfonamide derivatives:

According to the effect on COX-1 and COX-2

Non-selective - inhibit both types of enzyme, these include most of the NSAIDs.

Selective (coxibs) inhibit COX-2, do not affect COX-1:

• Celecoxib;
• Rofecoxib;
• Valdecoxib;
• Parecoxib;
• Lumiracoxib;
• Etoricoxib.

Selective and non-selective NSAIDs

Most NSAIDs are non-selective because they inhibit both types of COX. Selective NSAIDs are more modern drugs that act mainly on COX-2, and minimally affect COX-1. This reduces the risk of side effects.

However, the full selectivity of the action of drugs has not yet been achieved, and the risk of side effects will always be.

New generation drugs

The new generation includes not only selective, but also some non-selective NSAIDs that are highly effective, but less toxic to the liver and hematopoietic system.

Non-steroidal anti-inflammatory drugs of the new generation:

• - has an extended period of action;
• - has the strongest analgesic effect;
• - prolonged period of action and a pronounced analgesic effect (comparable to morphine);
• Rofecoxib- the most selective drug, approved for patients with gastritis, peptic ulcer without exacerbation.

Non-steroidal anti-inflammatory ointments

The use of NSAID preparations in the form for topical application (ointments and gels) has a number of advantages, first of all, the absence of a systemic effect and a targeted effect on the focus of inflammation. In diseases of the joints, they are almost always prescribed. The most popular ointments:

• Indomethacin;

NSAIDs in tablets

The most common dosage form of NSAIDs is tablets. It is used to treat various diseases, including articular.

Of the advantages - they can be prescribed for the treatment of manifestations of a systemic process that captures several joints. Of the shortcomings - pronounced side effects. The list of NSAID drugs in tablets is quite long, these include:

General application features

Non-steroidal anti-inflammatory drugs for the treatment of joints are prescribed in courses or as needed, depending on the course of the disease.

The main feature of their use is that it is not necessary to take several drugs of this group in the same dosage form at the same time (especially for tablets), since this increases side effects, and the therapeutic effect remains the same.

It is permissible to use different dosage forms at the same time, if necessary. It is important to remember that contraindications to taking NSAIDs are common to most drugs in the group.

NSAIDs remain the most important treatment for joints. They are difficult, and sometimes almost impossible to replace by any other means. Modern pharmacology is developing new drugs from this group in order to reduce the danger of their side effects and increase the selectivity of action.