Comparison of non-steroidal anti-inflammatory drugs. Indications for use of NSAIDs

NSAIDs today are a dynamically developing class of drugs. This is due to the wide range of applications of this pharmaceutical group, which has antipyretic and analgesic activity.

NSAIDs are a whole group of drugs

NSAIDs block the action of the enzyme cyclooxygenase (COX), inhibiting the synthesis of prostaglandins from arachidonic acid. Prostaglandins in the body are mediators of inflammation, lower the threshold of sensitivity to pain, inhibit lipid peroxidation and inhibit neutrophil aggregation.
The main effects of NSAIDs include:

• Anti-inflammatory. Suppress the exudative phase of inflammation, and, to a lesser extent, the proliferative phase. Diclofenac, Indomethacin are the most powerful this effect drugs. But the anti-inflammatory effect is less pronounced than that of glucocorticosteroids.
  Practitioners use a classification according to which all NSAIDs are divided into: drugs with high anti-inflammatory activity and drugs with weak anti-inflammatory activity. Aspirin, Indomethacin, Diclofenac, Piroxicam, Ibuprofen and many others have high activity. This group includes a large number of various drugs. Paracetamol, Metamizole, Ketorolac and some others have low anti-inflammatory activity. The group is small.
• Painkiller. Most pronounced in Diclofenac, Ketoralac, Metamizol, Ketaprofen. Used for pain of low and medium intensity: dental, muscle, headache. Effective for renal colic, because Not . Compared with narcotic analgesics(morphine group), do not have a depressing effect on the respiratory center, and are not addictive.
• Antipyretic. All drugs in varying degrees have this property. But it only appears in the presence of fever.
• Anti-aggregation. Manifests itself due to suppression of thromboxane synthesis. This effect is most pronounced with Aspirin.
• Immunosuppressive. It manifests itself secondarily due to deterioration of the permeability of capillary walls.

Indications for use of NSAIDs

The main indications include:

• Rheumatic diseases. Includes rheumatism, rheumatoid arthritis, ankylosing spondylitis, gouty and psoriatic arthritis, and Reiter's disease. For these diseases, the use of NSAIDs is symptomatic, without affecting the pathogenesis. That is, slow down the development of the destructive process when rheumatoid arthritis, taking NSAIDs cannot prevent joint deformation. But patient complaints of pain, stiffness in the joints initial stages diseases become less common.
• Diseases of the musculoskeletal system of a non-rheumatic nature. This includes injuries (bruises, sprains), myositis, tendovaginitis. For the above diseases, NSAIDs are used orally, in the form of injections. And external agents (ointments, creams, gels) containing active ingredients this group.
• Neurological diseases. Lumbago, radiculitis, myalgia. Combinations of various forms of drug release are often prescribed simultaneously (ointment and tablets, injections and gel, etc.)
• Renal, . Drugs from the NSAID group are effective for all types of colic, because... do not cause additional spasm of smooth cell muscle structures.
• Pain symptoms of various etiologies. Relief of pain in postoperative period, toothache and headache.
• Dysmenorrhea. NSAIDs are used to relieve pain in primary dysmenorrhea and to reduce the amount of blood loss. Naproxen and Ibuprofen have a good effect, which are recommended to be taken on the eve of menstruation and for three days thereafter. Such short-term courses prevent the occurrence of unwanted effects.
• Fever. Antipyretic drugs are recommended to be taken at body temperatures above 38.5 °C.
• Prevention of thrombosis. To prevent the formation of blood clots, low dosage of Acetylsalicylic acid is used. Prescribed to prevent heart attacks, strokes with various forms coronary heart disease.

Undesirable effects and contraindications

NSAIDs have a negative effect on:

1. and intestines
2. Liver
3. Kidneys
4. Blood
5. Nervous system

The most common area that suffers from taking NSAIDs is the stomach. This manifests itself as nausea, diarrhea, pain in the epigastric region and other dyspeptic complaints. There is even such a syndrome - NSAID gastropathy, the occurrence of which is directly related to the use of NSAIDs. Elderly patients, with a history of gastric ulcers, and concurrently taking glucocorticosteroid drugs are especially at risk of pathology.

NSAIDs - different drugs, but their effect is the same!

The likelihood of developing NSAID gastropathy increases with long-term use of drugs in high doses, as well as when taking two or more NSAIDs. Lansoprazole, Esomeprazole and other inhibitors are used to protect the gastric mucosa proton pump. may be in the form of severe toxic hepatitis, or may manifest itself transient disturbances functions with increased levels of transaminases in the blood.

The liver is most often affected when taking Indomethacin, Phenylbutazone, and Aspirin. On the part of the kidneys, decreased diuresis, acute renal failure, and nephrotic syndrome may develop as a result of damage to the kidney tubules. The greatest danger is represented by Ibuprofen and Naproxen.

In the blood, clotting processes are disrupted and anemia occurs. Diclofenac, Piroxicam, Butadione are dangerous in terms of side effects from the blood system. Often unwanted effects from the nervous system occur when taking Aspirin, Indomethacin. And they manifest themselves as headache, tinnitus, nausea, and sometimes vomiting, mental disorders. Taking NSAIDs is contraindicated in the case.

Drugs of the NSAID group are the most popular and used group by the population medicines. They relieve pain and inflammation well, and are excellent antipyretics. More than 30 million people use them every year, and many of these drugs are available in pharmacies without a prescription.

What are NSAIDs?

NSAIDs are non-steroidal anti-inflammatory drugs that are widely used in medicine not only for adults, but also for children. The term “non-steroidal” emphasizes that these drugs do not relate to hormones, therefore, in most cases, even with long-term treatment they do not cause withdrawal syndrome, which manifests itself in extreme sharp deterioration the patient’s condition after stopping taking one or another drug of this group.

Classification of NSAIDs

Today there are a huge number of drugs belonging to this group, but for convenience they are all divided into two large subgroups:

1. With a predominant anti-inflammatory effect.
2. With a pronounced antipyretic and analgesic effect (“non-narcotic analgesics”).

Drugs of the first group are prescribed mainly for diseases of the joints, including diseases of a rheumatic nature, and the second group - for acute respiratory viral infections and other infectious diseases, injuries, in the postoperative period, etc. However, even drugs belonging to the same group differ from each other in their effectiveness, the presence adverse reactions and the number of contraindications to their use.

Depending on the route of administration, NSAIDs are distinguished:

• injection;
• in the form of capsules or tablets for oral use;
• suppositories (for example, rectal suppositories);
• creams, ointments, gels for external use.

Mechanism of action

Under certain conditions, the body produces Various types prostaglandins, which cause an increase in temperature and increase the intensity inflammatory reactions. The leading mechanism of action of NSAIDs is the blocking (inhibition) of the cyclooxygenase (COX) enzyme, which is responsible for the production of these substances in the body, which in turn leads to a decrease in body temperature and a decrease in inflammation.

There are 2 types of COX in the body:

• COX1 - production of prostaglandins that protect the mucous membrane of the stomach and intestines from damage, controlling blood flow in the kidneys;
• COX2 - the synthesis of prostaglandins that cause inflammation and fever.

The first generations of non-steroidal drugs blocked both types of COX, which led to the formation of ulcers and other damage to the gastrointestinal tract. Then they were created selective NSAIDs, which block predominantly COX2, and therefore can be used in patients with diseases of the digestive system. However, they are not able to prevent platelet aggregation, and therefore are not a complete replacement for first-generation drugs.

Effect on the body

1. Relieving inflammation. IN to the greatest extent Diclofenac, indomethacin and phenylbutazone have anti-inflammatory effects.
2. Decline elevated temperature. Aspirin, mefenamic acid and nimesulide effectively reduce temperatures.
3. Analgesic effect. Medicines that include ketorolac, diclofenac, metamizole, analgin or ketoprofen have proven themselves as analgesics.
4. Preventing platelets from sticking together (anti-aggregation effect). In cardiological practice, aspirin is prescribed for this purpose in small doses (for example, aspecard or cardiomagnyl).

Sometimes non-steroidal drugs, when used for a long time, can have an immunosuppressive effect, which is used in the treatment of certain rheumatic diseases.

Indications

1. Rheumatism, rheumatoid arthritis, ankylosing spondylitis, different kinds arthritis.
2. Inflammatory diseases of the muscles and spine - myositis, injuries of the musculoskeletal system, tendovaginitis, degenerative diseases of bones and joints.
3. Colic: hepatic, renal.
4. Inflammation of the nerves or roots of the spinal nerves - sciatica, sciatica, trigeminal neuralgia.
5. Infectious and non-communicable diseases accompanied by elevated temperature.
6. Toothache.
7. Dysmenorrhea (painful periods).

Application features

1. Personal approach. Each patient needs to choose an anti-inflammatory drug non-steroidal drug, which will be well tolerated by the patient and cause minimal side effects.
2. To reduce temperature, NSAIDs are prescribed in moderate therapeutic doses, and in case of planned long-term use, first use minimum doses with their subsequent increase.
3. As a rule, almost all tablet forms of drugs are prescribed after meals with the obligatory intake of drugs that protect the gastric mucosa.
4. If low-dose aspirin is used to thin the blood, it is taken after dinner.
5. Most NSAIDs should be taken with at least ½ glass of water or milk.

Side effects

1. Digestive organs. NSAIDs—gastroduodenopathy, ulcers and erosions of the mucous membrane of the duodenum or stomach. The most unreliable in this regard are piroxicam, aspirin, and indomethacin.
2. Kidneys. “Analgesic nephropathy” (interstitial nephritis) develops, renal blood flow worsens, and renal vessels narrow. The drugs with the greatest toxicity from this group are phenylbutazone, indomethacin.
3. Allergic reactions. Can be observed when taking any drugs in this group.
4. Less commonly, disorders of blood clotting, liver function, bronchospasm, agranulocytosis or aplastic anemia may be observed.

List of drugs used during pregnancy

Almost all experts recommend that pregnant women refrain from taking non-steroidal drugs. However, in some cases and for health reasons, it is still necessary to take them, when the benefits of their use far outweigh their possible negative impact.

It should be remembered that even the “safest” of them can cause premature closure of the ductus bollus in the fetus, nephropathy and premature birth, therefore in the third trimester NSAID drugs are not assigned at all.

Non-steroidal drugs that can be prescribed for health reasons:

• aspirin;
• ibuprofen;
• diclofenac;
• indomethacin;
• naproxen;
• ketorolac, etc.

In any case, pregnant women should not take these medications on their own, but only if they are prescribed by a doctor.

CHAPTER 25. ANTI-INFLAMMATORY DRUGS

CHAPTER 25. ANTI-INFLAMMATORY DRUGS

Inflammation is one of the pathological processes that characterize numerous diseases. From a general biological point of view, this is a protective-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 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

By chemical structure NSAIDs are derivatives of weak organic acids. These drugs, accordingly, have similar pharmacological effects.

The classification of modern NSAIDs by chemical structure is presented in Table. 25-1.

However clinical significance It has NSAID classification, based on their selectivity for COX isoforms, presented in table. 25-2.

The main pharmacological effects of NSAIDs include:

Anti-inflammatory effect;

Analgesic (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

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

In 1971, a group of researchers from Great Britain 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 hypothesized that it was 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 pathology of these organs is a characteristic side effect that occurs in the process NSAID treatment.

In the early 90s, new facts emerged 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, cellular apoptosis, etc. The existence of two isoforms of COX was discovered: a structural isoenzyme (COX-1), which regulates the production of prostaglandins involved in ensuring the normal (physiological) functional activity of cells, and an inducible isoenzyme (COX -2), the expression of which 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 synthesized active substances participating in the physiological processes of the body (prostacyclin, thromboxane A 2, gastroprotective and vasodilating prostaglandins, etc.). Thus, the metabolism of arachidonic acid occurs in two ways (Fig. 25-1):

The cyclooxygenase pathway, as a result of which prostaglandins, including prostacyclin and thromboxane A2, 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 threshold pain sensitivity;

Increase the sensitivity of the vascular wall to other inflammatory mediators (histamine, serotonin), causing local vasodilation (redness), increased vascular permeability (edema);

They increase the sensitivity of the hypothalamic thermoregulation centers 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 has been established - COX-1 and COX-2 (Table 25-3). COX-1 is an isoform of cyclooxygenase expressed in normal conditions and 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. The analgesic, antipyretic and anti-inflammatory effects of NSAIDs are due to inhibition of COX-2, while adverse drug reactions (ulcerogenicity, hemorrhagic syndrome, bronchospasm, tocolytic effect) are due to inhibition of COX-1.

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 “small” differences are still noted (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 the following structure:

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

It is known that there are other mechanisms of anti-inflammatory action of NSAIDs:

It has been established that the anionic properties of NSAIDs allow them to penetrate 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 proliferation and synthesis of IL-2;

NSAIDs interrupt neutrophil activation at the G protein level. Based on their anti-inflammatory activity, NSAIDs can be classified

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

Those NSAIDs that, due to their chemical structure neutral, accumulate less in inflammatory tissue, penetrate the blood-brain barrier faster 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 antiexudative 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 A2. Thus, acetylsalicylic acid irreversibly inhibits COX-1 in platelets. When taking a single dose of the drug, a clinically significant decrease in platelet aggregation in the patient is observed for 48 hours or more, which significantly exceeds the time of its removal from the body. The restoration of aggregation capacity after irreversible inhibition of COX-1 by acetylsalicylic acid occurs, apparently, due to the appearance of new platelet populations 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 circulating substances is observed. vascular bed platelets.

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

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

Reducing the formation of hydroheptanotrienoic acid (reduces the chemotaxis of T-lymphocytes, eosinophils and polymorphonuclear leukocytes at the site of inflammation);

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

The most pronounced desensitizing effect is found in indomethacin, mefenamic acid, diclofenac and acetylsalicylic acid.

Pharmacokinetics

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

The half-life for most NSAIDs is 2-4 hours. However, drugs that circulate in the body for a long time, such as phenylbutazone and piroxicam, can be prescribed 1-2 times a day. All NSAIDs, with the exception of acetylsalicylic acid, have 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 the 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 joint syndromes to a certain extent associated with the rate of accumulation and the concentration of NSAIDs in synovial fluid, which increases gradually and persists much longer than in the blood after stopping the use of the drug. However, there is no direct correlation between their concentrations 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 renal excretory function 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 urine pH. Since many drugs in this group are weak organic acids, they are eliminated faster when alkaline reaction urine than with acidic urine.

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

Indications for use

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

A significant limitation when choosing 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 of the duodenum), detected by 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 any special clinical manifestations), mainly with a widespread erosive-ulcerative process, the risk of bleeding increases.

According to the analysis carried out by the Control Committee medicines(FDA), gastrointestinal tract damage associated with NSAIDs is the cause of 100,000-200,000 hospitalizations and 10,000-20,000 deaths annually.

The mechanism of development of NSAID gastropathy is based on 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 help increase the resistance of the mucous membrane to such damaging agents as ethanol, bile acids, solutions of acid and salts, 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;

Increased local blood flow to the mucous membrane;

Activation of cell proliferation in the processes of normal regeneration.

Erosive and ulcerative lesions of the stomach are observed both with 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 to hydrogen and sodium ions is observed. It has been suggested that NSAIDs (directly or through proinflammatory cytokines) may induce apoptosis epithelial cells. The proof is provided by enteric-coated NSAIDs, which cause significantly less frequent and less significant changes in the gastric mucosa in the first weeks of treatment. However, with long-term use, it is likely that the resulting systemic suppression of prostaglandin synthesis contributes to the appearance of gastric erosions and ulcers.

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

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

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

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

Taking high doses of NSAIDs (relative risk 2.5 for people taking low doses and 8.6 for people taking high doses of NSAIDs; 2.8 for treatment with standard doses of NSAIDs and 8.0 for treatment 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 long period half-life and non-selective for COX-2.

Possible risk factors:

The presence of rheumatoid arthritis;

Female;

Smoking;

Drinking alcohol;

Infection H. pylori(data are contradictory).

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

Erosion of the stomach and duodenum associated with the use of NSAIDs often does not manifest any clinical symptoms, or patients experience only mild, occasional pain in the epigastric region and/or dyspeptic disorders, to which patients often do not attach importance 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). It is believed that NSAIDs reduce the intensity of symptoms of gastrointestinal lesions due to their local and general analgesic effects.

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 possible risk and benefit from its appointment and pay special attention to risk factors for NSAID gastropathy.

In the presence of risk factors and the development of dyspeptic symptoms, it is indicated to carry out endoscopic examination. 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, can significantly reduce the risk of developing serious gastroduodenal complications. In the USA and Canada, misoprostol is considered a first-line drug for the treatment and prevention of NSAID-induced gastropathy. Based on misoprostol, combination drugs containing NSAIDs have been created, for example arthrotek*, containing 50 mg of diclofenac sodium and 200 μg of misoprostol.

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

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

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 medical and preventive action V to a large extent may depend on various endo- and exogenous factors, and primarily on the infection of the mucous membrane H. pylori. In conditions of Helicobacter pylori infection, proton pump inhibitors are much more effective. This is confirmed by studies by D. Graham et al. (2002), who 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 gastroprotector misoprostol.

Monotherapy with non-absorbable antacids (Maalox*) and sucralfate (a drug with film-forming, antipeptic and cytoprotective properties), despite its use to relieve symptoms of dyspepsia, is ineffective in 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 overall, NSAIDs are prescribed to more than a third of patients with arterial hypertension.

It is known that prostaglandins play an important role in the physiological regulation 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 against renal vessels (PGE 2 and prostacyclin), and have a direct natriuretic effect (PGE 2).

By inhibiting systemic and local (intrarenal) synthesis of prostaglandins, NSAIDs can cause an increase in blood pressure not only in patients with arterial hypertension, but also in individuals with normal blood pressure. It has been established that patients regularly taking NSAIDs experience an increase in blood pressure by an average of 5.0 mmHg. The risk of NSAID-induced hypertension is especially high in elderly people taking NSAIDs for a long time, with concomitant diseases of cardio-vascular system.

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

roxicam and naproxen in moderate therapeutic doses and ibuprofen (in high doses), have the ability to reduce the effectiveness of antihypertensive drugs, the hypotensive action of which is based on prostaglandin-dependent mechanisms, namely β-blockers (propranolol, atenolol), diuretics (furosemide), prazosin, captopril .

IN last years Certain confirmation has been received of the view that NSAIDs, which 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. It has been established that it is COX-1 that is expressed in the 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. An 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. hypertension compared with less selective drugs.

According to the cyclooxygenase concept, it is most advisable to prescribe short-lived, fast-acting, and rapidly clearing 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 hemorrhagic syndrome may occur when using these drugs.

Bronchospasm when using 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 NSAIDs COX-1 in the bronchi. In this case, the main pathway of metabolism of arachidonic acid is lipoxygenase, as a result of which the formation of leukotrienes, causing bronchospasm, increases.

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

A dangerous side effect of pyrazolone derivatives (metamizole, phenylbutazone) is hematotoxicity. The relevance 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 limited or

generally prohibited. This decision is based on the International Agranulocytosis Study (IAAAS), which demonstrated that the risk of developing agranulocytosis increases 16-fold with the use of metamizole. 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.).

It is also worth mentioning the rare, but prognostic unfavorable complication therapy with acetylsalicylic acid - 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 viral infections (influenza, 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%.

Renal dysfunction is caused by 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 for the nephrotoxic effect of NSAIDs. Risk factors for the development of renal complications are heart failure, arterial hypertension (especially nephrogenic), chronic renal failure, excess body weight. In the first weeks of taking NSAIDs, renal failure may be aggravated due to a slowdown in glomerular filtration. The degree of renal dysfunction varies from a slight increase in blood creatinine levels to anuria. Also, a number of patients receiving phenylbutazone, metamizole, indomethacin, ibuprofen and naproxen may develop interstitial nephropathy with or without nephrotic syndrome. Unlike functional renal failure, organic damage develops with long-term use of NSAIDs (more than 3-6 months). After drug withdrawal pathological symptoms regresses, the outcome of the complication is favorable. Fluid and sodium retention are also noted when taking NSAIDs (primarily phenylbutazone, indomethacin, acetylsalicylic acid).

Hepatotoxic effects can develop by immunoallergic, toxic or mixed mechanisms. Immunoallergic hepatitis most often develops at the beginning of a course of treatment with NSAIDs; There is no relationship between the drug dose and the severity of clinical symptoms. Toxic hepatitis develops against the background of long-term use of drugs and is usually 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 when using NSAIDs. Typically, skin lesions appear in the 1-3 weeks of use and often have a benign course, manifested by an itchy rash (scarlet fever or measles), 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 associated with 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.

It is extremely rare to develop when using NSAIDs. anaphylactic shock and Quincke's edema (0.01-0.05% of all complications). The risk factor for the development of allergic complications is atopic predisposition and allergic reactions history of exposure 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 have a teratogenic effect. For example, taking acetylsalicylic acid in the first trimester can lead to cleft palate in the fetus (8-14 cases per 1000 observations). Taking NSAIDs in last weeks pregnancy contributes to inhibition of labor (tocolytic effect), which is associated with inhibition of the synthesis of prostaglandin F 2a; this 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 use of NSAIDs - individual intolerance, peptic ulcer of the stomach and duodenum in the acute stage; gastrointestinal bleeding, leukopenia, severe kidney damage, first 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 significant increase the risk of cardiovascular complications, and above all chronic heart failure, myocardial infarction. For this reason, rofecoxib® was withdrawn from registration in all countries of the world. 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 conducting pharmacotherapy with 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 decompensations due to leveling positive effects ACE inhibitors and diuretics.

Tactics for choosing non-steroidal anti-inflammatory drugs

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

According to modern pain treatment strategies, 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 of not only their effectiveness, but also their 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 threshold for the perception of pain and interrupt, at least temporarily, the conduction of the pain impulse at the level of the spinal cord.

When planning pharmacotherapy, the following must be considered.

The anti-inflammatory effect of NSAIDs directly depends on their affinity for COX, as well as on the acidity level of the solution of the selected drug, which ensures concentration in the area of ​​inflammation. The analgesic and antipyretic effect develops the faster, the more neutral the pH of the NSAID solution. 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 the enterohepatic circulation, the lower the risk of accumulation and unwanted drug interactions, and the safer the NSAID.

The sensitivity of patients to NSAIDs, even of one group, varies widely. For example, if ibuprofen is ineffective for rheumatoid arthritis, naproxen (also a derivative of propionic acid) reduces joint pain. In patients with inflammation syndrome and accompanying 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 (ankylosing spondylitis), rheumatoid arthritis, erythema nodosum and etc.

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

Difficulty in choosing NSAIDs for 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 gastrointestinal complications when using non-steroidal anti-inflammatory drugs

Note. The risk of developing complications from the gastrointestinal tract when using placebo is taken as 1.

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

Schematically, NSAIDs can be arranged as follows:

In descending order of anti-inflammatory effect: indomethacin - diclofenac - piroxicam - ketoprofen - ibuprofen - ketorolac - lornoxicam - acetylsalicylic acid;

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

For the risk of accumulation and unwanted 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 interaction with the medications used and predicted adverse reactions.

Meanwhile, in children, the drug of choice as an antipyretic drug is paracetamol (acetaminophen*), which is not an NSAID. Ibuprofen can be used as a second-line antipyretic if paracetamol is intolerant or ineffective. 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 who have high risk bleeding or perforation due to NSAID-induced ulcers, coadministration of NSAIDs and inhibitors should be considered proton pump or a synthetic analogue of prostaglandin misoprostal*. H2-receptor antagonists have only been shown to prevent duodenal ulcers and are therefore not recommended for prophylactic purposes. An alternative to this approach is to prescribe selective inhibitors to such patients.

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

The criteria for the effectiveness of NSAIDs are determined by the disease for 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, complaining of pain, does not make any attempts (overt or hidden) to get rid of it, one should doubt its presence. On the contrary, if a patient suffers from pain, he always demonstrates it either to others or to himself, or seeks to see a doctor.

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

The most common methods are the use of a visual analogue scale and a pain relief scale.

When using a visual analogue scale, the patient notes the level of pain severity on a 100-mm scale, where “0” is no pain, “100” is maximum pain. When monitoring acute pain, the level of pain is determined before drug administration and 20 minutes after administration. When monitoring chronic pain The time interval for studying pain intensity is set individually (in accordance with visits to the doctor, the patient can keep a diary).

To assess the effectiveness of pain relief, a pain relief scale is used. 20 minutes after administration of the drug, the patient is asked the question: “Has the intensity of your pain decreased after administration of the drug compared to the pain before administration of the drug?” Possible answer options are scored: 0 - pain has not decreased at all, 1 - decreased slightly, 2 - decreased, 3 - greatly decreased, 4 - disappeared completely. 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 joint under study in the area of ​​the joint space. Pain in joints that are difficult to palpate is determined by the volume of active and passive movements (hip, spine) or compression (foot joints). Pain is assessed using a four-point system:

0 - no pain;

1 - the patient speaks of pain at the point of pressure;

2 - the patient speaks of pain and winces;

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 determine the possibility of fulfilling

a number of basic everyday activities involving various groups joints.

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

0 - absent;

1 - doubtful or weakly expressed;

2 - explicit;

3 - strong.

Swelling assessment is carried out 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 hand. The grip strength of the hand is assessed either using a special device or by squeezing a tonometer cuff filled with air to a pressure of 50 mm Hg. The patient performs three compressions with his hand. The average value is taken into account. If the leg joints are affected, a test is used that evaluates the time it takes to travel a segment of the path. A functional test that evaluates the range of motion in joints is called the Keitel test.

25.2. PARACETAMOL (ACETAMINOPHEN*)

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 through selective blockade of COX-3 (a CNS-specific isoform of COX) 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 lack of peripheral action, paracetamol practically does not cause such undesirable drug reactions as ulcers and erosions of the gastric mucosa, antiplatelet effect, bronchospasm, and tocolytic effect. Precisely because of the predominant central action paracetamol has no 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% undergoes conjugation 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 combines with glutathione to become an inactive compound excreted by the kidneys. The therapeutically effective concentration of paracetamol in blood plasma is achieved when administered at a dose of 10-15 mg/kg. Less than 1% of the drug passes into breast milk.

Paracetamol is used for symptomatic treatment 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 pain relief 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 doses of paracetamol should be increased. The maximum daily doses of paracetamol in children are presented in table. 25-7 (frequency of administration - 4 times a day).

Table 25-7. Maximum daily dose of paracetamol in children

Side effects and contraindications for use

Due to the central action of paracetamol, it is practically devoid of such undesirable drug reactions as erosive and ulcerative lesions, hemorrhagic syndrome, bronchospasm, and tocolytic effect. 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 analgesic antipyretics.

Most serious unwanted drug reaction paracetamol - hepatotoxicity. It occurs when there is an overdose of this drug (taking more than 10 g at once). The mechanism of the hepatotoxic action of paracetamol is associated with the peculiarities of its metabolism. At

Increasing 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 effective method treatment of intoxication with this drug is the use of N-acetylcysteine, which replenishes glutathione reserves 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 explained by two mechanisms: on the one hand, ethanol depletes glutathione reserves in the liver, and on the other, it causes the induction of the cytochrome P-450 2E1 isoenzyme.

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

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 “disease-modifying” drugs includes drugs that are heterogeneous in their chemical structure and mechanism of action and are used to treat long-term therapy 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 relieve inflammatory changes in connective tissue:

Immunosuppressants (cyclophosphamide, azathioprine, methotrexate, cyclosporine);

Sulfonamide drugs (sulfasalazine, mesalazine). The general pharmacological effects that these drugs share are as follows:

The ability to inhibit the development of bone erosions and destruction of joint cartilage during nonspecific inflammatory reactions;

The predominantly indirect effect of most drugs on the local inflammatory process, mediated through pathogenetic factors of the immune component of inflammation;

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

Continued signs of improvement (remission) for several months after discontinuation.

Mechanism of action and main pharmacodynamic effects

Gold preparations, reducing the phagocytic activity of monocytes, disrupt their capture of antigen and the release of IL-1 from them, which leads to inhibition of the proliferation of T-lymphocytes, 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-helper cells and 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 C1 component of complement, and 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 the therapeutic effect of quinoline derivatives is an immunosuppressive effect associated with a violation of nucleic acid metabolism. This leads to cell death. It is assumed that the drugs disrupt the process of macrophage cleavage and 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 drugs stabilize cellular and subcellular membranes, reduce the release of lysosomal enzymes, and therefore limit the source of tissue damage. In therapeutic doses, they have clinically significant anti-inflammatory, immunomodulatory, as well as antimicrobial, hypolipidemic and hypoglycemic effects.

Drugs of the second subgroup (cyclophosphamide, azathioprine and methotrexate) disrupt the synthesis of nucleic acids and proteins in all tissues; their effect is noted in tissues with rapidly dividing cells (in 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, more pronouncedly than methotrexate, suppress blast transformation of lymphocytes, antibody synthesis, inhibition of skin delayed hypersensitivity, and a decrease in the level of gamma and immunoglobulins. Methotrexate in small doses actively affects 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 for rheumatoid arthritis and other immunoinflammatory diseases does not correspond to the degree of immunosuppression. This probably depends on the local inhibitory effect on the cell phase. inflammatory process, and cyclophosphamide is also credited with an anti-inflammatory effect.

Unlike cytostatics, the immunosuppressive effect of cyclosporine is associated with selective and reversible suppression 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 killer cells) and a decrease in the number of cells expressing IL-2 receptors (Table 25-9).

Table 25-9. The most likely targets of action of anti-inflammatory drugs

Pharmacokinetics

Krizanol (an oil suspension of gold salt, contains 33.6% metallic gold) is used intramuscularly, the drug is absorbed from the muscles rather slowly. The maximum concentration in blood plasma is usually achieved after 4 hours. After a single dose intramuscular injection 50 mg (water-soluble drug, contains 50% metallic gold), its level reaches a maximum (4.0-7.0 μg/ml) in a period of 15-30 minutes to 2 hours. Gold preparations are excreted in urine (70%) and feces (thirty%). T1/2 in blood plasma is 2 days, and the half-life is 7 days. After a single administration, the level of gold in the blood serum decreases quickly during the first 2 days (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 the blood plasma increases, reaching a steady-state concentration of 2.5-3.0 mcg/ml after 6-8 weeks, however, there is no connection between the concentration of gold in the plasma and its therapeutic and side effects, and the toxic effect correlates with an increase in its free fraction. The bioavailability of the oral gold preparation - auranofin (contains 25% metallic gold) is 25%. With his daily

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

D-penicillamine, taken on an empty stomach, is absorbed from the gastrointestinal tract by 40-60%. Dietary proteins contribute to its conversion into sulfide, which is poorly absorbed from the intestine, so food intake significantly reduces the bioavailability of D-penicillamine. The maximum concentration in the blood plasma after a single dose is reached after 4 hours. In the blood plasma, the drug is intensively bound to proteins; in the liver it is converted into two inactive water-soluble metabolites excreted by the kidneys (penicillamine sulfide and cysteine-penicillamine disulfide). T1/2 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 digestive tract. The maximum concentration in the blood is achieved on average after 2 hours. With unchanged daily dose their level in the blood gradually increases, the time to reach equilibrium concentration in the blood plasma ranges from 7-10 days to 2-5 weeks. Chloroquine in blood plasma is 55% bound to albumin. Due to the connection 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 unchanged in the urine, a smaller part (about 1/3) is biotransformed in the liver. The half-life of chloroquine ranges from 3.5 to 12 days. When urine becomes acidic, the rate of chloroquine excretion increases, and when urine becomes alkalized, it decreases. After stopping use, chloroquine slowly disappears from the body, remaining in places of deposition for 1-2 months; after prolonged use, its content in the urine is detected for several years. The drug easily penetrates the placenta, intensively accumulating in the retinal pigment epithelium of the fetus, and also binding to DNA, inhibiting 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 protein is minimal. In the absence of liver and kidney dysfunction, up to 88% of the drug in the blood and liver is biotransformed into active metabolites, of which aldophosphamide is the most active. It can accumulate in the kidneys, liver, and spleen. Cyclophosphamide in unchanged form (20% of the administered dose) and in the form of active and inactive metabolites is excreted from the body in the urine. T 1/2 is 7 hours. If renal function is impaired, an increase in all, including toxic, effects is possible.

Azathioprine is well absorbed from the gastrointestinal tract, transforming in the body (in lymphoid tissue more actively than in others) into the active metabolite 6-mercaptopurine, the T1/2 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. T1/2 of azathioprine is 24 hours; it does not penetrate the BBB. It is excreted in the urine both unchanged and in the form of metabolites - S-methylated products and 6-thiouric acid, formed under the influence of xanthine oxidase and causing the development of hyperuricemia and hyperuricuria. Blockade of xanthine oxidase by 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 (on average 60-70%); absorption does not change with increasing dose. Methotrexate is partially metabolized by intestinal flora, bioavailability varies widely (28-94%). The maximum concentration is reached after 2-4 hours. Eating 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 eliminated by glomerular filtration and tubular secretion; about 10% of methotrexate entering the body is excreted in bile. T1/2 is 2-6 hours, however, its polyglutamated metabolites are detected intracellularly for at least 7 days after a single dose, and 10% (with normal renal function) is retained in the body, remaining mainly in the liver (several months) and kidneys ( how many weeks).

With cyclosporine, due to variability in absorption, bioavailability varies widely, ranging from 10-57%. Maxi-

The minimum concentration in the blood is reached after 2-4 hours. More than 90% of the drug is bound to blood proteins. It is distributed unevenly 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. 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% unchanged. The half-life is 10-27 (average 19) hours. Minimum concentration cyclosporine in the blood, at which a therapeutic effect is observed, is 100 ng/l, optimal is 200 ng/l, and nephrotoxic concentration is 250 ng/l.

Indications for use and dosage regimen

Drugs of this group are used for a number of immunopathological inflammatory diseases. Diseases and syndromes for which clinical improvement can be achieved with basic preparations, are presented in table. 25-13.

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

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

End of table. 25-10

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

*Only as intravenous shock therapy.

Treatment with gold preparations is called chrysotherapy or aurotherapy. The first signs of improvement are sometimes observed after 3-4 months of continuous chrysotherapy. Crizanol is prescribed starting with one or several test injections in small doses (0.5-1.0 ml of 5% suspension) with an interval of 7 days and then switching to weekly administration of 2 ml of 5% solution for 7-8 months. The result of treatment is most often assessed after 6 months from the start of use. Initial signs improvements may appear after 6-7 weeks, and sometimes only after 3-4 months. When the effect is achieved and good tolerability, the intervals are then increased to 2 weeks, and after 3-4 months, if signs of remission persist, 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. Myocrisin* is used similarly: test 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, myocrisin* is discontinued. Auranofin 6 mg per day, divided into 2 doses, is used for the same long time. Some patients need to increase the dose to 9 mg/day (if ineffective within 4 months), others - only at a dose of 3 mg/day, the dose is limited by side effects. Complete anamnestic data on drug allergies, skin and kidney diseases, a detailed blood test, biochemical profile and urinalysis. studied before starting chrysotherapy, reduce the risk of side effects. In the future, every 1-3 weeks it is necessary to repeat clinical blood tests (with determination of platelet counts) and general urine tests. When proteinuria exceeds 0.1 g/l, gold preparations are temporarily discontinued, although higher levels of proteinuria sometimes resolve 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 no earlier than 1 hour after taking any other medications. An intermittent regimen (3 times a week) is possible, which can reduce the frequency of adverse reactions while maintaining clinical effectiveness. Clinical and laboratory improvement occurs after 1.5-3 months, less often in earlier stages of therapy, a clear therapeutic effect is realized after 5-6 months, and radiological improvement - no 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, “secondary ineffectiveness” may develop: the clinical effect obtained initially is replaced by a persistent exacerbation of the rheumatoid process, despite ongoing therapy. During 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) of chloroquine and 400 mg (6.5 mg/kg) of hydroxychloroquine. In case of poor tolerance or when the effect is achieved, the dose is reduced by 2 times. Recommended low doses (no more than 300 mg of chloroquine and 500 mg of hydroxychloroquine), while being as effective as high doses, help avoid severe complications. During treatment, it is necessary to re-examine the hemogram; before starting treatment and then every 3 months, ophthalmological monitoring should be carried out with examination of the fundus and visual fields, and careful questioning about visual disorders.

Cyclophosphamide is prescribed orally after meals, in a daily dose of 1-2 to 2.5-3 mg/kg in 2 divided doses, and administered intravenously large doses bolus according to an intermittent scheme - 5000-1000 mg/m2. Sometimes treatment is started with half the dose. With both schemes, the level of leukocytes should not decrease less than 4000 per 1 mm 2. At the beginning of treatment, a complete blood count, platelet count and urinary sediment should be performed.

every 7-14 days, and when a 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, bringing it to the optimal dose of 1-3 mg/kg in 2-3 doses. The drug is prescribed orally after meals. Its clinical effect develops no earlier than 5-12 months from the start of therapy. At the beginning of treatment, laboratory monitoring (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 administered orally, this dose is divided into 3 doses every 12 hours (to improve tolerability). 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 and the drug is well tolerated, its dose is increased by 2.5 mg/week, but not more than 25 mg (preventing the development of toxic reactions and deterioration of absorption). At a maintenance dose of 1/3 - 1/2 of the therapeutic dose, methotrexate can be prescribed with quinoline derivatives and indomethacin. Parenteral methotrexate is administered in case of development of toxic reactions from the gastrointestinal tract or in case of ineffectiveness (insufficient dose or low absorption from the gastrointestinal tract). Solutions for parenteral administration are prepared immediately before administration. After discontinuation of methotrexate, as a rule, an exacerbation develops between the 3rd and 4th week. During treatment, the composition of peripheral blood is monitored every 3-4 weeks and liver tests are monitored every 6-8 weeks. The doses of cyclosporine used vary widely - from 1.5 to 7.5 mg/kg/day, however, exceeding the value of 5.0 mg/kg/day is not advisable, since, starting from the level of 5.5 mg/kg/day, the frequency of complications increases. Before starting treatment, a detailed clinical and laboratory examination is carried out (determining the level of bilirubin and the activity of liver enzymes, the concentration of potassium, magnesium, uric acid in the blood serum, lipid profile, general urine analysis). 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; if the creatinine level normalizes, treatment is continued, and if it is absent, it is stopped.

Side effects and contraindications for use

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

our reactions. The patient should be informed about the clinical symptoms that need to be paid attention to 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 frequent - pruritus, dermatitis, urticaria (sometimes in combination with stomatitis and conjunctivitis require discontinuation in combination with prescription antihistamines). For severe dermatitis and fever, unithiol* and glucocorticoids are added to treatment.

Proteinuria is often observed. If protein loss exceeds 1 g/day, the drug is discontinued 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 and chelating compounds. Pancytopenia and aplastic anemia are possible; the latter can also lead to fatal outcome(drug discontinuation is necessary).

Parenteral administration of myocrisin is complicated by the development of a nitrite 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, pulmonary infiltration ( "golden" light). In such cases, drug withdrawal is sufficient to provide relief.

Possible taste distortions, nausea, diarrhea, myalgia, megifonexia, 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 which 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 more than 2 g/day and nephrotic syndrome. These conditions require discontinuation of the drug.

It is necessary to pay attention to such complications as decreased taste sensitivity, dermatitis, stomatitis, nausea, loss of

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 discontinuation 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 (decreased T, ST on the electrocardiogram, conduction and rhythm disturbances), toxic psychosis, convulsions. These side effects disappear after discontinuation 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 manifests itself as a narrowing of the peripheral fields of vision, a central scotoma, and later - deterioration of vision. Discontinuation of the drug, as a rule, leads to their regression.

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

Immunosuppressants have common side effects characteristic of any drug in this group (see Table 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 body. The most dangerous complication is hemorrhagic cystitis, which results in fibrosis and sometimes 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.

For all drugs, the development of thrombocytopenia, leukopenia, and pancytopenia is possible, which, with the exception of azathioprine, develop slowly and regress after discontinuation.

Toxic complications in the form of interstitial pulmonary fibrosis are possible when taking cyclophosphamide and methotrexate. The latter causes such a rare complication as liver cirrhosis. They are extremely rare for azathioprine and require withdrawal and symptomatic therapy.

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

have a dose-dependent effect and most often occur when taking azathioprine. It can also cause hyperurecemia, requiring dose adjustment and administration of allopurinol.

Methotrexate is better tolerated than other basic drugs, although the incidence 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 discontinuation.

Cyclosporine has fewer immediate and long-term side effects than other immunosuppressants. 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 in case of persistent complications does the drug need to be discontinued.

In general, the onset of undesirable effects may significantly outpace the slowly developing therapeutic effect of immunosuppressants. This must be taken into account when choosing a basic drug. Common complications for them are presented in table. 25-12.

Table 25-12. Side effects of immunosuppressants

“0” - not described, “+” - described, “++” - described relatively often, “?” - no data available, “(+)” - clinical interpretation is unknown.

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

not related to the underlying disease being treated with these drugs. Diffuse kidney damage and chronic renal failure are a contraindication to the use of gold, quinoline, D-penicillamine, methotrexate, and cyclosporine drugs; with chronic renal failure, the dose of cyclophosphamide is reduced. For lesions of the liver parenchyma, gold, quinoline, and cytostatic drugs 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, and psychoses. 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 use 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, and individual 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 for active rheumatoid arthritis, including in patients resistant to treatment with gold preparations; Additional indications include the presence of a high titer of rheumatoid factor, rheumatoid nodules, Felty's syndrome, and rheumatoid lung disease. In terms of the frequency 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 the haplotype HLA-B27. D-penicillamine is considered the main component in the complex therapy of systemic scleroderma; its effectiveness in the treatment of biliary cirrhosis, palindromic rheumatism and juvenile arthritis has been shown.

The indication for the use 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 for discoid lupus erythematosus, eosinophilic fasciitis, juvenile dermatomysitis, palindromic rheumatism, and some forms of seronegative spondyloarthropathy. In rheumatoid arthritis, it is used as monotherapy for mild cases, as well as during the period of achieved remission. Quinoline drugs are successfully used in complex therapy with other basic drugs: cytostatics, gold drugs.

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

Zha-Strauss, Harton's disease, hemorrhagic vasculitis with kidney damage, Behçet'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 peculiarities in the prescription of drugs in this group: cyclophosphamide is the drug of choice for systemic vasculitis, rheumatoid vasculitis, lupus damage to the central nervous system and kidneys; methotrexate - for rheumatoid arthritis, seronegative spondyloarthritis, psoriatic arthropathy, ankylosing spondylitis; Azathioprine is most effective for cutaneous manifestations of systemic lupus erythematosus and lupus glomerulonephritis. It is possible to sequentially prescribe cytostatics: cyclophosphamide with subsequent transfer to azathioprine when the activity of the process decreases and to achieve stabilization, as well as to reduce the severity of side effects from cyclophosphamide.

Non-steroidal anti-inflammatory drugs (NSAIDs, NSAIDs) are drugs that have analgesic, antipyretic and anti-inflammatory effects.

The mechanism of their action is based on blocking certain enzymes (COX, cyclooxygenase), they are responsible for the production of prostaglandins - chemicals that promote inflammation, fever, pain.

The word “non-steroidal”, which is contained in the name of the group of drugs, emphasizes the fact that the drugs in this group are not synthetic analogues of steroid hormones - powerful hormonal anti-inflammatory drugs.

The most famous representatives of NSAIDs: aspirin, ibuprofen, diclofenac.

How do NSAIDs work?

While analgesics directly combat pain, NSAIDs reduce both of the most unpleasant symptoms of the disease: pain and inflammation. Most drugs in this group are non-selective inhibitors of the cyclooxygenase enzyme, suppressing the action of both of its isoforms (varieties) - COX-1 and COX-2.

Cyclooxygenase is responsible for the production of prostaglandins and thromboxane from arachidonic acid, which in turn is obtained from cell membrane phospholipids by the enzyme phospholipase A2. Prostaglandins, among other functions, are mediators and regulators in the development of inflammation. This mechanism was discovered by John Wayne, who later received the Nobel Prize for his discovery.

When are these drugs prescribed?

Typically, NSAIDs are used to treat acute or chronic inflammation accompanied by pain. Non-steroidal anti-inflammatory drugs have gained particular popularity for the treatment of joints.

Let us list the diseases in which these drugs are prescribed:

• (menstrual pain);
• bone pain caused by metastases;
• postoperative pain;
• fever (increased body temperature);
• intestinal obstruction;
• renal colic;
• moderate pain due to inflammation or soft tissue injury;
• lower back pain;
• pain when

Nonsteroidal anti-inflammatory drugs (NSAIDs, NSAIDs) are a group of drugs whose action is aimed at symptomatic treatment (pain relief, inflammation relief and temperature reduction) in acute and chronic diseases. Their action is based on reducing the production of special enzymes called cyclooxygenase, which trigger a reaction mechanism to pathological processes in the body, such as pain, fever, inflammation.

Medicines in this group are widely used throughout the world. Their popularity is ensured by good efficiency against the background of sufficient safety and low toxicity.

The most well-known representatives of the NSAID group for most of us are aspirin (), ibuprofen, analgin and naproxen, available in pharmacies in most countries of the world. Paracetamol (acetaminophen) is not a NSAID, since it has relatively weak anti-inflammatory activity. It acts against pain and fever according to the same principle (blocking COX-2), but mainly only in the central nervous system, almost without affecting the rest of the body.

Soreness, inflammation and fever are common pathological conditions that accompany many diseases. If we consider the pathological course at the molecular level, we can see that the body “forces” the affected tissues to produce biologically active substances - prostaglandins, which, acting on blood vessels and nerve fibers, cause local swelling, redness and soreness.

In addition, these hormone-like substances, reaching the cerebral cortex, affect the center responsible for thermoregulation. Thus, impulses are sent about the presence of an inflammatory process in tissues or organs, so a corresponding reaction occurs in the form of fever.

A group of enzymes called cyclooxygenases (COX) are responsible for triggering the mechanism for the appearance of these prostaglandins. . The main effect of non-steroidal drugs is to block these enzymes, which in turn leads to inhibition of the production of prostaglandins, which increase the sensitivity of nociceptive receptors responsible for pain. Consequently, painful sensations that bring a person suffering and unpleasant sensations are relieved.

Types by mechanism of action

NSAIDs are classified according to their chemical structure or mechanism of action. Long-known drugs of this group were divided into types according to their chemical structure or origin, since at that time their mechanism of action was still unknown. Modern NSAIDs, on the contrary, are usually classified according to their principle of action - depending on what type of enzymes they act on.

There are three types of cyclooxygenase enzymes – COX-1, COX-2 and the controversial COX-3. At the same time, non-steroidal anti-inflammatory drugs, depending on the type, affect the main two of them. Based on this, NSAIDs are divided into groups:

• non-selective inhibitors (blockers) of COX-1 and COX-2– act on both types of enzymes at once. These drugs block COX-1 enzymes, which, unlike COX-2, are constantly present in our body, performing various important functions. Therefore, exposure to them may be accompanied by various side effects, and a particular negative effect is on the gastrointestinal tract. This includes most classic NSAIDs.
• selective COX-2 inhibitors. This group affects only enzymes that appear in the presence of certain pathological processes, such as inflammation. Taking such drugs is considered safer and preferable. They do not have such a negative effect on the gastrointestinal tract, but at the same time the load on the cardiovascular system is greater (they can increase blood pressure).
• selective NSAID COX-1 inhibitors. This group is small, since almost all drugs that affect COX-1 also affect COX-2 to varying degrees. An example is acetylsalicylic acid in a small dosage.

In addition, there are controversial COX-3 enzymes, the presence of which has only been confirmed in animals, and they are also sometimes classified as COX-1. It is believed that their production is slightly slowed down by paracetamol.

In addition to reducing fever and eliminating pain, NSAIDs are recommended for blood viscosity. The drugs increase the liquid part (plasma) and reduce the formed elements, including lipids that form cholesterol plaques. Due to these properties, NSAIDs are prescribed for many diseases of the heart and blood vessels.

List of NSAIDs

Major non-selective NSAIDs

Acid derivatives:

• acetylsalicylic (aspirin, diflunisal, salasat);
• arylpropionic acid (ibuprofen, flurbiprofen, naproxen, ketoprofen, tiaprofenic acid);
• arylacetic acid (diclofenac, fenclofenac, fentiazac);
• heteroarylacetic (ketorolac, amtolmetin);
• indole/indene of acetic acid (indomethacin, sulindac);
• anthranilic (flufenamic acid, mefenamic acid);
• enolic acid, in particular oxicam (piroxicam, tenoxicam, meloxicam, lornoxicam);
• methanesulfonic acid (analgin).

Acetylsalicylic acid (aspirin) is the first known NSAID, discovered back in 1897 (all others appeared after the 1950s). In addition, this is the only drug that can irreversibly inhibit COX-1 and is also indicated to stop platelet aggregation. Such properties make it useful in the treatment of arterial thrombosis and for the prevention of cardiovascular complications.

Selective COX-2 inhibitors

• rofecoxib (Denebol, Vioxx discontinued in 2007)
• lumiracoxib (Prexige)
• parecoxib (Dynastat)
• etoricoxib (Arcosia)
• celecoxib (Celebrex).

Main indications, contraindications and side effects

Today, the list of NSAIDs is constantly expanding and new generation drugs are regularly arriving on pharmacy shelves that can simultaneously lower the temperature, relieve inflammation and pain in a short period of time. Thanks to its mild and gentle effect, the development of negative consequences in the form of allergic reactions, as well as damage to the gastrointestinal tract and urinary system is minimized.

Table. Non-steroidal anti-inflammatory drugs - indications

Property of a medical product	Diseases, pathological condition of the body
Antipyretic	High temperature (above 38 degrees).
Anti-inflammatory	Diseases of the musculoskeletal system - arthritis, arthrosis, osteochondrosis, muscle inflammation (myositis), spondyloarthritis. This also includes myalgia (often appears after a bruise, sprain or injury to soft tissues).
Painkiller	The drugs are used for menstrual pain and headaches (migraines), and are widely used in gynecology, as well as for biliary and renal colic.
Antiplatelet agent	Cardiac and vascular disorders: coronary heart disease, atherosclerosis, heart failure, angina pectoris. In addition, they are often recommended for the prevention of stroke and heart attack.

Nonsteroidal anti-inflammatory drugs have a number of contraindications that should be taken into account. The drugs are not recommended for treatment if the patient:

• peptic ulcer of the stomach and duodenum;
• kidney disease - limited intake is allowed;
• blood clotting disorder;
• the period of gestation and breastfeeding;
• Severe allergic reactions to medications in this group have previously been observed.

In some cases, a side effect may occur, as a result of which the composition of the blood changes ("fluidity" appears) and the walls of the stomach become inflamed.

The development of a negative result is explained by inhibition of the production of prostaglandins not only in the inflamed lesion, but also in other tissues and blood cells. In healthy organs, hormone-like substances play an important role. For example, prostaglandins protect the lining of the stomach from the aggressive effects of digestive juice on it. Consequently, taking NSAIDs contributes to the development of gastric and duodenal ulcers. If a person has these diseases and still takes “prohibited” drugs, then the course of the pathology may worsen, even to the point of perforation (breakthrough) of the defect.

Prostaglandins control blood clotting, so a lack of them can lead to bleeding. Diseases for which examinations should be carried out before prescribing a course of NVPS:

• hemocoagulation disorder;
• diseases of the liver, spleen and kidneys;
• Varicose veins;
• diseases of the cardiovascular system;
• autoimmune pathologies.

Side effects also include less dangerous conditions, such as nausea, vomiting, loss of appetite, loose stools, and bloating. Sometimes skin manifestations in the form of itching and small rashes are also recorded.

Application using the example of the main drugs of the NSAID group

Let's look at the most popular and effective medications.

A drug	Route of administration (form of release) and dosage						Application note
	external		through the gastrointestinal tract		injection
	ointment	gel	pills	candles	IM injection	Intravenous administration
Diclofenac (Voltaren)	1-3 times (2-4 grams per affected area) per day		20-25 mg 2-3 times a day	50-100 mg 1 time per day	25-75 mg (2 ml) 2 times a day	—	The tablets should be taken without chewing, 30 minutes before meals, with plenty of water.
Ibuprofen (Nurofen)	Strip 5-10 cm, rub 3 times a day	Strip of gel (4-10 cm) 3 times a day	1 tab. (200 ml) 3-4 times a day	For children from 3 to 24 months. (60 mg) 3-4 times a day	—	2 ml 2-3 times a day	For children, the drug is prescribed if the body weight exceeds 20 kg
Indomethacin	4-5 cm of ointment 2-3 times a day	3-4 times a day, (strip - 4-5 cm)	100-125 mg 3 times a day	25-50 mg 2-3 times a day	30 mg – 1 ml solution 1-2 r. per day	60 mg – 2 ml 1-2 times a day	During pregnancy, Indomethacin is used to reduce the tone of the uterus to prevent premature birth.
Ketoprofen	Strip 5 cm 3 times a day	3-5 cm 2-3 times a day	150-200 mg (1 tab.) 2-3 times a day	100-160 mg (1 suppository) 2 times a day	100 mg 1-2 times a day	100-200 mg dissolved in 100-500 ml of saline	Most often, the drug is prescribed for pain of the musculoskeletal system.
Ketorolac	1-2 cm of gel or ointment - 3-4 times a day		10 mg 4 times a day	100 mg (1 suppository) 1-2 times a day	0.3-1 ml every 6 hours	0.3-1 ml bolus 4-6 times a day	Taking the drug may mask the signs of an acute infectious disease
Lornoxicam (Xefocam)	—	—	4 mg 2-3 times a day or 8 mg 2 times a day	—	Initial dose – 16 mg, maintenance dose – 8 mg – 2 times a day		The medication is used for moderate to severe pain syndrome
Meloxicam (Amelotex)	—	4 cm (2 grams) 2-3 times a day	7.5-15 mg 1-2 times a day	0.015 g 1-2 times a day	10-15 mg 1-2 times a day	—	For renal failure, the permissible daily dose is 7.5 mg
Piroxicam	2-4 cm 3-4 times a day		10-30 mg 1 time per day	20-40 mg 1-2 times a day	1-2 ml 1 time per day	—	The maximum permissible daily dosage is 40 mg
Celecoxib (Celebrex)	—	—	200 mg 2 times a day	—	—	—	The drug is available only in the form of capsules coated with a coating that dissolves in the gastrointestinal tract
Aspirin (acetylsalicylic acid)	—	—	0.5-1 gram, take no more than 4 hours and no more than 3 tablets per day	—	—	—	If you have previously had allergic reactions to Penicillin, then Aspirin should be prescribed with caution.
Analgin	—	—	250-500 mg (0.5-1 tablet) 2-3 times a day		250 - 500 mg (1-2 ml) 3 times a day		In some cases, Analgin may have drug incompatibility, so mixing it in a syringe with other medications is not recommended. It is also banned in some countries

Attention! The tables indicate dosages for adults and adolescents whose body weight exceeds 50-50 kg. Many drugs are contraindicated for children under 12 years of age. In other cases, the dosage is selected individually, taking into account body weight and age.

In order for the drug to work as quickly as possible and not cause harm to health, you should adhere to the well-known rules:

• Ointments and gels are applied to the painful area, then rubbed into the skin. Before putting on clothes, you should wait until it is completely absorbed. It is also not recommended to take water procedures for several hours after treatment.
• Tablets must be taken strictly as directed, without exceeding the daily allowance. If pain or inflammation is too severe, then you should inform your doctor about this so that another, stronger drug can be selected.
• Capsules should be washed down with plenty of water without removing the protective shell.
• Rectal suppositories work faster than tablets. Absorption of the active substance occurs through the intestines, so there is no negative or irritating effect on the walls of the stomach. If the drug is prescribed to a child, then the young patient should be placed on his left side, then carefully insert the suppository into the anus and squeeze the buttocks tightly. Make sure that the rectal medication does not come out for ten minutes.
• Intramuscular and intravenous injections are given only by a medical professional! It is necessary to make injections in the manipulation room of a medical institution.

Although non-steroidal anti-inflammatory drugs are available without a prescription, you should always consult with your doctor before taking them. The fact is that the action of this group of medications is not aimed at treating the disease, at relieving pain and discomfort. Thus, the pathology begins to progress and stopping its development once identified is much more difficult than it would have been done before.