Comparison of non-steroidal anti-inflammatory drugs. Indications for the 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 - 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. They suppress the exudative phase of inflammation, and, to a lesser extent, the proliferative one. Diclofenac, Indomethacin are the most powerful drugs for this effect. But the anti-inflammatory effect is less pronounced than that of glucocorticosteroids.
  Practitioners use a classification according to which all NSAIDs are divided into: agents with high anti-inflammatory activity and agents with weak anti-inflammatory activity Aspirin, Indomethacin, Diclofenac, Piroxicam, Ibuprofen and many others have high activity. This group includes a large number of different drugs. Paracetamol, Metamizole, Ketorolac and some others have low anti-inflammatory activity. The group is small.
• Painkiller. The most pronounced in Diclofenac, Ketoralac, Metamizol, Ketaprofen. Used for pain of low and medium intensity: dental, muscular, headache. Effective in renal colic, tk. not . Compared with narcotic analgesics (morphine group), they do not have a depressing effect on the respiratory center, they are not addictive.
• Antipyretic. All drugs have this property to varying degrees. But it manifests itself only in the presence of fever.
• Antiaggregatory. Manifested by suppressing the synthesis of thromboxane. This effect is most pronounced in Aspirin.
• Immunosuppressive. It manifests itself for the second time, due to the deterioration of the permeability of the capillary walls.

Indications for the use of NSAIDs

The main indications include:

• Rheumatic diseases. They include rheumatism, rheumatoid arthritis, ankylosing spondylitis, gouty and psoriatic arthritis, Reiter's disease. In these diseases, the use of NSAIDs is symptomatic, without affecting the pathogenesis. That is, to slow down the development of the destructive process in rheumatoid arthritis, to prevent deformity of the joints, taking drugs from the NSAID group cannot. But patients' complaints of pain, stiffness in the joints in the initial stages of the disease become less frequent.
• Diseases of the musculoskeletal system of a non-rheumatic nature. These include injuries (bruises, sprains), myositis, tendovaginitis. With the above diseases, NSAIDs are used orally, in the form of injections. And external agents (ointments, creams, gels) that contain the active substances of this group are very effective.
• neurological diseases. Lumbago, sciatica, myalgia. Often, combinations of various forms of drug release are prescribed simultaneously (ointment and tablets, injections and gel, etc.)
• Renal,. Drugs of the NSAID group are effective for all types of colic, tk. do not cause additional spasm of smooth cell muscle structures.
• Pain symptoms of various etiologies. Pain relief in the postoperative period, toothache and headache.
• Dysmenorrhea. NSAIDs are used to relieve pain in primary dysmenorrhea and to reduce blood loss. A good effect is provided by Naproxen, Ibuprofen, which are recommended to be taken on the eve of menstruation and then for three days. Such short-term courses prevent the occurrence of undesirable effects.
• Fever. Antipyretic drugs are recommended to be taken at a body temperature of more than 38.5 ° C.
• Prevention of thrombosis. To prevent the formation of blood clots, Acetylsalicylic acid is used in a low dosage. It is prescribed to prevent heart attacks, strokes in various forms of coronary heart disease.

Undesirable effects and contraindications

Drugs of the NSAID group have a negative effect on:

1. and intestines
2. Liver
3. kidneys
4. Blood
5. nervous system

The stomach is most commonly affected by NSAIDs. This is manifested by 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 intake of NSAIDs. Particularly at risk of pathology are elderly patients with a history of gastric ulcers who are simultaneously taking glucocorticosteroid drugs.

NSAIDs are different drugs, but their action is the same!

The likelihood of developing NSAID gastropathy increases with long-term use of drugs at a high dose, as well as when taking two or more NSAIDs. To protect the gastric mucosa, Lansoprazole, Esomeprazole and other proton pump inhibitors are used. may be in the form of severe toxic hepatitis, and may manifest as transient dysfunction with an increase in the level of transaminases in the blood.

The liver is most often affected when taking Indomethacin, Phenylbutazone, Aspirin. On the part of the kidneys, a decrease in diuresis, acute renal failure, nephrotic syndrome, as a result of damage to the kidney tubules, may develop. The most dangerous are Ibuprofen, Naproxen.

In the blood, there is a violation of coagulation processes, anemia occurs. Dangerous in terms of side effects from the blood system Diclofenac, Piroxicam, Butadione. Often, undesirable effects from the nervous system occur when taking Aspirin, Indomethacin. And they are manifested by headache, tinnitus, nausea, and sometimes vomiting, mental disorders. Taking NSAIDs is contraindicated in case of.

NSAIDs are the most popular group of medicines used by the population. They relieve pain, inflammation well, 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 is an NSAID?

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 belong to hormones, therefore, in most cases, even with long-term treatment, they do not cause a withdrawal syndrome, which manifests itself in an extremely sharp deterioration in the patient's condition after stopping taking one or another drug in 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").

The drugs of the first group are prescribed mainly for diseases of the joints, including rheumatic diseases, 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 of 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

In the body, under certain conditions, various types of prostaglandins are produced, which cause an increase in temperature and increase the intensity of 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-steroid drugs blocked both types of COX, which led to the formation of ulcers and other lesions in the gastrointestinal tract. Then, selective NSAIDs were created that block predominantly COX2, so they can be used in patients with diseases of the digestive system. However, they are not able to prevent platelet aggregation, therefore they are not a full replacement for first-generation drugs.

Action on the body

1. Removal of inflammation. Diclofenac, indomethacin and phenylbutazone have the greatest anti-inflammatory effect.
2. Decrease in elevated temperature. Aspirin, mefenamic acid and nimesulide effectively reduce temperatures.
3. Pain-relieving action. As analgesics, drugs have proven themselves well, which include ketorolac, diclofenac, metamizole, analgin or ketoprofen.
4. Prevention of platelets sticking together (antiaggregation action). In cardiology practice, for this purpose, aspirin is prescribed in small doses (for example, aspecard or cardiomagnyl).

Sometimes nonsteroidal drugs with long-term use can have an immunosuppressive effect, which is used in the treatment of certain rheumatic diseases.

Indications

1. Rheumatism, rheumatoid arthritis, Bechterew's disease, various types of 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-infectious diseases accompanied by fever.
6. Toothache.
7. Dysmenorrhea (painful periods).

Application features

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

Side effects

1. Digestive organs. NSAIDs - gastroduodenopathy, ulcers and erosion of the mucous membrane of the duodenum or stomach. The most unreliable in this regard are piroxicam, aspirin, indomethacin.
2. Kidneys. "Analgesic nephropathy" (interstitial nephritis) develops, renal blood flow worsens, kidney vessels narrow. The most toxic drugs from this group are phenylbutazone, indomethacin.
3. Allergic reactions. Can be observed when taking any drugs of this group.
4. Less commonly, there may be violations of blood clotting, liver function, bronchospasm, agranulocytosis or anemia of an aplastic nature.

List of drugs used in pregnancy

Almost all experts recommend that pregnant women refrain from taking nonsteroidal 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.

At the same time, it should be remembered that even the most “safe” of them can cause premature occlusion of the ductus arteriosus in the fetus, nephropathy and premature birth, therefore, in the third trimester, NSAIDs are not prescribed 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 drugs 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 characterizing numerous diseases. From a general biological point of view, this is a protective and adaptive reaction, however, in clinical practice, inflammation is always considered as a pathological symptom complex.

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

Steroid anti-inflammatory drugs - glucocorticoids;

Basic, slow-acting anti-inflammatory drugs.

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

25.1. NON-STEROID ANTI-INFLAMMATORY DRUGS

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

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

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

The main pharmacological effects of NSAIDs include:

Anti-inflammatory effect;

Anesthetic (analgesic) effect;

Antipyretic (antipyretic) effect.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pharmacokinetics

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

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

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

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

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

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

Indications for use

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

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

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

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

NSAID enteropathy.

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

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

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

Stimulation of the secretion of protective bicarbonates and mucus;

Strengthening the local blood flow of the mucous membrane;

Activation of cell proliferation in the processes of normal regeneration.

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

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

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

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

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

Absolute risk factors:

Age over 65;

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

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

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

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

Simultaneous use of several NSAIDs (the risk doubles);

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

Combined intake of NSAIDs and anticoagulants;

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

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

Possible risk factors:

The presence of rheumatoid arthritis;

Female;

Smoking;

Alcohol intake;

Infection H. pylori(data are inconsistent).

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

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

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

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

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

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

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

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

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

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

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

[Nasonov E.L., 1999].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Tactics of choosing non-steroidal anti-inflammatory drugs

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

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

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

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

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

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

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

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

When planning pharmacotherapy, the following should be considered.

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

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

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

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

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

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

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

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

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

Schematically, NSAIDs can be arranged as follows:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

0 - no pain;

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

2 - the patient talks about soreness and frowns;

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

pain on palpation.

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

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

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

0 - absent;

1 - doubtful or weakly expressed;

2 - explicit;

3 - strong.

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

25.2. PARACETAMOL (ACETAMINOPHENE*)

Mechanism of action and main pharmacodynamic effects

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

Pharmacokinetics

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

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

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

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

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

Side effects and contraindications to the appointment

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

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

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

Table 25-8. Symptoms of paracetamol intoxication

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

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

Interaction with other drugs

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

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

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

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

Slow-acting drugs with non-specific immunomodulatory effects:

Gold preparations (aurotioprol, myocrysin*, auranofin);

D-pericillamines (penicillamine);

Quinoline derivatives (chloroquine, hydroxychloroquine).

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

Immunosuppressants (cyclophosphamide, azathioprine, methotrexate, cyclosporine);

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

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

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

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

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

Mechanism of action and main pharmacodynamic effects

Gold preparations, reducing the phagocytic activity of monocytes, disrupt the uptake of the 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-helpers, suppression of the production of immunoglobulins by B-lymphocytes, including rheumatoid factor, and the formation immune complexes.

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

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

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

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

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

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

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

Pharmacokinetics

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

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

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

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

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

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

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

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

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

Indications for use and dosing regimen

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

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

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

The end of the table. 25-10

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

*Only as intravenous shock therapy.

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

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

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

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

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

Side effects and contraindications to the appointment

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 25-12. Side effects of immunosuppressants

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

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

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

Choice of medicines

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Their mechanism of action is based on the blocking of certain enzymes (COX, cyclooxygenase), they are responsible for the production of prostaglandins - chemicals that contribute to 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?

If analgesics fight directly with pain, then NSAIDs reduce both the most unpleasant symptoms of the disease: both pain and inflammation. Most drugs in this group are non-selective inhibitors of the cyclooxygenase enzyme, inhibiting 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.

List the diseases that prescribe these drugs:

• (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 at .

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

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

The most famous representatives of the NSAID group are for most of us aspirin (), ibuprofen, analgin and naproxen, available in pharmacies in most countries of the world. Paracetamol (acetaminophen) is not an NSAID because it has a relatively weak anti-inflammatory activity. It acts against pain and temperature on the same principle (by 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 the vessels and nerve fibers, cause local swelling, redness and pain.

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

Responsible for triggering the mechanism for the appearance of these prostaglandins is a group of enzymes called cyclooxygenases (COX) . The main action of non-steroidal drugs is aimed at blocking 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 suffering to a person, unpleasant sensations, are stopped.

Types behind the mechanism of action

NSAIDs are classified according to their chemical structure or mechanism of action. The long-known drugs of this group were divided into types according to their chemical structure or origin, since then the mechanism of their action was still unknown. Modern NSAIDs, on the contrary, are usually classified according to the 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 immediately on both types of enzymes. These drugs block COX-1 enzymes, which, unlike COX-2, are constantly present in our body, performing various important functions. Therefore, exposure to them can 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 affect the gastrointestinal tract so negatively, but at the same time, the load on the cardiovascular system is greater (they can increase pressure).
• selective NSAID COX-1 inhibitors. This group is small, since almost all drugs that affect COX-1 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 been confirmed only in animals, and they are also sometimes referred to 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 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, thiaprofenic acid);
• arylacetic acid (diclofenac, fenclofenac, fentiazac);
• heteroarylacetic (ketorolac, amtolmetin);
• indole/indene of acetic acid (indomethacin, sulindac);
• anthranilic (flufenamic acid, mefenamic acid);
• enolic, in particular oxicam (piroxicam, tenoxicam, meloxicam, lornoxicam);
• methanesulfonic (analgin).

Acetylsalicylic acid (aspirin) is the first known NSAID, discovered back in 1897 (all others appeared after the 1950s). In addition, it is the only agent capable of irreversibly inhibiting COX-1 and has also been shown to stop platelets from sticking together. 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 NVPS is constantly expanding and pharmacy shelves regularly receive new generation drugs that can simultaneously lower the temperature, relieve inflammation and pain in a short period of time. Due to the mild and gentle effect, the development of negative consequences in the form of allergic reactions, as well as damage to the organs of the gastrointestinal tract and urinary system, is minimized.

Table. Non-steroidal anti-inflammatory drugs - indications

property of a medical device	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 soft tissue injury).
Painkiller	The drugs are used for menstrual and headaches (migraines), are widely used in gynecology, as well as for biliary and renal colic.
Antiplatelet agent	Cardiological and vascular disorders: ischemic heart disease, atherosclerosis, heart failure, angina pectoris. In addition, it is often recommended for the prevention of stroke and heart attack.

Non-steroidal anti-inflammatory drugs have a number of contraindications that must be taken into account. 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;
• Previously, pronounced allergic reactions to drugs of this group were observed.

In some cases, the formation of a side effect is possible, as a result of which the composition of the blood changes (a “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 focus, 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. Therefore, taking NVPS contributes to the development of gastric and duodenal ulcers. If a person has these diseases, and he still takes "prohibited" drugs, then the course of the pathology can be aggravated up to 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:

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

Also, side effects include less dangerous conditions, such as nausea, vomiting, loss of appetite, loose stools, and bloating. Sometimes skin manifestations in the form of itching and a small rash are also fixed.

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

Consider the most popular and effective medicines.

A drug	Route of administration into the body (form of release) and dosage						Application note
	outdoor		through the gastrointestinal tract		injection
	ointment	gel	tablets	candles	Injection in / m	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 once a day	25-75 mg (2 ml) 2 times a day	—	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 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 of solution 1-2 r. per day	60 mg - 2 ml 1-2 times a day	During pregnancy, indomethacin is used to reduce uterine tone 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 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 - 8 mg - 2 times a day		The drug is used for pain syndrome of moderate and high severity
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	—	In renal failure, the allowable 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 once a day	—	The maximum allowable daily dosage is 40 mg
Celecoxib (Celebrex)	—	—	200 mg 2 times a day	—	—	—	The drug is available only in the form of coated capsules that dissolve 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 there have been allergic reactions to Penicillin in the past, then Aspirin should be prescribed with caution.
Analgin	—	—	250-500 mg (0.5-1 tab.) 2-3 times a day		250 - 500 mg (1-2 ml) 3 times a day		Analgin in some cases may have drug incompatibility, so it is not recommended to mix it in a syringe with other medicines. It is also banned in some countries.

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

In order for the drug to act as soon as possible and not cause harm to health, one 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, it is worth waiting for complete absorption. It is also not recommended to take water procedures for several hours after treatment.
• Tablets must be taken strictly as directed, not exceeding the daily allowable rate. If the pain or inflammation is too pronounced, then it is worth informing the attending physician about this in order to select another, stronger drug.
• Capsules should be washed down with plenty of water without removing the protective shell.
• Rectal suppositories act faster than tablets. Absorption of the active substance occurs through the intestines, so there is no negative and irritating effect on the walls of the stomach. If the drug is prescribed for a baby, then the young patient should be laid on his left side, then gently insert the candle into the anus and tightly clamp the buttocks. Within ten minutes, make sure that the rectal medication does not come out.
• 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.

Despite the fact that 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 medicines is not aimed at treating the disease, at relieving pain and discomfort. Thus, the pathology begins to progress and it is much more difficult to stop its development upon detection than it would have been done before.