Selective cyclooxygenase inhibitors 2. VIII. Other. General information about cyclooxygenase inhibitors
Parecoxib (dynastat) Nabumetone () Relafen)
VIII. Others
Nabumetone (Rhodanol S) Benzydamine (Tantum)
*analgesics-antipyretics (practically do not have anti-inflammatory effect
CLASSIFICATION BY MECHANISM OF ACTION
I Selective COX-1 inhibitors
Acetylsalicylic acid in low doses (0.1-0.2 per day)
II Non-selective inhibitors of COX-1 and COX-2
Acetylsalicylic acid in high doses (1.0-3.0 per day or more) Phenylbutazone Ibuprofen Ketoprofen Naproxen Niflumic acid Piroxicam Lornoxicam Diclofenac
Indomethacin and a number of other NSAIDs
III Selective COX-2 inhibitors
Meloxicam
Nimesulide
Nabumethon
IV Highly selective COX-2 inhibitors
Celecoxib
Parecoxib
V Selective inhibitors of COX-3(?)
Acetaminophen
Metamizole
The use of NSAIDs for human treatment dates back several millennia. Celsus (1st century BC) described 4 classic signs of inflammation: flushing, fever, pain, swelling and used willow bark extract to relieve these symptoms.
IN 1827 The glycoside salicin was isolated from willow bark.
IN 1869 company employee Bayer (Germany) Felix Hofmann synthesized acetylsalicylic acid (at the request of his father, who suffered from severe rheumatism) with a more acceptable taste than the extremely bitter extract of willow bark.
IN 1899 Bayer began commercial production of aspirin.
IN Currently, there are more than 80 non-steroidal anti-inflammatory drugs. The drugs are collectively callednon-steroidal anti-inflammatory drugs, because they differ from
steroidal anti-inflammatory glucocorticoids by chemical properties and mechanism of action. Every year, more than 300 million people worldwide take NSAIDs, of which 200 million purchase the drugs without a prescription.
30 million people are forced to take them constantly
MECHANISM OF ACTION
INFLAMMATION
Main components of inflammation
Alteration, hyperemia, exudation, proliferation.
The combination of these phenomena underlieslocal signs inflammation: - redness, - increased temperature, - swelling, - pain,
Impaired function.
IN As a result of the generalization of the process, along with local changes, general - intoxication, - fever, - leukocytosis,
Immune system response.
According to the nature of the inflammation, it can be acute and chronic. Acute inflammation lasts from several days to several weeks. It is characterized by:
Vivid signs of inflammation and the predominance of either alteration or vascular-exudative phenomena.
Chronic inflammation- This is a more sluggish, long-term process. Prevail:
Dystrophic and proliferative phenomena.
IN the process of inflammation under the influence of various damaging factors
(microbes, their toxins, lysosome enzymes, hormones)
the “cascade” of arachidonic acid is activated
(during inflammation, arachidonic acid is released from membrane phospholipids). 1) phospholipase A is activated 2, which releases arachidonic acid from cell membrane phospholipids.
Arachidonic acid is a precursor of prostaglandins (PGs) – mediators of inflammation. 2) Prostaglandins at the site of inflammation they take part in the development of -vasodilation, -hyperemia, -fever.
3) Arachidonic acid is involved in the metabolic process: cyclooxygenase and lipoxygenase.
With the participation of cyclooxygenase arachidonic acid is converted into inflammatory mediators - cyclic endoperoxides1 - prostaglandins2 - prostacyclins - thromboxanes 3
With the participation of lipoxygenase
Arachidonic acid is converted into leukotrienes - mediators of immediate allergic reactions and mediators of inflammation.
Cyclooxygenase (COX) - key enzyme in arachidonic acid metabolism.
This enzyme catalyzes two independent reactions:
1) cyclooxygenase
addition of an oxygen molecule to an arachidonic acid molecule to form PGG2
New generation non-steroidal anti-inflammatory drugs, without exaggeration, are the most popular drugs all over the world.
There is not a single medical field where, for a particular disease, a representative of this group would not be prescribed in the standard of treatment.
They are highly effective, but their use in most countries is limited to prescriptions, since self-administration of this group of drugs can be harmful.
What drugs are classified as non-steroidal anti-inflammatory drugs (NSAIDs)
There are just over 30 representatives of this group, however, about 10 drugs are widely used.
The group of NSAIDs includes drugs that inhibit the enzyme cyclooxygenase, which is involved in the synthesis of inflammatory markers: prostaglandins, thromboxanes and prostacyclins. These substances are involved in the process of fever and pain. There are three types of cyclooxygenase enzyme (isoforms) that have different functions.
Cyclooxygenase type 1 is constantly present in the body, it is involved in the synthesis of prostaglandins and similar substances that protect the stomach, kidneys, and also regulate microcirculation processes.
Cyclooxygenase type 2 - is formed in the body during inflammation, is not constantly present. Synthesizes substances involved in the processes of inflammation and cell division.
Cyclooxygenase type 3 - receptors for this enzyme are mainly located in the nervous system, the third isoform is involved in the processes of increasing temperature and plays a role in the appearance of pain.
According to the fact that there are 3 types of enzyme, there are 3 groups of NSAIDs.
- Selective (selective) COX 1 blockers - the most popular representative of all NSAIDs is aspirin.
- Non-selective (non-selective) blockers of COX 1 and COX 2 - most NSAIDs: diclofenac, indomethacin, ketoprofen, ketorolac, piroxicam.
- Selective COX 2 inhibitors – nimesulide, meloxicam, rofecoxib, celecoxib.
- Selective COX 3 inhibitors - paracetamol, analgin.
Selective COX 1 inhibitors and non-selective COX 1, 2 inhibitors are the “old” generation of this group of drugs. Aspirin is widely used in small doses as an antiplatelet agent (blood thinner) in the prevention of cardiovascular accidents.
COX 3 inhibitors are a separate group, and it should be noted that analgin (metamizole sodium) is not approved for use in most countries, but is approved for use in our country. Paracetamol is widely used as a pain reliever in Europe and the USA.
New generation of COX inhibitors, mechanism of action
COX 2 inhibitors are non-steroidal drugs of the so-called “new” generation; they are mainly used in the practice of a modern doctor.
COX 2 inhibitors are divided into:
- Drugs with preferential inhibition of COX 2 - nimesulide, meloxicam. They still have a slight inhibitory effect on COX 1, especially with long-term use.
- Highly selective COX 2 inhibitors - celecoxib, rofecoxib.
Mechanism of action of COX 2 inhibitors (nimesulide, meloxicam)
During inflammation, the cyclooxygenase 2 isoform is formed; when taking a COX 2 inhibitor, it is quickly absorbed from the digestive tract, 89% of the active substance enters the blood. Once in the bloodstream, the drug replaces receptors that are receptors for COX 2, thus reducing the number of inflammatory markers (prostaglandins).
In addition to the blockade of these receptors, competitive replacement of COX 1 receptors also partially occurs, especially when taking drugs of this group for a long time or when the therapeutic dosage is exceeded.
A feature of this group is a decrease in selectivity with long-term use or use of the drug in large doses. Which accordingly increases the frequency of side effects, since under these conditions COX 1-dependent undesirable effects of drugs may occur.
Mechanism of action of highly selective COX 2 inhibitors (celecoxib, rofecoxib)
When it enters the body, the drug is absorbed from the digestive tract, entering the systemic bloodstream and competitively blocks COX 2 receptors. At standard therapeutic concentrations, it has no effect on COX 1.
How do “old” inhibitors differ from “new” drugs?
In contrast to selective COX 1 inhibitors and non-selective COX 1 and 2 inhibitors, selective and highly selective inhibitors of the cyclooxygenase isoform 2 during treatment are not inferior in effectiveness to the “old” generation, and the incidence of damage to the digestive system is four times lower compared to non-selective inhibitors, in some, such as celecoxib, sevenfold.
Also different from COX 1 inhibitors is the lack of effect on the blood coagulation system (this is a COX 1 dependent effect), therefore the frequency of side effects in the form of increased blood coagulation is much less common in drugs of this group.
When using COX 2 inhibitors, the effects of bronchospasm, worsening of bronchial asthma or heart failure are less likely to occur. Safer use in older people has also been noted.
Modern research is discovering NSAID COX 2 inhibitors on the other hand - as possible antitumor agents. In laboratory studies, celecoxib showed antiproliferative and antitumor effects.
General contraindications and indications for the use of selective COX 2 inhibitors
The indications for taking NSAID inhibitors are very broad. In official instructions for the use of this group of drugs, various diseases of the joints and spinal column mainly prevail, since the vast majority of studies have been carried out in this area and this is the most common cause of pain.
Indications
- Pain syndrome.
- Joint diseases: rheumatoid arthritis, arthritis, osteoarthritis, consequences of injuries, gout, etc.
- Pain syndrome in neurological practice.
- Toothache.
- Menstrual pain.
- Headache.
- As a pain reliever during the postoperative period.
Contraindications
All contraindications of drugs in this group are combined:
- “aspirin triad”: bronchial asthma, aspirin intolerance, polyposis of the nose and paranasal sinuses;
- ulcerative lesions of the digestive tract in exacerbation;
- bleeding in the brain;
- severe heart failure;
- severe renal failure;
- hemophilia;
- period after coronary artery bypass surgery;
- pregnancy and lactation;
- drug addiction and alcoholism.
Features of the use of COX 2 inhibitors
Although the side effects of this group of drugs are much less pronounced than with the use of non-selective COX inhibitors, most of the side effects of COX 2 blockade are still present. Therefore, taking a COX 2 inhibitor should be at least half an hour after a meal; if there is an ulcer in any part of the gastrointestinal tract, then taking a COX 2 inhibitor is combined with prophylactic use of a proton pump blocker (omeprazole, pantoprazole, etc. .), and the dose should be two times a day.
Long-term use of this group of drugs is acceptable, but it should be remembered that in this case the risk of developing undesirable effects increases in direct proportion to the duration of therapy.
Some representatives of the “new” non-steroidal drugs
Celecoxib
It is a highly selective COX 2 inhibitor. When taken orally, it is easily absorbed, reaching a maximum concentration in the blood after 3 hours. The drug is used after meals; when taken together with fatty foods, the absorption of the drug significantly slows down.
According to the official instructions, celecoxib is used for rheumatoid arthritis, osteoporosis, psoriatic arthritis, and ankylosing spondylitis. The most common side effect is headache and dyspepsia. Celecoxib is taken orally at a dose of 200 mg x 2 times a day, the maximum allowable dose is 400 mg x 2 times a day.
Meloxicam
When taken orally, it is quickly absorbed from the gastrointestinal tract, the maximum level is reached after 5 hours, while 89% of the drug appears in the plasma. According to the instructions, meloxicam is used for inflammatory processes in the joints, arthritis, arthrosis, and unspecified joint diseases.
The drug is available in the form of tablets, injections, and rectal suppositories. Meloxicam is prescribed once a day. It is recommended to take the drug with meals. The most common undesirable effect from taking Meloxicam is dyspepsia and headache. With long-term use of meloxicam or use above therapeutic doses, its selectivity decreases.
Nimesulide
The most common selective inhibitor of COX 2. The maximum value is achieved in the blood plasma after 1.5 - 2 hours from administration; with simultaneous ingestion of food, the absorption time increases significantly. The indications for use of this drug, unlike other representatives, include pain caused by various reasons.
The most common undesirable effects: diarrhea, nausea, vomiting, increased liver transaminases. The drug is taken orally; there are water-soluble forms; a maximum of 200 mg of nimesulide can be taken per day.
Why are these drugs prescribed?
It would seem that there are fewer side effects, you can take it for a long time and for any reason, so why is this group dispensed in some pharmacies with a doctor’s prescription? For each medicine there are certain indications that can only be given by a doctor.
It is impossible to take new generation NSAIDs for minor reasons, since this group has many severe individual side effects, for example, sudden acute renal failure, drug-induced hepatitis, etc., which can occur suddenly in a young, healthy person and lead to his death.
Also, a large number of people have a low threshold for pain sensitivity, and they tend to take painkillers for any minor pain syndrome, and the NSAID group becomes addictive over time, the body can no longer function normally without the next dose of the drug, this is due to the adaptation of cyclooxygenase receptors to inhibition of NSAIDs.
Also, an ordinary person not involved in medicine will not be able to assess all the risks of simultaneous use of the drug with other medications. For example, taking COX 2 blockers reduces the effect of some blood pressure lowering drugs. Therefore, independent use of these medications cannot be justified in any case.
Selective COX-2 inhibitors are the main class of drugs used in the treatment of rheumatic diseases. In terms of anti-inflammatory and analgesic activity, they are not inferior to both traditional and specific (“highly selective”) COX-2 inhibitors, surpassing them in the degree of safety of use and the least number of side effects. Selective COX-2 inhibitors from national pharmaceutical manufacturers are effective and affordable agents for the treatment of a wide range of rheumatic diseases.
All over the world, the incidence of rheumatic diseases is continuously increasing, which is due, on the one hand, to the aging of the population, and on the other, to the unfavorable influence of technogenic factors.
According to Russian authors, by the age of 20, every second resident of Russia has one or another rheumatic disease, and by the age of 65 this figure reaches 100%. In Ukraine, 3.5 million (2.2%) people suffer from osteoarthritis alone, and 170 thousand people (0.4%) suffer from rheumatoid arthritis.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main class of drugs successfully used in the treatment of most patients with rheumatic diseases. This is primarily due to their clinical effectiveness, direct influence on the manifestations of the main pathological process (pain, swelling, fever), the rapid appearance of the clinical effect, the absence of a decrease in effectiveness with prolonged use and the formation of the phenomenon of dependence. And just as important, NSAIDs, in addition to their own anti-inflammatory and analgesic effect, help inhibit the pathological process, reducing tissue destruction of articular cartilage by inhibiting cell proliferation.
The most significant problem with long-term and sometimes short-term use of NSAIDs is the development of gastropathy, which can significantly worsen the quality of life of patients and force them to refuse further use of drugs. Sometimes gastropathy can really threaten the lives of patients with rheumatic diseases.
In patients with rheumatic diseases who often take NSAIDs, the frequency of erosive and ulcerative changes is almost equal to the frequency of such pathology in gastroenterological patients. Numerous erosions and ulcers with a high risk of developing severe complications are observed in 22.2% of cases.
Based on the potential for damage to the mucous membrane of the digestive tract, when prescribing NSAIDs, one should take into account possible risk factors, which are divided into uncontrolled and controlled.
Uncontrolled (independent of the actions of the doctor and the patient) risk factors for NSAID gastropathy include:
— age and gender of the patient;
— the nature and severity of the underlying disease;
- a history of peptic ulcer disease;
- presence of concomitant diseases.
Controllable (those that can be changed by the doctor and the patient) risk factors include:
- dose of the drug;
- duration of treatment;
- connection between NSAID use and food intake;
— form of the drug and method of administration;
- simultaneous use of other drugs;
— drug class;
- presence of Helicobacter pylori infection.
With the exception of Helicobacter pylori infection, monitoring effectiveness comes down to prescribing effective and safe medications.
Before the discovery of the role of cyclooxygenase (COX) in the development of erosive and ulcerative lesions of the gastroduodenal zone, it was believed that the cause of these lesions was a direct irritant effect, therefore the following ways to reduce the damaging effect were identified:
- reducing the dose of the drug;
— use of improved dosage forms (coated drugs, instant forms);
- changing the route of administration of the drug (from oral to parenteral or rectal);
- replacing one anti-inflammatory drug with another.
The use of high doses of NSAIDs is usually associated with an increased risk of developing NSAID gastropathy. However, as it turned out, when using NSAIDs in doses above and below the average therapeutic level, the frequency of erosions and ulcers was not statistically different, which gives grounds to believe that the ulcerogenicity of NSAIDs remains at approximately the same level in a fairly wide range of doses.
The risk of NSAID gastropathy is often also associated with the form of the drug and the route of its administration. It was believed that improving the dosage form (for example, creating rapidly soluble forms of acetylsalicylic acid (ASA), enterally coated ASA) or changing the route of drug administration would help reduce the incidence of gastrointestinal complications.
However, it turned out that a fairly high risk of developing NSAID gastropathy remains both when using rapidly soluble forms of ASA and ASA with enteral coating, and when administering NSAIDs parenterally. Lesions of the digestive tract are observed in 10-40% of patients and can occur with any route of drug administration.
When administered parenterally, local complications may occur in the form of hematomas, induration or subcutaneous nodules. The use of NSAIDs as ointments sometimes results in local erythema, eczema, or swelling.
Intestinal lesions when taking NSAIDs rectally can manifest themselves in the form of nonspecific colitis (ASA, ibuprofen, naproxen, phenylbutazone, indomethacin), terminal ileitis (diclofenac sodium, ibuprofen, mefenamic acid), ulceration or perforation of the intestine, intestinal bleeding.
Since changing the route of administration and the use of rapidly dissolving forms and forms with enteral coating have not solved the problem of the safety of NSAIDs, the main route of drug administration remains oral, provided that drugs are taken that do not have an adverse effect on the mucous membrane of the gastrointestinal tract.
The possibility of using such drugs appeared with the discovery of the physiological role of COX and its isoforms - COX-1 and COX-2. It turned out that the vast majority of anti-inflammatory drugs, simultaneously with their anti-inflammatory effect (due to blockade of COX-2), carry out a number of undesirable effects (due to blockade of COX-1), which primarily lead to the development of NSAID gastropathy due to inhibition of the formation of prostaglandins, providing gastroprotection. It turned out that the damaging effect of NSAIDs on the mucous membrane is determined not so much by their direct damaging effect as by their systemic effect, which does not depend on the method of administration of the drug into the body.
Clarification of the significance of COX and its isoenzymes led to the discovery of a new class of drugs - COX inhibitors, divided into 4 groups:
1) selective COX-1 inhibitors (acetylsalicylic acid in low doses);
2) COX-1 and COX-2 inhibitors (most classic standard NSAIDs);
3) predominantly selective COX-2 inhibitors - nimesulide, meloxicam;
4) specific (“highly selective”) COX-2 inhibitors - celecoxib, parecoxib.
Although logically the most effective and safe NSAIDs should be specific COX-2 inhibitors, there is a point of view that it is predominantly selective COX-2 inhibitors that are superior to specific ones. Evidence of this advantage is evidence that not only COX-2, but also COX-1 is involved in the development of inflammation and pain. On the other hand, there is no direct relationship between the degree of inhibition of COX-2 and the level of cytoprotection, and significant inhibition of COX-2 adversely affects ovulation, as well as the formation of prostacyclin by vascular endothelial cells.
Since their discovery and introduction into clinical practice, selective COX-2 inhibitors have proven their effectiveness and safety compared to other NSAIDs.
Nimesulide synthesized in 1985 and is one of the first selective COX-2 inhibitors with an original structure, during the study of which its higher selectivity for COX-2 was noted than for COX-1. According to the chemical structure, nimesulide belongs to sulfonamide derivatives and in its clinical effects resembles specific COX-2 inhibitors (in particular, celecoxib).
According to data obtained in several large-scale open clinical trials (22,239 patients with osteoarthritis who took nimesulide at a daily dose of 100-400 mg for 5-21 days), the overall incidence of side effects, mainly from the gastrointestinal tract, amounted to 8.2%. At the same time, the development of side effects became the basis for discontinuation of treatment in only 0.2% of cases (498 patients), and no serious anaphylactic reactions or complications from the gastrointestinal tract (ulcers, bleeding) were registered. According to another multicenter study, which included 12,607 patients with various rheumatic and orthopedic diseases, during treatment with nimesulide the incidence of side effects was even lower (6.8%). In a special analysis of the treatment results of 8,354 patients over the age of 60 years, the frequency of side effects was 8.9% and did not differ from that in the general patient population.
The high safety of nimesulide was proven in a double-blind, placebo-controlled study involving 4,945 patients. It has also been shown that nimesulide causes gastric erosion less frequently than indomethacin in patients with rheumatoid arthritis, and has a lesser ulcerogenic effect compared to diclofenac, without being inferior to it in effectiveness.
The therapeutic effectiveness of nimesulide is determined by a number of mechanisms not related to the regulation of prostaglandin synthesis (Table 1).
In recent years, nimesulide has begun to be widely used as an anti-inflammatory and analgesic agent for rheumatoid arthritis and osteoarthritis. In terms of effectiveness, nimesulide is not inferior to such well-known and widely used NSAIDs as naproxen, ibuprofen, and piroxicam. According to the results of a multicenter open study, which included examination and treatment of 23,000 patients with osteoarthritis, nimesulide was effective in 80% of cases. Similar results were obtained in another double-blind study, which compared the clinical effects of nimesulide with placebo, piroxicam and ketoprofen. Studies conducted in Russia and Ukraine also confirmed the high effectiveness of nimesulide in the treatment of patients with osteoarthritis, which was provided primarily by its anti-inflammatory and analgesic effect.
Domestic experience with the use of nimesulide in the form of tablets and gel has proven the high effectiveness of their combined use, which allows you to reduce oral doses without reducing the therapeutic effect.
Meloxicam used in clinical practice since 1995. The effectiveness and safety of meloxicam have been established in compliance with all modern requirements of evidence-based medicine in more than 230 clinical studies lasting up to 1.5 years. The results of clinical studies are confirmed by data from the use of the drug in clinical practice.
Among all the drugs that selectively inhibit COX-2, only meloxicam is recommended for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and now over 100 million patients in most countries of the world are treated with meloxicam.
The clinical effectiveness of meloxicam was convincingly proven in the multicenter, double-blind study Meloxicam Large International Study Safety Assessment (MELISSA), conducted in 27 countries involving 9,323 patients. The results showed a relatively identical therapeutic effect of meloxicam and the so-called “gold standard” of anti-inflammatory therapy, diclofenac. However, the incidence of gastroenterological complications was significantly higher with diclofenac (19%) than with meloxicam (13%). Compared with meloxicam, the need to discontinue treatment due to complications was twice as common in patients taking diclofenac. It is also important that peptic ulcers of the stomach and duodenum occurred 3 times less frequently when taking meloxicam than when treated with diclofenac, and the need for hospitalization due to the development of conditions threatening the body - perforation or gastrointestinal bleeding (in 0.09%) was much less likely. when taking meloxicam and 0.23% when taking diclofenac).
That is, at the beginning of the 21st century, sufficient evidence appeared indicating the advisability of prescribing meloxicam as an effective and safe medication in comparison with other NSAIDs, which in clinical effectiveness is not inferior to diclofenac, piroxicam, naproxen, and in gastrointestinal tolerability and safety correlates with celecoxib and parecoxib .
At the annual European Congress of Rheumatology (Prague, 2001), the subject of expert discussion was the advantages of selective COX-2 inhibitors (meloxicam, celecoxib) over “standard” NSAIDs. It was concluded that these drugs are not inferior in anti-inflammatory effectiveness to traditional ones, but are accompanied by fewer adverse effects from the digestive tract.
Domestic experience in studying the effectiveness of meloxicam allowed us to draw conclusions about the high effectiveness and safety of meloxicam in the treatment of patients with osteoarthritis and rheumatoid arthritis. Unlike standard NSAIDs, which led to the development of damage to the mucous membrane of the stomach and intestines, meloxicam only with prolonged use (over 6 months) in a small number of cases provoked exacerbations of existing chronic gastritis and peptic ulcers, while standard NSAIDs caused gastropathy even with condition of short-term use. The study authors conclude that if long-term use of NSAIDs is necessary in patients with rheumatoid arthritis and osteoarthritis, preference should be given to selective COX-2 inhibitors.
In Ukraine, the production of selective COX-2 inhibitors is carried out by one of the leaders of the national pharmaceutical market - JSC Farmak. These are nimesulide under the trade name REMESULID ® and meloxicam under the trade name REUMOXICAM ® .
Our studies have confirmed the clinical effectiveness and safety of the use of domestic selective COX-2 inhibitors REMESULIDE ® and REUMOXICAM ®.
Recently, 121 cases of adverse reactions caused by NSAIDs were evaluated. The author makes only preliminary conclusions, which indicate that in a comparative analysis, the largest number of cases of systemic manifestations of side effects occur with diclofenac and the smallest with meloxicam. For the sake of truth, it should be noted that it is likely that significantly more patients took diclofenac than nimesulide or meloxicam, so when analyzing the incidence of injuries, the total number of patients who took part in the study should be taken into account. Cases of side effects were analyzed using message cards that were received from doctors and regional branches of the State Financial Center of the Ministry of Health of Ukraine from a number of regions. However, unfortunately, doctors and patients often note only manifest manifestations that worsen the quality of life. With a thorough targeted examination of patients with endoscopic examinations and morphological examination of biopsies of the gastric mucosa, gastropathy is found in more than half of the patients who take standard NSAIDs.
It is probably also advisable when studying side effects to determine not only which active substance or drug caused the side effect, but also the manufacturer.
In our comparative analysis of diclofenac and meloxicam (REUMOXICAM ® produced by JSC Farmak), it was found that in patients with osteoarthritis, the effect of treatment with REUMOXICAM ® according to the results of the Lee test, the Stanford questionnaire (main and additional scales), the Ritchie index, and morning stiffness of the joints was not inferior to effectiveness of diclofenac. However, the frequency of side effects when taking diclofenac was significantly higher (52.4%) than when taking REUMOXICAM ® (up to 20%). A fairly high percentage of side effects is due to the thoroughness of the examination and the inclusion of clinical manifestations in the side effects - heartburn, dry mouth, rumbling in the abdomen, a feeling of fullness in the stomach, pain in the epigastric region, as well as the results of an endoscopic examination performed at the end of treatment with morphological analysis of biopsy samples.
The analysis gives every reason to believe that selective COX-2 inhibitors are an effective and promising class of therapeutic agents in the treatment of rheumatic diseases, and the drugs of the domestic pharmacological industry REMESULID ® and REUMOXICAM ® can today be considered the “golden mean” in terms of safety among NSAIDs. And in terms of effectiveness, they are not inferior to drugs defined as the “gold standard” of antirheumatic therapy.
Bibliography
1. Dmitriev M.T. // New drugs. - 1987. - No. 5. — P. 17-19.
2. Zhdan V.M., Katerenchuk I.P., Yarmola T.I. Diagnosis, prevention and treatment of NSAID gastropathy. - Poltava, 2005. - 135 p.
3. Zupanets I.A., Kovalenko V.M., Dzyak G.V. ta in. Rational administration of non-steroidal anti-inflammatory drugs during the treatment of sickness of the joints: Method. recommendations. - Kyiv; Kharkiv, 2002. - 23 p.
4. IMPROVE study: patients report greater satisfaction with meloxicam compared to other NSAIDs // Medicine of the world. - 2001. - T. 11, Part 3. - P. 1-4.
5. Karataev A.E., Nasonova V.A. Prevalence, structure and risk factors for the development of gastropathy induced by non-steroidal anti-inflammatory drugs // Russian. magazine gastroenterology, hepatology, coloproctology. - 2000. - No. 4. — P. 34-39.
6. Katerenchuk I., Tkachenko L., Yarmola T., Starodubtsev G. Efficacy and safety of meloxicam in the treatment of patients with osteoarthritis // Faces of Ukraine. - 2005. - No. 4. — pp. 115-117.
7. Kashuba O. Assessment of the side effects of other anti-inflammatory drugs // Faces of Ukraine. - 2005. - No. 12. — P. 101-105.
8. Kovalenko V., Ivanitska L., Shuba N. and in. The influx of so many non-steroidal anti-inflammatory drugs on the development and exacerbation of gastropathy in rheumatological patients // Faces of Ukraine. - 2004. - No. 1. - pp. 87-88.
9. Kovalenko V.N., Sholokhova L.B. Efficacy of selective COX-2 inhibitors in the treatment of patients with osteoarthritis // Ukr. rheumatol. magazine - 2000. - No. 1. — P. 37-40.
10. Nasonov E.L., Tsvetkova E.S., Balabanova R.M. and others. New aspects of anti-inflammatory therapy of rheumatic diseases: therapeutic prerequisites and clinical use of meloxicam // Klin. honey. - 1996. - No. 4. — P. 1-5.
11. Trinus F.P., Klebanov B.M., Ganja I.M., Seifulla R.D. Pharmacological regulation of inflammation. - Kyiv, 1987. - 212 p.
12. Tsvetkova E.S., Panasyuk E.Yu., Ionichenko N.G., Rubtsov O.V. Prospects for the use of cyclooxygenase-2 inhibitors in osteoarthritis // Consilium melicum. - 2004. - No. 6.
13. Shuba N.M. Results of multicenter studies, clinical effectiveness of new anti-inflammatory drugs // Materials of the Ukrainian Rheumatological School. - Kyiv: Chetverta Khvilya, 2002. - P. 154-165.
14. Distel M., Mueller C., Bluhmki E. Fries J. Safety of moxicam: a global analysis of clinical trials // Br. J. Phum. - 1996. - V. 35 (Suppl. 1). — P. 68-77.
15. Ferrari E., Pratesi C., Scaricabarossi I. A comparison of nimesulid and placebo in the treatment of minor traumatic soft tissue lesions in children // Arthritis Rheum. - 1993. - V. 28. - P. 197-199.
16. Dreiser R.L. Open long term study in 133 osteoarthritic patients // Drugs. - V. 46 (suppl. 1). — P. 195-197.
17. Pochbratsky M.G. et al. Post marketing surveys of nimesulidenin the short term treatment of osteoarthritis // Drugs Exper. Clin. Res. - 1991. - V. 1. - P. 197-204.
18. Ramella G., Costagli V., Vetere M. et al. A comparison of nimesulid and diclofenac in the prevention and treatment of painful inflammatory postoperative complications of general surgery // Drugs. - 1993. - V. 46, No. 1. — P. 159-161.
19. Silverstein F.E. Improving the gastrointestinal safety of NSAIDs. The development of misoprostol-from hypothesis to clinical ptactice // Dig. Dis. Sci. - 1998. - V. 43. - P. 447-458.
20. Steil D. Exploring the link between gastrointestinal complications and over-the-counter analgesis: current issues and considerations // Amer.Y. Ther. - 2000. - V. 7. - P. 91-98.
O.V.Kotova
GBOU VPO First Moscow State Medical University named after. I.M.Sechenov Ministry of Health of the Russian Federation
The high effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) for pain, inflammation and fever, and the possibility of purchasing medications without a prescription explains their “popularity” among different groups of the population. In the United States, about 30 billion NSAID tablets are sold annually; in developed countries, 20-30% of elderly people receive these drugs, among whom about 30% are forced to take these drugs, despite the presence of risk factors for the development of adverse events both from the gastrointestinal tract ( Gastrointestinal tract) and cardiovascular system. The enormous consumption of NSAIDs results in serious clinical and economic problems. In the United States in 1997, NSAIDs were responsible for 107,000 hospitalizations and 16,500 deaths. For comparison, it must be said that in the same year 4,441 people died from cervical cancer, 10,503 from multiple myeloma, and 16,665 from HIV infection. The cost of treating NSAID gastropathy and its complications in the United States exceeds $4 billion. in year.
Cyclooxygenase and NSAID side effects
The history of the use of NSAIDs has already passed the century mark, and the mechanism of their action was deciphered relatively recently: in 1971, J. Vane, J. Smith and A. Willis explained it by inhibition of the synthesis of cyclooxygenase (COX), a key enzyme in the metabolism of arachidonic acid, which is precursor of prostaglandins (PG). In recent years, two main isoforms of COX have been discovered: COX-1, which provides the synthesis of PGs that regulate the physiological activity of cells, and COX-2, which takes part in the synthesis of PGs involved in the processes of inflammation and cell proliferation. COX-1 is a structural enzyme that is constantly present in most cells (with the exception of erythrocytes) and regulates the production of PGs, which are involved in ensuring the normal functional activity of cells. In 1994, J. Vane formulated a hypothesis according to which the anti-inflammatory effect of NSAIDs is associated with their ability to inhibit COX-2, while the most common side effects: damage to the gastrointestinal tract, kidneys, impaired platelet aggregation (Table 1) - with suppression of COX activity -1.
Classification of NSAIDs
Based on the mechanism of action of NSAIDs, all existing NSAIDs can be divided into 4 groups (and the division into “predominant” and “specific” COX-2 inhibitors is largely arbitrary).
1. Selective COX-1 inhibitors (low doses of acetylsalicylic acid).
2. Non-selective COX inhibitors (most “standard” NSAIDs).
3. Mainly selective COX-2 inhibitors (nimesulide, meloxicam).
4. Specific (highly selective) COX-2 inhibitors (coxibs).
The last two groups of NSAIDs were developed in connection with the assumption that the anti-inflammatory, analgesic and antipyretic effects of NSAIDs are due to inhibition of COX-2, and the most common side effects are associated with inhibition of COX-1 activity. This became the basis for the synthesis of new NSAIDs - selective COX-2 inhibitors (nimesulide, meloxicam), and then even more selective, specific COX-2 inhibitors (coxibs).
The desire to achieve selectivity regarding COX-2 was dictated primarily by the desire to obtain drugs that are no less effective than “standard” NSAIDs, but less dangerous in terms of undesirable effects, primarily in terms of their effect on the gastrointestinal mucosa. The comparable therapeutic efficacy of COX-2-selective and traditional NSAIDs has been repeatedly demonstrated in animal and clinical studies.
Selective COX-2 inhibitor nimesulide
Nimesulide (4-nitro-2-phenoxymethanesulfonanilide), a representative of a new class of selective COX-2 inhibitors, has been used in clinical practice since 1985. It first appeared on the pharmaceutical market in Italy and is currently registered in more than 50 countries around the world. In the Russian Federation, nimesulide preparations first appeared in 1997.
Nimesulide (Nise®) has additional COX-independent effects: it affects the production and action of oxidative radicals and other components of neutrophil activation, which enhances the anti-inflammatory and analgesic effects and reduces the likelihood of gastrointestinal ulceration. The advantage of nimesulide is its rapid onset of action. Also, nimesulide is a highly effective remedy for relieving acute pain. Due to its chemical properties, nimesulide can easily penetrate into areas of inflammation and accumulate there (for example, in an inflamed joint) in a concentration greater than in blood plasma.
Selective COX-2 inhibitors, unlike classical NSAIDs, do not have a negative effect on articular cartilage. Nimesulide, in addition, inhibits interleukin-1(5 and chondrocyte apoptosis factor, suppresses the activity of metalloproteases, thereby exerting a pronounced protective effect on cartilage, which is especially important for patients with joint diseases (osteoarthrosis, damage to the articular apparatus of the spine ).
Nimesulide is characterized by high bioavailability. Already 30 minutes after oral administration, its concentration in the blood is 25-80% of the maximum level and an analgesic effect is noted. The peak concentration of the drug, and, accordingly, the maximum analgesic effect, is achieved after 1-3 hours.
Safety
Nimesulide rarely causes severe gastrointestinal complications.
In the Russian Federation, the safety of Nise in patients suffering from combined pathology of the joints and damage to the upper gastrointestinal tract was assessed in a study that included 600 patients who received the drug for 1-3 months at a dose of 200 mg/day. Although 10% of these patients had a history of ulcers, none of them developed perforation or bleeding from the gastrointestinal tract.
Irish researcher F. Bradbury assessed the frequency of gastrointestinal complications when using diclofenac (n=3553), nimesulide (n=3807) and ibuprofen (n=1470) in real clinical practice. The majority of patients (77.8%) received NSAIDs for no more than 14 days. It turned out that the total incidence of gastrointestinal complications when using nimesulide did not differ from that when using ibuprofen (8.1 and 8.6%), but was significantly lower compared to diclofenac (2.1%; p<0,05). Двойное слепое эндоскопическое исследование (гастродуоденальное) показало, что у пациентов, испытывающих диспепсию, нимесулид в суточной дозе 100 или 200 мг через 7 дней приема практически не отличается от плацебо по воздействию на слизистую оболочку.
A comparative analysis of adverse liver reactions induced by nimesulide and non-selective NSAIDs, including randomized and post-marketing clinical studies, showed that nimesulide causes an increase in liver enzymes no more often than “traditional” NSAIDs.
Of particular interest is a study conducted at the Institute of Rheumatology of the Russian Academy of Medical Sciences on the tolerability of nimesulide in patients with gout. These patients have many risk factors for drug-induced liver damage (alcohol consumption, fatty liver hepatosis, frequent development of cholelithiasis, etc.). However, they did not show changes in biochemical parameters reflecting the functional capacity of the liver.
From 1985 to 2000, 192 significant liver complications associated with taking this drug were registered, and only 81 episodes were considered serious - the accumulated experience of the manufacturer. Taking into account the fact that by 2000, 280 million patients were treated with nimesulide, the total frequency of dangerous hepatotoxic reactions when prescribed was 0.1 per 100 thousand courses of therapy.
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Side effects of NSAIDs |
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Cardiovascular system |
Hematopoietic system |
central nervous system |
Respiratory system |
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Heartburn, nausea, vomiting, diarrhea, gastralgia, erosive and ulcerative lesions of the gastrointestinal tract, bleeding |
Arterial hypotension, feeling of heat, hyperemia of the skin; extrasystole, tachycardia, hypertension, peripheral edema, superficial thrombophlebitis |
Leukopenia, agranulocytosis, thrombocytopenia, agranulocytosis |
Headache, dizziness, insomnia, drowsiness; rarely - paresthesia |
Widal syndrome, or “aspirin” asthma, is manifested by a severe attack of suffocation, cyanosis of the skin and can lead to pulmonary edema |
Speaking about the effect of nimesulide on the cardiovascular system, we can cite data from several studies. The risk of myocardial infarction while taking nimesulide was studied in a large population-based study conducted in Finland. In this study, 33,309 cases of myocardial infarction were assessed and 138,949 controls were matched. For nimesulide, the relative risk of developing this severe complication reached 1.69, i.e. was close to the corresponding values for nabumetone, etodolac and non-selective NSAIDs.
Nimesulide does not affect blood pressure (BP) and the effectiveness of drugs to lower blood pressure; in general, it has a positive effect on the condition of the vascular endothelium.
There are several reports in the domestic literature regarding the effect of nimesulide (Nise) on the development of arterial hypertension (AH). Thus, N.V. Chichasova et al. evaluated the results of 24-hour blood pressure monitoring in 48 patients with rheumatoid diseases (40 osteoarthritis and 8 rheumatoid arthritis) with concomitant hypertension and coronary heart disease (27 patients). In connection with hypertension, patients received angiotensin-converting enzyme inhibitors or (5-blockers. After a 3-day break from taking NSAIDs, patients were divided into 2 groups. Patients of the 1st group received diclofenac 100-150 mg/day, 2nd - Nise ® 200-400 mg/day for 20 days. Blood pressure was recorded 6 times a day. An increase in average daily systolic blood pressure (SBP) was recorded in group 1 by 15.74 ± 11.0 mm Hg, in group 2 - y - by 1.71±5.22 mm Hg. When taking diclofenac, an increase in diastolic blood pressure (DBP) was noted, cardialgia appeared in 16 patients, and the dose of antihypertensive drugs was increased in 6. In patients receiving Nise® , no significant increase in blood pressure was detected, all of them successfully completed the study.
In a study by O.A. Nizovtseva et al. The effect of diclofenac and Nise was compared in 40 patients with osteoarthritis, 1/2 of whom had hypertension and received enala-pril 5-10 mg 2 times a day. In patients with initially normal blood pressure, when taking Nise, SBP increased from 108±6.4 to 127±5.7 mm Hg. Art., and DBP - from 70.1±5.3 to 72.3±4.6 mm Hg. Art., while the patients did not note any unpleasant subjective sensations. In patients with hypertension, a decrease in both SBP and DBP was noted. When using diclofenac, an increase in blood pressure was noted in 2 subgroups, which was accompanied by a deterioration in health, the appearance of shortness of breath, edema and required correction of antihypertensive therapy. No changes in hemodynamics were detected in patients taking Nise ® . The authors explain the mechanism of increased blood pressure when taking NSAIDs by sodium and water retention, disruption of pro-oxidant balance and nitric oxide metabolism, as well as endothelial function. Similar results were obtained by B.F. Nemtsov and I.A. Shishkina, who assessed the effect of diclofenac and Nise in 40 patients with rheumatoid arthritis who received methotrexate at a dose of 7.5-10 mg/week as basic therapy. The dynamics of blood pressure and PGE2 concentration were studied in patients, which initially did not differ in the groups of patients receiving non-selective or selective NSAIDs. After 6 months of therapy, the decrease in the concentration of prostaglandin PGE2 in those receiving Nise® was not significant, unlike in patients receiving diclofenac (by 12.4 and 42.7%, respectively). There were no cases of increased blood pressure, unfavorable changes in the daily profile or blood pressure variability.
In an open-label 4-week Russian clinical trial that studied the effectiveness of high and medium therapeutic doses of nimesulide and diclofenac in early rheumatoid arthritis (n=268), hypertension was also observed only in a few patients. Although more than 20% of patients initially had diseases of the cardiovascular system, and more than 5% had uncontrolled hypertension at the time of inclusion, a significant increase in blood pressure was recorded only in 5.6% of those receiving nimesulide 400 mg, 2.6% - nimesulide at 200 mg, 9.7% - diclofenac 200 mg and 7.3% - diclofenac 100 mg/day (p>0.05).
Nimesulide is a drug with a relatively low risk of allergic reactions, and with short-term use (less than 15 days) it does not differ in safety from placebo and the most commonly used analgesics-antipyretics (paracetamol, ibuprofen).
Selective inhibition of COX-2 with nimesulide avoids complications such as bronchospasm or changes in the course of bronchial asthma (its special form is “aspirin” asthma), which is facilitated by nimesulide blocking the release of histamine from basophilic granulocytes and mast cells. Since COX-2 is involved in the activation of osteoclasts, nimesulide is the drug of choice in the treatment of patients with osteoporosis or risk factors for its development.
If we talk about the safety of long-term treatment with nimesulide, we can cite the data from W. Kriegel et al., who assessed the effectiveness and safety of nimesulide 200 mg and naproxen 750 mg in 370 patients with osteoarthritis for 12 months. The effectiveness of both NSAIDs was comparable, with some advantage of nimesulide: the reduction in the WOMAC index (Western Ontario and Mc-Master Universities Arthrose index) at the end of the observation period was 22.5 and 19.9%, respectively. The incidence of side effects from the gastrointestinal tract when using nimesulide was also lower - a total of 47.5% versus 54.5% in those receiving naproxen.
Efficiency
Nimesulide has a good and rapid analgesic and anti-inflammatory effect, which is confirmed by data from numerous clinical studies, in particular, in anesthesiological practice. In a study by A. Binning et al. patients (n=94) who underwent arthroscopic surgery were prescribed nimesulide 200 mg, naproxen 1000 mg or placebo as an analgesic for 3 days. The results showed that both NSAIDs were significantly more effective than placebo, but nimesulide provided a more pronounced analgesic effect in the first 6 hours after surgery.
Urgent use of nimesulide is justified for the relief of nonspecific pain in the lower back. According to a study conducted in Finland (n=102), nimesulide 100 mg, prescribed 2 times a day, was superior to ibuprofen at a dose of 600 mg, prescribed 3 times a day, both in terms of the severity of the analgesic effect and in restoring motor function of the spine. By the 10th day from the start of treatment, while taking nimesulide, a more than twofold improvement in functional activity was noted. Nimesulide was significantly less likely (about 2 times - 7% versus 13%) to cause side effects from the gastrointestinal tract compared to the control drug - the non-selective NSAID ibuprofen.
The effectiveness of nimesulide was also assessed in patients with a combination of osteoarthritis of the knee joint and pain in the lower back. The study was double-blind, prospectively controlled and lasted for 30 days (nimesulide was prescribed 100 mg 2 times a day). As a result of the study, the authors noted a significant decrease in the severity of pain, an increase in the range of active movements in the affected joints, a decrease in the initially increased muscle tone, as well as a decrease in the severity of radicular syndrome. The administration of nimesulide was well tolerated.
If we talk about the Russian experience of using nimesulide, we should recall a study on the use of this drug in early rheumatoid arthritis - a 4-week randomized study of the effectiveness of nimesulide in daily doses of 400* and 200 mg in 268 patients with rheumatoid arthritis. The comparison drug was diclofenac at doses of 200 and 100 mg/day. According to the results of the study, a statistically significant decrease in the number of inflamed joints and morning stiffness was noted in all groups. At the same time, nimesulide turned out to be somewhat more effective in its analgesic effect: a decrease in pain level by 50% or more (on a visual analogue scale) was noted in 44.8 who received nimesulide, and 40.8% who received diclofenac, more than 1/3 patients - a significant (50% or more) improvement in general well-being. In 5 patients, during monotherapy with nimesulide, complete disappearance of clinical manifestations of arthritis was noted.
Conclusion
Nimesulide (Nise®) is a drug with a favorable safety/efficacy ratio, has a powerful analgesic, anti-inflammatory effect and is well tolerated, which is confirmed by clinical studies and extensive experience in using this drug in real clinical practice. The risk of developing side effects with long-term use of nimesulide is overall lower than with the use of “traditional” (non-selective) NSAIDs, and since when prescribing NSAIDs for long-term use, the doctor must not only remember the goals of the patient’s pharmacotherapy, but also take into account the potential risk of developing drug complications, then the drug Nise ® can be offered as a drug of choice for the treatment of patients with chronic pathology.
*This study was conducted in 2007, when the permitted maximum dosage was 400 mg/day.
In terms of clinical effectiveness and frequency of use, nonsteroidal anti-inflammatory drugs (NSAIDs, NSAIDs or NSAIDs) occupy one of the leading places. This is explained by their ability to quickly stop the inflammatory process, relieve pain, eliminate swelling, inflammation, and fever. NSAIDs do not contain hormones, do not cause dependence, addiction, and do not lead to the development of serious diseases. But with long-term use, patients experienced various adverse reactions. To reduce the risk of complications, more modern selective anti-inflammatory drugs have been developed.
Mechanism of action of NSAIDs
NSAIDs act on cyclooxygenases (COX), inhibiting their activity. COXs are key enzymes in the synthesis of metabolic regulators and are responsible for the production of prostanoids, some of which support the inflammatory response and are the direct cause of pain.
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COX-1 is a structural enzyme that is constantly present in the tissues of a healthy person and performs useful, physiologically important functions. Contained in the mucous membrane of the stomach, intestines, kidneys and other organs;
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COX-2 is a synthesized enzyme, under normal conditions it is absent in most tissues, and is found in small quantities only in the kidneys, brain, spinal cord, bone tissue, and female reproductive organs. During inflammation, the level of COX-2 in the body and the rate of synthesis of prostaglandins, related to prostanoids, increase, which contributes to pain and the development of the inflammatory process.
Classification of NSAIDs
NSAIDs are classified based on their common structure, chemical properties and pharmacological action.
Based on their chemical origin, they are traditionally divided into acidic - preparations based on a weak organic acid, and non-acidic - derivatives of other compounds. The first group includes drugs that are derivatives of the following acids:
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salicylic acid - from it Acetylsalicylic acid, widely known as Aspirin, is obtained quickly and completely absorbed from the gastrointestinal tract;
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acetic - represented by its related compounds, such as Indomethacin, Aceclofenac, a powerful analgesic that also has an antitumor effect;
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propionic acid - its derivatives Ibuprofen, Ketoprofen are included in the list of the most important and vital drugs;
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enolic - pyrazolones: Analgin, Phenylbutazone and oxicams: Lornoxicam, Tenoxicam, selectively suppressing COX Meloxicam.
Classification according to the mechanism of action, based on the selectivity of inhibition of COX activity, is of clinical significance for humans.
All NSAIDs are divided into 2 groups:
- Non-selective - drugs that inhibit both types of cyclooxygenase enzyme at once, which is accompanied by serious side effects. This group includes most drugs.
- Selective - modern non-steroidal anti-inflammatory drugs, developed to increase efficiency and reduce the negative consequences caused by selectivity of action. Complete selectivity has not yet been achieved and the possibility of side effects cannot be ruled out. But drugs that minimally affect COX-1 are preferable, because are more secure. They are divided into selective - predominantly COX-2 blocking drugs, such as Nimesulide and highly selective inhibitors of the COX-2 enzyme - coxibs: Celecoxib, Etoricoxib, Dynastat.
Features of therapy
Due to their universal spectrum of action - the ability of NSAIDs to simultaneously provide analgesic and antipyretic effects, suppress the inflammatory process, and minimize the development of negative consequences - they are widely used in clinical practice for symptomatic therapy.
Most often, NSAIDs are prescribed in the following cases:
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injuries, bruises, postoperative period;
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neurological disorders;
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infectious diseases;
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renal and biliary (hepatic) colic, intestinal obstruction;
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malignant neoplasms of the colon;
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temperature over 38 degrees, menstrual pain, toothache, migraine;
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in cardiological practice, for the treatment of thrombosis, vascular disorders, prevention of strokes, heart attacks.
Contraindications and side effects
In anti-inflammatory treatment, a personal approach is important, because The same drug causes a different reaction in the body of each person.
Particular caution and close monitoring should be used when treating the elderly and people with heart defects, blood diseases, bronchial asthma, kidney or liver failure.
The selection of NSAIDs should be based on the personal experience of the doctor or patient - on previously identified individual intolerance.
Despite the relative safety of most NSAIDs and their clinical effectiveness, there are a number of contraindications for use that must also be taken into account:
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the presence of erosion, ulcerative lesions of the stomach, esophagus, duodenum;
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allergic reaction to certain components of the medication;
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pregnancy, breastfeeding period.
- Short-lived - half-life no more than 4-5 hours.
- Long-lived - for the drug to lose half of its pharmacological effect it will take 12 hours or more.
The elimination period depends on the chemical composition of the drug and the metabolic rate of the patient.
It is advisable to start treatment with the least toxic drugs and minimal doses. If, with a gradual increase in dose, within acceptable limits, over 7-10 days. no effect is observed, change to another drug.
The ability of the substance to be quickly eliminated from the body and selectively inhibit COX enzymes reduces the risk of developing undesirable side reactions. These are:
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impaired urination, proteinuria, decreased renal blood flow, impaired renal function;
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decreased blood clotting in the form of bleeding, bruising, and in rare cases, cardiovascular complications;
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nausea, diarrhea, difficult digestion, erosions and ulcers of the stomach and duodenum;
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various skin rashes, itching, swelling;
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increased fatigue, drowsiness, dizziness, loss of coordination.
NSAIDs should not be prescribed to persons whose professional activities require precision, speed of reaction, increased attention and coordination of movements.
Interactions with other drugs
When carrying out treatment, it is also important to take into account the ability of NSAIDs to interact with each other and with other drugs, especially with the following substances:
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reduce the effectiveness of diuretics and antihypertensive drugs used for hypertension;
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enhance the effect of oral antidiabetic drugs, indirect anticoagulants - anticoagulants, activating blood thinning;
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increase the toxicity of digoxin, prescribed for heart failure, and aminoglycosides, which are bactericidal antibiotics;
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steroid hormones, sedatives, gold preparations, immunosuppressants, narcotic analgesics enhance the analgesic and anti-inflammatory effect of NSAIDs.
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eating;
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Cholestyramine;
What are the release forms?
To increase the efficiency of use and the possibility of choosing a drug for a particular patient, based on the general characteristics of his health condition, the type and characteristics of the course of the disease, NSAIDs are produced in all dosage forms.
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capsules or tablets – ensure rapid absorption and good digestibility of the active substance;
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injection solutions: intramuscular, subcutaneous, - allow you to quickly reach the source of inflammation, eliminating penetration into other organs and minimizing side effects;
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rectal suppositories - suppositories do not irritate the gastric mucosa and small intestine;
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creams, gels, ointments - used in the treatment of joints, for targeted impact on the source of the disease.
Most popular NSAIDs
The most popular, classic drugs for over-the-counter use include:
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Aspirin – has all the properties characteristic of non-steroidal anti-inflammatory drugs. It is included in various medications; it is used independently and in combination with other medications. It has been found to help treat infertility and reduce the risk of cancer. Causes damage to the gastric mucosa and bleeding.
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Paracetamol - for the treatment of colds, infections, as an analgesic and antipyretic for a children's first aid kit. Does not have anti-inflammatory effect. Low toxicity, excreted by the kidneys in 1-4 hours.
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Ibuprofen is a safe and well-studied drug with a predominant analgesic and antipyretic effect. In terms of potency, it is somewhat inferior to other NSAIDs in this group.
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Diclofenac is a potent anti-inflammatory drug, a longer-acting analgesic, with a wide range of applications - from surgery and sports medicine, to oncology, gynecology and ophthalmology. Has a low cost. Long-term use increases the risk of heart attack.
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Ketoprofen - has an analgesic and antipyretic effect, and by the end of the 1st week of use, an anti-inflammatory effect is also achieved. Used for joint diseases, injuries and various types of pain syndromes.
Melbek) – relieves pain, relieves inflammation, fever, is indicated for arthritis, osteoarthritis, menstrual pain. With high doses and use for a long time, its selectivity decreases, which requires regular medical monitoring. It is a long-lasting drug, which allows it to be taken once a day.
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Celecoxib (Celebrex, Dilax) - due to its anti-inflammatory and analgesic activity, it is used to treat intestinal polyposis, diseases associated with damage to cartilage tissue and small joints, to reduce pain during menstruation. The drug is harmless to the digestive system.
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Lornoxicam (Xefocam, Larfix) is a strong anti-inflammatory and antirheumatic drug, belongs to oxicams. Long-term use requires regular medical supervision, because NSAIDs can affect the gastrointestinal mucosa, renal blood flow, hematopoietic system, and the number of platelets in the blood.
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Nimesulide (Nise, Mesulide, Aulin) is an inexpensive medicine that has a comprehensive effect on the problem. It has antioxidant properties, relieves acute pain, incl. post-traumatic, menstrual, muscle and dental, prevents the destruction of cartilage tissue, improves mobility. Prescribed for systemic connective tissue diseases, knee bursitis, inflammation and degeneration of tendon tissue. The formulation comes in a variety of dosage forms.
