Non-steroidal anti-inflammatory drugs COC 2. Selective anti-inflammatory drugs: clinical efficacy, mechanism of action, side effects. with severe anti-inflammatory activity

a) irreversible Central Inhibitors

1. Proms of salicylic acid - salicylates:acetylsalicyl K-TA (aspirin), Acetylsalicylate Lizina

b) reversible COG inhibitors

2. Pyrazolidins:Phenylbutazone (Butadion), Analgin

3. Indomethacin (Metindol), Sulindak (Clinic), etodolac (Elderin)

4. Diclofenac Sodium (Voltaren, Ortofen), Potassium (Rapten Rapid)

5. Oxycams:Pyroxikov (Felden), Lorunoksikov (Ksefokam), Meloxico (Movied)

II. COG-2 electoral inhibitors

1. C-bes containing a sulfonamide group:nimesulid, Celloxib

In activity and chemical structure

Acid derivatives:

with severe anti-inflammatory activity:

Salicylates:Acid of acetylsalicylic, lysine monoacetylsalicylate, difluorizal (dams), methylsalicylate

Pyrazolidins: PhenylButazone (butadion)

Indolux derivatives K-you:Indomethacin (Metindol), Sulindak (Clinic), etodolac (Elderin)

Phenyloxus derivatives K-you:Diclofenac Sodium (Voltaren, Ortofen), Potassium (Rapten Rapid)

Oksikama:Pyroxikov (Felden), Lorunoksikov (Ksefokam), Meloxico (Movied)

With moderate anti-inflammatory activity

Propionic acid derivatives:Ibuprofen (bruphen, nurofen), naproxen (Narosin), Ketoprofen

Anthralic acid derivatives:Acid Methenamovaya, Fufenamic acid

NSPVS with severe anti-inflammatory activityNon-acid derivatives

Alcanons:Nammaton (relaphen)

Sulfonamide derivatives:Nimesulide (Nimesil, Naz), Celecoxib (Kebrex), Ropecoxib (Viox)

NSAIDs with weak anti-inflammatory activity \u003d antipyretics analgesics

Pyrazolones: metamizole ( Analgin), Aminophenazone ( Amidopin)

Para-aminophenol (aniline) derivatives: fenacetin, acetamofen ( Paracetamol, Perfalgang, Panadol, Effergangan, Calpol)

Heteroarylumsus derivatives: Ketorolak (Ketorol), Tolm

Mechanism of action non-steroidal anti-inflammatory funds(NSAIDs) is associated with competitive inhibition of the COW. The blockade of non-steroidal anti-inflammatory agents of the COG leads to a violation of the synthesis of prostaglandins E 2 and 1 2 and the development of three main effects:

Anti-inflammatory;

Analgesic;

Antipyretic.

Mechanism Dr.:

Anti-inflammatory:

· Suppression of PGE generation 2 and PGI 2, associated with inhibitoring 2 (in small doses);

· Inhibition of neutrophils associated with the impact on the associated G-protein (in large doses)

· Reducing education and inactivation of inflammation mediators;

· Braking of lipid peroxidation

· Stabilization of lysosomal membranes (which prevents the exit of lysosomal enzymes and prevents damage to cellular structures);

· Brake of the processes of formation of macroeergic compounds in the processes of oxidative phosphorylation (violation of the inflammatory energy supply);

· Suppressing Chemokine secretion

· Suppressing the synthesis and expression of cell adhesion molecules and, accordingly, the locomotor function of leukocytes;

· The braking of adhesion of neutrophils and the interaction with receptors (the release of the mediators of inflammation, inhibition of synthesis, is disturbed;

Analgesic effect (after 20-40 min in moderate doses)

Peripheral component:

· Reduce the number of receptors, stabilizing the membrane

· Increasing the threshold of the pain sensitivity of receptors;

· Reducing the activity of proteolytic enzymes

· Restriction of exudation (after 5-7 days), followed by a decrease in squeezing pain expounds by exudate in closed cavities (joints, muscles, periodontal, brain shells).

Central

· Reducing the formation of PG-E 2 in the structures of the spinal and brain involved in the conduct and perception of pain;

· Inhibit COF-2 and Synthesis of PGA in the central nervous system, where it participates in the perception of pain

· Reduce hyperalgesia as a result: blockages of PG and prostacyclin synthesis, which potentiate irritating. Dei-E IL-1, TNF-α, histamine, serotonin, bradykinin and neuroknins on pain receptors.

· Violate pain pulses according to the conducting spinal cord paths, the lateral kernels of the thalamus are oppressed.

· Stimulate the release of endorphins and therefore reinforcing the inhibitory effect of the occasional gray matter on the transmission of nociceptive impulsation

Antipyretic effect (after 20-40 minutes)

1. Inhibit the synthesis of endogenous pyrogen on the periphery (IL-1) in MON / MF

2. Inhibiting COF, reduce the synthesis of PG-E 1 and PG-F 2, on and serotonin in the central nervous system

· Restore the equilibrium of heat-product centers and heat transfer in neurons of the prevention area of \u200b\u200bthe hypothalamus.

· Expand skin vessels and increase sweating

Braking Energy Products in the Heat of Inflammation

Biochemical reactions underlying inflammation - highly energy consumption: synthesis of inflammation mediators, chemotaxis, phagocytosis, connective tissue proliferation

NSAIDs violate the synthesis of ATP (suppress glycoliz and aerobic oxidation, disagree from)

Effect of NSAIDs on proliferation processes

NSAIDs inhibit the formation of connective tissue (collagen synthesis):

1. Reduce the activity of fibroblasts

2. Violate the power supply of proliferative processes

The greatest antiproliferative effect is: indomethacin, sodium diclofenac, acecloofenak, pyroxics, lorunoxy, meloxicami

Anti-aggregation effect TXA 2 / PGI 2

· Inhibiting COX 1 in platelets, suppress the synthesis of endogenous proagringent of thromboxane.

· Selective COG 2 inhibitors do not have an anti-aggregation effect.

The immunotropic effect of the NSAIDs: suppress the activation of the transcription factor (NF-KB) in T-lymphocytes

Inhibit the synthesis of cytokines (Il-1,6,8, interferon-β, FNF-α), rheumatoid factor, complement and adhesion molecules

Reduce general immunological reactivity

Oppress specific reactions to NUTIGEN

Indications NSAIDs: sharp rheumat. Diseases- Gout, pseudoadagad, exacerbation of osteoarthrosis . Cron. rheumatic. Diseases- rheumatoid arthritis, spondyloarthropathy, osteoarthritis . Smeal irregular. Diseases- injuries, back pain, postoperative pain, renal colic, dysmenorrhea, migraine, etc. Other diseases -pleurisy, pericarditis, knocked erythema, polyposis of a large intestine; Prevention - thrombosis, colon cancer.

Acetylsalicylic acid - Salicylic acid derivative, irreversibly blocks CHA due to acetylation of the active center of the enzyme. It has a much greater affinity for COX-1 than to COX-2. BUT nalhetating, antipyretic, anti-inflammatory, anti-aggregation.

1. Inhibits cyclooxygenase (COX-1 and COG-2) and irreversibly slows down the cyclooxygenase path of arachidonic acid metabolism, blocks the synthesis of PG (PGA 2, PGD 2, PGF 2Allf, PGE 1, PGE 2, etc.) and thromboxane. Reduces hyperemia, exudation, capillary permeability, hyaluronidase activity, limits the energy supply of the inflammatory process by oppressing ATP products.

2. affects subcortex centers of thermoregulation and pain sensitivity. Reducing the PG content (mainly PGA 1) in the center of thermoregulation leads to a decrease in body temperature due to the expansion of the skin vessels and an increase in sweating.

3. The anesthetic effect is due to the effect on the centers of pain sensitivity, as well as the peripheral anti-inflammatory effect and the ability of salicylate to reduce the algogue effect of bradykinin.

4. Reducing the content of thromboxane A 2 in platelets leads to an irreversible suppression of aggregation, somewhat expands the vessels. Antiagragerant action is preserved for 7 days after one-time reception. During a number of clinical studies, it was shown that substantial inhibition of blood plates gluable is achieved with doses up to 30 mg. Increases the fibrinolytic plasma activity and reduces the concentration of vitamin K-dependent coagulation factors (II, VII, IX, X). Stimulates the removal of uric acid, since its reabsorption in the kidney channels is disturbed.

5. F / kinetics: T 1/2 acetylsalicylic acid is no more than 15-20 minutes. In the body circulates (by 75-90% due to albumin) and is distributed in tissues in the form of an anion of salicylic acid. C MAX is achieved around 2 hours. With blood plasma proteins, acetylsalicylic acid is practically not associated. When biotransformation, metabolites found in many tissues and urine are formed in the liver. The excretion of salicylate is carried out mainly by actively secretion in the kidney channels in unchanged form and in the form of metabolites.

6. Application: Effective anti-aggregant in doses of 100-150 mg per day for the prevention of coronary vessels in ischemic heart disease, for the prevention of ischemic stroke. Treatment of acute and chronic rheumatic diseases; Neuralgia, Malgy, articular pain.

Contraindications: Hypersensitivity, incl. "Aspirin" Triad, "Aspirin" Asthma; Hemorrhagic diathesis (hemophilia, Willebrand disease, Teleangioectasya), Aortic aneurysm, heart failure, acute and recurrent erosive-ulcerative diseases gastrointestinal tract, gastrointestinal bleeding, acute renal or hepatic insufficiency, initial hypoprothrombinemia, vitamin K, thrombocytopenic deficit, thrombocytopenic purple , glucose-6-phosphatehydehydrogenase, pregnancy (I and III trimester), breastfeeding, children's and adolescent age up to 15 years old when applying as an antipyretic agent (risk of deeper's syndrome in children with fever against viral diseases).

8. Specific side effects of acetylsalicylic acid are irritation and ulceration of the gastric mucosa, bronchospasm - "Aspirin Asthma." Bronchospasm is due to the activation of the lipoxygenase path of the metabolism of arachidonic acid.

9. Poisoning: Headache, ringing in the ears, frowning, psyche; nausea, vomiting, diarrhea, epigastric pain; Respiratory alkalosis or metabolic acidosis.

Sodium diclofenac -phenyloxic acid derivative. The drug is one of the most frequently used anti-inflammatory funds with severe analgesic and antipyretic activity. It has pronounced analgesic properties, antipyretic activity. It has low toxic activity.

Lorunoksikov- indiscriminate COG inhibitor. It has pronounced painful and anti-inflammatory effects. The antipyretic effect occurs only when taking large doses.

Inhibitors cyclooxygenase (COF-1 and COF-2). Reduces GHG, leukotriene products, affects the gastric mucosa, platelet function and renal blood flow. Inhibits the release of active forms of oxygen, the kinin system.

It has an influence mainly on the exudative and proliferative phase of the inflammatory response. When prescribing with rheumatoid arthritis, it shows a pronounced analgesic effect, reduces the duration of the morning stiffness, the articular index of Richie, the number of inflamed and painful joints; A number of patients reduces ESO.

Indications: Paintaking with inflammatory processes: osteoarthritis, rheumatoid arthritis) + postoperative period + pain associated with tumors. Enter 2-3 times a day. When taking inside quickly and completely absorbed, bioavailability approaches 100%. The achievement time C Max is about 2 h (at a per / m introduction - 15 min). Plasma is almost entirely associated with proteins. The liver is hydroxylized and turns into a pharmacologically inactive metabolite. T 1/2 - 4 hours. About 30% of the dose is derived from the urine, mainly in the form of metabolites, the rest is with biliary. The side effects of the side effects should be noted the frequent reactions from the gastrointestinal tract.

Ibuprofen -phenylpropionic acid, which is used for pain caused by inflammation.

pharmachologic effect .

Injectively, inhibits COG-1 and COG-2, reduces the synthesis of PG. The anti-inflammatory effect is associated with a decrease in the permeability of the vessels, the improvement of microcirculation, decrease in the release of inflammation mediators (GHG, Kinina, Lt) and the suppression of the inflammatory energy supply.

An analgesic effect is due to a decrease in inflammation intensity, decreasing bradykinin production and its algunity. With rheumatoid arthritis, it affects the exudative and partly on the proliferative component of the inflammatory reaction, has a fast and pronounced painkillers, reduces the swelling, morning stiffness and limiting mobility in the joints.

Reducing the excitability of heat-regulating intermediate centers is resulted in an antipyretic effect. The severity of the antipirelic effect depends on the initial body temperature and dose. With a single reception, the effect lasts up to 8 hours. With primary dysmenorrhea, reduces intrauterine pressure and the frequency of uterine contractions. Reversibly inhibits platelet aggregation.

Since PG is detained the closure of arterial duct after birth, it is believed that the suppression of the COF is the main mechanism of action of ibuprofen at in / used in newborns with an open arterial duct.

Analgesic effect compared to anti-inflammatory develops when appropriate less doses. In the pain of the syndrome, the beginning of the drug is observed after 0.5 hours, the maximum effect - after 2-4 hours, the duration of action is 4-6 hours. The drug is well and quickly absorbed when taking inside, penetrates well into the synovial fluid, where its concentration reaches more High values \u200b\u200bthan in blood plasma. t.is 2 hours.

For ibuprofen, all typical SFID side effects are characterized, at the same time it is considered (especially in the US) more secure compared to diclofenac and indomethacin.

The drug is contraindicated with the danger of angioedema edema, with bronchospastic syndrome.

Celecoxib is the electoral inhibitor of COG-2.Mostly depresses the activity of the enzyme, which is formed in the focus of inflammation.

pharmachologic effect - anti-inflammatory, analgesic, antipyretic.

Selectively inhibits COF-2 and blocks the formation of pro-inflammatory GHG. In therapeutic concentrations does not inhibit COF-1. In clinical trials, healthy volunteers celecoxib in one-time doses up to 800 mg and multiple - 600 mg twice a day for 7 days (above the recommended therapeutic doses) did not reduce platelet aggregation and did not increase the bleeding time. The suppression of the synthesis of PG 2 can lead to a fluid delay due to an increase in reabsorption in a thick ascending segment of the loop of gene and, possibly, other distal areas of nephron. PGA 2 inhibits the reabsorption of water in the collecting tubes, preventing the action of antidiuretic hormone.

The aggregation of the shopping center does not affect, because COG-2 in platelets is not formed. Activity has been detected to prevent the development of the tumor and polyposis of the colon and the rectum.

When taking inside, it is quickly absorbed, C MAX is achieved by about 3 hours. Emission of food, especially rich in fats, slows down suction. The degree of binding with plasma proteins is 97%. Equilibrium concentration is achieved by the 5th day. It is evenly distributed in the tissues, penetrates through the BGB. Biotransformed in the liver mainly with the participation of Cyp2C9 cytochrome R450. T 1/2 - 8-12 hours, general clearance - 500 ml / min. Displays in the form of inactive metabolites, mainly through the gastrointestinal tract, a small amount (less than 1%) of unchanged celecoxib is found in the urine.

Indications:Rheumatoid arthritis, osteoarthritis, ankylosing spondyloarthritis, psoriatic arthritis.

Side effect NSAIDs

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in medical practice. They are prescribed with various diseases that are accompanied by pain syndrome, fever, as well as for pain reliefing patients in the postoperative period.
NSAIDs are symptomatic means, since they most often eliminate the clinical manifestations of the disease, without affecting the mechanism of development of the pathological process. These drugs have a number of serious side effects, so in recent years, pharmacists try to develop new NSAIDs - not only effective, but also more secure.
The mechanism of operation of the NSAID is explained by the ability to suppress the production of prostaglandins, special substances affecting the manifestation of inflammatory response and pain. Blocking the synthesis of prostaglandins by non-steroidal anti-inflammatory means is due to the leveling of the activity of the cyclooxygenase enzyme activity (COF). According to the data obtained in the human body of cyclooxygenase, two isomeric forms of COF 1 and COF 2. There is such a concept that the anti-inflammatory and analgesic effect of the NSAID is due to their ability to suppress the activity of COF 2, and the development of side effects from the gastrointestinal tract, kidneys, blood formation is connected With inhibition of COW 1. Based on this concept, new NSAIDs were synthesized, which had a selective action (that is, preferentially) to suppress the activity of COF 2. The drugs of this group include: nimesulide, meloxico, celecoxib, etodolac, ropecoxib. When carrying out clinical trials, it was revealed that the NSAIDs of the new generation was not inferior to the effectiveness of their therapeutic effects by traditional NSAIDs, but at the same time they were quoted four times in the process of treating complications from the gastrointestinal tract.
But, despite this, patients receiving the therapy of the NSAIDs of selective action can also occur various side effects (abdominal pain, nausea, vomiting, etc.), which sometimes forces the doctor to cancel the appointed treatment. And in some cases, selective COG2 inhibitors as well as traditional NSAIDs can lead to the development of very serious complications from the gastrointestinal tract, the patient's threatening life (gastric bleeding, perforation of the stomach or duodenal ulcers). Therefore, persons having a high risk of developing such diseases should be defined intensive prophylactic treatment of ulcerative disease and gastritis, regardless of which NSAIDs are obtained.
The NSAIDs of the selective action to COG 2 can lead to an increase in blood clotting increase, and, therefore, and increase the risk of developing myocardial infarction, ischemic stroke. Therefore, patients having diseases of the cardiovascular system (atherosclerosis, varicose veins, hypertension, etc.) simultaneously with the appointment of the NSPIDs of the selective action recommended aspirin microindoses (in the amount of 0.25 g / day). But since the acetylsalicylic acid itself is capable of developing serious complications from the gastrointestinal tract organs, the question arises: "Is it worth simultaneously prescribing these drugs?".
Of all the above, it becomes clear that the NSAIDs belonging to the group of selective inhibitors of COW 2 is not devoid of flaws. They also, as well as traditional NSAIDs (although much less often), can lead to the development of various, and sometimes threatening life of complications. Therefore, before starting treatment, any of nonsteroidal anti-inflammatory funds, it should be consulted with a doctor. Only a specialist will be able to select the most suitable drug for this patient, as well as, if necessary, prescribe a prophylactic treatment of existing other somatic diseases. Only with this approach to the selection of NSAIDs can significantly reduce the likelihood of the development of complications.

The mechanism of action of all NSAIDs is to suppress the activity of the cyclooxygenase enzyme (COW), which produces prostaglandins and thromboxane from arachidonic acid. In the human body there are two isoenzyme cyclooxygenases: COX-1 and COF-2. COF 1 is contained under normal conditions in the blood vessels, stomach, kidneys and catalyzes the synthesis of prostaglandins, which are involved in the regulation of organism physiological processes. COF-2 is formed in peripheral tissues only when inflammation. Traditional NSAIDs, such as indomethacin and diclofenac, act indiscriminately, inhibiting equally "useful" COF-1 and COF-2, which causes pain and inflammation. With long-term intake, such NSAIDs are affected by the mucous membrane of the stomach and duodenum with the formation of ulcers and bleeding. The disadvantages of non-selective NSAIDs served as the creation of a new generation NSAID, which have the selectivity in relation to COX-2.

The most selective COF-2 inhibitor in Russia is the drug "" (Ryricoxib), which was dedicated to the symposium "A new drug for treating pain: the first year in Russia", which was held in the framework of the XVII Russian National Congress "Man and Medicine". It inhibits 106 times more cycloxygenase-2 than cyclooxygenase-1, i.e., it practically does not affect COF-1, and therefore should not cause a large number of complications from the gastrointestinal tract. This is confirmed by clinical trial data: metaanalysis 10 clinical studies, in which patients with coarlet, osteoarthritis, rheumatoid arthritis and chronic back pain showed that the risk of gastrointestinal perforations, expressions and bleeding 50% lower at the appearance of Arkoxy than When receiving non-selective NSAIDs. The incidence of therapy due to symptoms from the heading of the gastrointestinal and unwanted phenomena is also lower at the reception of Arkoxy than when receiving non-selective NSAIDs.

Coesecoxib (CELECOXIB., Celebrex) Codecoxib was created in the 90s of the 20th century and gave rise to a whole class of highly specific inhibitors of COX-2 - "Koksibov".

MD: Cellotoxib is 375 times the selective COG-2 blocks, compared with the COF-1 of the enzyme isoform. It is believed that this is due to the presence of celexib for the celexib, rigidly fixed at an angle: the polar sulfonanildal group of the molecule blocks the hydrophilic side pocket of COX-2, and the arylpirazolny part of the molecule occupies the main hydrophobic enzyme channel. Due to the fact that the COG-1 molecule does not have a hydrophilic side pocket of the celecoxib, it is not capable of entering the active center of the enzyme and the connection of the drug with COX 1 is sufficiently continuing. It is realized only when taking high doses of celecoxib (the blockade of COF-2 is developing already when prescribing celecoxib in a dose of 0.2 mg / kg or 150-200 mg / day, while the blockade of COF-1 requires a dose of 200 mg / kg or about 14,000. mg / day).

Table 7. Comparative characteristics of the NSAID

Medicine	Antipiretic	Anti-inflammatory	Analgesic	Effect.	COF-1. † COF-2.
Aspirin (ASC)
Difluunisals
Paracetamol
Phenylbutazon
Ibuprofen
Naproxen
Indomethacin
Sulindak
Diclofenak
Pyroxikam
Thosexicams
Ketorolak
Mesphenam. K-TA
Nammaton
Kesetoxib

Note: † - the less the ratio of COF-1 / COF-2 \u003d -lG[ IC. 50 COF-1 /IC. 50 COG-2], the selective to the agent for COF-2.

FC: celecoxib has very low solubility in water, so creating a parenteral form of medication is extremely difficult. When oral administration, the bioavailability of celecoxib is about 75%, food intake can reduce the absorption rate by 20-30%, but the bioavailability becomes fuller and increases by 7-20%. In the blood of celecoxib, 97% is associated with blood proteins. After one-time reception at a dose of 200 mg, the maximum serum concentration is 1500 ng / ml and 5 times exceeds the boundary of the minimum therapeutic level (300 ng / ml). Since the period of semi-elimination of the drug is 10-12 hours, the decrease in the concentration to the minimum therapeutic level occurs during a little more than 2t ½, i.e. Codexibe can be taken 1 time per day.

The codoxib metabolism proceeds in the liver (\u003e 90%) mainly due to the isoform of cytochrome p 450 2c9. This cytochrome does not take part in the metabolism of the overwhelming majority of drugs (for example, aminoglycosides, anticonvulsants and oral suarrangeing agents), therefore, in the treatment of celecoxib, the dose correction is not required to be accepted together with it.

FE: for celecoxib, pronounced anti-inflammatory and analgesic effects are characteristic. In its effectiveness, celecoxib in a dose of 100-400 mg / day is not inferior to ASK, naproxen and diclofenac. It is interesting to note that the anti-inflammatory and analgesic effects of medication do not wear a dose-dependent nature. When used in a dose of less than 100 mg / day, the effect of the medication is absent, in the range of doses from 100 to 400 mg / day, it arises, but a further increase in dose from 400 mg / day to 1200 mg / day almost does not lead to an increase in effect.

Since celecoxib practically does not affect COX-1, it does not change the aggregation of platelets and does not lead to the development of disaggregative action.

Indications for use and dosing modes: celecoxib are used to treat chronic inflammatory lesions of the organs of the musculoskeletal system:

osteoarthritis - at 100-400 mg / day in 1 reception;

rheumatoid arthritis - 200-800 mg / day in 1-2 receptions.

Since there are theoretical prerequisites for the possible participation of COF-2 in the process of carcinogenesis in the area of \u200b\u200bthe colorectal zone, the development of Alzheimer's disease, then some authors consider celecoxib as a promising means for the prevention of these diseases in the senior age groups.

NE: due to high selectivity for COW-2 and maintaining the normal functioning of the physiological isoform of COG-1, celecomb is considered to be more secure NPIDs, compared with non-selective COF inhibitors.

Celecoxib less often causes the formation of ulcerative defects on the mucous membrane of the tract, does not lead to the development of bleeding due to a decrease in platelet aggregation and does not have a tocolic effect (does not reduce the miometrium tone). In people with arterial hypertension, his reception is not accompanied by a pressure destabilization.

However, the initial hopes for the complete safety of selective COF-2 inhibitors and the very celecoxib generally not justified. Currently it has been established that its reception is accompanied by the emergence of the following undesirable effects:

As mentioned earlier, the celecoxib does not cause the development of ulcerative damage to the mucous gastrointestinal tract, but it delays the process of healing the already existing ulcerative defects. It is assumed that this is due to the fact that control over the processes of repair and mitosis of the Epithelium GTS is carried out by prostaglandins, which are formed under the influence of COF-2.

SulfonanLide group of celecoxib can cause skin allergic reactions and cross-sensitization to sulfanilamine means and oral suarrangeing drugs from a group of sulfonylurea derivatives.

In 1% of people who have long taken the celecoxib developed acute renal failure.

For celecomb, as well as for Nimesulide, the ability to induce the development of thrombosis has been proved in the Class (2000) study. As it is believed, this is due to the fact that the synthesis of thromboxane A 2 is controlled mainly by COX-1, and the synthesis of prostacyclin - COF-2. Therefore, against the background of the blockade of COF-2 in the body, the prevalence of thromboxane level over the prostacycline and the aggregation of platelets will increase, up to the development of the myocardial infarctional infarction.

It should be noted, however, that later studies performed in 2002 did not confirm the findings of the Class research. Therefore, the question of the effect of celecoxib for hemostasis remains up to the present time.

The intake of celecoxib in women leads to the development of reversible infertility (the frequency of which was 2 times higher than in the control population of women who did not accept the inhibitors of COF-2).

FV: Capsules 100 and 200 mg.

Ropecoxib (Rofecoxib, Vioxx) Also, as well as celecoxib refers to powerful selective COX-2 inhibitors. The mechanism of action of the ropecoxib is similar to that in the celecoxib, but the role of the hydrophobic main channel blocker is performed by an arylfuraous part of the molecule.

F. K: Ropecoxib is well absorbed from the gastrointestinal tract, but when the dose increases its absorption. It is believed to be related to the peculiarities of the dissolution of the drug. Unlike celecoxib, it is worse than protein (87%), but nevertheless its period of semi-elimination is greater than that of the celecoxib and is about 17 hours (therefore ropecoxib can be prescribed 1 time per day). The metabolism of ropecoxib proceeds with the participation of the isoform of cytochrome P 450 3A4, which actively oxidizes the medicine both in the liver and in the intestinal wall.

PE: Ropecoxib has well-pronounced analgesic, anti-inflammatory and antipirective effects. At the same time, it is devoid of antiagregant activity by other selective inhibitors of COG-2.

Application and dosing: Ropecoxib is used to treat osteoarthrosis and rheumatoid arthritis at a dose of 25 mg / day once.

NE: In general, the unwanted effects of rofekoxib are similar to the effects of celecoxib.

FV: Tablets at 12.5 and 25 mg.

Means affecting predominantly on lipoxygenase path

ekosanoid metabolism.

Classification:

5-lipoxygenase inhibitors: zileuton;

Antagonists leukotriene Cyslt 1 -receptors: zafirlukast, Montelukast, Werlfry, Prange, Cinaulukast, Iralucast, Brillucast.

Zileuton (Zileuton., Zyflo.) Zileuton was the first drug that influenced the functioning of the lipoxygenase path of eikosanoid metabolism.

M. D: In the inflamed tissue, part of arachidonic acid, which was formed from the phospholipids of the cell membrane, is metabolized by a lipoxygenase path. At the same time, the 5-log enzyme oxidizes arachidonic acid at first to 5-hydroperoxycake-tetranenic acid, and then hydrolyzes this product to leukotriene A 4 (see diagram 3).

Further metabolism LTA 4 may flow over 2 alternative paths, the choice of each of which depends on the type of cell where the chemical reaction proceeds.

In neutrophils and monocytes, with the participation of oxygen and enzyme hydrolase, LTB 4 is formed. In eosinophils, basophilas and fat cells LTA 4, conjugation with sh-glutathione to LTC 4, which is further split to Ltd 4 and LTE 4. The most intensive processes of leukotriene synthesis proceeds in the inflamed bronchial tissues. So, in persons with bronchial asthma they are 5-10 times more intense than in healthy people.

In the target tissues, leukotrienes affect special membrane receptors and cause responses (see Table 8.):

Table 8. Effects of leukotriennes and types of leukotriene receptors.

Lakeotriene	Tissue-target	Receptor: Effect
LTC 4, Ltd 4, LTE 4	muscles bronchi	cYSLT 1: Bronchon Reduction, Cell Proliferation
	glands bronchi.	cysLT 1: mucus hypersecretion
		cYSLT 1: enhancing permeability and edema cyslt 2: , then  Hell, coronary blood flow
	eosinophila	cyslt 1: Chemotaxis in the focus of inflammation
	n. Vagus.	cYSLT 1: Highlight Ach and the development of bronchospasm
	neutrophila	LT: Chemotaxis in the focus of inflammation

Thus, leukotrienes contribute to the development of bronchospasm and the attack of bronchial asthma. According to the strength of the bronchospast effect, they are 1000 times superior to histamine (reference agent for asthma in animals) 20.

Zileuton reversibly binds to the active center of the 5-log and blocks the synthesis of all leukotrienes.

PE: It has an anti-asthma effect. The reception of zileutonium reduces the synthesis of leukotrienes and as a result the probability of the development of bronchospasm, edema of the mucous membrane of the bronchi decreases.

Application and dosing: Zileuton is used for the prevention of bronchial asthma attacks (especially the "aspirin" form of asthma, which is provoked by the reception of NSAIDs inhibiting the COF-dependent paths of the metabolism of arachidonic acid, and compensatoryly increasing its log-dependent metabolism). To relieve the already developed attack of asthma, Zileuton is not used, because at the same time the synthesis of leukotriennes has already ended, they managed to activate receptors and run the cage reduction. Thus, zileuton is a means of basic (long) asthma planned therapy.

According to the effectiveness of anti-asthma action, Zileuton is inferior to glucocorticosteroids and  2 -adrenomimetics. The use of zileuton is usually recommended for the following situations:

With bronchial asthma of the lung persistent flow, zyleuton is used for monotherapy, as a single base agent.

With the bronchial asthma of the average severity, it is used in addition to the basis therapy with glucocorticosteroids, as an alternative to  2 -adrenomimetics of a long-acting (i.e., a combination of "GKS +  2 -am" can be replaced by "GKS + Zileuton"). The use of zileutona allows you to sometimes lower the daily dose of accepted steroids by 20%.

As a rule, Zileuton takes 600 mg 4 times a day.

NE: The most significant undesirable effect of Zileuton is its hepatotoxicity, which largely limits the use of the drug.

FV: Tablets 600 mg.

Zafirlukast (Zafirlukast., Accolate.) MD: Zafirlukast is associated with Cysteinyl Cyslt 1 -type leukotriene receptors and blocks them. In this case, leukotrienes with 4, d 4 and e 4 are not able to activate these receptors and cause the corresponding effects from the smooth muscles of the bronchi.

FE: Zafirlukast warns the development of an attack of bronchial asthma, reduces the swelling of the bronchi mucosa. Unfortunately, the already developed attack of Asthma Zafirlukast is not able to eliminate, because After activating the leukotriene receptors, the process of reducing the bronchi is launched using intracellular intermediaries, regardless of whether the receptor remains associated with the leukotroien or it is displaced by the medicine.

W. zafirlukast discovered a weak anti-inflammatory effect - it oppresses the synthesis of pro-inflammatory cytokines: IL-4.5 and GM-CSF (see Table 2.) and therefore suppresses the processes of chronic inflammation that take place in the bronchial tree during asthma.

By efficiency, the reception of the Zafirlukast is comparable to the intake of inhalation steroids at a dose of 400-500 μg / day (in the Becmetazon equivalent). Therefore, if earlier the patient acted corticosteroids at a dose of up to 400 μg / day when switching to Zafirlukast, they can be canceled, and if the daily dose of steroids was above 400 μg / day, it can be reduced by 200-400 μg / day.

FC: Zafirlukast is well absorbed when taking inside. Sharing with food by 40% reduces the bioavailability of the Zafirlukast. The metabolism of drugs flows in the liver with the participation of cytochrome P 450 2c9. The hydroxylated derivatives formed in the process of metabolism are 90 times less active than the Zafirlukast itself. The removal of Zafirlukast is 90% with biliary. It should be remembered that the reception of the Zafirlukast is accompanied by the oppression of the functions of cytochromes P 450 (and not only isoform 2c9, but also 3A4, which takes part in the metabolism of the overwhelming majority of drugs).

Application: Zafirlukast is taken as a rule on an empty stomach in 20 mg 2 times a day, if necessary, a dose can be increased to 40 mg 2 times a day.

Zafirlukast is used to prevent asthma attacks in adults and children over 12 years old. With the easiest of asthma, the Zafirlukast is used in the form of monotherapy, and with media

vile flow is usually in addition to inhalation steroids 21. It should be remembered that the reception of the Zafirlukast is not able to stop the already beginning attack of Asthma.

NE: Zafirlukast Malotoxic tool. The main undesirable effect (although quite rare) is the possibility of the development of Churg-Strauss syndrome. This syndrome is a variant of the system eosinophilic vasculitis - the disease in which the autoimmune inflammation of the blood circulation vessels develops and the following symptoms arise: the increase in asthma attacks, the appearance of light cloud-like infiltrates from eosinophils, which on radiographs resemble the picture of pneumonia, eosinophilia in peripheral blood.

In recent years, it was found that the greatest risk of developing this syndrome in patients who, before the start of therapy, the Zafirlukast was taken glucocorticosteroids in high doses, and after the appointment of Zafirlukast, they suddenly stop their reception. The basis of the therapy of Churg-Strauss syndrome is the use of high doses of glucocorticosteroids systematic (inside or intravenous).

It is extremely rare, the reception of the Zafirlukast (especially in doses of more than 80 mg / day) can lead to the development of hepatotoxic effects and accompanied by a sharp increase in the level of transaminase in peripheral blood.

FV: Tablets of 0.02 and 0.04.

Montelukast (MonteLukast., Singulair.) Montelukast according to his mechanism of action and the main pharmacological effects resembles a burnlukast, but has a number of positive features:

FV: Tablets in the shell of 10 mg, chewing tablets at 5 and 4 mg.

Drugs with prostaglandin activity.

The use of natural origin in the medical practice of prostaglandins is not always possible. This is due to the fact that the period of their existence in the body is calculated by moments (usually not more than 10-15 minutes), after which they are destroyed and irreversibly lose their activity.

Table 9 summarizes information about the basic medicines with the activity of prostaglandins and their synthetic analogues.

Table 9. Means based on prostaglandins and their synthetic analogues.

Means		A brief description of
		FE:It affects the EP receptors in the uterus and enhances its rhythmic cuts. The action is manifested regardless of the period of pregnancy and its presence. Activates the cervical collagenase. This leads to the destruction of the collagen network in the neck, an increase in the content of hydrophilic glycosaminoglycans and hyaluronic acid in it. As a result, the cervix softens. FC:metabolism flows into the tissue of the lungs. The period of semi-elimination is 2.5-5.0 min. Indications:Induction of childbirth: gel is introduced intravaginalin 500 μg, then 500-1000 μg every hour or intravenous infusion at a rate of 0.25 μg / min (if after 0.5 h effect does not develop speed increase to 0.5-1.0 μg / min). Abstortion: 20 mg suppositories every 3-5 h Intravaginal or intravenous infusion with an initial rate of 2.5 μg / min, after 0.5 hours, if necessary, increase to 5-10 μg / min. NE:running the uterus, riding, nausea, vomiting, diarrhea. FV:gel 0.5 mg in syringes for 3.0 g
Dinoprost.		FE:It acts similarly to DinoprostonTon, but the effect is stronger and sharp. Indications:Apply according to the same testimony as Dinoprotonton Abstraction in terms of up to 15 weeks: 250-1000 mg Anthramnial every 1-2 hours. After 15 weeks of pregnancy: 40 mg once. For induction of labor: intravenous infusion at a rate of 5.0-7.5 μg / min, increasing every 10-20 min by 2.5 μg / min (maximum speed of 25 μg / min). NE:from the gastrointestinal tract - abdominal pain, nausea, vomiting, diarrhea; From the side of the cardiovascular system - tachycardia, hesitation hell, bronchospasm. FV:a solution of 0.5% in ampoules of 1 ml.
Alprostadil		FE:Causes the expansion of vessels and reduces the smooth muscles of the internal organs. When introduced into a penis member, this leads to an increase in the bloodstraying of the cavernous bodies and reduce the sphincters near the mouth of the veins, which contributes to the emergence and maintenance of the erection. Reduces the aggregation and enhances platelet disaggregation. FC:Metabolism flows into the lung vessels. The period of semi-elimination is 0.5-1.0 min. Indications: Treatment of erectile dysfunction. Enter intratureral at 125-250 μg once (per day no more than 2 times). Perhaps intracavernous administration (in the fabric fabrics of the penis). Treatment of oblique diseases of the vessels of the lower limb (atherosclerosis, endarteritic, Trombangit, etc.). We administered intravenously at 10-40 mg in the form of infusion within 1-3 hours. NE:Pain in the sexual penis, Priapism (arises in 4% of persons), hematomas in intracavernous administration, the feeling of heat in the penis, hesitation of blood pressure, arrhythmia. FV:powder in ampoules of 0.00002; 0.01 and 0.04; Pellets for penile appliqués at 125, 250 and 500 μg.
Latanoprost.		FE:He is a prodrug. Esterators of the front chamber of the eye is hydrolyzed to phenylprostanic acid, which selectively activates the Vascular receptors of the screer, causing their expansion. In this case, the outflow of intraocular fluid is activated according to an inlet path (vessels that are directly connected by the vascular sheath of the eye and the scler), bypassing the traditional path through the angle of the front chamber of the eye and the helmets of the channel. As a result, intraocular pressure decreases. Indications:To control intraocular pressure with an open-angle glaucoma. Impact 1 drop in the eyes in the evening. The effect develops after 3-4 hours and saved up to 24 hours. NE:Feeling of the foreign body in the eye, changing the pigmentation of the iris (darkening), an increase in the eye slit. FV:a solution of 0.005% in 1 ml bottles.
Misoprostol		FE:He is a prodrug. After intake, biotransformation into misoprostic acid, which selectively activates EP-prostaglandine receptors of parietal and gastric mucous cells selectively activates EP-prostaglandine receptors. As a result, it is reduced both basal, night and stimulated by the food rate of the secretion of gastric juice and hydrochloric acid. The products of mucus and bicarbonates increase. The effect develops after 30 minutes and persists for 3 hours. Causes a reduction in the smooth muscles of the intestines and myometrium. FC:Relatively stable analogpge 1. The semi-elimination period is 20-40 minutes. Indications:Prevention and treatment of erosive-ulcer lesions of the mucous membrane of the gastrointestinal tract caused by the reception of the NSAIDs. Take inside 200 μg 2-4 times a day during or immediately after eating and before bedtime. NE:abdominal pain, nausea, vomiting, diarrhea; Menstrual violations, Algodismenorrhea. FV:tablets at 0.0002.

Anti-duty agents

GUBER WITH POUKHOV HELL HELL ON LIGHT BORN:

Rumor this lamp was dissolved.

I will not post and measure it

How truth is here, and how, and why;

Moreover, it seems to him

Looking through the bass you can believe.

And, it became no doubt that

That hell was born gout with spider.

I.A. Wings "Gout and Spider".

Anti-protractic drugs are called drugs that are used to relocate gout attacks, as well as for their warning during the intercreant period.

The gout is a hereditary metabolic disease associated with a violation of purine exchange, the accumulation of uric acid in the body and manifested by repeated attacks of arthritis, due to the deposits of urates in the joints and cartilage. Sometimes the gout is not hereditary and can be associated with a period of intense decay of nucleic acids in the body (for example, when the tumor is decayed due to cytostatic therapy or radiotherapy).