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Home , Acemetacin, Benoxaprofen, Felbinac, Fenamic acid, Ibuproxam, Pirprofen

Drugs Affecting Muscular-Skeletal System

Antirheumatic drugs

1 The treatment of rheumatic diseases is difficult because the pathomechanism of these disorders has not been completely explained.

Because the etiology of rheumatic disorders remains unknown it is difficult to create drugs acting causally to ensure the patient’s complete recovery.

Because of that in the treatment of rheumatic diseases drugs acting symptomatically are used, which requires long-term therapy.

Symptoms of rheumatic diseases are pain, edema, restricted arthral mobility, inflammatory states.

2 Because of a large number of cases of these disorders and long-term therapy it is a serious social problem. Approximately 15% of the U.S. population suffers from rheumatic diseases with females being affected about twice as much as males. In Poland the incidence of rheumatic diseases is similar. Approximately 6 million Poles suffer from diseases of the osteoarticular system and one third of them are in danger of becoming disabled. The most widespread are:  Rheumatoid  Degenerative joint disease

3 It is thought that rheumatism can be caused by microorganisms, such as bacteria, fungi and viruses (septic arthritis) or can have an auto-immunological basis, which has not been well understood.

In the treatment of rheumatic disorders two basic groups of drugs are used:  Non-steroidal anti-inflammatory drugs (NSAIDs)  Disease-modifying antirheumatic drugs (DMARDs)

4 1. Non steroidal anti-inflammatory drugs (NSAIDs)

In addition to anti-inflammatory action, NSAIDs, possess analgetic- properties but only some of them are used as , for example acetylsalicylic acid and . The analgetic action of many NSAIDs (e.g indomethacin) is caused only by their anti- inflammatory action, so such derivatives do not relieve headache. Certain NSAIDs also show anti-aggregative action. Because of this action acetylsalicylic acid (ASA) is used in the prevention (mainly secondary) of myocardial infarction and ischemic apoplexy. NSAIDs also have an effect on apoptosis. This action is observed during long-term administration of, for example ASA, in small doses. NSAIDs are COX inhibitors. The details of COX inhibition by NSAIDs have not been completely understood.

5 1.1. The mechanism of action COX occurs in the form of various isoenzymes:  Constitutive COX-1, responsible for the physiological functions of the digestive and excretory (kidneys) systems  Constitutive COX-2 (cCOX-2) present in the brain, spinal cord, urinary bladder (in the endothelium of vessels COX-2 induced by the blood flow)  Induced COX-2 (iCOX-2) is found, in inflammatory cells (for example in macrophages), responsible for the synthesis of (PGs) subpopulations, which are inductors of the inflammatory process.  COX-3; it is thought that the inhibition of this isoenzyme is responsible for the action of non- analgesics at the spinal cord level.

NSAIDs inhibit COX-1 and COX-2 to a different degree. 6 1.1. The mechanism of action

Bearing in mind the ratio of IC50 of COX-2/COX-1, NSAIDs are divided into three groups (generations):  Classical NSAIDs (the first generation), whose affinity for COX-1 is from several to over a hundred times greater (, acetylsalicylic acid, , ) than for COX-2  Preferential COX-2 inhibitors (the second generation), whose affinity for COX-2 is slightly greater than for COX-1 (, , nabumeton, nimesulid)  Selective COX-2 inhibitors (the third generation), whose affinity for COX-2 is approx. 200 times greater than for COX-1 (, , , , ). 7 1.1. The mechanism of action

The values IC50 of COX-2 and COX-1 in various publications differ considerably, depending on the model used (in vitro, in vivo, animal , human enzymes, time of incubation). The anti-inflammatory action of NSAIDs is caused by the inhibition of iCOX-2 in tissues with inflammatory changes. Over the last 15 years research as new NSAIDs has focussed on the synthesis of selective COX-2 inhibitors. However, selective COX-2 inhibitors also inhibit COX-2 produced by the endothelium of vessels, which causes their adverse effect on the cardiovascular system and a greater risk of myocardial infarction.

8 1.1. The mechanism of action

NSAIDs can inhibit COX in the following ways:  Competitively – action typical of most NSAIDs with acidic or enolic structure  Irreversibly – action typical of acetylsalicylic acid, which acetylates the Ser 530 of COX-1 or the Ser 516 of COX-2.

COX is not the only which reacts with NSAIDs. Salicylates also inhibit lysosomal enzymes such as -glucosidase and lysozyme, which are the main factors of chronic inflammatory states. Antranil and arylacetic acid derivatives reduce the activity of lysozyme and because of that they disturb the influx of Ca2+ ions into cells.

9 NSAIDs also inhibit the activity of proteases and decarboxylases and because of that reduce the production of many inflammatory mediators, such as serotonin, histamine, bradykinin and other kinins, and other factors that influence the permeability of blood vessels. prevent an increase in the activity of -glutamyl-transferase in plasma. Other NSAIDs, for example , inhibit the aggregation of platelets and decrease the concentration of uric acid in the blood. NSAIDs demonstrate different directions of action described above. Because of that NSAIDs show not only anti-inflamatory but also analgetic and antipyretic action.

10 The inhibition of the biosynthesis of (PGs) by NSAIDs reduces not only the remission of inflammatory states, but also suppresses the functions of systems depending on PGs such as the control of ion transport through certain cell membranes, the regulation of the blood flow to some organs and the modulation of information transmission in synapses.

The inhibition of cCOX-1 results in unwanted actions, such as:  Adverse influence on the digestive system (dyspepsia, ulceration, bleeding from gastric and duodenal ulcers, perforation, damage of the lower segment of the digestive system)  Nephrotoxicity

 Anti-aggregative action. 11 Selective and preferential COX-2 inhibitors produce a similar effect to classical, non-selective COX inhibitors. However,  They cause fewer serious complications in the gastric system, such as ulceration, perforation or bleeding  They do not inhibit platelet aggregation and do not increase the time of bleeding.

12 Selective COX-2 inhibitors have adverse effects too. The most important adverse effects of COX-2 inhibitors are , headache, diarrhoea, increased susceptibility to infections of the upper airways. There is also the risk of damage to the kidneys. COX-2 inhibitors cause retention of fluids, which results in hypertension and/or cardiac insufficiency. They also increase the risk of ischemic heart disease and myocardial infarction. For this reason, COX-2 inhibitors should not be used in patients with cardiovascular diseases.

13 1.2. Classic COX inhibitors (the first generation)

14 In spite of a large diversity of the chemical structures of NSAIDs, they have certain common properties: • One of them is the acidic character of most NSAIDs. • They are acids of medium potency (pKa 3-5). The acidic properties of NSAIDs mainly determine their ability to bind with plasma proteins. • Another common element of the structure of NSAIDs is the presence of lipophilic and hydrophilic groups. • The hydrophilic group is a carboxyl or enol group. • The lipophilic centre is an aromatic ring, whose lipophilicity is increased by halogen substituents, mainly chlorine or fluorine atoms.

15 • The introduction of an additional hydrophobic centre (phenyl or heteroaryl substituent) increases the potency of action and also influences certain pharmacokinetic parameters.

• For example, the t0.5 of (naphtyl derivative) is approx. 12 hours, whereas the t0.5 of (benzoxazole derivative) is approx. 35 hours. • The ani-inflammatory action of oxicams can be increased by introducting a heterocyclic substituent into benzothiazine-3- carboxamide. • This compound – piroxicam – acts 10 times more strongly than other oxicams.

16 1.2.1. Salicylates

Acetylsalicylic acid (ASA) is the most important in that group of drugs. Other derivatives, ethers or esters, do not exceed the action of ASA, but some of them have favourable properties.

O OH Acetylsalicylic acid, R = -CH3 O R (E), POLOPIRYNA O

17 Salsalat (salicylsalicylic acid) is not metabolised to 2 molecules of until it reaches the intestines and because of that the stomach mucosa is protected against the irritant action of salicylic acid. Irritant action on the stomach mucosa is one of the disadvantages of almost all NSAIDs.

HO O OH O R R = , DISALGESIC O 2-Hydroksybenzoesan 2- karboksyfenylu

18 Diflunisal has an additional aromatic ring in position 5 substituted with 2 atoms of fluorine. Both rings are not in the same plane. These changes increase potency and the time of action. Parsalmide is a derivative of 5-aminosalicylic acid (). Mesalazine is an anti-inflammatory drug, in contrast to 4-aminosalicylic acid, which acts tuberculostatically.

O OH

OH Diflunisal, DIFLUSAL Kwas 5-(2,4-difluorofenylo)salicylowy F F

H O N CH3 SINOVIAL O C Parsalmide, CH 5-Amino-N-butylo-2-(2-propinyloksy)-benzamid H2N

19 1.2.2. Anthranilic (fenamic) acid derivatives

Fenamanes are derivatives of N-phenylanthranilic acid ( = 2-aminobenzoic acid).

O OH CH3 H , MEFACIT N CH3

O OR H ; R = -H ARLEF N CF3

Etofenamate, REUMON R = CH2-CH2-O-CH2-CH2OH

O OH Cl H N CH3 , MECLOMEN

Cl 20 The N-aryl substituent is responsible for the lipophilic character of the polar structure of anthranilic acid. The lipophilic character of the molecule determines the potency of anthranilate action.

Because of that lipophilic substituents such as CF3, CH3, Cl were introduced into the aryl ring. However, these changes have no significant influence on the therapeutic value of anthranilates. Another modification of the structure of anthranilates involves replacing the ring with the pyridine ring. The obtained azaderivatives do not show any significant difference in action.

F3C , R = H; NIFLURIL

R = N O N NH OR , NIFLURIL-SUSPOS 21 O 1.2.3. Arylacetic acid derivatives

The majority of derivatives of arylacetic acid are indolacetic acid derivatives. They are  indomethacin and its ester derivative ,  zidometacin (indol-3- derivatives) and  clometacin (indol-1-acetic acid derivative).

The change of the position of the rest of acetic acid, from position 3 to position 1, increases the potency of action.

22 O , R = H; INDOMETACIN, METINDOL Cl N Acemetacin (pro-lek), R= -CH2-COOH CH3 H3CO COOR

O N3 N Zidometacin, ZIDOCID CH3 H3CO COOH

COOH H3CO N CH3

Cl Clometacin, DUPERAN O

23 Sulindac is a derivative of O O O O indenacetic acid. S S H3C H3C UDPGA Sulindac is a pro-drug. It undergoes CH3 CH3 reversible reduction in the colon to F F COOH COOGlu sulfide with anti-inflammatory and Sulindac - Sulfone analgesic action, and irreversible O oxidation to sulfone. S S H C H C 3 3 Sulfide is a strong inhibitor of PG

CH3 CH3 biosynthesis. F F COOH COOH The sulfone of sulindac, also known Sulindac Sulindac - Sulfide as Exisulind, act as an SAAND (Selective Apoptoic Antineoplastic O O

S S Drug) and the place of its action is H C 3 UDPGA H3C located in neoplastic cells, and in

CH OH cells with a decreased apoptosis 2 CH2OH F F 24 COOH COOGlu rate. SAANDs act as phosphodiesterase cGMP inhibitors, so they lead to increase in the concentration of cGMP and, in consequence to the activation of apoptosis. Exisulind (APTOSYN) is the first SAAND which in combination with chemotherapeutic drugs is in clinical trials aimed at evaluating its usefulness in the treatment of lung, breast and prostate tumors.

25 The indol or inden structure can be replaced with a benzene ring on condition that it is connected with another aryl or heterocyclic ring. Examples of drugs with anti-inflammatory action are and . Phenylacetic acid, in contrast to diphenylacetic acid (felbinac) does not show anti-inflammatory action. Arylacetic acid derivatives act more strongly than salicylates.

COOR Diclofenac, R = H DICLOFENAC, VOLTAREN NH Kwas 2-[(2,6-dichlorofenylo)amino]benzenooctowy Cl Cl

Aceclofenac, R = -CH2-COOH

COOH Felbinac, DOLINAC

26 1.2.4. derivatives (Profens)

The majority of profens are derivatives of -methyl--phenylacetic acid. Among them are derivatives containing an alkil substituent in position 4 of the phenyl ring (ibuprofen, ) or an aryl substituent (, , ).

Ibuprofen; R = -OH, IBUPROFEN, ZUPAR CH 3 Kwas -Methyl-4-(2-methylpropyl)- R CH3 benzenacetic acid O H3C S(+)-Ibuprofen, SERACTIL Ibuproxam, IBUDROS; R = -NH-OH

27 CH3 CH3 OH F OH O O O

Ketoprofen, PROFENID Flurbiprofen, FROBEN CH CH3 3 OH OH

O O N O Cl Pirprofen, RENGASIL , LOXONEN

O CH3 CH3 OH S OH O O H3CO Naproxen, ANAPRAN , SURGAM NAPROSYN, NAPROXEN 28 CH3 R CH3 * O H3C

Ibuprofen, containing an isobutyl rest in position 4 of the ring, demonstrates less anti-inflammatory activity than aryl derivatives, but it also shows analgetic action. Ibuproxam is an amide derivative of ibuprofen and hydroxamic acid (pro-drug). Profens contain a chiral centre, so they exist as 2 enantiomers: levorotatory R(-) and dextrorotatory S(+). These enantiomers have different profiles of action. In vitro S(+)-enantiomers show significantly greater anti-inflammatory activity than R(-)-enantiomers. 29 For example, S(+)-ibuprofen inhibits COX 160 times and flurbiprofen 1000 times more strongly than their R(-)-isomers. The degree of inversion depends on the kind of a derivative. In the case of ibuprofen it is 70%. At present the S(+) isomers of naproxen, ibuprofen (SERACTIL) and flurbiprofen are used.

The R(-) isomer of flurbiprofen also acts analgesically, but this action is located at the level of the spinal cord. It does not inhibit the biosynthesis of PGs in tissues changed inflammatorily.

30 It is important to remember that R(-) isomers form potentially toxic tiol-CoA esters, which with triacylglicerols form “esters hybrides”. They increase the permeability of the cell membrane and accumulate in fat tissue. Profens are eliminated mainly as the glucuronates of parent compounds and of their first- phase metabolites (hydroxyl derivatives). Not all activity and adverse effects of first-phase metabolites are known. About 5% of a pirprofen dose is eliminated as epoxide and 8-12% as diol. It is very likely that the epoxide of pirprofen acts mutagenically.

31 1.2.5. Oxobutanes

Examples of oxobutanes are and (preferential COX-2 inhibitor). They are pro-drugs, which are metabolised to active derivatives of arylacetic acid. Fenbufen is a very weak inhibitor of PG- synthase, but it is metabolized to active biphenylacetic acid, which is used in therapy as felbinac. O O -oksydaza O OH OH

Fenbufen (pro-drug) Aktywny metabolit LEDERFEN Felbinac, DITAC, TRAXAM

Fenbufen shows anti-inflammatory and analgesic action. It is absorbed after oral administration. Its biological half-life is 10-17 hours. ASA32 decreases the action of fenbufen by about 10-20%. 1.2.6. Oxicams

Oxicams used in therapy – piroxicam and meloxicam - are enolic acids, mainly 4-hydroxybenzene-1,2-thiazine-3-carboxyamides.

O O Piroxicam, FELDENE, PIROXICAM S CH3 N 4-Hydroxy-2-methyl-N-2-pyridinyl-2H-benzene- H N -1,2-thiazine-3-carboxamide 1,1-dioxide

OH O N

For their therapeutic action a heteroaryl substituent such as pyridinyl, thiazolyl, isoxazolyl at the nitrogen atom of the amide group is the most profitable.

33 • Oxicams have anti-inflammatory and analgesic properties. • Piroxicam inhibits the migration of polymorphonuclear cells into inflammatory sites and inhibits the release of lysosomal enzymes from these cells. It also inhibits collagen-induced platelet aggregation. • Approximately 20% of individuals on piroxicam report adverse reactions. • Not unexpectedly, the greatest incidence of side effects is those resulting from GI disturbances. • However, the incidence of peptic ulcers reported is less than 1%.

34 O O S N CH3 , TILCOTIL S NH HO O N

Lornoxicam, XEFO

35 Tenoxicam is used to relieve inflammation, swelling, stiffness, and pain associated with , tendinitis (inflammation of a tendon), bursitis (inflammation of a bursa, a fluid-filled sac located around joints and near the bones), and periarthritis of the shoulders or hips (inflammation of tissues surrounding these joints).

Contraindications • The drug is contraindicated for patients who are seniors who have been given anesthesia or surgery; • are at risk of increased bleeding or kidney failure; have an active inflammatory disease involving the stomach or intestine have an active stomach or intestinal ulcer; • have had an acute asthmatic attack, hives, rhinitis (inflammation of the inner lining of the nasal passage), or other allergic reactions caused by acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (for example diclofenac, ibuprofen, indomethacin, naproxen).

36 ( chlortenoxicam; trade name Xefo, is available in oral and parenteral formulations

Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints, , surgery, and other inflammations.

Contraindications • The drug is contraindicated in patients that must not take other NSAIDs, possible reasons including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and severe impairment of heart, liver or kidney function. • Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy

Adverse effects Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like gastrointestinal disorders (nausea and diarrhea) and headache. Severe but seldom side effects include bleeding, bronchospasms and the extremely rare Stevens-Johnson syndrome 37 1.2.7. Pyrazolidinedione derivatives

The first drug in this group was , introduced into therapy in 1949.

Fenylbutazone, BUTAPIRAZOL N O N 4-Buthyl-1,2-diphenylpirazolidine-3,5-dione H C 3 O H The presence of two benzene rings and a butyl group causes the significant lipophilicity of this compound and its complete absorption from the digestive tract. Phenylbutazone is transported to an inflammatory site, where its concentration is several times greater than in healthy tissues. 38 The presence of carbonyl groups and a hydrogen atom in position 4 determines the keto-enol tautomerism and acidic properties of this compound (pKa = 4.5). Phenylbutazone, similarly to all pirazolones, causes allergic reactions, which significantly limits its use.

Phenylbutazone is metabolized as a result of:  p- and -hydroxylation  -oxydation of the hydroxy derivative  coupling of phenylbutazone and its metabolites with glucuronic acid

39 OH N N N O-Glu O N O N O N H C H C R O 3 O 3 O Glu H H C4-Phenybutazone PHENYLOBUTAZONE Oxyphenylobutazone glucuronide

C4--hydroxy- OH phenylbutazone N Glucuronide N O glucuronide O N N H C H3C 3 O O H H OH OH -Hydroxyphenylobutazone p,-Dihydroxyphenylobutazone

N -Oxophenylobutazone O N H C 3 O O H 40 After administration of an individual dose of 400 mg, in the period 0– 336 h the following compounds were determined in plasma: - 63% unchanged phenylbutazone, - 23% oxyphenylbutazone, - 2% -hydroxy-phenylbutazone, - 0.5% p,-dihydroxyphenylbutazone.

41 Phenylbutazone and its metabolites are slowly eliminated by the kidneys and intestines (over a period 21 days 61% and 27% of the dose, respectively). In urine,  1% of the dose is found as unchanged phenylbutazone;  approx. 10% of the dose are hydroxyl derivatives such as oxybutazone, -hydroxyphenylbutazone, p,-dihydroxy- phenylbutazone and unchanged phenylbutazone;  approx. 40% of the dose is phenylbutazone C4-glucuronate;  approx. 12% of the dose is -hydroxyphenylbutazone C4-glucuronate. Oxybutazone is eliminated as O-glucuronate, but only in small amounts. 42 Such metabolites as  p-hydroxyphenylbutazone (oxybutazone, TANDERIL) and

 -oxophenylbutazone (ketazone, KEBUZON) show a similar profile of action as phenylbutazone, but slightly less activity. Their advantage is lower toxicity.

43 1.2.8. The pharmacokinetic properties of non-selective (classical) NSAIDs

Because of their acidic character NSAIDs in gastric juice are found in a lipophilic, protonated form, so they are well absorbed. The small intestine is also known to have conditions conducive to resorption of weak acids. In plasma, NSAIDs are fully ionised. The distribution volume of NSAIDs ranges from 0.1 to 1, which indicates that they are weakly distributed in the extravascular system. Because NSAIDs bind strongly with proteins they displace other drugs from their bonds with proteins.

With respect to t0.5 values, NSAIDs are classified as follows:

 short-acting drugs (t0.5 from 1 to 6 hours)

 intermediate –acting drugs (t0.5 from 10 to 20 hours)

44  long-acting drugs (t0.5 over 26 hours). 1.3. Preferential COX-2 inhibitors demonstrates anti-inflammatory, analgetic and antipyretic action. The mechanism of its anti-inflammatory action is both COX- dependent and COX-independent. HN-SO2-CH3 O Nimesulide, AULIN, MINESULIN

Nimesulide: NO2  decreases the production and release of free radicals (inhibits the activity of myeloperoxidase, which is essential for the release of a strong oxidant – oxochlorate(I) acid) and reduces the production of superoxide anion radicals  is a free radicals scavenger. It prevents the inactivation of alpha-1-antitrypsin, which blocks elastase - an enzyme responsible for the destruction of the connective tissue.45 Etodolac shows anti-inflammatory, relatively strong analgetic action and uricosuric action. This drug is rapidly absorbed from the digestive tract, strongly binds with plasma proteins (>95%) and has a relatively long half-life period (~7 hours). It is eliminated as inactive metabolites.

CH H3C H 3 N O COOH

Etodolac 1,8-diethyl-1,3,4,9-tetrahydropiran[3,4-b]indol-1-acetic acid

46 Meloxicam differs from other first-generation oxicams (piroxicam, tenoxicam). It relatively selectively inhibits COX-2 and has a shorter half-life period (~20 hours) than piroxicam and tenoxicam. Meloxicam is very well absorbed from the digestive tract and permeates to the , where its concentration is 50% of its concentration in plasma.

O O S CH3 Meloxicam, N H METACAM N N OH O S

CH3

47 Nabumeton (oxobutane derivative) is a pro-drug. It does not have any acidic character. Nabumeton is rapidly metabolised to an active metabolite – 6-methoxynaphtalenacetic acid (6-MNA). O O CH3 OH H3CO H3CO Nabumeton, ARTOXAN Aktywny metabolit (pro-lek) 6-MNA

Nabumeton demonstrates low toxicity and is well tolerated by patients. The active metabolite, 6-MNA, does not reach the enterohepatic circulation, has a long half-time period (~23 hours) and is eliminated in urine in a conjugated form. Its adverse effect on the digestive tract and kidneys is not significant.

48 1.4. Selective COX-2 inhibitors

In the early 1990s induced COX-2 was discovered. It is responsible for synthesis of PG subpopulations, which are inductors of the inflammatory process. This discovery inspired scientists to synthesise selective inhibitors of this isoenzyme in the hope that they would demonstrate less adverse action on the digestive tract and kidneys. In these organs constitutive COX-1 is found, which is responsible for their proper functioning. The first selective COX-2 inhibitors (celecoxib, ) were introduced into therapy in 1999 and were followed by – parecoxib, waldecoxib, etoricoxib. The latest selective COX-2 inhibitor is lumiracoxib, introduced in 2002. 49 NH2

O S O O O O O O S CH3 S N Hydroliza NH2 H3C H enzymatyczna N N N N O O

CF3 Celecoxib, CELEBREX Parecoxib, DYNASTAT

O O H3C S CH H C O N 3 3 COOH CH3 S NH O F Cl N O O Cl Etoricoxib Lumiracoxib, PREXIGE Rofecoxib COX 189

50 It was soon discovered that in certain tissues (the kidneys, brain, spinal cord and epithelium of blood vessels) constitutive COX-2 is present in addition to induced COX-2. The inhibition of cCOX-2 causes adverse effects. The inhibition of the biotransformation of by cyclo- oxygenases increases its transformation to leukotrienes (LT) by lipo- oxygenases (LOX). Leukotrienes LTB4, LTC4, LTD4 and LTE4 are responsible for the strong contraction of the bronchial smooth muscles and they damage the mucosa of the digestive tract. Selective COX-2 inhibitors do not inhibit platelet aggregation, and some of them even show opposite action (rofecoxib), which increases the risk of cardiac infarction. Because of that rofecoxib was withdrawn from therapy in 2005.

51 Indications for the use of celecoxib are degenerative joint disease and joint rheumatic inflammation. Parecoxib is a pro-drug which is rapidly and almost completely transformed into valdecoxibe and propionic acid in the liver. It is administered i.v. and i.m, as water-soluble sodium salt in the short- term treatment of postoperative pain. Valdecoxib in therapeutic doses is a selective COX-2 inhibitor and does not influence COX-dependent processes in tissues, especially in the stomach, intestines and platelets. However, COX-2 participates in physiological processes such as ovulation, implantation, the closure of Botall’s duct, and is present in the CNS (pain perception, cognitive functions, fever). Other coxibs – etoricoxib, lumiracoxib are in clinical trials.

52 1.5. LOX/COX inhibitors

Inflammatory action is shown not only by prostaglandins but also by leukotrienes (LT). Because of that for many years there have been attempts to synthesise NSAIDs inhibiting both tracks of arachidonic acid transformation. Many compounds with these properties have been synthesised, but they have not been accepted as drugs for various reasons.

At present Licofenone, inhibiting COX and LOX, is in clinical trials.

53 1.6. NSAIDs releasing (NO-NSAIDs)

NO-NSAIDs demonstrate the anti-inflammatory and antipyretic properties of NSAIDs but they show less adverse action on the digestive tract. NO-NSAIDs are non-selective COX inhibitors and they show NO-dependent action. They reduce the production of cytokins, interleukin 1b, and -interferon by inhibition of the S-nitrosylation of caspase-I.

54 Clinical trials on animals indicated that:

 NO-naproxen demonstrates 10 times stronger analgesic action than naproxen  NO-acetylsalicylic acid exhibits stronger anti-aggregative action than ASA, because COX-dependent and NO-dependent anti-aggregative actions add up  In a model of a damaged kidney, NO-flurbiprofen, does not damage it and even improves its function  In an animal model of neurodegenerative disease, NO-flurbiprofen and NO-ASA decrease cerebral inflammatory response.

55 1.7. The adverse effects of NSAIDs

When classical NSAIDs are used in joint diseases (large dose and long- term use), there is a high incidence of side effects – particularly in the but also in the liver, kidney, spleen, blood and bone marrow.

Gastrointestinal disturbance Adverse gastrointestinal events are the commonest unwanted effects of the NSAIDs and result mainly from inhibition of COX-1. COX-1 is responsible for the synthesis of the PGs that normally inhibit acid secretion, as well as having a protective action on the mucosa. 56 Common gastrointestinal side–effects are dyspepsia, diarrhoea (but sometimes constipation), nausea and vomiting and, in some cases, gastric bleeding and ulceration. It has been estimated that one in five chronic users of non-selective NSAIDs will have gastric damage, which can be silent but which carries a small but definite risk of serious haemorrhage and/or perforation. Oral administration of PG analogues such as can diminish the gastric damage produced by these agents. It had been predicted that the use of COX-2 selective inhibitors would result in less gastric damage. In patients who require platelet inhibition, selective COX-2 inhibitors seem to be an attractive alternative to classical NSAIDs combined with gastroprotective strategies. It is advisable that gastrologists and rheumatologist should routinely consider gastroprotection alongside cardioprotection. 57 Adverse renal effects Therapeutic doses of NSAIDs in healthy individuals pose little threat to kidney function, but in susceptible patients they cause acute renal insufficiency, which is reversible on stopping the drug. It is caused by the inhibition of the biosynthesis of the

PGE2 and PGI2 () involved in the maintenance of renal blood dynamics, and particularly in the PGE2-mediated compensatory vasodilatation that occurs in response to the action of noradrenaline or angiotensin II. Chronic administration of high doses of NSAIDs can cause ‘analgesic nephropathy’ (chronic nephritis and renal papillary necrosis), which is often irreversible.

58 Skin reactions Skin reactions are other most common adverse effects of NSAIDs, especially with mefenamic acid (10-15% frequency) and sulindac (5-10% frequency). The type of skin condition observed varies from mild rashes, urticaria and photosensitivity reactions, to more serious and potentially fatal diseases (which are fortunately rare).

59