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 arthritis 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- antipyretic properties but only some of them are used as analgesics, for example acetylsalicylic acid and ibuprofen. 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 prostaglandin (PGs) subpopulations, which are inductors of the inflammatory process. COX-3; it is thought that the inhibition of this isoenzyme is responsible for the analgesic action of non-opioid 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 (sulindac, acetylsalicylic acid, tolmetin, piroxicam) than for COX-2 Preferential COX-2 inhibitors (the second generation), whose affinity for COX-2 is slightly greater than for COX-1 (etodolac, meloxicam, nabumeton, nimesulid) Selective COX-2 inhibitors (the third generation), whose affinity for COX-2 is approx. 200 times greater than for COX-1 (celecoxib, etoricoxib, parecoxib, valdecoxib, lumiracoxib). 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 enzymes, 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 enzyme 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. Oxicams prevent an increase in the activity of -glutamyl-transferase in plasma. Other NSAIDs, for example diflunisal, 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 prostaglandins (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 nausea, 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 naproxen (naphtyl derivative) is approx. 12 hours, whereas the t0.5 of benoxaprofen (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 ASPIRIN(E), POLOPIRYNA O 17 Salsalat (salicylsalicylic acid) is not metabolised to 2 molecules of salicylic acid 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 R = Salsalate, DISALGESIC O OH 2-Hydroksybenzoesan 2- O R karboksyfenylu O 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). 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 (anthranilic acid = 2-aminobenzoic acid). O OH CH3 H Mefenamic acid, MEFACIT N CH3 O OR H Flufenamic acid; R = -H ARLEF N CF3 Etofenamate, REUMON R = CH2-CH2-O-CH2-CH2OH O OH Cl H N CH3 Meclofenamic acid, 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 benzene ring with the pyridine ring.