Lesson-1-2 (NSAIDs) 2.pdf

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Assoc. Prof. Rezzan Gülhan M.D. Ph.D. Marmara University School of Medicine Dept. of Medical Pharmacology Inflamation The inflammatory process is the response to an injurious stimulus. – by a wide variety of noxious agents (e.g., infections, antibodies,...

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Assoc. Prof. Rezzan Gülhan M.D. Ph.D. Marmara University School of Medicine Dept. of Medical Pharmacology Inflamation The inflammatory process is the response to an injurious stimulus. – by a wide variety of noxious agents (e.g., infections, antibodies, or physical injuries). – The process of acute inflammation is initiated when resident tissue leucocytes (macrophages or mast cells) detect a challenge (eg., pathogenic bacteria). This leads to a cascade of intracellular signalling – Immune system → release of soluble cytokines such as tumour necrosis factor-α (TNFα), interleukin-1 (IL-1) and interleukin-6 (IL-6), endogenous substances (prostaglandins, leukotriens, serotonin, bradykinin, histamin, chemotactic agents,…) The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury. In some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences. 2 Inflammatory responses 3 distinct temporal phases, each apparently mediated by different mechanisms: 1. acute phase: - transient local vasodilation and increased capillary permeability 2. delayed, subacute phase: - infiltration of leukocytes and phagocytic cells 3. chronic proliferative phase: - tissue degeneration and fibrosis classic inflammatory response No matter what the initiating stimulus, includes dolor (pain), calor (warmth), rubor (redness), tumor (swelling) Inflamation Prostaglandins induce vasodilatation of the microcirculation and are important in pain signalling from locally inflamed tissue. Platelet-activating factor and thromboxane A 2 affect the coagulation and fibrinolytic cascades. Leukotrienes promote the activation and accumulation of leucocytes at sites of inflammation. 5 The treatment of patients with inflammation involves two primary goals: (1) relief of pain (2) slowing or-in theory-arrest of the tissue-damaging process. Reduction of inflammation with non-steroidal antiinflammatory drugs (NSAIDs) often results in relief of pain for significant periods. Most of the non-opioid analgesics (aspirin, etc) also have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions. Anti-inflamatory drugs 1. NSAIDs: “Rapidly-Acting” Nonsteroidal Antiinflammatory Drugs(NSAIDs) – Anti-inflamatory + analgesic + antipyretic effects – different from anti-inflamatory glucocorticoids and narcotic analgesics – Non-narcotic analgesics/antipyretics – Older agents: nonselective COX inhibitors – Newer “COX-2 inhibitors” 2. 3. 4. 5. Glucocorticoids SAARDs (Slow-acting anti-rheumatoidal drugs) DMARDs (Disease-modifying anti-rheumatoidal drugs) The new anticytokine, and other biological agents. 7 NSAIDs More than 20 different nonsteroidal anti-inflammatory drugs (NSAIDs) are available commercially 30 million individuals consume NSAIDs every day as they are available over the counter (OTC) in most countries (Bertolini et al., 2001) Approximately 10-40% of people over the age of 65 use NSAIDs, with or without a prescription. 1. Salicylates: Aspirin, Na-salicylate, diflunisal 2. Para-aminophenol derivatives: Paracetamole (acetaminophen) 3. Indole derivatives: Indomethacin, Tolmetin, Sulindac, Zomepirac 4. Phenylpropionic acid (profens): Ibuprofen, Naproxen, fenoprofen, benaroprofen, ketoprofen, flurbiprofen, oxaprozin 5. Phenylacetic acid: Diclofenac (voltaren) 6. Fenamates: Mefenamic acid, meclofenamate, ethofenamate (Rheumon) 7. Oxicams: Piroxocam (Feldene), Tenoxicam (Tilcotil) 8. Pyrazolones: Phenylbutazone, oxyfenbutazone 9. Pyranocarboxylic acid: Etodolac (Etol), 10. Pyrrolo-pyrrole: Ketorolac (Ketrodol) 11. Napthyalkanones: Nabumetone (Relifex) 12. Diaryl susbstituted pyrazole (COX2 inhibitors): Celecoxib(Celebrex), Rofecoxib(Vioxx), Valdecoxib 8 NSAIDs Analgesic effect: Antipyretic effect: Peripheral Central, esp. for paracetamol Peripheral Central (hypothalamus) Antiinfalamatory effect: Peripheral NSAIDs are widely used for the treatment of pain due to acute soft tissue injury; ligaments, muscles or tendons, the relief of acute postoperative pain, symptoms of chronic inflammatory conditions such as osteoarthritis and rheumatoid arthritis. 9 How do they act? Vane and Moncada Vane, Nature New Biol, 231:232-235 (1971) Ferreira, G. H., Moncada, S., and Vane, J. R., Nature New Biology, 231, 237 (1971). 10 11 Prostoglandins Leucocytes Endothelial cells Platelets → PGE2, PGF2 → vasodilatation, vasoconstriction, inflamatory response → PGI2 → vasodilatation, inhibition of platelet aggregation → TxA2 →vasoconstriction, aggregation 12 -- PG’s from COX-1 are in GI tract, platelets, endothelial, renal medulla -- PG’s from COX-2 in synovial lining, vascular endothelial cells, macrophages 13 14 PGF 2 (labour) the inflammatory prostanoids and cytokines—interleukin (IL)-1, tumour necrosis factor (TNF)-α, etc. 15 16 17 Antiinflamatory effect Inhibition of COX pathway Inhibition of IL-1, IL-6, TNF-alfa and INF-gamma production Inhibition of activation of PMNL Inhibition of Gq activation Inhibition of integrin upregulation Inhibition of reactive oxygen radicals formation (esp. Na-salicylate, indometasine, phenylbutazon, sulindac, diclophenac, meclophenamate) Stabilization of lyzozomal memebranes 18 NSAIDs The anti-inflammatory action (and probably most analgesic and antipyretic actions) of the NSAIDs are related to inhibition of COX-2. The unwanted effects of NSAIDs —particularly those affecting the gastrointestinal tract—are largely a result of their inhibition of COX-1. in pateint we want to slectely in habit cox 1 which drug can be used ? All “classical” NSAIDs (e.g. aspirin, ibuprofen, naproxen) inhibit both COX-1 & COX-2. l Low doses of aspirin selectively inhibit COX-1, while higher doses inhibit both isoforms. 19 NSAIDs Weak organic acids – Except Nabumetone: a ketone prodrug that is metabolized to the acidic active drug Rapidly absorbed from GI Bound to plasma proteins (albumin)– small Vd Food does not impair absorption – Except aspirin and fenoprofen Absorption best at acidic pH Extensively metabolized in the liver (by CYP3A or CYP2C) and excreted by the kidneys – Nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). – Sulindac and meclofenamete are mostly excreted in the bile →side effects in lower intestine – Sulindac and nabumetone are prodrugs →less gastric irritation 20 in a pateint with gi bleeding which on of the NASIDS cane be given ? NSAIDs COX-1 specific: COX-nonspesific: low dose aspirin ibuprofen, naproxen, meclofenamate, indomethacine, sulindac COX-2 preferential: etodolac, meloxicam, nimesulide (diclofenac and nabutemone: not at therapeutic concentrations) COX-2 specific: celecoxib, etoricoxib, rofecoxib, valdecoxib, Lumaricoxib, parecoxib flosulide 21 22 Salicylates  Willow bark (söğüt) contains Salicin (Salicylic acid) Used in folk medicine for mild pain and fever – 5 grams of willow bark may corresponds to about 45 milligrams of total salicin but there are many 23 ASPIRIN AND OTHER SALICYLATES Aspirin Salsalate (Salicylsalicyclic acid) Magnesium salicylate Choline magnesium–trisalicylate Diflunisal 24 ASA Acetylsalicylic acid Aspirin  1763 - Edward Stone wrote about his success in treating fevers with willow bark 1831 - Buchner (Austrian pharmacologist and professor) isolated a yellowish mass found in willow bark and called salicin → replaced quinine derived from the cinchona tree. Acetylsalicylic acid is a derivative of salicylic acid 1840s, the German chemist, Hermann Kolbe artificially produced salicylic acid. 1897 - German chemist, Felix Hoffmann synthesized ASA 1899- Bayer & Co. - the trademark ASPIRIN was registered at the Imperial Patent Office in Berlin. Widely introduced in 1900s Hybiak et al., Aspirin and its pleiotropic application. European Journal of Pharmacology 866 (2020) 1727622 25 The aspirin story – from willow to wonder drug CH3 British Journal of Haem atology, Volume: 177, Issue: 5, Pages: 674-683, First published: 20 January 2017, DOI: (10.1111/bjh.14520) ASA Acetylsalicylic acid (ASA) or salicylate The prototype “rapidly acting” NSAIDS Today salicylates are available in hundreds of forms First alternative: phenylbutazone, 1949 Indomethacin : 1960s Other NSAIDs : 1970s COX II inhibitors : 1990s 27 ASA Pharmacokinetics what are the advantages of asa that we use them ? Rapidly absorbed from GI, 50-70% reaches systemic circulation 50-80% plasma-protein binding, displaces many other bound drugs – The rest remains in the active, ionized state. – Protein binding is concentration-dependent. – Saturation of binding sites leads to more free salicylate and increased toxicity. Metabolized in liver and blood into salicyluric acid Excreted in urine, but acidic urine favors reabsorption, urine pH > 8 increase secretion and clearence 28 ASA Pharmacokinetics Half-life: metabolic pathways have only a limited capacity 3-4 hours for acute administration of low dose (first order kinetics) 5-6 hours after 1 gram, which one of below in correct about the kinetics od ASA secreation in low and high dose? 15-30 hours for chronic high dose treatment (after 10 gram) (zero order kinetics) 29 ASA which statment about asa is wrong ? ASA achives antiinfmalaltomy effect by inhibition of pg biosythesis ASA achives antiplate effect by inhahtion of thx sythesis and platelet afrregation it binds reversibaly to both cox 1 and cox 2 Analgesic effect Relieves pain of mild to moderate intensity Antipyretic (lowers temperature) Inhibition of PG synthesis in hypothalamus-thermoregulatory center Antiinflammatory effect (at high doses) Inhibits prostaglandin biosynthesis Antiplatelet effects how is doses asa achive its pervention of mi effect Inhibits Thromboxane synthesis and platelet aggregation Effects last 8 days (until new platelets are produced) Prevents myocardial infarction, reduce vascular mortality, Prevents stroke and systemic embolism and further ischaemic events 30 cox 1 and cox 2 are reversivly midfiied by asprin. flase -- In contrast to ASA, COX inhibition with other NSAIDs is REVERSIBLE; all the NSAIDS are reversible inhibitors of the enzyme 31 Reproduced from: ISIS‐2 collaborative group. (1988) Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction British Journal of Haematology, Volume: 177, Issue: 5, Pages: 674-683, First published: 20 January 2017, DOI: (10.1111/bjh.14520) The aspirin story – from willow to wonder drug Dose related effect Therapeutic Levels 1. Plasma salicylate level 2 g/day → decreases urate reabsorption from renal tubules and lowers serum Uric Acid Doses > 4 g/day → lowers serum Uric Acid increase effects of other drugs (tolbutamide, sulfonylureas, phenytoin, etc) Aspirin-warfarin (COUMARIN) interaction Inhibitors of PG synthesis can inhibit actions of high-ceiling diuretics Ibuprofen inactivates Aspirin anticoagulation effect 1. Competes for same receptors 2. Naproxen and Indometacin do not do this 42 Salicylism Low-grade aspirin “toxicity” Chronic or acute, worrisome or not Signs and symptoms:what is the primary symptom of salicyism ? – tinnitus – – – – – – headache dizziness, drowsiness, confusion paresthesias GI upset (incl. nausea, vomiting) blurred vision increased ventilatory rate → respiratory alkalosis 43 Salicylate Poisoning A medical emergency - major disturbance of acid-base and electrolyte balance Average lethal doses, taken at once by otherwise healthy: adults: 10 - 30 g (30-100 regular aspirins) children: 5 - 8 g 44 Overdosage levels Plasma salicylate level 10-20 g at once – Toxicity can be prevented by intravenous administration of sulfhydryl donors such as N-acetylcysteine (NAC) if treatment is administered quickly. peptic ulcer pt., prolongation of bleeding time. 54 ACETAMINOPHEN TOXICITY Acetaminophen overdose constitutes a medical emergency. Severe liver damage occurs in 90% of patients with plasma concentrations greater than 300 mg/ml at 4 hours or 45 mg/ml at 15 hours after the ingestion of the drug. Perhaps 10% of poisoned patients who do not receive specific treatment develop severe liver damage; 10% to 20% of these eventually die of hepatic failure despite intensive supportive care. Activated charcoal, if given within 4 hours of ingestion, decreases acetaminophen absorption by 50% to 90% and is the preferred method of gastric decontamination. Gastric lavage generally is not recommended. N-acetylcycsteine to increase congugation of toxic metabolite ACETAMINOPHEN urine < %5 Sulphate Acetaminophen > 90 Glucuronide < %5 CYP2E1, CYP1A2, CYP3A4 N-acetyl-p-benzoquinonemine (NAPQI) Nontoxic cystein and mercapturic acid conjugates Hepatocellular necrosis 56 ACETAMINOPHEN TOXICITY NON-TOXIC METABOLITES RENAL EXCRETION ACETOMINOPHEN +Glutathione N-acetyl-p benzoguinoneimine (NAPQI) Toxic NAC N-acetylcysteine Cell Death * NAC functions by detoxifying NAPQI. * NAC protect against hepatic injury by its antioxidant and antiinflammatory properties PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN. Peak blood concentration: 30-60 min Half-time: 2.5 hr – Overdose→7.3 hr Dose: 500-1000 mg, 4-6 hr intervals Max. Dose: – 2,6 - 4 g/day – in children: 10 mg/kg – 6-12 years of age: 20-30 mg/kg Absorption can be affected by food 58 59 Indoles Indomethacin – the prototypical high potency NSAID – Highly COX-1 specific – FDA approved for closure of persistent patent ductus arteriosus. – A typical regimen involves the iv administration of 0.1 to 0.2 mg/kg every 12 hours for three doses. Successful closure can be expected in more than 70% of neonates treated with the drug. Such therapy is indicated primarily in premature infants who weigh between 500 and 1750 g, who have a hemodynamically significant patent ductus arteriosus – Patient intolerance (GI side effects) generally limits its use to shortterm dosing; reserved for the management of moderate to severe acute inflammatory conditions. 60 Indoles Indomethacin – A very high percentage (35% to 50%) of patients experience untoward symptoms, and about 20% must discontinue its use. Most adverse effects are dose-related. Gastrointestinal complaints are common and can be serious. Diarrhea, ulcerative lesions. Acute pancreatitis has been reported, rare, but potentially fatal, cases of hepatitis. Underlying peptic ulcer disease is a contraindication to indomethacin use The most frequent CNS effect (indeed, the most common side effect) is severe frontal headache, occurring in 25% to 50% of patients who take the drug for long periods. Dizziness, vertigo, light-headedness, and mental confusion may occur. Seizures have been reported, as have severe depression, psychosis, hallucinations, and suicide. Caution is advised when administering indomethacin to elderly patients or to those with underlying epilepsy, psychiatric disorders, or Parkinson's disease, because they are at greater risk for the development of serious CNS adverse effects. Hematopoietic reactions include neutropenia, thrombocytopenia, and rarely aplastic anemia. As is common with other tNSAIDs, platelet function is impaired transiently during the dosing interval. 61 Indoles which drug can be givn to pateints with familial intestinal polyposis ? Sulindac – well tolerated because spares renal prostaglandin production – no effect on PGI2 synthesis – less than half as potent as indomethacin – Prodrug : its sulfide metabolite which is more than 500 times more potent as an inhibitor of cyclooxygenase than sulindac. – a long acting agent with less GI effects than either Aspirin or indomethacin. – It suppresses familial intestinal polyposis. – It may inhibit the development of colon, breast, and prostate cancer in humans. Etodolac – - of all traditional NSAID, this one is the most COX-2 selective Ketorolac – It has potent analgesic activity. – Has iv and im forms, used in post-surgical pain management 62 Phenylacetic acid Diclofenac which one of the drugd below have longer half lif e due to its abiloty to accumlate in synovial fluid ? used commonly, COX1/2 equipotent one of the most potent NSAIDs known clinically and in animal models for both inflammation and pain. analgesic, antipyretic and antiinflammatory activity. substantially greater than indomethacin, naproxen, and several other agents. appears to reduce intracellular concentrations of free AA in leukocytes, perhaps by altering its release or uptake. Accumulates in synovial fluid after oral administration, which may explain why its duration of therapeutic effect is considerably longer than the plasma half-life. approved for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. 63 Phenylacetic acid Diclofenac Has rapid absorption, extensive protein binding, and a short half-life. There is a substantial first-pass effect → 50% of diclofenac is available systemically. metabolized in the liver CYP2C to 4-hydroxydiclofenac, the principal metabolite, and other hydroxylated forms after glucuronidation and sulfation the metabolites are excreted in the urine (65%) and bile (35%). one of the best NSAIDs for lower incidence of GI bleeding. Diclofenac (75mg) and Misoprostol (Cytotec) (200μg) have been formulated together in a preparation called Arthrotec 3 formulations are available: an intermediate-release potassium salt, a delayed-release form and an extended-release form. The usual daily dosage for those indications is 100 to 200 mg, given in several divided doses. 64 Phenylproprionic Acid Derivatives Differ in potency because they all have analgesic, antipyretic, antiinflammatory effects Ibuprofen ❑ prototype for low-potency, short-acting NSAID ❑ COX-1/COX-2 equipotent Ketoprofen ❑ COX-1 preference, can also inhibit lipoxygenase pathway Naproxen ❑ prototypical long-acting NSAID ❑ COX1/2 equipotent 65 Ibuprofen Absorbed rapidly, bound avidly to protein, Metabolized in liver (90% is metabolized to hydroxylate or carboxylate derivatives) and metabolites are excreted by kidney. Half-life: 2 hours. Slow equilibration with the synovial space → its antiarthritic effects may persist after plasma levels decline. Better tolerated than aspirin and indomethacin and has been used in patients with a history of gastrointestinal intolerance to other NSAIDs. Nevertheless, 5% to 15% of patients experience gastrointestinal side effects. Other adverse effects of ibuprofen have been reported less frequently: thrombocytopenia, rashes, headache, dizziness, blurred vision, and in a few cases toxic amblyopia, fluid retention, and edema. Patients who develop ocular disturbances should discontinue the use of ibuprofen. Ibuprofen can be used occasionally by pregnant women; however, the concerns apply regarding third-trimester effects, including delay of parturition. Ibuprofen Ibuprofen is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. The oral and intravenous routes are equally effective for this indication. Naproxen Food delays the rate but not the extent of absorption. Peak concentrations in plasma occur within 2 to 4 hours and are somewhat more rapid after the administration of naproxen sodium. Absorption is accelerated by the concurrent administration of sodium bicarbonate but delayed by magnesium oxide or aluminum hydroxide. Naproxen also is absorbed rectally, but more slowly than after oral administration. Naproxen's free fraction is significantly higher in women than in men, although albumin binding is very high in both sexes Enolic acids - oxicam family Piroxicam Potent anti-inflammatory action with low side-effect incidence. Long acting once a day dosing, half-life: 50 hours Long-term treatment of rheumatoid arthritis or osteoarthritis. It may be tolerated better than aspirin or indomethacin. Due to its slow onset of action and delayed attainment of steady state, it is less suited for acute analgesia but has been used in acute gout attacks. 69 Enolic acids - oxicam family Meloxicam COX-2 prefrential inhibitor on average in ex vivo assays. There is significantly less gastric injury compared to piroxicam (20 mg/day) in subjects treated with 7.5 mg/day of meloxicam, but the advantage is lost with 15 mg/day Its efficacy in osteoarthritis and rheumatoid arthritis is comparable to that of other NSAIDs. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Drug Interaction May interfere with the action of antihypertensive and diuretic agents (diuretics, ACE inhibitors). Antihypertensives effect is lessened due to sodium retention by inhibition of renal prostaglandin formation. – antagonizes the natriuretic and antihypertensive effects of furosemide and thiazide diuretics, reduce diuretic efficacy. – blunts the antihypertensive effect of beta receptor antagonists, AT1 receptor antagonists, and ACE inhibitors ACE inhibitors and angiotensin II receptor blockers: There is a risk of renal impairment and hyperkalaemia. Quinolone antimicrobials: Convulsions may occur if NSAIDs are co-administered. Drug Interaction Anticoagulants (warfarin) and antiplatelet agents (Dipyridamole,clopidogrel): Increased risk of gastrointestinal bleeding with NSAIDs Cyclosporine and tacrolimus: Nephrotoxic effect is exacerbated by NSAIDs Cytotoxics: Renal tubular excretion of methotrexate is reduced by competition with NSAIDs 73 74 75 The New Generation of Rapidly-Acting NSAIDs: COX-2 Inhibitors 76 77 78 COX-2 Inhibitors Prototype: Celecoxib (CELEBREX) “Selectively” inhibits COX -2, so... Six COX-2 inhibitors specifically designed for such purpose, the coxibs, were initially approved for use in the U.S. or E.U.: celecoxib, rofecoxib, valdecoxib and its prodrug parecoxib, etoricoxib, and lumiracoxib. Lower risk of gastric irritation and ulceration than older NSAIDs -- This drug has 4% rate of ulceration, compared to Naproxen = 26%, so these drugs do cause ulceration, just at a lower rate ? Reduction of other risks (e.g., bronchospasm, antiplatelet effects)? Cardiovascular risk !!!! – Most coxibs have been either severely restricted in their use or withdrawn from the market in view of their adverse event profile (cardiovascular events, stroke). – Celecoxib (CELEBREX) currently is the only COX-2 inhibitor licensed for use in the U.S. 79 80 COX-2 Inhibitors The relative degree of selectivity for COX-2 inhibition is lumiracoxib = etoricoxib > valdecoxib = rofecoxib ≫ celecoxib. diclofenac, meloxicam, and nimesulide exhibit selectivity for COX-2 that is close to that of celecoxib in vitro Indeed, meloxicam achieved approval in some countries as a selective inhibitor of COX-2. Thus, selectivity for COX-2 should not be viewed as an absolute category; the isoform selectivity for COX-2 (just like selectivity for 1 adrenergic receptors) is a continuous rather than a discreet variable 81 Clinical pharmacology & Therapeutics | VOLUME 85 NUMBER 2 | FEBRUARY 2009 82 Lippincott Illustrated Reviews Pharmacology Seventh Edition-2019 87 İlaç Türkiyede Bulunan Müstahzarlar Asetilsalisilik asit Asprin, atapsin, Algo-Bebe Alka-Seltzer, Asinprine, Aspinal, Babyprin, Corasprin, Dispril, Ecoprin, Nötras, Opon, Pharmasprin Sodyum salisilat Brulex, Cystex, Plax,Saliject, Tussirex Diflunisal Dolphin Metilsalisilat Mentho-Plast, Capsimed Yakı, Sadrüd Jel Şanlı Kapsikumlu Liniment, Ben-Gay B, Capsi-Gel Fenbufen Flurbiprofen Yabancı Müstahzarlar Basifen, Lederfen Majezik SR, Majezik, Maxaljin SR, Maxaljin Strefen Pastil, Flurflex, Ansaid, Fortine, Fiera, ZeroP İbuprofen Brufen, Nurofen, Suprafen, Artril, Gerofen, Profen, Suprafen, Advil Liquigels, Dolgit, Kidyfen, Pedifen, Ibufen, Dolven, Brufen Retard, Siyafen Ketoprofen Profenid , Fast-Jel, Profenid-jel, Profenid Naproksen Naponal , Naprodev , Mednap, Naprosyn Oksaprozin Duraprox Pranoprofen Oftalar Tiaprofenik asit Surgam İlaç Türkiyede Bulunan Müstahzarlar Asemetasin Rantudil Diklofenak Yabancı Müstahzarlar Miyadren, Voltaren, Volfenaks, Diklojik, Diclomec, Dikloron, Diklo-S, Romatim, Actinoma, Aftojel,Voltaren Ophta, Difenak İndometazin Endol, İndocolir, Endol Ketorolak Ketrodol, Acular, Ketadon Nabumeton Relifex Sulindak Türkiyede yok Tolmetin Tolectin Etofenamat Doline, Flexo, Rheumon,Thermove Mefenamik asit Ponstan Meklofenamat Lenidolor, Movens Lornoksikam Xefo, Quando, Piroksikam Felden, Oksikam Tenoksikam Oksamen-L, Tilcotil, İlkoten, Tenoksan, Tenox, Tilko,Zikaral Algocetil, Apo-sulin, Arthrocine, Artribid,Clinoril, Sulindal İlaç Türkiyede Bulunan Müstahzarlar Yabancı Müstahzarlar Azapropazon Üretilmiyor Üretilmiyor Fenilbutazon Türkiyede yok Ambene, Butadion, Butaprin, Butazolidin, Kadol, Rheosolon Metamizol Adepiron, Andolor, Devaljin, Geralgine, Novalgin, Novo-Plan, Novopyrine, Adepiron, Feninox, Andolor Oksifenbutazon Türkiyede yok Propifenazon Aljil, Minoset, Panalgine Benzidamin Tantum, Benzidan, Tanflex, Ternex, Andorex, Farhex, Geral, Klodamin, Kloroben, Oroheks, Perimex Parasetamol Perfalgan, Calpol, Parol, Polmofen. Tamol, Termacet, Tylol, A-Per, Asomal, Babinoks, Ekosetol, Gripin, Minafen, Paracetamol, Parcetol, Pirofen, Sedalon, Deminofen, Paranox, Minocet, Paracet, Setamol, Pirofen Butazonic, Diflamil, Mysite, Oxybutazone, Tanderil, Tandacote İlaç Türkiyede Bulunan Müstahzarlar Yabancı Müstahzarlar Etorikoksib Türkiyede yok Lumirakoksib Rofekoksib Türkiyede yok Türkiyede yok Algix, Arcoxia, Auxib, Ebov, Etoxib, Etozox Exxiv, Nucoxia, Tauxib, Turox Prexige Rofib, Rofiz Selekoksib Türkiyede piyasadan çekildi (2011 Şubat) has voluntarily withdrawn celebrex from the Turkish market. Valdekoksib Etodolak Dolarit, Edolar, Esodax, Etodin, Etol, Etopan, Etoteva, Lodine, Tadolak, Tilac Meloksikam Exen, Melox, Zeloxim, Enflar, Exen, Meksun, Melcam, Romacox, Runomex, Zeloxim, Nimelid, Nimes, Romasulid, Sulidin, Motival Nimesulid Aclarex, Celcox, Celebra, Celebrex,Celedol Celib, Cobix, Onsenal, Orthocel,Solexa, Zycel -- PG’s from COX-1 are in GI tract, platelets, endothelial, renal medulla -- PG’s from COX-2 in synovial lining, vascular endothelial cells, macrophages 95 96