ARTHRITIS AND GOUT

1. ARTHRITIS AND GOUT • NSAIDS, DMARDS, BRMs and Drug Therapy of Arthritis • Drug Therapy of Gout Garold S. Yost, Ph.D. Department of Pharmacology and Toxicology 390C Biomedical Polymers 581-7956 gyost@pharm.utah.edu

2. Aspirin for Thrombotic Diseases - decreases platelet aggregation 24 % reduction in major vascular events (myocardial infarction) Prevention of myocardial infarction in low-risk patients may not compensate for possible increased risk of hemorrhagic stroke.

3. Ibuprofen Blocks Aspirin Anti-platelet Effects Catella-Lawson, et al., New Engl. J. Med., 25, 1809-1817 (2001) Concomitant administration of ibuprofen – but not acetaminophen or diclofenac – inhibits antiplatelet effect of aspirin

4. http://www.archrheumatol.net/atlas/case31.html Rheumatoid Nodules

5. Cytokines Play Important Role Anakinra The Lancet Vol 358,Issue 9285, 15 Sep 2001, pg 903-911

6. Cyclooxygenase Enzymes • COX-1 • Constitutively expressed in most tissues • Inhibition leads to GI, renal, other toxicities • Not induced in response to cytokines (inflammation) • COX-2 • Constitutively expressed at low levels • Neurons, kidney, gastric mucosa • Highly induced by inflammation (10 to 1000-fold) - IL-1 and TNF

7. COX-3 – Boom or Bust? • Produced by alternate splicing of the COX-1 gene • Was an exciting new discovery of a potential target for new analgesics, because dog form was inhibited by acetaminophen • However, human form does not appear to be an active enzyme • Search is intense tosee if other splice variants exist in humans Chandrasekharan et al. PNAS 99, 1396-31 (2002)

8. Balancing Therapy and Toxicities of COX Inhibition Warner and Mitchell, PNAS, 99, 13371-13373 (2002)

9. COX-2 Selective Drugs • Celecoxib (Celebrex) • Only COX-2 selective drug still available - Vioxx voluntarily withdrawn by Merck and Bextra was removed by FDA • High doses (>400 mg bid) may have increased cardiovascular risk • Contraindicated in patients allergic to sulfonamides • May be effective for cancer (colon, and possibly pancreas, lung, breast, and brain) or Alzheimer’s Disease

10. COX-2 SELECTIVE DRUGS – TOXICITIES? • Cardiovascular – 2.4 relative risk of major event with rofecoxib compared to naproxen (VIGOR - Vioxx study), but CLASS (celecoxib) study showed no increase in cardiovascular events • High dose > 25 mg/day of rofecoxib increased CHD (coronary heart disease) risk by 70-90 % • Renal – celecoxib associated with a few reports of acute renal failure (celecoxib - edema in 2 % patients) (refecoxib – edema in 3.8 %)

11. Vioxx® Recalled Due to Risk Of Heart Attacks and Strokes ! “Although the risk that an individual patient would have a heart attack or stroke related to Vioxx is very small, the study that was halted suggests that, overall, patients taking the drug chronically faced twice the risks of a heart attack compared to patients receiving a placebo” …..FDA News

12. Recent fallout following the Adenomatous Polyp Prevention on Vioxx (APPROVe) study …

13. Nonsteroidal Anti-Inflammatory Drugs • All organic anions – bound to plasma proteins • All cause GI ulceration or bleeding and renal toxicity • Misoprostol (Cytotec) used to prevent or treat GI injury • Omeprazole (Prilosec) also effective prophylactic or treatment for gastritis • All inhibit platelet aggregation, but reversibly • All potentially cross-reactive with aspirin hypersensitivity – including COX-2 selective drugs

14. Specific NSAIDs • ibuprofen (Motrin); naproxen (Naprosyn); diclofenac (Voltaren) • indomethacin (Indocin) or phenylbutazone may be drugs of choice for gout – inhibit neutrophil phagocytosis • diclofenac available with misoprostol (Arthrotec) to decrease GI toxicity

15. Anakinra The Lancet Vol 358,Issue 9285, 15 Sep 2001, pg 903-911

16. Slow-Acting Anti-Inflammatory Drugs (Disease-Modifying Antirheumatic Drugs; DMARD) • methotrexate is first line therapy 2.5 mg/week maintenance dose. Monitor serum enzymes for hepatotoxicity • gold: aurothioglucose (Solganal) and aurothiomaleate (Myochrysine) are i.m. forms • Bone marrow depression (blood counts mandatory), and renal toxicities • auranofin (Ridaura) is oral form with latency 4-6 months but 50% of patients have severe diarrhea during this period • diet – glucosamine and chondroitin may decrease pain and decrease progression of disease

17. Less Frequently Used DMARDS • hydroxychloroquine (Plaquenil) • Retinal damage often major problem – requires vision checks • sulfasalazine (Azulfidine) • D-penicillamine (Cuprimine) • Mechanism may be to alter T-lymphocyte function • Side effects include nephrotoxicity

18. Newer Anti-Inflammatory Agents Biological Response Modifiers (BRMs) • leflunomide (Arava - oral); etanercept (Enbrel – s.c.); infliximab (Remicade – i.v.); anakinra (Kineret – s.c.); adalimumab (Humira – s.c.) • leflunomide inhibits T-cell proliferation – oral pyrimidine synthesis inhibitor – slows joint damage; carcinogen and teratogen • etanercept is recombinant human TNF-a receptor

19. Newer Anti-inflammatory (cont.) • infliximab is a monoclonal antibody to TNF-a and inhibit its binding to cell surface receptors. Combination with methotrexate showed 100% response (285 patients – halt in progression of joint damage). • anakinra is IL-1 receptor antagonist. Has been approved for severe rheumatoid arthritis when a DMARD drug doesn’t work. • adalimumab is another new TNF-a inhibitor (monoclonal antibody) for use in DMARD-refractive RA patients. All of the TNF-a inhibitors may cause lymphomas

20. Key Concepts – Arthritis Drugs • NSAID inhibition of PGs still primary treatment for arthritis • DMARDs can be helpful, but toxicities are major problems – methotrexate is generally the exception, i.e. effective and lower toxicities • New BRIs may provide dramatic, life-style altering therapy – but immune system alterations are a concern

21. The Gout The Gout” by James Gilray, 1799. Gout depicted as an evil demon attacking a toe. http://www.hopkins-arthritis.som.jhmi.edu/other/gout.html

22. Thomas Sydenham (1624-1689)"the Shakespeare of Medicine" The victim goes to bed and sleeps in good health. About 2 o'clock in the morning, he is awakened by asevere pain in the great toe; more rarely in the heel, ankle or instep.This pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then followschills and shiver and a littlefever. The pain which at first moderate becomes more intense. With its intensity the chills and shivers increase. After a time this comes to a full height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Now it is a violent stretching and tearing of the ligaments-- now it is a gnawing pain and now a pressure and tightening. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room.

23. http://medicine.ucsd.edu/clinicalimg/extremities-gout.jpg Redness and Swelling of Acute Gouty Attack

24. http://arthritis.about.com/od/goutdiag/ Tophaceous Deposits of Urate

25. Causes of Gout Hyperuricemia Idiopathic Renal retention of urate Unexplained associations (hypertension, obesity, hypolipidemia) Increased urate production Renal retention, specific Drug effects (diuretics - hydrochlorothiazide, acetylsalicylic acid) Renal damage (glomerular or tubular) Metabolic (lactate, -OH-butyrate) Increased nucleic acid turnover (polycythemias, myeloproliferative disorders) Specific enzyme defects Hypoxanthine-guanine phosphoribosyl transferase Phosphoribosylpyrophosphate synthetase Local Factors Local decrease in urate solubility (pKa = 5.6) Low temperature Low pH Possible tissue factors Possible local increase in urate concentration

26. Purines in the Diet • Highest purine content (150-1000 mg/g) – herring, sardines, mussels, liver, kidney, meat extracts (gravy) • High purine content (75-150 mg/g) – bacon, beef, pork, scallops, trout, turkey, veal, salmon, ham, beans, lobster, mushrooms, oysters, peas, spinach • Low purine content (0-15 mg/g) – vegetables, fruits, milk, cheese, eggs, cereal

27. Drugs Used for Therapy of Gout

28. Rational Therapeutic Strategies • Inhibit PMN Function – Colchicine • Inhibit Prostaglandin Formation – NSAIDS • Increase Urate Excretion – Probenecid • Inhibit Urate Formation - Allopurinol

29. Colchicine • Mechanism – interferes with neutrophil function • Uses – acute gout • Combination therapy with allopurinol and probenecid

30. Normal Urate Excretion

31. Probenecid and Sulfinpyrazone • Treatment of choice for chronic gout • Initiation of therapy may induce acute attack • Caused by mobilization of urate from other sites to inflammed joints • Prophylactic use of NSAIDs prevent pain and inflammation when probenecid started • Decreases secretion of anionic drugs – causes significant drug interactions

32. Mechanism of Allopurinol Action

33. Side Effects of Allopurinol D. Toxicity and Problems Acute attacks may be observed during initiation of therapy and may be treated with an NSAID. E. Interactions Xanthine oxidase inactivates 6-mercaptopurine and azathioprine; doses of these drugs must be reduced to one-fourth of usual dose when the patient is also taking allopurinol.

34. Key Concepts Rational Treatment in Two Phases: Phase I – control pain and inflammation: NSAIDs (ibuprofen – may use indomethacin) or colchicine Phase II – decrease the serum urate (< 4.0 mg/dL) > 800 mg in 24 hr urine suggests overproduction – use allopurinol < 500 mg in 24 hr urine suggests decreased renal clearance – use probenecid