Gout Disease Pharmacology and Medicine.pptx

Gout treatment

1. Gout Disease Drugs Used in Gout By: Dr. Amira Badr Dr. Saad Alobaid

2. Objectives 01 Define Gout 03 Describe Treatment of Acute Gouty Arthritis 05 Identify Mechanism of Action and Side Effects of the Drugs 02 Describe Outlines of Treatment 04 Describe Treatment of Chronic Gout

3. Table of contents 01 ABOUT THE DISEASE 03 Anti-inflammatory Drugs 05 Uricosuric Agents 02 Treatment Goals 04 Uric Acid Synthesis inhibitors 06 New Medications

4. About the disease 01 You can enter a subtitle here if you need it

5. Introduction Gout is one of the most common crystal-induced arthropathies . Gout is caused by monosodium urate monohydrate crystals; The primary risk factor for the development of gout is the elevation of serum uric acid (urate) levels or hyperuricemia. As uric acid levels rise and exceed the physiological saturation threshold of uric acid in body tissues, the formation and deposition of MSU crystals occur in and around joints.

6. Signs and Symptoms Arthritis Podagra Monoarticular involvement most commonly In gout, attacks that begin abruptly and typically reach maximum intensity within 8 hours Without treatment, symptom pattern change over time; attacks can become more polyarticular , involve more proximal and upper-extremity joints, occur more often, and last longer In some cases, the eventual development of chronic polyarticular arthritis that can resemble rheumatoid arthritis

7. Symptoms of the disease REDNESS STIFFNESS TENDERNESS 01 02 03 SEVERE PAIN WARMTH SWELLING 04 05 06

8. Physical Findings Involvement of a single (most common) or multiple joints Signs of inflammation – Swelling, warmth, erythema and tenderness Fever Tophi in soft tissues (helix of the ear, fingers, toes, prepatellar bursa, olecranon) Eye involvement – Tophi, crystal-containing conjunctival nodules, blurred vision, scleritis . Complications: Severe degenerative arthritis Secondary infections Urate or uric acid nephropathy Increased susceptibility to infection Urate nephropathy Renal stones Nerve or spinal cord impingement Fractures in joints with tophaceous gout

9. About the disease ACUTE GOUT Interaction with inflammatory system Urate crystal formation Under-excretion of uric acid Overproduction of uric acid Elevated uric acid levels

10. Treatment Goals 02

11. Treatment Gout is managed in the following 3 stages: 01 02 03 Treating the acute attack Providing prophylaxis to prevent acute flares Lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals

12. Treating the Acute Attack Acute treatment of proven crystal-induced arthritis is directed at the relief of pain and inflammation. Agents used in this setting include the following: Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin Corticosteroids Colchicine (now less commonly used for acute gout than it once was) Adrenocorticotropic hormone (ACTH) Combinations of drugs (colchicine plus NSAIDs, oral corticosteroids plus colchicine, intra-articular steroids plus colchicine or NSAIDs)

13. Prophylaxis to Prevent Acute Flares Colchicine or low-dose NSAIDs Low-dose prednisone (if patients cannot take colchicine or NSAIDs) Long-term Management of Gout: Is focused on lowering uric acid levels. Agents used include the following: Interfering with uric acid synthesis; Allopurinol and Febuxostat Increasing uric acid excretion; Probenecid, Pegloticase , sulfinpyazone

14. Pathophysiologic events in a gouty joint. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1;

15. Anti-inflammatory Drugs 3

16. NSAIDs Mechanism of Action: - used to treat pain and inflammation, block cyclooxygenase, and thereby reduce the generation of prostaglandins.  Indomethacin, Naproxen, and sulindac are the most commonly used in acute gout attacks. Others can also be used, such as Ibuprofen and Diclofenac. Aspirin is not used because it causes renal retention of uric acid at low doses (≤2.6 g/d). Side Effects: Heartburn, Gastric ulcer, increased blood pressure, Nausea, Abdominal pain

17. NSAIDs The selective COX-2 inhibitor celecoxib offers the possibility of relieving inflammation and pain, but with a lower risk of GI side effects. It has been suggested that COX-2 expression in monocytes is induced in response to urate crystals. Several studies have found that selective COX-2 inhibitors are comparable to other NSAIDs for treating acute gouty arthritis. However, celecoxib requires particularly high doses to provide pain relief comparable to that provided by indomethacin in acute gout.

18. Corticosteroids Mechanism of Action: Used to reduce inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. They can be given orally, intramuscularly (IM), intravenously (IV), or intra- articularly . e.g. Oral prednisone, intra-articular triamcinolone Side Effects: Systemic corticosteroids may be associated with hyperglycemia, salt and water retention, gastric ulcers, immunosuppression, osteoporosis, and other conditions .

19. ACTH ( Corticotropin ): Cosyntropin Corticotropin stimulates endogenous production of corticosteroids and directly and rapidly acts on peripheral leukocyte activation. It decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability. Side Effects : Like corticosteroids

20. Colchicine Mechanism of Action: Colchicine inhibits microtubules and may thereby inhibit phagocytosis, neutrophil mobility, and chemotaxis. It also may inhibit the generation of prostaglandins.  It also inhibits the formation of leukotriene B4 and IL-1β. Colchicine relieves the pain and inflammation of gouty arthritis without altering the metabolism or excretion of urates and without other analgesic effects. Pharmacokinetics: Colchicine is absorbed readily after oral administration, reaches peak plasma levels within 2 hours,

21. Colchicine Side Effects : Several of colchicine’s adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis. GI effects ( eg , diarrhea , nausea, cramping, abdominal pain, vomiting)  Less frequent: Neuromuscular toxicity ( eg , muscle pain, weakness), Myelosuppression , Disseminated intravascular coagulation Injury to cells in the renal, hepatic, circulatory, and central nervous systems, Headache, alopecia. It may also affect fertility.

22. Pharmacokinetics

23. Uric Acid Synthesis Inhibitors 4

24. Xanthine Oxidase Inhibitors Mechanism of Action: Inhibition of xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine, reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines. This results in the reduction of the tissue stores of uric acid. The goal of therapy is to lower the serum uric acid level to approximately 5-6 mg/ dL . These agents should not be started during an attack of acute gouty arthritis without adequate control of the gouty inflammation.

25. Xanthine Oxidase Inhibitors Allopurinol: It is the most effective therapy for lowering serum uric acid. Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. Allopurinol is metabolized by xanthine oxidase, but the resulting compound, alloxanthine , retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.

26. Inhibition of uric acid synthesis by allopurinol occurs because allopurinol and alloxanthine inhibit xanthine oxidase. Inhibits Inhibits

27. Xanthine Oxidase Inhibitors Side Effects : Rash, nausea, Renal failure, and vomiting. In addition to precipitating gout, peripheral neuritis and necrotizing vasculitis, epistaxis, bone marrow suppression, thrombocytopenia and aplastic anemia may rarely occur. Hepatic toxicity and interstitial nephritis have been reported. An allergic skin reaction characterized by pruritic maculopapular lesions occurs in 3% of patients.

28. Xanthine Oxidase Inhibitors Drug Interaction : Inhibits warfarin and dicumarol metabolism. Reduces the metabolism of anticancer, 6-mercaptopurine and azathioprine, requires dosage reduction by about 80 %. With ampicillin increases the risk of skin rash Prolongs the half-life of chlorpropamide by competing for renal excretion.

29. Xanthine Oxidase Inhibitors Febuxostat : Febuxostat is a potential alternative to allopurinol.   It is structurally different and lacks a purine ring. More potent and more selective than allopurinol and does not affect other enzymes of purine or pyrimidine metabolism. Given once daily. Side Effects : It increases the number of gouty attacks. Common adverse events include upper respiratory tract infections, arthralgias , diarrhea , nausea, headache, and liver function abnormalities. Atrioventricular block or atrial fibrillation and cholecystitis have also been reported.

30. Uricoseuric Agents 5

31. Uricosuric Agents Uricosuric drugs—probenecid, sulfinpyrazone, as well as fenofibrate , and losartan—inhibit active transport sites for reabsorption and secretion in the proximal renal tubule so that net reabsorption of uric acid in the proximal tubule is decreased. Because aspirin in doses of less than 2.6 g daily causes net retention of uric acid by inhibiting the secretory transporter, it should not be used for analgesia in patients with gout. Uricosuric agents also reduce the secretion of other weak acids (e.g., penicillin).

32. Uricosuric Agents As the urinary excretion of uric acid increases, the size of the urate pool decreases, although the plasma concentration may not be greatly reduced. In patients who respond favorably , tophaceous deposits of urate are reabsorbed, easing arthritis and remineralizing bone. With the ensuing increase in uric acid excretion, a predisposition to the formation of renal stones is augmented rather than decreased; therefore, the urine volume should be maintained at a high level, and at least early in treatment, the urine pH should be kept above 6.0 by the administration of alkali. Therapy should not be started until 2–3 weeks after an acute attack.

33. Uricosuric Agents Probenecid: Probenecid lowers tissue stores of uric acid by increasing net renal excretion of uric acid through inhibition of tubular reabsorption. Some authorities recommend alkalizing the urine when starting probenecid to reduce the risk for renal stone formation.  Probenecid is indicated for long-term management of hyperuricemia associated with gout.

34. Uricosuric Agents Probenecid: Side Effects : Nausea, Vomiting, Loss of appetite, GI upset, Rash, Flushing, Dizziness, Fever, Aplastic anemia , Hemolytic anemia , Leukopenia, Renal calculi, Nephrotic syndrome (rare), Exacerbation of gout, Gouty arthritis Contraindications: Previous renal stones, renal impairment, recent attack, coadministration with low dose aspirin (aspirin may prevent probenecid from being fully active)

35. Uricosuric Agents Sulfinpyrazone: Side Effects : Can aggravate peptic ulcer Can enhance the action of certain diabetic medications.

36. Selective Uric acid Reabsorption Inhibitor (SURI) Lesinurad ( Zurampic ) Lesinurad is the first selective uric acid reabsorption inhibitor to be approved in the United States. It acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid. It also inhibits organic anion transporter 4 (OAT4). It is indicated in combination with a xanthine oxidase inhibitor for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.

37. Selective Uric acid Reabsorption Inhibitor (SURI) Lesinurad ( Zurampic ) Side Effects: Headache (5.3%), Influenza (5.1%), GERD (2.7%), Renal failure (1.2%) Warnings Black Box Warnings Acute renal failure has occurred and was more common when lesinurad was given alone. Should be used in combination with a xanthine oxidase inhibitor Contraindications Severe renal impairment 

38. New Medications 6

39. Others Pegloticase ( Krystexxa ) Pegloticase is a recombinant uricase , absent in humans and some higher primates. Uricase facilitates the conversion of urate to allantoin . Unlike uric acid, allantoin is soluble and easily excreted by the kidneys.  Thus, hyperuricemia is reduced, with little risk of acute kidney injury. Pegloticase has been shown to maintain low urate levels for up to 21 days after a single dose Pharmacokinetics: The recommended dose for pegloticase is 8 mg/2 weeks, administered as an intravenous infusion. It is a rapidly acting drug, achieving a peak decline in uric acid level within 24–48 hrs. The serum half-life ranges from 6 to 14 days.  

40. Others Pegloticase ( Krystexxa ) Side Effects : Gout flare, infusion reactions, nausea, and urticaria , chest discomfort, nephrolithiasis, arthralgia, muscle pain, headache, and anaphylaxis. Black Box Warnings Anaphylaxis and infusion reactions have been reported; these reactions may occur with any infusion, including the first,  Contraindications History of serious hypersensitivity G6PD-deficiency (increased risk of hemolysis and methemoglobinemia , because of the formation of hydrogen peroxide by uricase )  

41. Others Interleukin Inhibitors ( Canakinumab , Anakinara ) Interleukin-1β (IL-1β) is involved in mediating gouty inflammation. Inhibiting IL-1β may decrease gout-related pain and inflammation.  Canakinumab ( Ilaris ) A recombinant, human monoclonal antibody that binds to human interleukin (IL)-1β and neutralizes its activity by blocking its interaction with IL-1 receptors. Indicated for gout flares in adults in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an adequate response,  and in whom repeated courses of corticosteroids are not appropriate.  Side Effects : Diarrhea, influenza, headache, rhinitis, weight increase, musculoskeletal pain, leukopenia, and thrombocytopenia. Contraindications: Hypersensitivity

42. Others Other agents lower uric acid levels as a secondary effect. The angiotensin-receptor blocker (ARB) losartan is moderately uricosuric at 50 mg/day.  The lipid-lowering agent fenofibrate reduces serum urate 19% and increases clearance by 40% at a dose of 200mg daily

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