Gout (drug and treatment )

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1. GOUT Ravish Yadav

2. Gout Increased availability of purines from any of these sources -- exogenous, diet, endogenous, or tissues -- leads to excess urate, either by overproduction or underexcretion, producing hyperuricemia. Tissue deposition long before there are any symptoms Systemic manifestations such as nephrolithiasis or interstitial deposits

3. Gout At the proximal convoluted tubule, where there is reabsorption, secretion, reabsorption, and then finally excretion again. Net total of 90% of filtered uric acid is reabsorbed, and only approximately 10% is excreted.

4. Gout Uric acid has limited solubility in body fluids, which allows it to precipitate out in the tissues. There are impaired uric acid excretion mechanisms as well as overproduction mechanisms. Much primary or idiopathic gout is actually impaired excretion, and then there are a number of secondary mechanisms including a general decrease in renal function and effects on secretion or reabsorption from drugs or acidosis. Lower temperatures and lower pH can influence the site of location of deposition of urate crystals

5. Gout In hyperuricemia there are deposits of uric acid in the connective tissue -- and when the deposits are released into the joint space they are primarily phagocytized by synovial lining cells. These lining cells release a variety of chemotactic factors that draw in the neutrophils and then draw in the whole variety of pro-inflammatory molecules that have been so well studied in gout.

6. Gout

7. Clinical Progression

8. Termination of flares NSAIDs Colchicine Corticosteroids Injectable adrenocorticotropic hormone (ACTH). 

9. NSAIDs Indomethacin, naproxen, piroxicam, diclofenac or etoricoxib is given in relatively high and quickly repeated doses. Response is somewhat slower than with colchicine, but they are generally better tolerated; Their strong anti-inflammatory (not uricosuric) action is responsible for the benefit. Naproxen and piroxicam specifically inhibit chemotactic migration of leucocytes into the inflamed joint. After the attack is over, they may be continued at lower doses for 3-4 weeks while drugs to control hyperuricemia take effect. They are not recommended for long term management due to risk of toxicity.

10. Colchicine Colchicine is an antimitotic alkaloid that binds to specific sites on the cytoskeletal protein tubulin and disrupts microtubule polymerization. This disruption of normal cytoskeletal assembly results in a range of biologic effects on essential cell functions, including inhibition of intracellular vesicle transport, decreased secretion of chemokines and cytokines, impairment of cell migration, and inhibition of cell division

11. Colchicine appears to impair phagocytosis of uric acid crystals Colchicine potentially interferes with the inflammasome complex, inhibiting IL-1β activation It is postulated that Colchicine may prevent neutrophil migration Colchicine is believed to prevent the activation and degranulation of neutrophils, which is thought to mediate some gout symptoms, including pain.

12. Colchicine

13. Colchicine Neither analgesic nor anti-inflammatory, It does not inhibit the synthesis or promote the excretion of uric acid. But it specifically suppresses gouty inflammation. By binding to protein tubulin, it inhibits granulocyte migration into the inflamed joint and thus interrupts the vicious cycle. Colchicine does not affect phagocytosis of uric acid crystals but inhibits release of the glycoprotein and the subsequent events. Other actions of colchicine are: Antimitotic: causes metaphase arrest : binding to microtubules of mitotic spindle was tried for cancer chemotherapy but abandoned due to toxicity.

14. Colchicine Toxicity is high and dose related. Nausea, vomiting Watery or bloody diarrhea- abdominal cramps occur as dose limiting adverse effects. Accumulation of the drug in intestine- inhibition of mitosis in its rapid turnover is responsible for the toxicity. ln overdose, kidney damage CNS depression intestinal bleeding death is due to muscular paralysis and respiratory failure. Chronic therapy with causes aplastic anemia, agranulocytosis, myopathy and loss of hair

15. Corticosteroids Intraarticular injection of a soluble steroid suppresses the symptoms of acute gout. Crystalline preparations should not be used. It is indicated in refractory cases and those not tolerating NSAIDs/colchine Systemic steroids are very effective and produce a rapid response similar to colhicine, but are reserved for patients with renal failure/history of peptic ulcer bleed in whom NSAIDs are contraindicated

16. ACTH Parenteral ACTH is useful in acute gout, particularly in patients with renal and/or gastrointestinal contraindications to other therapies. Melanocortin's have strong anti-inflammatory properties and serve as natural inhibitors of inflammatory responses. Melanocortin's may even antagonize the action of interleukin (IL)-1, the key cytokine in gout pathophysiology.

17. Treating Hyperurecimia and prevent progression

18. Uricosuric agents The uricosuric agents act by blocking reabsorption of uric acid, thereby forcing more uric acid out through the collecting systems.  The other way of lowering uric acid is to block uric acid production Inhibit xanthine oxidase, the enzyme that is responsible for converting the relatively soluble hypoxanthine to the less soluble xanthine to the very insoluble uric acid. Allopurinol

19. Uricosuric Agents The advantages of these 2 types of agents are as follows. The uricosurics - probenecid in this case - reverse the most common physiologic abnormality in gout, since about 90% of primary gout people are under excreters. The advantages of allopurinol are that it is effective in both overproducers and underexcreters.

20. Probenecid The first step in urate reabsorption is its uptake from tubular fluid by a transporter that exchanges urate for either an organic or an inorganic anion. Uricosuric drugs compete with urate for the brush-border transporter, thereby inhibiting its reabsorption via the urate–anion exchanger system. However, transport is bidirectional, and depending on dosage, a drug may either decrease or increase the excretion of uric acid.

21. Probenecid Inhibits the transport of organic acids across epithelial barriers. Probenecid inhibits the tubular reabsorption of uric acid. Uric acid is the only important endogenous compound whose excretion is known to be increased by probenecid. The uricosuric action of probenecid is blunted by the coadministration of salicylates. Probenecid is well tolerated. Approximately 2% of patients develop mild GI irritation. Should be used with caution in those with a history of peptic ulcer. It is ineffective in patients with renal insufficiency and should be avoided Liberal fluid intake should be maintained throughout therapy to minimize the risk of renal stones. Probenecid should not be used in gouty patients with nephrolithiasis or with overproduction of uric acid

22. Sulfinpyrazone It is a pyrazolone derivative related to phenylbutazone having consistent uricosuric action, but is neither analgesic nor anti-inflammatory. At the usual therapeutic doses, it inhibits tubular reabsorption of uric acid. Its uricosuric action is additive with probenecid but antagonized by salicylates. It inhibits platelet aggregation. Gastric irritation is the most common side effect-contraindicated in patients with peptic ulcer.

23. URIC ACID SYNTHESIS INHIBITOR Xanthine Oxidase Inhibitor: Allopurinol Allopurinol is often the first-line agent for the treatment of chronic gout Allopurinol inhibits xanthine oxidase and prevents the synthesis of urate from hypoxanthine and xanthine. It is used to treat hyperuricemia in patients with gout and to prevent it in those with hematological malignancies about to undergo chemotherapy (acute tumor lysis syndrome). Even though underexcretion rather than overproduction is the underlying defect in most gout patients, allopurinol remains effective therapy.

24. Allopurinol Both allopurinol and its primary metabolite oxypurinol inhibit xanthine oxidase. Allopurinol competitively inhibits xanthine oxidase at low concentrations and is a noncompetitive inhibitor at high concentrations. Allopurinol also is a substrate for xanthine oxidase; the product of this reaction, oxypurinol, is also a noncompetitive inhibitor of the enzyme. The formation of oxypurinol, together with its long persistence in tissues, is responsible for much of the pharmacological activity of allopurinol. During allopurinol treatment, the urinary purines include hypoxanthine, xanthine, and uric acid.

25. Allopurinol Allopurinol facilitates the dissolution of tophi and prevents the development or progression of chronic gouty arthritis by lowering the uric acid concentration in plasma below the limit of its solubility. The formation of uric acid stones virtually disappears with therapy, which prevents the development of nephropathy. The incidence of acute attacks of gouty arthritis may increase during the early months of allopurinol therapy as a consequence of mobilization of tissue stores of uric acid. Coadministration of colchicine helps suppress such acute attacks Allopurinol increases the t1/2 of probenecid and enhances its uricosuric effect, while probenecid increases the clearance of oxypurinol, thereby increasing dose requirements of allopurinol

26. Febuxostat Febuxostat is a non-purine xanthine oxidase inhibitor. Febuxostat is a potent and selective inhibitor of xanthine oxidase, thereby reducing the formation of xanthine and uric acid without affecting other enzymes in the purine or pyrimidine metabolic pathway. As with allopurinol, prophylactic treatment with colchicine or NSAIDs should be started at the beginning of therapy to avoid gout flares. The most frequent treatment-related adverse events are liver function abnormalities, diarrhea, headache, and nausea.

27. Pegloticase Pegloticase is a recombinant mammalian uricase that is covalently attached to methoxy polyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic response. Pegloticase is a rapidly acting intravenous drug

28. Rasburicase Rasburicase is a recombinant urate-oxidase that catalyzes the enzymatic oxidation of uric acid into the soluble and inactive metabolite allantoin. It lowers urate levels more effectively than allopurinol and is indicated for the initial management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and significant hyperuricemia.