4_5900139072940153276.pharmacotherapy.pptx

Therapy

1. Lecture notes on DRUGS USED IN THE TREATMENT OF GOUT (for Bpharm. II-year) 6/6/2018 1

2. Introduction Gout, is characterized by elevated levels of uric acid (as urate ion) in the plasma and urine. can take two forms, acute and chronic. It is most common inflammatory arthritis Risk factors include obesity, hypertension, ingestion of alcohol, the use of diuretics, and diets rich in meats and seafood . Gout is associated with an increased risk of kidney stones . 6/6/2018 2

3. Introduction contd … Acute gouty arthritis results from the accumulation of needle-like crystals of monosodium urate monohydrate within the joints, synovial fluid, and periarticular tissue Initiating factors can be minor trauma, fatigue, emotional stress, infection , overindulgence in alcohol or food, or drugs, such as penicillin or insulin. The increase in extracellular urate can result from increased uric acid biosynthesis, decreased urinary excretion of uric acid, or perhaps, a combination of both . Uric acid is a weak acid with a very low water solubility. 6/6/2018 3

4. Introduction contd … The formation of uric acid from adenine and guanine is illustrated in the following figure. 6/6/2018 4

5. Classification 1. Treatment of Acute Gout Colchicine 2. Treatment of Chronic Gout Probenecid Sulfinpyrazone Treatment of Gout 3. Drugs that decrease Uric acid formation Allopurinol Febuxostat 4. Drugs acting by enhancing the degradation of Uric acid Pegloticase 6/6/2018 5

6. Classification contd … 6/6/2018 6

7. Hyper- uricemia It is defined as having serum uric acid levels of >7.0mg/dL in men or >6,0mg/dL in women . Most people with high serum urate levels are asymptomatic and may never develop gout . Uric acid is a normal metabolic end product of purine nucleotide catabolism ( i.e , adenine and guanine), but unlike other mammals, humans lack a critical enzyme, urate oxidase ( uricase ), needed to further break down uric acid into more water-soluble allantoin . 6/6/2018 7

8. Risk factors In addition to hyperuricemia , other factors include hypertension renal insufficiency, obesity the use of diuretics, high intake of alcoholic beverages and purine-rich foods such as meats, liver, fish, and beans. organ-transplant patients who are treated with cyclosporine . Furthermore, early onset of gout (between 20 & 30 yrs of age) is most likely a result of hereditary disorders of purine metabolism, esp . in those who have a hypoxanthine-guanine phospho-ribosyl transferase deficiency , 6/6/2018 8

9. 1. Treatment of Acute Gout The main goal of the p’therapy of acute gouty arthritis is a rapid resolution of pain and debility (weakness ). NSAIDs for patients with an established diagnosis of uncomplicated gout (I.e ., those with out heart failure, renal insufficiency, or GI disease ). For patients who have active peptic ulcers or renal impairment, the choice is either an IM dose of C orticotrophin (ACTH) or an intra-articular injection of G lucocorticoids . Colchicine is reserved for prophylaxis of recurrent, acute flare-ups of gouty arthritis or in patients in whom the diagnosis of gout is not yet confirmed. 6/6/2018 9

10. 1. Treatment of Acute Gout contd … Colchicine It is an alkaloid isolated from the dried corns and seeds of Colchicum autumnal . It is specifically indicated for acute treatment of gouty arthritis b’coz of its ability to block the production and release of the crystal-induced chemotactic factor (CCF) that mediates the inflammatory response because of urate crystals. 6/6/2018 10

11. 1. Treatment of Acute Gout contd … Colchicine It is often quite effective in aborting an acute gouty attack if given within the first 10-12 hours after the onset of arthritis. It can be administered orally or intravenously. A low oral dose of 0.6mg is taken every 1-2 hrs . until either the resolution of gouty symptoms or the occurrence of GI toxicities such as increased peristalsis, abdominal discomfort, nausea and vomiting, and diarrhea. 6/6/2018 11

12. 1. Treatment of Acute Gout contd … Colchicine Moreover, oral colchicine is also recommended only as a 2 nd line therapy for acute gout treatment when NSAIDs or corticosteroids are contraindicated or ineffective. 6/6/2018 12

13. 2. Treatment of Chronic Gout Probenecid It is the most widely used uricosuric agent in the US. It is selectively excreted into the renal tubules by the organic anion transporter system (OATS ). It is extensively metabolized via N- dealkylation of  -oxidation , followed by phase II conjugation into the active metabolite, p- sulfamoyl hippurate , for binding to OATS, thereby preventing uric acid reabsorption from the renal proximal tubules. 6/6/2018 13

14. Sulfinpyrazone It produces its uricosuric action in a similar manner to that of Probenecid and is indicated for the treatment of chronic and recurrent gouty arthritis . It is well absorbed with approximately 50% of the administered dose excreted as unchanged drug into the renal tubule. The rest of the drug is primarily metabolized into the corresponding sulfide and sulfone metabolites, thus it can potentiate the anticoagulant effect of warfarin. 2. Treatment of Chronic Gout contd … 6/6/2018 14

15. Sulfinpyrazone contd … 2. Treatment of Chronic Gout contd … 6/6/2018 15

16. Sulfinpyrazone contd … In general, if a patient who has hyperuricemia and the recurrence of gouty arthritis attacks ( ie ., <2 attacks/ year), their gout can be controlled by maintaining serum urate levels below the limit of solubility ( ie ., at 6mg/dL or lower ) with drugs that block uric acid synthesis by inhibiting xanthine oxidase or with uricosuric drugs that promote uric acid elimination from the renal tubules. 2. Treatment of Chronic Gout contd … 6/6/2018 16

17. Xanthine Oxidase inhibitors Allopurinol & Oxypurinol Allopurinol is rapidly metabolized to its active isomer oxypurinol , an experimental drug currently in phase III trials, that has half-life of approximately 15 hours. Allopurinol and its active metabolite, oxypurinol , works by effectively competing with the substrate hypoxanthine and xanthine, respectively . 6/6/2018 17

18. Xanthine Oxidase inhibitors contd … Allopurinol & Oxypurinol contd … B’coz of their structural similarity to xanthine , for xanthine oxidase, thus blocking uric acid formation from purine nucleosides, adenine, and guanine. 6/6/2018 18

19. Xanthine Oxidase inhibitors contd … Febuxostat It is a novel and selective , non-purine inhibitor of xanthine oxidase currently awaiting FDA approval for treatment of chronic gout . It is more effective , at a daily dose of 80-120mg, than allopurinol at the commonly recommended daily dose of 300mg in lowering serum urate levels . Unlike allopurinol, it has minimal effects of other enzymes involved in purine and pyrimidine metabolisms. 6/6/2018 19

20. THANK You 6/6/2018 20