Pharmacology of gout

Question 1

Pathogenesis and principles of gout Rx

Answer 1

• Recurrent hyperuricemia leads to deposition of urate crystals in tissues (especially joints)
• The urate crystals are phagocytosed by synoviocytes, which release crystal-induced chemotactic factor (CICF), LTB4, and other chemokines (prostaglandins, IL1) as wells as lactic acid
• Drugs that relieve inflammation (used during acute attacks): colchicine, NSAIDs
• Drugs that decrease hyperuricemia (long-term Rx of gout): uricosuric agents (increase excretion of uric acid), allopurinol (decrease production of uric acid)

Question 2

Colchicine

Answer 2

• Specific for relieving pain and inflammation w/in 12-24 hr
• No changes in uric acid metabolism/excretion
• No inhibition of COX/LOX: no analgesic or antipyretic activity
• Mechanism of action: high concentrations in PMNs, inhibits the production of CICF, and also binds to tubulin and prevents its polymerization
• Results in inhibition of leukocyte migration, phagocytosis, and secretion. Also less release of lactic acid, superoxide, lysosomal nzs, less production of leukotrienes and prostaglandins

Question 3

Adverse affects of colchicine

Answer 3

• Affects rapidly proliferating epithelial cells in GI tract (blocks tubulin polymerization and thus mitosis)
• Leads to diarrhea, nausea, vomiting
• Can cause transient leukopenia and alopecia
• Toxic doses can produce severe BM depression

Question 4

NSAIDs in gout Rx

Answer 4

• NSAID selection for gout Rx different from RA Rx
• Most commonly used is Indomethacin, and the one that is NOT used is aspirin
• In gout the major role in inducing inflammation is LOX (for RA its COX), LOX produces LTB4 (a leukotriene)
• Aspirin only blocks COX, whereas most other NSAIDs block both COX and LOX
• Aspirin is good for RA b/c its safe for long-term use and blocks only COX (major player in RA), but is not good in gout b/c it does not block LOX (major player in gout) and it decreases uric acid excretion
• Indomethacin is good for acute gout b/c it blocks LOX (as well as COX)

Question 5

Using NSAIDs vs colchicine

Answer 5

• For acute attacks: Indomethacin > Colchicine b/c Indomethacin are safe for short periods of time (a few days) at high doses (colchicine is toxic at high doses)
• Prophylaxis: Colchicine > Indomethacin b/c colchicine is good @ low doses for long periods of time, where as Indomethacin is toxic over long periods of time

Question 6

Uricosuric agents 1

Answer 6

• Probenecid (and sulfinpyrazone) is used in tophaceous (chronic) gout, for pts that are not hyper excreting uric acid (<600mg/day, over this and they should take allopurinol)
• Mechanism: Uric acid is 100% filtered by kidney, then 90% of it is reabsorbed into the blood in the tubules (a small amount is secreted from the blood straight to tubule)

Question 7

Uricosuric agents 2

Answer 7

• There is active transport of the uric acid as it moves from the tubule to the blood (or vice versa), performed by organic acid transport carrier (OATC)
• Probenecid is an organic acid and therefore impairs the active transport (primarily the reabsorption of uric acid into the blood) via competition
• Result: plasma uric acid decreases and urine uric acid increases

Question 8

Other effects of probenecid and sulfinpyrazone

Answer 8

• Sulfinpyrazone also acts as antiplatelet agent (is chosen if that is needed)
• Switch to allopurinol if not working or allergic rxn, switch to uricosuric agents if allopurinol hypersensitivity rxn
• They also interfere w/ excretion of other drugs that utilize the renal OATC system: indomethacin, MTX, ampacillin and penicillin
• But for penicillin the opposite effect happens: there is increased plasma concentration of penicillin when using probenecid
• Therefore it is used conjunctively to Rx gonorrhea

Question 9

Adverse effects and contraindications of uricosuric agents

Answer 9

• Renal stone formation: w/ increase irate excretion there is a high chance of forming renal stones
• Acute gouty attacks: during initial day of Rx the mobilization of uric acid from tophi can result in acute attacks (use colchicine for prophylaxis)
• Contraindications: uric acid overproducers (>600mg/day-> use allopurinol), pts w/ uric acid stones, pts w/ lowered GFR, pts on aspirin (salicylate interferes w/ uricosuric agents function)

Question 10

Allopurinol

Answer 10

• Inhibits uric acid synthesis in chronic (tophaceous) gout by inhibiting the nz xanthine oxidase (XO)
• XO produces uric acid, but allopurinol and its active metabolite alloxanthine are both analogs of hypoxanthine, thus they competitively inhibit XO and reduce synthesis of uric acid
• Alloxantine has a long t1/2, and the result is a decrease in both uric acid in plasma and urine

Question 11

Clinical uses of allopurinol

Answer 11

• Used when uricosuric drugs are contraindicated, pt is allergic to uricosuric agents
• Used if renal urate stones are present, pt has impaired renal function
• Most important: when pt uric acid excretion exceeds 600 mg/day
• Long term Rx may produce skin rashes (hypersensitivity syndrome) which can get worse, so first line of Rx for non-hyperexcreeters is uricosuric agents

Question 12

Allopurinol drug interactions

Answer 12

• Acute gout attacks occur w/in the first mo, colchicine should be give for prophylaxis
• Combining allopurinol w/ uricosuric agents is avoided
• Uricosuric agents increase excretion of allopurinol (must increase dose)
• Allopurinol decreases the activity of CYP450, increasing the T1/2 and toxicity of uricosuric drugs (must decrease dose)
• Allopurinol also increases t1/2 and toxicity of other drugs by decreasing the activity of mixed function oxidases
• Allopurinol increases the toxicity of 6-mercaptopurin by inhibiting its oxidation by XO