Week 2 Pharmacology of gout Flashcards
How do irate crystals induce gout inflammation?
- synoviocytes phagocytose urate crystals, and release crystal-induced chemotactic factor LTB4, prostaglandins, and Il-1
- PMNs and macrophages migrate into joint spaces due to chemotactic factors and amplify inflammation
- lactic acid is high and favors promotion of uric acid deposition
List the drugs used for acute attacks of gout and long term therapy of gout.
Acute-relieve inflammation
1. colchicine
2. NSAIDS
Colchicine is preferred for prophylactic therapy and NSAIDS is better for acute attacks
Chronic- decrease hyperuricemia
1. uricosuric agents-increase excretion of uric acid
2. Allopurinol-decrease production of uric acid
Describe mechanism of colchicine.
Two possible explanations
1. inhibits production of crystal induced chemotactic factor
2. binds to tubulin and prevents its polymerization, leading to inhibition of leukocyte migration, superoxide, and lysosomal enzymes
Results: less lactic acid, superoxide, lysosomal enzymes, less production of leukotrienes and prostaglandins
What are adverse effects of colchicine?
- Affects rapidly proliferating epithelial cells in GI
- diarrhea, nausea, vomiting
- can cause transient leukopenia or alopecia
- toxic doses can produce myelosuppression
What NSAIDs would you use in gout and why?
Indomethacin, naproxen, ibuprofen, sulindac
NO ASPIRIN
-RA-prostaglandins have greater role than leukotrienes, and requires long term therapy
-in gout- leukotrienes have greater role, treatment is only for few days. Indomethacin inhibits COX and lipoxygenase
-Aspirin inhibits excretion of uric acid and is contraindicated
What are uricosuric agents used for? List them.
Used in chronic or tophaceous gout
- Probenecid: increases secretion of uric acid
- Sulfinpyrazone: uricosuric acid activity and anti platelet activity
What is the mechanism of uricosuric agents?
- uric acid is at leas 90% reabsorbed by active transport in glomerulus
- renal active transport of uric acid is perform by organic acid transport carrier in proximal tube
- probenecid and sulfinpyrazone compete with uric acid for carrier and inhibit active reabsorption of uric acid
- probenecid increases plasma retention of penicillin-used therapeutically
What are adverse effects uricosuric agents?
- Renal stone formation-predisposition to formation of renal stones due to increased irate excretion. Can administer sodium bicarbonate to maintain urine pH above 6 and maintain urine volume
- Acute gouty attacks -in initial days of treatment due to mobilization of uric acid from tophi. Colchicine used for prophylactic therapy.
What are contraindications for uricosuric agents?
- uric acid overproducers
- patients with uric acid stones in kidney
- patients with lowered GFR-glomeruli filtration rate
- patients on aspirin/salicylates
What is the mechanism of allopurinol?
- analog of hypoxanthine with greater affinity to xanthine oxidase
- inhibits xanthin oxidase and reduce synthesis of uric acid
- therefore concentration of uric acid decreases in both plasma and urine
What are the clinical uses of allopurinol?
- when uricosuric drugs are contraindicated and urinary excretion of uric acid exceeds 600mg/day
- uricosuric agents have allergic effects
- renal urate stones are present
- impairment of renal function - conservative use of allopurinol bc long term therapy may produce skin rashes
- drug of choice for gout associated with intense cancer chemo. only for few days
- proeduct tissues from repercussion injury.
What are drug interactions that allopurinol has?
- avoid combo with uricosuric agents
- need to increase dose of allopurinol bc uricosuric drugs prevents tubular reabsorption of alloxanthine, active metabolite
- allopurinol decreases cyt p450 activity, need to decrease dose of uricosuric drugs - allopurinol increases half life and toxicity of certain drugs
- allpurinol increases toxicity of 6-mercaptopurine by inhibiting its oxidation by xanthine oxidase
