Gout and Hyperuricemia Flashcards
Indomethacin (indocin)
Mechanism of action - Reversible inhibitor of cyclooxygenase. Inhibits prostaglandin synthesis mediating inflammation, fever and pain. Treatment and mediation of symptoms within an hour.
Indications: Acute gouty arthritis (drug of choice), ankylosing spondylitis, osteoarthritis of the hip.
Drug is not likely to be used for long. No specific for gout. Patient has to re-dose for 4 hours.
Adverse reactions: dyspepsia (upset stomach - even patients that don’t have this issue will develop it); pregnancy category B (not recommended for 3rd trimester; inhibition of platelet aggregation.
Serious adverse reactions (toxic) - Gastric ulceration and bleeding (Black box warning). Cardiovascular or cerebrovascular event if the drug is used repeatedly long term (Black box warning) (Myocardial infarction, Stroke, Hypertension), Nephrotoxicity, hepatoxicity, hypersensitivity.
Allopurinol
Treatment of long-term Gouty Arthritis: Decreasing uric acid production or increasing excretion
- inhibits uric acid synthesis
Mechanism of action - Inhibits xanthine oxidase required for uric acid biosynthesis. Precursors xanthine and hypoxanthine are more water soluble than uric acid. (doesn’t matter mechanistically in patient)
Indications
Drug of choice in treatment of chronic tophaceous gout, hyperuricemia of gout, hyperuricemia secondary to other conditions
Has to be biotransformed to alloxanthine (oxypurinol) activated by xanthine oxidase.
Adverse effects - Hypersensitivity reactions (rashes - cannot use for acute attack; patient must be stable) Gout flare-up (concurrent treatment with colchicine and indomethacin recommended instead)
(drug interactions) Mercaptopurine (anticancer) or azathioprine (immunosuppresive) Allopurinol inhibits inactivation of these cytotoxic agents. Requires dosage reduction to ¼ normal dose (dictated by WBC and bone marrow function). Patient will likely die due to bone marrow disruption.
Febuxostat (Uloric)
Chemically different from allopurinol but pharmacodynamically similar in mechanism and toxicity - inhibits xanthine oxidase.
Advantages - Possibly more effective in lowering uric acid levels, once daily dosing.
(drug interactions) Mercaptopurine (anticancer) or azathioprine (immunosuppresive) Allopurinol inhibits inactivation of these cytotoxic agents. Requires dosage reduction to ¼ normal dose (dictated by WBC and bone marrow function). Patient will likely die due to bone marrow disruption.
Probenecid
Uricosuric agents - for hypoexcreters
Mechanism of Action - Inhibits urate-anion exchanger in proximal tubule, inhibiting irate reabsorption. At low doses they block proximal tubular secretion of uric acid. (This effect may make acute gouty arthritis worse by increasing serum uric acid levels) - may want to pretreat with Indomethacin
Adverse reactions - Precipitation of acute gouty arthritis and stone formation. Due to low dosing. Serious reactions (more common than other drugs) - Bone marrow depression, hypersensitivity. Pregnancy category B.
Drug interactions - Interferes with renal secretion (NSAIDS, penicillin, sulfonamides). Could increase gouty arthritis.
Sulfinpyrazone
Uricosuric agents - for hypoexcretor
Mechanism of Action - Inhibits urate-anion exchanger in proximal tubule, inhibiting urate reabsorption. At low doses they block proximal tubular secretion of uric acid. (This effect may make acute gouty arthritis worse by increasing serum uric acid levels) - may want to pretreat with Indomethacin
Adverse reactions - Precipitation of acute gouty arthritis and stone formation. Due to low dosing. Serious reactions (more common than other drugs) - Bone marrow depression, hypersensitivity. Pregnancy category C
Drug interactions - Interferes with renal secretion (NSAIDS, penicillin, sulfonamides) Could increase gouty arthritis)
Acute Gouty Arthritis
Rapid onset of pain, swelling and inflammation
First metatarsophalangeal joint (great toe) most common followed by insteps, ankles, heels, knees, wrists, fingers and elbows.
Crystal formation triggers vasodilation, increased vascular permeability and chemotactic activity form polymorphonuclear leukocytes. Uric acid crystal phagocytosis by leukocytes triggers cel lysis and inflammatory response.
Lasts between 3-14 days (untreated)
Uric Acid Nephrolithiasis
Occurs in 10% to 20% of gout patients.
Most common when uric acid in urine is excessive >1100mg/day uric acid.
Urine is acidic (treat through alkalinize urine)
Urine is concentrated (add water to diet)
Crystallize uric acid in urine; can be destructive to tissues.
Tx: alkalinization of urine by sodium bicarbonate or acetazolamide, avoid purine-containing foods, Allopurinol, hydration 2-3L/day
Idealistically you will need to examine the patient mechanistically - overproducer or underexcreetor
Gouty Nephropathy
Acute uric acid nephropathy - blockade of urine flow secondary to uric acid crystal formation in collecting duct and ureters.
Chronic uric acid nephropathy - long-term deposition of uric acid crystals in renal parenchyma. Triggers localized inflammatory response, may precipitate hypertension, nephrosclerosis, and even renal failure.
Colchicine
Treatment of Acute Gouty Arthritis: Termination of inflammatory process
Mechanism of Action - bind tubulin causing depolymerization - disrupting mobility of granulocytes to affected area (first step in preventing white cells from moving to area). Inhibits the synthesis and release of inflammatory leukotrienes (decreasing attraction of neutrophils to affected area).
Anti-Inflammatory activity is VERY specific for gout.
Alleviates pain of acute gouty arthritis within 12 hours. (slow onset - better for recurrent attacks)
Pregnacy D category
Adverse: Abdominal pain, severe diarrhea, bone marrow toxicity (often limiting therapeutic use to <7 days)
Non-steroidal anti-inflammatory drugs
Treatment of Acute Gouty Arthritis: Termination of inflammatory process
Glucocorticoids
Treatment of Acute Gouty Arthritis: Termination of inflammatory process
Asymptomatic Hyperuricemia
There is some interest in treating asymptomatic hyperuricemia in patients with risk of coronary artery disease as hyperuricemia is often associated with increased risk of renal impairment in patients with hypertension and coronary artery disease
