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69 Cards in this Set
- Front
- Back
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What does gout result from?
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long-standing hyperuricemia caused by increased production or decreased excretion of uric acid
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What's an acute gout attack look like?
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severe joint pain most often in the distal phalangeal joints
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Why do gout attacks occur?
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a result of an inflammatory reaction to crystals of sodium urate (the end product of purine metabolism in human beings) that are deposited in the joint tissue
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What happens after urate crystals are deposited in a joint?
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Granulocytes infultrate to phago
pH decreases due to high lactate production, leading to further deposition |
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Where else can urate deposit besides joints?
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the interstitial tissues of the kidney = kidney stones.
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What is gout positively correlated with?
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height, body weight, BUN/creatinine, BP, warm climate, DM, hyperlipidemia, alcohol, social status, intelligence!
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Who's gout most common in?
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males (95% of cases) with peak incidence in the fifth decade (840/100,000)
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What are gout levels in kids and when do they rise in boys/girls?
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3-4 mg/dl in children
Elevated in boys after puberty. Levels are lower in women but rise after menopause |
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What's the serum solubility of uric acid?
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7 mg/dL
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Track metabolism to form uric acid? How does that then form urate?
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AMP converted to IMP by adenosine deaminase which then goes to hypoxanthine to xanthine to uric acid, who's enol form converts urate by losing an H at pH 5.4
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What's Adenosine deaminase deficiency associated with?
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severe combined immunodeficiency syndrome.
[self mutilation, spasticity, choreoathetosis, retardation] |
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What does Hypoxanthine-guanine phosphoribosyl transferase do?
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Converts hypoxanthine back to IMP or guanine back to GMP
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What's Hypoxanthine-guanine phosphoribosyl transferase deficiency?
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X-linked, Lesch-Nyhan = hyperuricemic, nephrolithiasis, gout
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What are male and female normal uric acid levels?
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2.4-6.0 mg/dL (female) and 3.4-7.0 mg/dL (male)
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What causes secondary gout?
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↑production urate 2nd to ↑ breakdown blood cells (leukemia)
Chemotherapy or radiation. ↓excretion urate due to alcohol, thiazide diuretics or low doses of aspirin. |
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What's the disease progression in gout?
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ASx hyperuricemia: (> 7 mg/dl)→ Acute Gout→ Intercritical period (remission) → Chronic tophaceous →
Nephrolithiasis |
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What's acute gout?
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Exquisitely painful monoarticular arthritis (mostly 1st metatarsal) w/ 90% untx'd pts having involvement of great toe.
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What's Chronic tophaceous gout?
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Frank gouty arthritis with crytals in the synovium and some degree of erosion of bone.
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What percent of patients get uric acid kidney stones?
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20%
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What's a tophus?
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Chalky mass formed by urate deposition most likely to found in soft tissues, including tendons and ligaments, around joints
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What will you see in the synovium of gout patients?
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sodium urate crystals: observed under polarized light they appear yellow (negatively birefringent)
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What do you see if you see a weakly positive rhomboid crystal on joint aspiration?
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crystal of calcium pyrophosphate = pseudogout
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What's Colchicine?
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an alkaloid of Colchicum autumnale (autumn crocus, meadow saffron) that's is a unique antiinflammatory agent
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Clinical uses of Colchicine?
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It is effective only against gouty arthritis: provides dramatic relief of acute attacks and is effective in prophylaxsis
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Does Colchicine alter uric acid levels?
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No - it does not influence the renal excretion of uric acid or its concentration in blood
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Mechanism of action for Colchicine?
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Interferes with the function of mitotic spindles, causing depolymerization and disappearance of fibrillar microtubules in granulocytes and other motile cells by binding tubulin
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How does Colchicine help with gout?
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Inhibs migration of granulocytes and ↓ activity = ↓ release of lactic acid and proinflamm enzymes which breaks inflam response cycle
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What's the “causative agent” of acute gouty arthritis?
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glycoprotein released by neutrophils after exposure to and ingestion of urate crystals
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What's Colchicine's effect on neutrophilic glycoprotein? What about mast cells?
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Prevents leukocyte elaboration of this glycoprotein.
Inhibits release of histamine-granules from mast cells |
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Absorption and peak concentration of Colchicine?
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rapidly absorbed after oral administration, peak concentrations by 0.5 to 2 hours
Can give IV to avoid GI probs |
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What may explain the prominence of GI issues in Colchicine poisoning?
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Large amounts of the drug and metabolites enter the intestinal tract in the bile and intestinal secretions
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What organs have high Colchicine concentrations? Which have none?
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High conc = kidney, liver, and spleen
Low/none = heart, skeletal muscle, and brain |
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How long does Colchicine stay in the system?
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The drug can be detected in leukocytes and in the urine for at least 9 days after a single intravenous dose.
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Colchicine metabolization?
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Metabolized to a mixture of compounds by CYP 3A4. Most drug is excreted in feces but 10-20% is excreted in urine
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What happens in liver disease patients taking Colchicine?
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hepatic uptake and elimination are reduced and a greater fraction of the drug is excreted in the urine
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What are the most common and earliest effects of Colchicine OD?
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Nausea, vomiting, diarrhea, and abdominal pain
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Do OD symptoms from Colchicine happen right away?
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There is a latent period of several hours between administration and sx onset not altered by dosage or route = may be unavoidable when starting the med.
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What's the clinical use of Allopurinol?
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effective for the treatment of both primary gout and that secondary to hematological disorders or antineoplastic therapy
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Mechanism of action of Allopurinol?
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inhibits the terminal steps in uric acid biosynthesis = rational approach to therapy since overproduction is common
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What exactly does Allopurinol block?
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xanthine oxidase
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What type of block does allopurinol do?
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At low concentrations it's a competitive inhibitor; at high concentrations, it's a noncompetitive inhibitor.
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What's responsible for much of the pharmacological activity of allopurinol?
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Allopurinol's metabolite, xypurinol (alloxanthine), which is a noncompetitive inhib that stays for a long time in tissues
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Kinetics of allopurinol?
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Absorbed rapidly orally, peak plasma conc = 30-60 mins. About 20% is excreted in feces in 48-72 hrs as unabsorbed drug
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Half life and urine excretion of allopurinol?
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T1/2= 2-3 hrs, primarily by conversion to alloxanthine. <10% of single dose or 30% ingested during long-term Tx is excreted unchanged in urine
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What explains the dose-dependent elimination of allopurinol?
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Self-inhibition of the metabolism of allopurinol to alloxanthine
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Half life and excretion of Alloxanthine?
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slowly excreted in urine by net balance of glomerular filtration and probenecid-sensitive tubular reabsorp. T1/2 = 18-30 hrs.
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Name 3 Uricosuric agents.
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Probenecid
Sulfinpyrazone (antiinflam and uricosuric) Benzbromarone (potent, effective, dosed QD) |
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Mechanism of action for the Uricosuric agents?
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increase the excretion of uric acid by blocking its reabsorption for the urine
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Is Probenecid used for acute gout?
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No - not effective for acute attacks of gout and actually can aggravate inflammation if administered during the initial stages.
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Mechanism of action for Probenecid?
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competitively inhibits the active reabsorption of uric acid at the proximal convoluted tubule
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Does Probenecid affect GFR or reabsorption of glucose, arginine, urea, Na, K, Cl, or phosphate?
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Nope
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Metabolism of Probenecid?
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undergoes hepatic metabolism resulting in active metabolites
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Excretion of Probenecid?
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Both parent and active metabolites are eliminated renally by tubular secretion. Parent drug is nearly completely reclaimed via tubular reabsorption.
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Half life of Probenecid?
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dose-dependent: ranges from 3-8 hours for a 500 mg dose and 6-12 hours for larger doses
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Probenecid increases plasma levels of which drugs?
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Benzodiazepines
Cephalosporins NSAIDs Penicillins Salicylates Sulfonamides Sulfonylureas Thiazide diuretics |
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What NSAIDs are approved to tx acute gout?
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indomethacin
naproxen sulindac |
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What are the benefits of NSAIDs txment of gout?
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Faster onset of relief
Less toxic (better tolerated) Widespread use and familiarity Cost |
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Are corticosteroids used to tx gout? Why/why not?
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Not used very often in acute gout because they do not work as well as NSAIDs or colchicine. They are the "last resort" therapy.
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What is Rasburicase used for?
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pediatric management of elevated uric acid in patients receiving chemotherapy for leukemia, lymphoma, or solid tumors and are anticipated to develop tumor lysis syndrome
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When does tumor lysis syndrome occur?
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In malignancies that are highly proliferative and have high tumor burdens, such as lymphomas and leukemias
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What happens in tumor lysis syndrome?
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Metabolic abnorms like hyperphosphatemia, hyperkalemia, hyperuricemia and/or hypocalcemia, and renal dysfunction
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What's a hallmark finding of tumor lysis syndrome?
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Hyperuricemia (generally a uric acid level ≥8 mg/dL)
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Mechanism of action for Rasburicase?
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Converts uric acid to allantoin, which is 5-10 x more soluble in urine than uric acid (produces hydrogen peroxide and CO2)
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How is Rasburicase different than allopurinol?
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It can affect existing plasma uric acid whereas allopurinol affects only the future production of uric acid
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When is Rasburicase contraindicated?
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Pts with G6PD deficiency because they can't break down hydrogen peroxide, a byproduct of rasburicase, which can lead to hemolysis
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Dosing schedule recommended for Rasburicase?
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0.15 or 0.2 mg/kg QD for a maximum of 5 days. First dose should be given 24 hrs before starting chemo.
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Which has higher incidence of adverse effects, Rasburicase or allopurinol?
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Rasburicase
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Common adverse effects with Rasburicase?
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50% of patients have vomiting and fever. 25% have h/a, nausea, abd pain, constipation, and diarrhea. 15% = mucositis and rash.
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Whic is more expensive, Rasburicase or allopurinol?
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Rasburicase (nearly $14,000 versus $2,400 for 5 days of treatment)
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