Gout treatment Flashcards
Causes of gout
increased uric acid in the blood. High urate concentrations 6-7 mg/dl at pH 7.4 causes exceeds its solubility and desposits in and around joints to initiate an attack of gout.
more men have hyperuricemia than women. Women normally show signs of gout post menopause
Origin of uric acid
purine metabolism
Gout causes: idiopathic
renal rentetion of urate.
Unexplained associations (hypertension, obesity, hyperlipidemia)
increased urate production
Gout causes: renal retenion specific
drug effects (diuretics, acetylsalicyclic acid (aspirin). Anticancer drugs can kill large number of cells. Decrease renal secretion of urate by proximal tubular cells
renal damage (glomerular or tubular)
metabolic (lactate, B OH butyrate)
Increased nucleic acid turnover (polycythemias, myeloproliferative disorders)
Gout causes: enzyme defects
decreased hypoxanthine guanine phosphoribosyl transferase
increased phosphoribosylpyrophosphate
Gout causes: local factors
low temperature, low pH, possible tissue factors. Possible local increase in urate concentration.
when crystals of urate deposit, granulocyte infiltrate the area and phagocytize the crystals. Inflammation release of kinins and lysosomal enzymes from granulocytes, cause decreased pH.
Excretion of urate
urate excreted primarily by kidneys and all urate is filtered at the glomerulus.
Most are actively reabsorbed in early proximal tubule. (S1)
Active secretion of urate occurs in mid section of proximal tubule (S2). Inhibition of secretion by weak acids occur here and results in urate retention.
active reabsorption then occurs in late proximal tubule S3 and or distal tubule.
Approximately 10% of urate initially filtered at the glomerulus ends up excreted in urine.
Non drug therapy of gout (3)
avoid obesity: foods high in purine content
avoid dehydration causes increased uric acid and cause urate crystal formation
avoid alcohol: decrease ADH which causes increased UA and additionally decreases pH. Also cause of metabolism to lactic acid
Colchinicine MoA
antimitotic, antiinflammatory properties.
decrease leukocyte mobiliaztion: colchicine binds to microtubular protein and interfers with microtubule function to inhibit mobilization of leukocytes
decreased lactic acid production, decrease release of lysoosomal enzymes from leukocytes
decreased release of histamine from mast cells
decreased release of inflammatory glycoprotein from neutrophils following phagocytosis of urate crystals.
inhibition of leukotrienes synthesis vai inhibition of lipoxygenase pathway
Colchinicine Toxicity
primarily GI distrubances (N/V/D). Chronic use causes in increased risk of aplastic anemia, agrunlocytosis, myopathy and alopecia.
Colchinicine Theraputic uses
treat acute attacks of gout: a drug of choice along with NSAIDS
prophylactic usage to prevent acute attacks of gout in patients with frequent reoccurring attacks of gout.
Allopurinol MoA
antimetabolite of hypoxanthine which inhibits the enzyme xanthine oxidase to UA formation. At low concentrations, allopurinol is a competitive inhibitor, while at high concentrations, it is anon competitive inhibitor of xanthine oxidase. An active metabolite of allopurinol (alloxanthine) is a non competitive inhibitor of xanthine oxidase at all concentration.
preferred in patients with impaired renal function or a history of renal urate stone since allopurinol usage does not increase renal urate levels.
allopurinol is often combined with antineoplastic agents to prevent hyperuricemia. However, allopurinol also inhibits the biotransformation of 6 mercapopurine and the dose of 6 MP should be reduced when combined with allopurinol.
Allopurinol toxicity
uncommon. rash, fever, vasculitis, hepatoxicity bone marrow toxicity
allopurinol gout theraputic uses
chronic gout and secondary hyperuricemia
allopurinol in its start may cause an acute attack of gout due to fluctuations in serum urate levels and the resulting dissolving of deposited urate crystals.
febuxostat MoA
inhibition of xanthine oxidase. A non purine drug that forms a stable complex with xanthine oxidase (reduced or oxidized form) and inhibits enzyme acitvitiy in either state
febuxostat pharmacokinetics
absorption reduced by magnesium hydroxide and aluminium hydroxide antacids. Absorption slightly reduced by food
approved for use in hyperuric patients with gout attacks but is not recommended for patients with asymptomatic hyperuricemia
febuxostat toxicity
liver function abnormalities, nausea, joint pain, and rash
may cause an acute attack of gout. Maybe an increased rate of myocardial infarction or stroke; causal relationship to drug use not fully established.
Rasburicase MoA
recombinant urate oxidase enzyme that catalyzes the oxidation of uric acid into soluble allantoin. Lowers uric acid plasma levels better than allopurinol.
Rasburicase Indications
initial treatment of elevated plasma urate levels in pediatric patients with leukemia, lymphoma and solid tumors who are receiving cancer chemotherapy treatments that will result in cell lysis and hyperuricemia
efficacy can be reduced by antibody production against the ezyme in rasburicase treated paitnets
Rasburicase toxicity
hemolysis in GGPD deficient patients, methemoglobinemia, acute renal failure and anphylaxis have been observed.
Uricosuric agent (probenecid) and sulfinpyrazone MoA
competitively inhibit active reabsorptino of urate by primarily URAT-1 in the proximal tubule of the nephorn to increase urate excretion. Low dose only inhibit active secretion ( a more sensitive system) of urate to cause UA rentention.
Uricosuric agent (probenecid) and sulfinpyrazone Toxicity
GI irritation with aggravation of peptic ulcere (sulfinpyrazone > probenecid)
uricosuric agents increase the UA concentration in urine by inhibiting reabsoprtion. To minimize intrarenal urate stone formation, fluid intake should be increased and the urine can be alkalinized (bicarbonate) when initiating therapy.
Although less frequently than allopurinol, uricosuric agents may precipitate an acute attack of gout and colchicine or an NSAID may be used prophylactically when initiating therapy
Uricosuric agent (probenecid) and sulfinpyrazone: terapeutic
chronic gout
hyperuricemic states
sulfinpyrazone has been shown to decreased platelet aggregation and is an experimental agent in the prophylactic treatment of myocardial infarction
sulfinpyrazone not available in US
Benzbromarone: increases urate excretion without urate retention. maybe used in patients with decreased renal function or paitnets allergic to probenecid or sulfinpyrazone. In use in europe.
NSAIDS
effective to decrease inflammation (excepte acetaminophen) and reduce pain in acute attacks of gout. Although NSAIDS are effective, indomethacin, naproxen and sulindac are the only FDA approved NSAIDS to treat acute attacks of gout. Aspirin should be avoided in gout patients because at normal doses, aspirin decrease urate secretion d at high doses aspirin increase the risk of renal calculi. In acute attacks of gout, NSAIDS or glucocorticoids may be preferred to colchiicine in elderly paitnets with cardiac, renal or GI disease
Glucocorticoids
used for acute gout when other conventional therapies fail to control an acute attak or in elderly paitents where colchicine should be avoided.
