Gout treatment

Question 1

Causes of gout

Answer 1

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

Question 2

Origin of uric acid

Answer 2

purine metabolism

Question 3

Gout causes: idiopathic

Answer 3

renal rentetion of urate.

Unexplained associations (hypertension, obesity, hyperlipidemia)

increased urate production

Question 4

Gout causes: renal retenion specific

Answer 4

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)

Question 5

Gout causes: enzyme defects

Answer 5

decreased hypoxanthine guanine phosphoribosyl transferase

increased phosphoribosylpyrophosphate

Question 6

Gout causes: local factors

Answer 6

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.

Question 7

Excretion of urate

Answer 7

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.

Question 8

Non drug therapy of gout (3)

Answer 8

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

Question 9

Colchinicine MoA

Answer 9

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

Question 10

Colchinicine Toxicity

Answer 10

primarily GI distrubances (N/V/D). Chronic use causes in increased risk of aplastic anemia, agrunlocytosis, myopathy and alopecia.

Question 11

Colchinicine Theraputic uses

Answer 11

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.

Question 12

Allopurinol MoA

Answer 12

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.

Question 13

Allopurinol toxicity

Answer 13

uncommon. rash, fever, vasculitis, hepatoxicity bone marrow toxicity

Question 14

allopurinol gout theraputic uses

Answer 14

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.

Question 15

febuxostat MoA

Answer 15

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

Question 16

febuxostat pharmacokinetics

Answer 16

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

Question 17

febuxostat toxicity

Answer 17

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.

Question 18

Rasburicase MoA

Answer 18

recombinant urate oxidase enzyme that catalyzes the oxidation of uric acid into soluble allantoin. Lowers uric acid plasma levels better than allopurinol.

Question 19

Rasburicase Indications

Answer 19

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

Question 20

Rasburicase toxicity

Answer 20

hemolysis in GGPD deficient patients, methemoglobinemia, acute renal failure and anphylaxis have been observed.

Question 21

Uricosuric agent (probenecid) and sulfinpyrazone MoA

Answer 21

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.

Question 22

Uricosuric agent (probenecid) and sulfinpyrazone Toxicity

Answer 22

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

Question 23

Uricosuric agent (probenecid) and sulfinpyrazone: terapeutic

Answer 23

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.

Question 24

NSAIDS

Answer 24

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

Question 25

Glucocorticoids

Answer 25

used for acute gout when other conventional therapies fail to control an acute attak or in elderly paitents where colchicine should be avoided.