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Flashcards in GOUT Deck (13):
1

PATHOPHYSIOLOGY OF GOUT

-gout is a metabolic disorder cahracterized by HIGH LEVELs of URIC ACID in the blood

-HYPERURICEMIA can lead to deposition of sodium urate crystals in tissues 

--> Hyperuricemia does NOT always lead to gout, but gout is always preceeded by hyperuricemia

-in humans, sodium urate is the end product of purine metabolism

-the deposition of urate crystals initiates an inflammatory process

2

2 MAIN STRATEGIES for Tx of GOUT

1) Management of ACUTE ATTACKS of GOUTY ARTHRITIS

--> goal is to CONTROL PAIN

2) LONG-TERM MANAGEMENT of CHRONIC GOUT

--> goal is to ACHEIVE NORMAL CONCENTRATIONS OF PLASMA URATE

 

3

ACUTE GOUT DRUGS

DRUGS THAT SUPPRESS LEUKOCYTE RECRUITMENT + ACTIVATION

1) NSAIDS

2) COLCHICINE

3) GLUCOCORITCOIDS

4

NSAIDS: WHICH DRUG USED?

-first-line drugs for ACUTE GOUT

-INDOMETHACIN is the most popular

Note: ASPIRIN IS CONTRINDICATED, b/c it competes with uric acid for the oragnic acid secretion mechanism in the proximal tubule of the kidney 

ADVERSE EFFECTS: bleeding, salt and water retention, and RENAL INSUFFICIENCY

-COX-2 selective inhibitors may decrase the risk of GI bleeding, but concerns about adverse CV effects limit their long-term use 

5

COLCHICINE

ACUTE MANAGEMENT OF GOUT

Cole's CINEmax experience --> he's a dentist so has the moviestar teeth --> when cleaning teeth, uses the TUBES --> binds tubes --> inhibits polymerization of microtubules --> disrupts mobility of GRANULOCYTES --> but cole always complains about his shits --> his side effect is DIARRHEA --> has been replaced by NSAIDS sorta

MOA:

1) binds to TUBULIN, inhibiting its polymerization and preventing formation of microtubules

--> disrupts mobility of granulocytes, decreasing their migration into the affected area

2) colchicine BLOCKS CELL DIVISION by DISRUPTING the MITOTIC SPINDLE

3) Inhibits synthesis and release of leukotrienes

AEs: nausea, vomiting, abdominal pain, diarrhea

-chronic administration may cause myopathy, neutropenia, aplastic anemia, and alopecia

-should NOT be used in pregnancy 

-should be used with CAUTION in patients with HEPATIC, RENAL, or CV disease

Note: NSAIDS have replaced colchicine because of the troublesome DIARRHEA associated with colchicine therapy

6

GLUCOCORTICOIDS

ACUTE GOUT TREATMENT

-have ANTI-INFLAMMATORY and IMMUNOSUPPRESSIVE effects

-when an acute attack of gout occurs in a single joint and is unresponsive to NSAIDS, or colchicine,

DEPOT PREPARATIONS OF A GLUCOCORTICOID can be injected directly into the site of inflammation

7

ALLOPURINOL

CHRONIC GOUT: AGENTS THAT DECREASE PLASMA URATE CONCENTRATION

MOA: is a PURINE analog that INHIBITS XANTHINE OXIDASE

--> facilitates the dissolution of tophi by lowering uric acid plasma concentration 

-the incidence of acute attacks of gouty arthritis may increase during early months of therapy with allopurinol --> is d/t MOBILIZATION of TISSUE STORES of uric acid 

-->**** an NSAID or colchicine is coadminsitered during the first 4-6 months of allopurinol therapy to reduce the chance of an acute gout attack ****

8

ALLOPURINOL ADVERSE EFFECTS

ALLOPURINOL --> see steven johnson syndrome b/c is the most PURE white names (along with AL). White people often get skin rashes/hypersensititivy reactions

-is well tolerated in most patients

-get HYPERSENSITIVITY REACTIONS, especially SKIN RASHES, are the most common adverse effects

-in rare instances the rash may progress to STEVEN-JOHNSON SYNDROME

--> all patients who develop a cutaneous reaction to allopurinol should discontinue the drug 

9

ALLOPURINAL DRUG INTERACTIONS

1) MERCAPTOPURINE (anticancer drug) and

2) AZATHIOPRINE (immunosuppresent) are both PURINE ANALOGUES which are metabolized by XANTHINE OXIDASE

--> inhiibitoin of xanthine oxidase by allopurinal can result in TOXIC LEVELS of coadminstered mercaptopurine or azathioprine

-therefore, DOSE REDUCTION of these drugs is required

10

PROBENECID

 

URICOSURIC AGENT

PROBENICID --> is the PRO BENDER --> bends around in the kidneys and competes with the urate for transport exchanger, inhibiting urate's absorption

-urate is filtered, secreted, and reabsorbed by the kidneys

-reabsorption predominates: the amount excreted is 10% of that filtered

-this process is mediated by a SPECIFIC TRANSPORTER

--> the transporter EXCHANGES URATE FOR AN ANION, thus uricosuric drugs compete with urate for the transporter, therby inhibiting its reabsorptoin 

NOTE: Colchicine or NSAIDS are give nearly in the therapy to avoid precipitating an attack of gout

-probenecid should nOT be used in gouty patients with

  • 1) NEPHROLITHIASIS or
  • 2) with OVERPRODUCTION of URIC ACID

ADVERSE EFFECTS: KNOW THESE!!!

1) mild GI irritation

2) hypersensitivity reactions; usually mild. Serious hypersensitiviy is extremely rare --> RASH + FEVER!!!!  (occurs more with this drug than sulfinpyrazone, so may ask it here) 

-a liberal fluid intake should be maintained to minimize risk of renal stones **

11

SULFINPYRAZONE

URICOSURIC AGENT

-urate is filtered, secreted, and reabsorbed by the kidneys

-reabsorption predominates: the amount excreted is 10% of that filtered

-this process is mediated by a SPECIFIC TRANSPORTER

--> the transporter EXCHANGES URATE FOR AN ANION, thus uricosuric drugs compete with urate for the transporter, therby inhibiting its reabsorptoin 

NOTE: Colchicine or NSAIDS are given early in the therapy to avoid precipitating an attack of gout

AE: KNOW THESE!!!!! 

1)GI irritation

2)HYPERSENSITIVIY REACTIONS, usually a RASH WITH FEVER, occur less fequently than with probenecid

3) DEPRESSION OF HEMATOPOIESIS

4) Should NOT be used by patients with UNDERLYING BLOOD DYSCRASIAS

--> a liberal fluid intake should be maintained to minimize risk of renal stones 

12

SULFINPYRAZONE DRUG INTERACTIONS

-inhibits WARFARIN METABOLISM

sulfinPYRAzone --> is a PYRO that's why it inhibits the WARfarin 

13

RASBURICASE

RASBURICASE --> comes from RASPERBERRY CASES (aspergillosis) --> oxidizes uric acid to ALLANTOIN (all ant's all ove rthe raspberry bush) 

-most mammals other than humans express the enzyme URICASE

--> this enzyme oxidizes uric acid to ALLANTOIN, a soluble compound that is easily excreted by the kidney 

-in cancer chemotherapy, the rapid lysis of tumor cells can release free nucleotides and increase plasma urate levels --> can lead to massive renal injury

-EXOGENOUS URICASE can reduce plasma urate levels and prevent renal damage

-allopurinol can also be used to prevent this component of tumor lysis syndrome 

-a recombinant versin of ASPERGILLUS URICASE is available in the US