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Flashcards in Gout Drugs Deck (25)
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What is Gout?

Metabolic Disorder characterized by high levels of uric acid in the blood
(hyperuricemia does not always lead to gout but gout is always preceded by hyperuricemia)


Hyperuricemia can lead to deposition of sodium urate crystals in tissues, esp?

Joints and Kidneys


Urate is the end product of what metabolism?

Purine metabolism


The deposition of urate crystals initiates an inflammatory process involving the infiltration of granulocytes that phagocytize the urate crystals. This process generates what?

Oxygen metabolites
---damage tissues --- results in release of lysosomal enzyme that evoke an inflammatory response
(increased production of lactate in the synovial tissues leads to decrease in pH fostering further deposition of urate crystals)


Moving on to treatment of gout, there are two main strategies. What are they?

1. Management of acute attacks of gouty arthritis: control pain, using drugs that limit joint inflammation
2. Long-term management of chronic gout: achieve normal concentrations of plasma urate.


First lets discuss the management of acute gout. This includes agents that suppress leukocyte recruitment and activation. First drugs in acute gout are the NSAIDS. Which NSAIDs are used?

First ling drugs for acute gout
--Indomethacin used most often to treat acute attacks of gout


What NSAID is contraindicated with gout?

--competes with uric acid for the organic acid secretion mechanism in the proximal tubule of the kidney
(increasing uric acid levels by decreasing secretion and therefore excretion)


What are the adverse effects of NSAIDs and acute gout treatment?

1. Bleeding, salt and water retention, and renal insufficiency
2. COX-2 inhibitors are useful because they may decrease the risk of GI bleeding (However dont forget the thrombotic risk)


Next drug used for acute gout is Colchicine, what is the MOA?

Binds to tubulin, inhibiting it polymerization and preventing formation of microtubules
--disrupts cellular functions, such as mobility of granulocytes, thus decreasing their migration to the affected area.
Blocks cell division by disrupting the mitotic spindle
Inhibits synthesis and release of leukotrienes


What is the effectiveness of Colchicine?

Must be administered within 24 to 48 hour of onset of attack to be effective
--relieves pain within 12 hours


What are the adverse effects of Colchicine?

1. Nausea, Vomiting, abd pain, diarrhea
2. Chronic use: myopathy, neutropenia, aplastic anemia and alopecia
3. Not used in pregnancy
4. NSAIDS have replaced this drug due to the diarrhea it causes


The last drug for acute gout treatment are glucocorticoids. What are their MOA and use?

Anti-inflammatory and immunosuppressive effects
Inhibit several steps in the inflammatory response
Systemically given only when:
--acute polyarticular gout or contraindications to other effective therapies


When an acute attack of gout occurs in a single joint and is unresponsive to NSAIDs or colchicine, what is the option?

Depot preparations of glucocorticoid can be injected directly into the site of inflammation


Moving on to Management of Chronic Gout these are agents that lower plasma urate concentration. First is allopurinol, what is the MOA?

Purine Analog
---reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase


What is the use of Allopurinol?

Dissolution of Tophi and prevents development or progression of chronic gouty arthritis by lowering the uric acid concentration in plasma below the limit of its solubility
--uric acid stones disappear


Incidence of acute attacks of gouty arthritis may increase during the early months of therapy with allopurinol as a consequence of the mobilization of tissue stores of uric acid. Therefore what drugs should be coadministered?

During the first 4-6 months of allopurinol therapy
--NSAIDS or colchicine to reduce the chance of precipitating an acute attack of gout


What are the adverse effects of allopurinol?

Well tolerated
Hypersensitivity reactions are the most common adverse reaction
--rare instances the rash may progress to Steven-Johnson syndrome


What are the drug interactions with allopurinol?

Anticancer drug mercaptopurine
Immunosuppressant drug azathioprine
--purine analogues which are metabolized by xanthine oxidase
Inhibition of xanthine oxidase by allopurinol results in toxic levels of coadministered mercaptopruine or azathioprine


Next set of drugs for chronic gout are agents that enhance uric acid excretion (uricosuric agents). What is the MOA of these agents?

Increase the rate of excretion of uric acid
--normally urate is filtered, secreted, and reabsorbed by the kidneys. reabsorption predominates and the amount excreted is about 10%. this process is mediated by a transporter that can be inhibited
Urate reabsorption is its uptake from tubular fluid by a transporter that exchanges urate for either an organic or inorganic anion.
Uricosuric drugs compete with urate for the brush border transporter, thereby inhibiting its reabsorption


The first uricosuric agent is Probenecid, what are some features?

Tx of chronic hyperuricemia
--shifts the balance between renal excretion and endogenous formation of urate
Concomitant colchicine or NSAIDs are indicated early in the course of therapy to avoid precipitating an attack of gout.


Probenecid should be avoided in what patients?

Avoid in gouty patients with nephrolithiasis or overproduction of uric acid
Ineffective in patients with renal insufficiency
Probenecid inhibits the secretion of most anions,the dose of other drugs excreted by this pathway should be reduced.
Do not give aspirin, may antagonisze probenecid


What are the adverse effects of Probenecid?

GI irritation
Hypersensitivity reactions
Liberal fluid intake should be maintained to minimize risk of renal stones


The next uricosuric drug is Sulfinpyrazone, what are some features?

Same mechanism of action as Probenecid
Do not use in patients with renal insufficiency
Adverse Effects:
GI irritaiton
Hypersensitivity reactions
Depression of hematopoiesis occurs
Do not use in patients with underlaying blood dyscrasias
Liberal fluid intake should be maintained


What are the drug interaction with Sulfinpyrazone?

Inhibits warfarin metabolism
--anticoagulant effects of warfarin are increased due to this drug
Certain drug, particularly thiazide diuretics and immunosuppressants agents (cyclosporine) may impair urate excretion and therefore increase gout.


The last drug in chronic gout is an agent that enhances uric acid metabolism, Rasburicase. What are some features?

Uricase: oxidizes uric acid to allantoin and this is excreted by the kidneys
--humans dont have this enzyme
Exogenous uricase can be coadministered with cancer chemotherapy to reduce plasma urate levels rapidly, and thereby preventing renal damage
--recombinant version of Aspergillus uricase, Rasburicase is available. used for initial management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy.

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