Gout is the result of increased serum uric acid levels, which results in uric acid crystal deposition in the joints.  High levels can be caused by over-production or under-excretion.

Uric acid crystals damage the synoviocytes, which release prostaglandins and leukotrienes.  PMNs and macrophages are recruited, and an inflammatory process is ignited in the joint.

To stop acute attacks, use anti-inflammatory drugs (NSAIDS, glucocorticoids)

Indomethacin or prednisone are the most commonly used.

If NSAIDs/Glucocorticoids are ineffective or contraindicated, colchicine may also be tried.

To prevent gouty attacks, give drugs that will lower the uric acid levels! 

Recall that when already in an attack, symptomatic relief is given with anti-inflammatory drugs, but these do not correct the origin of the attack (high urate).

To prevent future attacks, lower the urate levels with allopurinol or the excretion promoters probenecid/sulfinpyrazone

Colchicine is a mitotic poison that inhibits microtubule polymerization.  This inhibits normal leukocyte function and migration.  The release of chemotactic factors is also impaired because of impaired vesicle transport across the microtubules.

However, remember that colchicine has a low benefit/toxicity ratio, so it is really only used to terminate acute gout attacks if NSAIDs or glucocorticoids are ineffective.

Colchicine blocks microtubule polymerization and can result in diarrhea and myelosuppression.

In fact, diarrhea (because of decreased gut epithelial turnover) is the first sign of colchicine toxicity.  Stop colchicine if this occurs!

Sulfinpyrazone and probenecid inhibit uric acid re-uptake by the proximal convoluted tubule, thereby increasing its excretion.

(normally 90% of uric acid in the tubule is reabsorbed)

Allopurinol is a competetive inhibitor of xanthine oxidase.  This enzyme catalyzes two steps in the formation of uric acid.  Therefore, allopurinol inhibits uric acid synthesis.

This decreases uric acid serum levels, which is beneficial for tophaceous gout, as it will promote the dissolution of tophi!

Allopurinol is converted to an active metabolite, alloxanthine.  (Both allopurinol and alloxanthine inhibit xanthine oxidase)

Alloxanthine has a very long half life (20hrs)

Azathioprine and mercaptopurine are also metabolized by xanthine oxidase.  (azathioprine is converted into mercaptopurine)

Because allopurinol is a competetive inhibitor of xanthine oxidase, azathioprine and mercaptopurine will not be metabolized as readily and can reach toxic levels if their dose is not decreased!

You must wait 4-6 weeks between the time of the acute attack and the beginning of chronic therapy.  This is because starting the treatment right away will only worsen the inflammatory process:

As the blood urate levels decrease due to chronic therapy, the uric acid crystals will leave the joints, causing further damage and aggravation to the inflamed region.  Nobody wants uric acid crystals scraping across an already inflamed joint!

NSAIDS, glucocorticoids, and DMARDS are used to treat rheumatoid arthritis

DMARDS= disease modifying antirheumatic drugs

Methotrexate is a DOC for rheumatoid arthritis.

Methotrexate is an antimetabolite that is a folic acid look-alike.  It is polyglutamated in the cell and then competetively binds dihydrofolate reductase (DHFR).  DHFR is a critical enzyme in purine and pyrimidine synthesis.  It is responsible for converting folate into the one-carbon carrier tetrahydrofolate (THF).  Lymphocyte proliferation is inhibited.

in cancer chemotherapy, methotrexate is toxic to the bone marrow.  In levels used here, the toxicities are much less.  Additionally, liver enzyme levels may rise while taking methotrexate.

Probenecid inhibits methotrexate secretion, causing increased levels.

Salicylates and Sulfonamides also increase methotrexate levels by displacing the drug from plasma proteins.

Leflunomide is an immunosuppressive drug that is used in rheumatoid arthritis.  It prevents lymphocyte proliferation by inhibiting dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis.  The resulting inhibition of DNA and RNA synthesis leads to depression of T-Cell and mononuclear function.

It is considered a DOC for rheumatoid arthritis (an alternative to methotrexate)

What are Gold Salts used for?

Gold Salts may be used in the treatment of Rheumatoid Arthritis.  They inhibit phagocytic activity, histamine release, and cytokine action.  However, it takes 3-6 months for their effects to occur!

The gold salts are Auranofin, Aurothioglucose, and Sodium Aurothiomalate

Recall that long term use of glucoids carries with it serious adverse effects.  Because of this, the preferred uses of glucocorticoids is limited to induce remission while starting other DMARDs with more delayed action.  (glucocorticoids produce their effect faster than other DMARDs). 

Glucocorticoids can also be used for short-term therapy during flare ups.

Continuous use of glucocorticoids should be done at low doses (background therapy added to other drugs like NSAIDs/DMARDs)

Hydroxychloroquine is an antimalarial drug that is also used in SLE and Rheumatoid Arthritis therapy.  It is one of the less toxic DMARDs and inhibits leukocyte function including phagocytosis, chemotaxis, and superoxide production.

Side effects= Visual! and GIT

Like most DMARDs, it has a slow onset of action... in this case 6 months!!

These three drugs are antibodies against TNF-a.

Etanercept is a fusion protein of TNF-a receptors and an Fc fragment of IgG.  (it has receptor in the name)

Infliximab is a chimeric antibody (mouse and human) against TNF-a.  It is best used in combination with MTX therapy

Adalimumab is another IgG monoclonal antibody against TNF-a

What are adverse effects of TNF-a blocking agents.

TNF-a blocking agents can cause serious infections an sepsis.  Opportunistic infections may also result. 

Additionally, increased risk of lymphoma has also been reported.

You must do a PPD and get a chest x-ray before beginning this therapy because it places patients at great risk for TB re-activation!

Anakinra is the IL-1 receptor antagonist

It competetively inhibits IL-1 binding

(It's adverse effects are similar to the TNF-a blockers: infections and lymphomas)

Over producers of uric acid, because this will lead to greatly increased uric acid levels in the urine, predisposing to kidney stones.

Anyone with renal impairment because the action of probenecid/sulfinpyrazone will be impaired

Anyone that is predisposed to renal stone formation

Methotrexate is given to patients on infliximab to prevent antibody development against infliximab.

Recall that infliximab is a chimeric antibody against TNF-a