PATHOGENESIS
Gouty arthritis is due to the crystallisation and deposition of poorly soluble urate.  Uric acid arises from the metabolism of endogenous purines, either from excess nucleic acids or increased cell death as in certain disease states (cancer).  The purines are metabolised to hypoxanthine which then undergoes further metabolism by the enzyme xanthine oxidase to xanthine, which is again oxidised by xanthine oxidase to uric acid.  The urate may then deposit in soft tissues, such as the skin, as a urate tophus, or in joints.  Crystals of urate in the joint undergo phagocytosis by local synoviocytes.  This releases prostaglandins, interleukin 1, and other inflammatory mediators.  These substances then cause the chemotaxis of leukocytes and macrophages to the joint, magnifying the inflammatory response.  Alternately, the urate may be excreted.  Urate is highly filtered through the glomerulus.  Additionally, it is actively secreted in the tubules.  However, massive tubular reabsorption of urate also occurs so that only about 10% of filtered urate is actually excreted.  If urinary conditions are conducive, the urate may crystallise in the urine, forming urinary urate calculi.

TREATMENT OF GOUTY ARTHRITIS

COLCHICINE
Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale.   Pharmacologically, it is classified as an anti-mitotic.  This is due to its mechanism of action, which is to inhibit tubulin formation and/or polymerisation.  Since tubulin is required in the formation of spindles, it prevents mitosis or cell division.  This action is responsible for many of the side effects of colchicine.  Additionally, tubulin formation and polymerisation are the steps necessary for the migration of inflammatory cells.  Since this is inhibited, the cells cannot undergo chemotaxis to the insulted area, thus inhibiting subsequent inflammation.

Colchicine is indicated for the treatment of acute attacks of gouty arthritis at a dose of 0.5 to 1 mg stat, followed by 0.5 mg q2h until the pain has subsided or until side effects (nausea, vomiting) occur.  Colchicine is also used in the prophylaxis of gouty attacks at a dose of 0.5 mg q.d. to t.i.d.  Note that colchicine has a very narrow therapeutic index with as little as 8 mg in a 24h period resulting in fatality.  For this reason, the use of colchicine in acute attacks should be limited to no more than once per week.

Side effects of colchicine most commonly encountered are diarrhoea, nausea, vomiting, and abdominal cramping.  Less often are alopecia and bone marrow depression.  Acute toxicity of colchicine may include the above plus a burning pain in the throat, bloody diarrhoea, shock, haematuria, oliguria, and CNS depression.  The diarrhoea, bone marrow depression, and alopecia reflect the ability of colchicine to inhibit the replication of these relatively rapidly dividing cells.

NOTE that colchicine therapy inhibits the inflammatory response but does not alter either plasma or urine urate levels.
 

URICOSURICS
These agents increase the urinary excretion of urate by inhibiting its active reabsorption.  NOTE that the urinary excretion of urates is complicated and varies greatly across species.  In humans, it is filtered, secreted, and reabsorbed in great quantities.  Furthermore, a single drug may act to either increase or decrease its excretion by affecting either its secretion or reabsorption, often in a dose dependent manner.  To further complicate the issue, drugs may interact to offset each other's effect or produce a synergistic effect.  However, for the purposes of this course, only those agents that act as uricosurics will be covered.  These agents will decrease plasma urate levels and increase urinary urate levels (thus increasing the risk of renal stones caused by urate crystallisation).

Mechanistically, these drugs compete with and inhibit the active reabsorption of urate from the renal tubules, thus lowering the plasma urate levels, increasing its urinary excretion, and decreasing total body load of urate.

Specific uricosurics:

Probenecid -- may cause allergic dermatitis, GI upset, nephrotic syndrome, aplastic anaemia
Sulphinpyrazone -- higher incidence of GI upset, may also cause rash, kidney damage, aplastic anaemia
Phenylbutazone -- High incidence of GI effects, blood dyscrasia, and  kidney damage, no longer used
Azapropazone -- a PBZ derivative that produces less agranulocytosis
Benzbromarone -- a product currently available in Europe that has fewer side effects.
Uricosurics are most often used when gouty attacks are frequent, there are numerous tophi present, and/or plasma urate levels are high.
ALLOPURINOL
Allopurinol competitively inhibits the enzyme xanthine oxidase.  In addition to inhibiting xanthine oxidase it is metabolised by XO to the active metabolite alloxanthine, which also inhibits XO.  This mechanism reduces the formation of urate, whose precursors are more water soluble and therefore, excretable.  Allopurinol will lower both plasma and urinary concentration of urate.  NOTE that since allopurinol does not eliminate urate it is NOT effective in an acute attack.  In fact, the decreased formation of urate will shift the plasma concentration such that the concentration gradient favours the movement of urate from deposited tophi to the plasma which may actually PRECIPITATE an acute attack early in therapy.  For this reason, uricosurics are often co-administered, at least initially, with allopurinol.

Side effects observed with allopurinol include GI upset (nausea, vomiting, diarrhoea) which are most common, and bone marrow depression, aplastic anaemia, neuritis, vasculitis, nephrotoxicity, hepatotoxicity, and cataracts (due to deposition of allopurinol on the lens).

Allopurinol will interact with the mercaptopurine class of anti-metabolites (azathioprine), inhibiting their metabolism.  Therefore the dose of the drugs may have to be reduced.
 

NSAIDs
Those NSAIDs which are most effective in gouty arthritis include oxaprozin, etodolac, and naproxen.  Any NSAID, by virtue of their analgesic, anti-inflammatory, and uricosuric effects may be useful in gout.  The specific drugs noted above appear to have slightly greater uricosuric activity.  Additionally, the pronounced anti-inflammatory effects of indomethacin, as described previously, make it especially useful in the treatment of acute gouty attacks.  It may be as effective as colchicine without the immediate adverse reactions observed with colchicine.
COMBINATION PRODUCTS
ColBenemid® -- Colchicine and Probenecid -- for prophylaxis of gouty attacks.  This product provides the anti-inflammatory effect of colchicine and the uricosuric effect or probenecid.  Allopurinol is often added to reduce urate synthesis.  This combination is generally reserved for patients with severe gout.

DIETARY INTERVENTION IN GOUTY ARTHRITIS

A diet that is rich in purines may precipitate an attack of gout.  Therefore, as well as drinking copious amount of water to prevent renal calculi, a low-purine diet is desirable in these patients (95% of whom are men).  Food that should be limited or avoided include the following:
Foods that may be eaten sparingly: dried beans, peas, lentils, oatmeal, whole wheat bread, unprocessed grains and cereals, asparagus, mushrooms, cauliflower, and spinach.  Other vegetables that have been associated with gouty attacks include collard, turnip, and mustard greens, broccoli, and Brussels sprouts.  In general meats, seafood, and poultry should be limited to once daily.

Foods that should be avoided (higher in purines and incidence of attack) include: shrimp, scallops,  sardines, anchovies, herring, mackerel, cured pork (ham, bacon, luncheon meats -- both pork and beef based), game meats, and organ meats (liver, kidney, sweetbreads, brains).

Alcohol intake should be limited since it may also precipitate an attack.
 

The overall diet should be relatively rich in carbohydrates and low in fat, avoiding the above foods and replacing meat with milk, cheese, and other sources of dietary protein.

Note that methylated xanthine containing beverages (coffee, tea, chocolate, colas) have NOT been associated with gouty attacks (due to a different metabolic pathway for the methylated xanthines than that for the xanthines).