PHARMACOLOGY OF GOUT AND ITS LEARNING OBJECTIVES

1) DESCRIBE THE FACTORS WHICH CONTRIBUTE TO THE DEVELOPMENT OF

HYERURICEMIA AND GOUT
Hyperuricemia (high serum urate levels) does not necessarily lead to gout, but MANY of the
patients with gout have hyperuricemia. Remember in ICM, they said that about 1/3 of the patients
with gout had normal serum levels. Where hyperuricemia is high serum urate levels, gout is
considered a clinical syndrome due to the deposition of sodium urate crystals in joints. This can
lead to acute inflammation and sudden onset arthritis. The sites of interest are the big toe, feet,
ankles, knees, and hands.
If the underlying conditions are not treated, then symptoms, episodes, and complications become
more prominent. For instance, urate deposits can be seen in the soft tissue. These urate deposits
are called tophi and are related to hyperuricemia.

Causes of Sustained Hyperuricemia

Division 1: Increased Urate Production
Genetic Causes
Enzyme Mutations
Acquired Causes
Myeloproliferative disorder
High Purine Intake- Meats, Yeast, Beans
Obesity and High TG
Alcohol consumption
Fructose Consumption
Exercise

Division 2: Reduced Urate Excretion (90% here)

Genetic Causes
Reduced clearance or fractional excretion
Acquired Causes (Potentially reversible)
Intrinsic Renal Disease-Not reversible
Drugs (Thiazides, Low dose salicylate)
Metabolites (Lactate,Ketones,Angiotensin,ADH)
Renal Cause- HTN, P-V contraction, Obesity
Reduced Urine Flow x< 1ml/min

Causes of Acute and Chronic Gout

Acute Gouty Arthritis

Chronic Gout

Joint Trauma, Surgery, Starvation or Dehydration,

Acidosis, Alcohol or Purine Ingestion, Medications
that increase or lower serum urate levels, and
sudden changes in urate concentrations.
Depositions of Urate in Joints and Tissues. This is
especially evident in the kidneys and urinary tract.
There is also usually both high serum levels of
urate, as well as high total body pools.

Summary
-

Acute gout Use NSAID, injected steroid or colchicines. Must be followed by chronic treatment to
prevent recurrences, normalize serum levels, reduce tophi formation, and limit renal involvement.
- Chronic gout Use a Uricosuric and/or Allopurinol
- Initial treatment of chronic Add colchicines or NSAID to prevent acute attack
- Do not start chronic therapy until acute attack has subsided

Gout Drugs
Colchicine

o
o

o
o

Probenecid (Uricosuric)

o
o
o
o
o
o

Allopurinol

o
o

o
o
o
o
o

What: Anti-mitotic
Mechanism Inhibits Leukocyte entry into affected site, as well as phagocytosis
of urate by neutrophils therefore inhibiting release of inflammatory mediators

Breaks the inflammatory cycle

Wont Affect serum urate levels

Not a typical anti-inflammatory works only with gout

Adverse Effects

GI toxicity: Anti-mitotic effect on gut (80% with D/Discomfort)

Dose reduce with elderly, renal or liver disease

Administration

Oral: Low dose to Prevent Toxicities

If given IV there is no GI effects but will increase the risk of bone

marrow depression, liver, CNS, and Kidney Injury
Used frequently: At a low dose for prophylaxis- 6-12 months to prevent
recurrence of acute attack. Can also be useful in pseudo-gout due to Ca2+ stones.
Contraindicated: IBD, Renal, or Hepatic Failure
Works best with impaired excretion of urate; leads to shrinkage of tophi
Mechanism- Reduce PCT reabsorption of urate and enhance renal excretion.
Paradoxical effect at sub therapeutic levels; interferes with excretion of urate and
will cause hyperuricemia. This is overridden with therapeutic doses
Administer: With fluids and Possibly alkalinize the urine
C.I.: GI Ulcers, Urate Nephropathy, or Nephrolithiasis
Use with care with renal impairment especially with a GFR <50
Salicylates will interfere so do not co-administer
Inhibit formation of urate (Overproduction Division): x < 6 mg/dl
Less Preformed Purines and De novo synthesis, Lowers Hyperuricemia, reduces
nephropathy and urate deposit by the following (3) mechanisms

Inhibits xanthine oxidase prevents formation of uric acid

The increased level of xanthine/hypoxanthine are not a

problem because they are very soluble

Inhibits de novo purine synthesis

Formation of ribotides by allopurinol blocks synthesis by false

feedback inhibition

Oxypurinol derivative

Allopurinol is an active drug and also a prodrug

Converted into oxypurinol which actually works better than

allopurinol. Long half-life responsible for action
Prevents tophi formation and Decreases likelihood of acute attacks
Used prophylactically with lymphoma/leukemia to decrease the likelihood of
excessive formation of uric acid (Secondary Gout)
May also be Useful in Pseudo-gout ( Calcium Oxalate stones)
Do not administer during acute attacks, but Co-administer with colchicines or
NSAIDs to prevent acute attacks
Toxicities

Skin related and very frequent (3%)-Use caution in patients with

dermatitis

Also GI, Hepatitis, Fever, BM suppression

20% cannot tolerate this and 5% discontinue it

Will increase levels of 6-mercaptopurine and azathioprine because both

of these are metabolized by xanthine oxidase, so reduce their doses

Dose reduce with renal problems

NSAIDS
Indomethacin and Naproxen

o
o
o
o
o

Does Not: It does not affect Urate Synthesis and/or excretion.

Not Recommended: Aspirin- Actually can aggravate gout because at low doses it
inhibits urate secretion
Administration- High doses for the 1st few days and then dose is lowered. May
also be used in the first months of chronic treatment to prevent acute attacks
Preferred in treatment of Acute Gout because they are less toxic than colchicines
Special Care: Elderly, Renal problems due to decreased sodium excretion, and
PUD patients