GOUT

Key terms
Hyperuricaemia
Gouty arthritis
Inflammation
Purines
Uric acid
Xanthine oxidase
• Gout is an arthritic syndrome caused by an
inflammatory response to crystals of monosodium
urate monohydrate deposited in joints, renal
tubules, and other tissues.
Causes
1. Reduced elimination may be caused by an inability
to excrete uric acid properly.
2. Overproduction associated with a primary defect in
purine metabolism.eg. a deficiency of the enzyme
phosphoribosyl transferase, or caused by certain
hematologic disorders, leukemias, cancer
chemotherapy, or effects of ethanol.
• In humans, uric acid is the end product of the
degradation of purines.
• Because uric acid serves no known physiologic
purpose, it is regarded as a waste product.
• Hyperuricemia refers to abnormally high levels of
circulating uric acid (urate), which are >6.8–7.0
mg/dL.
• Humans have higher uric acid levels than other
mammals because they do not express the enzyme
uricase, which converts uric acid to the more soluble
allantoin.
Metabolism of uric acid
Inflammation in a gouty joint
• Deposition of urate crystals in synovial fluid results in:-
• Inflammation,
• Vasodilation,
• Increased vascular permeability,
• Complement activation, and
• Chemotactic activity for polymorphonuclear
leukocytes.
• Phagocytosis of urate crystals by leukocytes results in rapid
lysis of cells and discharge of proteolytic enzymes into
cytoplasm.
• The ensuing inflammatory reaction causes intense joint
pain, erythema, warmth, and swelling.
• An acute attack of gout is started by the precipitation of urate
crystals in the synovial fluid.
• On being engulfed by the synovial cells, they release
mediators and start an inflammatory response.
• Chemotactic factors are produced →granulocyte migration
into the joint; they phagocytose urate crystals and
release a glycoprotein which aggravates the inflammation by:
• i) Increasing lactic acid production from inflammatory
cells → local pH is reduced → more urate crystals are
precipitated in the affected joint.
• ii) Releasing lysosomal enzymes which cause joint
destruction.
• When uric acid is deposited in the kidneys-
• Acute uric acid nephropathy can occurs because of blockage of
urine flow from massive precipitation of uric acid crystals in collecting
ducts and ureters.
• Chronic urate nephropathy is caused by long-term deposition of
urate crystals in the renal parenchyma.
• Clinical manifestations of gout derive from the precipitation of sodium
urate from extracellular fluids when and where it exceeds the limits of
solubility.
• Clinical manifestations include:-
 acute gouty arthritis
 tophaceous deposits (sodium urate deposits in cartilage, bone, bursae, and
subcutaneous tissue in and around joints)
 uric acid nephrolithiasis
 gouty kidney with various degrees of impairment of renal function.
 Conditions Associated with Hyperuricemia
• Obesity • Pernicious anemia Hypoparathyroidism
• Diabetic ketoacidosis Sarcoidosis • Glycogen storage disease type 1
• Myeloproliferative disorders • Acromegaly
• Congestive heart failure • Psoriasis Hypothyroidism
• Lactic acidosis • Hypoxanthine-guanine
• Renal dysfunction
phosphoribosyltransferase deficiency
• Lymphoproliferative disorders
• Phosphoribosylpyrophosphate
synthetase overactivity
• Down syndrome • Polycythemia vera
• Starvation • Berylliosis(inhalation of Berylium)
• Lead toxicity • Renal transplantation.
• Chronic hemolytic anemia
• Hyperparathyroidism
• Toxemia of pregnancy
• Acute alcoholism
Drugs Capable of Inducing Hyperuricemia and Gout
• Diuretics
• Ethanol
• Ethambutol
• Nicotinic acid
• Pyrazinamide
• Cytotoxic drugs
• Salicylates(<2g/day)
• Levodopa
• Cyclosporine
• Two enzyme abnormalities resulting in an
overproduction of uric acid.
• The first is an increase in the activity of phosphoribosyl
pyrophosphate (PRPP) synthetase, which leads to an
increased concentration of PRPP.
• PRPP is a key determinant of purine synthesis and thus uric
acid production.
• The second is a deficiency of hypoxanthine-guanine
phosphoribosyltransferase (HGPRT).
• HGPRT is responsible for the conversion of guanine to
guanylic acid and hypoxanthine to inosinic acid.
• These two conversions require PRPP as the co-substrate
and are important reuse reactions involved in the synthesis
of nucleic acids.
 Purine metabolism

HGPRT = hypoxanthine-guanine phosphoribosyltransferase, PRPP = phosphoribosyl

pyrophosphate
• A deficiency in the HGPRT enzyme leads to increased
metabolism of guanine and hypoxanthine to uric acid, and
more PRPP to interact with glutamine in the first step of the
purine pathway.

• Complete absence of HGPRT results in the childhood

Lesch-Nyhan syndrome, characterized by choreoathetosis,
spasticity, mental retardation, and markedly excessive
production of uric acid.
• A partial deficiency of the enzyme may be responsible for
marked hyperuricemia in otherwise normal, healthy
individuals.
Treatment
• The goals in the treatment of gout are:
• To terminate the acute attack,

• Prevent recurrent attacks of gouty arthritis,

• Prevent complications associated with chronic

deposition of urate crystals in tissues, &

• Prevent or reverse features commonly associated

with the illness including obesity, elevated
triglycerides, and hypertension
 Drugs used in gout
• SUPPRESSORS OF LEUKOCYTE RECRUITMENT AND
ACTIVATION
• Mechanism—Interrupt inflammatory pathways that cause
inflammation in a gouty joint
• INHIBITORS OF URIC ACID SYNTHESIS
• Mechanism—Inhibit xanthine oxidase, the enzyme that
converts hypoxanthine and xanthine to uric acid; decreased
uric acid levels lead to less urate crystal formation
• AGENTS THAT INCREASE URIC ACID EXCRETION

• AGENTS THAT ENHANCE URIC ACID METABOLISM

• Mechanism—Enzyme that converts sparingly soluble urate
to the more soluble allantoin
 Drugs used in gout
• Acute gout
• NSAIDs
• Glucocorticoids
• Colchicine
• Chronic gout
• Uricosurics e.g. Probenecid
• Xanthine oxidase inhibtors e.g. allopurinol
Uric acid metabolism and sites of drug action
 Colchicine
• Colchicine a plant alkaloid, is used for the treatment of acute
gouty attacks.
• It is neither a uricosuric nor an analgesic agent, although it
relieves pain in acute attacks of gout.
• It specifically suppresses gouty inflammation.
• Mechanism of action:
• The mechanism of action in acute gout is unclear.
• By binding to fibrillar protein tubulin, it inhibits granulocyte migration
into the inflamed joint and thus interrupts the vicious cycle. (prevents
polymerization of tubulin into microtubules and inhibits
leukocyte migration and phagocytosis).
• It does not inhibit the synthesis or promote the excretion of
uric acid. Thus, it has no effect on blood uric acid levels.
• Therapeutic uses:
• Treatment of acute gout
• The anti-inflammatory activity of colchicine is specific
for gout & alleviates the pain of acute gout within 12
hours.
• Prophylaxis
• Colchicine 0.5–1 mg/day can prevent further attacks of
acute gout, but NSAIDs are generally preferred.
• Pharmacokinetics:
• Colchicine is administered orally and is rapidly absorbed from the GI
tract.
• Colchicine is recycled in the bile and is excreted unchanged in feces or
urine.
• Adverse effects:
• Colchicine may cause nausea, vomiting, abdominal pain, and diarrhea.
• Chronic administration may lead to myopathy, neutropenia, aplastic
anemia, and alopecia.
• The drug should not be used in pregnancy, and it should be used
with caution in patients with hepatic, renal, or cardiovascular disease
• Higher doses may (rarely) result in liver damage and blood dyscrasias.
• Dosage adjustments are required in patients taking CYP3A4 inhibitors,
like clarithromycin, itraconazole, and protease inhibitors.
• For patients with severe renal impairment, the dose should be reduced
• Nonsteroidal antiinflammatory drugs (NSAIDS) e.g. naproxen,
piroxicam, diclofenac, indomethacin or etoricoxib.
• They inhibit cyclooxygenase enzymes and with that, synthesis of pain-
potentiating prostaglandin E2.
• NSAIDs inhibit urate crystal phagocytosis.
• Aspirin is not used because it causes renal retention of uric acid at low
doses.
COMMON ADVERSE EFFECTS
• Side effects of these drugs include gastrointestinal distress and
bleeding, headache, confusion, dizziness, hypersensitivity, renal
disturbances, fluid and electrolyte imbalances, and haematological
reactions such as thrombocytopenia and aplastic anaemia.
• Contraindications for use include peptic ulceration, blood dyscrasias and
allergy.
• NSAIDs should not be used in patients with renal failure or gastric
conditions, as these drugs may worsen renal function and are
associated with a high incidence of gastrointestinal irritation.
 Injectable corticosteroids
• The injectable corticosteroids betamethasone, methylprednisolone
and triamcinolone can be used to relieve an acute attack of gout.
MECHANISM OF ACTION
• Corticosteroids are potent anti-inflammatory agents that suppress
immune function.
• They affect the responsiveness of immune cells and inhibit
inflammatory mediator synthesis.
COMMON ADVERSE EFFECTS
• Corticosteroids may induce local and systemic adverse effects, including
irritation at the injection site, brief joint discomfort, flare reactions,
headache and flushing.
 Xanthine Oxidase Inhibitors: Allopurinol
• Allopurinol is a xanthine oxidase inhibitor, is a purine analog.
• It reduces the production of uric acid by competitively
inhibiting the last two steps in uric acid biosynthesis that are
catalysed by xanthine oxidase.
• Allopurinol is used to prevent gout attacks in persons who
overproduce uric acid, as indicated by a 24-hour uric acid excretion
that is greater than 800 mg.
• Allopurinol is an effective urate-lowering therapy in the treatment of
gout and hyperuricemia secondary to other conditions, such as that
associated with certain malignancies (those in which large amounts of
purines are produced, particularly after chemotherapy) or in renal
disease.
• Pharmacokinetics:
• Allopurinol is completely absorbed after oral
administration.
• The primary metabolite is alloxanthine (oxypurinol),
which is also a xanthine oxidase inhibitor with a half-life
of 15 to 18 hours.
• The effective inhibition of xanthine oxidase can be
maintained with once-daily dosage.
• The drug and its active metabolite are excreted in the
feces and urine. The dosage should be reduced if the
creatinine clearance is less than 50 mL/min.
 Adverse effects
• Allopurinol is well tolerated by most patients.
• Hypersensitivity reactions, especially skin rashes, are the
most common adverse reactions.
• The risk is increased in those with reduced renal function.
• Because acute attacks of gout may occur more frequently
during the first several months of therapy, colchicine,
• NSAIDs, or corticosteroids can be administered concurrently.
• Allopurinol interferes with the metabolism of 6-
mercaptopurine, the immunosuppressant azathioprine, and
theophylline, requiring a reduction in dosage of these drugs.
 Febuxostat
• Febuxostat is a xanthine oxidase inhibitor.
• It works by non-competitively blocking the molybdenum
pterin center which is the active site on xanthine oxidase.
• Xanthine oxidase is needed to successively oxidize both
hypoxanthine and xanthine to uric acid.
• Its adverse effect profile is similar to that of allopurinol,
although the risk for rash and hypersensitivity reactions may
be reduced.
• Febuxostat does not have the same degree of renal
elimination as allopurinol and thus requires less adjustment in
those with reduced renal function.
 Uricosuric Drugs: Probenecid and sulfinpyrazone
• Probenecid is a uricosuric drug.
• It is a weak organic acid that promotes renal clearance of uric acid by
inhibiting the urate anion exchanger in the proximal tubule that mediates
urate reabsorption.
• It blocks proximal tubular reabsorption of uric acid.
• Probenecid and sulfinpyrazone undergo rapid oral absorption.
• Probenecid blocks the tubular secretion of penicillin and is sometimes used
to increase levels of β-lactam antibiotics.
• It also inhibits the excretion of methotrexate, naproxen,
ketoprofen, and indomethacin.
• Probenecid should be avoided if the creatinine clearance is less than 50
mL/min.
• Common adverse effects include GI disturbances and dermatitis; rarely,
these agents cause blood dyscrasias.
Catabolic Enzyme Preparations: Pegloticase
• Humans ( and great apes) do not have functional uricase as do other
mammals. Uricase converts uric acid to the water-soluble allantoin.
• Pegloticase is a recombinant form of porcine uricase that is also
pegylated to slow its degradation.
• It acts by converting uric acid to allantoin, a water-soluble
nontoxic metabolite that is excreted primarily by the kidneys.
• Pegloticase can reduce serum urate in a matter of hours. It is
approved for use in patients with gout who have been unresponsive
to other drug therapies.
• The most serious side effect with pegloticase s serious allergic
reactions.