Drugs For Gout

Front 1

Uric acid disposition

Back 1

1. Uric acid serves no biological function; it is the end product of purine
metabolism. Unlike animals, humans lack the enzyme uricase, which degrades uric acid into more soluble products (allantoin) for excretion.
2. Uric acid is primarily excreted renally
3. Increased serum uric acid concentrations result from an increase in production or a decrease in renal excretion of uric acid, or a combination of
these two mechanisms.

Front 2

Overproduction of Uric Acid

Back 2

1. Overproduction of uric acid accounts for about 10% of gout cases.
2. It can result from excessive de novo purine synthesis, which is associated primarily with rare genetic enzyme mutation defects; neoplastic diseases (e.g., multiple myeloma, leukemias, lymphomas, Hodgkin disease); and myeloproliferative disorders (e.g., myeloid metaplasia, polycythemia vera).
Aggressive cytotoxic chemotherapy can cause tumor lysis syndrome and increased uric acid production from increased nucleoprotein turnover.
3. Overproduction of uric acid can also be the result of excessive intake of
dietary purines from meat, seafood, dried peas and beans, certain vegetables (e.g., mushrooms, spinach, asparagus), beer, and other alcoholic beverages. Dietary restrictions are seldom of much benefit and patients should feel comfortable in eating “modest” quantities of meats,
seafood, and vegetables.

Front 3

Under excretion Uric Acid

Back 3

1. A defect in the renal clearance of uric acid is the main cause of hyperuricemia and gout in about 90% of patients.
2. Uric acid is filtered in the renal glomerulus and is almost completely (98%–100%) reabsorbed in the proximal tubule. Uric acid is then secreted distal to the proximal tubular reabsorption site, and most is reabsorbed again. In normal patients, homeostasis between reabsorption and secretion
of urate is maintained. However, many factors (e.g., renal impairment, certain drugs [thiazide diuretics, low dose aspirin, others], alcohol excess, metabolic syndrome, hypertension, cardiovascular disease) can cause this balance to fail, resulting in excess serum concentrations of uric acid and
tissue deposition.

Front 4

Pathophysiology

Back 4

During an acute attack of gout, urate crystals in the synovial fluid and synovial tissue activate complement. Complement activation leads to phagocytosis of opsonized crystals by monocyte/macrophages and release of chemotactic factors such as C3a and C5a. Monocyte-secreted factors and other chemotactic factors stimulate neutrophil recruitment. The combination of these factors constitutes the inflammatory response typical of acute gout. The ensuing inflammatory reaction is associated with intense joint pain, erythema,
warmth, and swelling. Untreated attacks may last from 3 to 14 days before spontaneous recovery.

Front 5

NSAIDS for Gout

Back 5

Acute Attack
1. A number of NSAIDs (e.g., naproxen, ibuprofen, indomethacin, and celecoxib) are effective in relieving the inflammation of acute gout. There is no evidence that any given NSAID is superior to all the others in the
management of acute gout.
2. By inhibiting the activity of cyclooxygenase, prostaglandin production is reduced-->antiinflammatory and analgesia
3. The pharmacology of the NSAIDS have been discussed elsewhere.

Front 6

Glucocorticoids

Back 6

Acute Attack
1. Glucocorticoids (e.g., prednisone) may be used to treat acute attacks of gouty arthritis, but they are reserved primarily for resistant cases or for patients with a contraindication to colchicine and NSAID therapy. Intraarticular administration of may be useful in treating acute gout limited to one or two joints.
2. Long term use associated with serious side effects

Front 7

Colchicine--1. Mechanism of action

Back 7

a. The drug binds to the intracellular tubulin, inhibiting its polymerization and preventing microtubule formation which inhibits mitosis.
b. This leads to inhibition of several leukocyte and macrophage actions including migration and phagocytosis, and release of inflammatory
mediators.

Front 8

Colchicine--Adverse Effects

Back 8

a. Nausea and vomiting, abdominal pain
b. Bloody diarrhea (due to inhibition of mitosis in the intestinal mucosa)
c. Myelosuppression leading to leukopenia, thrombocytopenia, agranulocytosis (after chronic administration)

Front 9

Probenecid (uricosuric drug)---1. Mechanism of action

Back 9

Prophylaxis of Gout
a. Inhibition of the anion exchanger of the proximal tubule.
b. Inhibition of reabsorption in the proximal tubulepredominates (uric acid is 99% reabsorbed in the proximal tubule).

Front 10

Prodenecid -- Drug Interaxn

Back 10

a. Inhibition of tubular secretion of many weak acids including, penicillins, cephalosporins, methotrexate, sulfonylureas, indomethacin. The dose of these other drugs should be reduced.
b. Aspirin in low doses can antagonize completely the uricosuric effect of probenecid (mechanism likely involves competition for renal tubular
transport).

Front 11

Probenecid--Adverse Effects

Back 11

a. Hypersensitivity reactions (the drug is a sulfonamide)
b. Increased risk of uric acid stones (due to increased urate excretion; can be prevented by maintaining fluid intake)
c. Increased risk of gout attack during the early phase of treatment (can be prevented by colchicine)

Front 12

Probenecid--Contraindications

Back 12

a. Patients allergic to sulfa drugs
b. Patients with impaired renal function (use allopurinol)

Front 13

Allopurinol---a. Mechanism of action

Back 13

(1) Irreversible inhibition of xanthine oxidase (the drug is suicide inhibitor).
(2) Inhibition of conversion of hypoxanthine to xanthine and xanthine to uric acid.
(3) Decreased hyperuricemia, which decreases the risk of precipitation of uric acid crystals in joints and tissues.

Front 14

Allopurinol--ADME

Back 14

Dosage adjustment (decrease dose or increase dosing interval) is required in patients with impaired renal function

Front 15

Allopurinol--Adverse Effects

Back 15

(1) Maculopapular rash (an allergic skin reaction)
(2) Increased risk of gout attack during the early phase of treatment (can be prevented by colchicine)

Front 16

Allopurinol---Drug Interaxns

Back 16

The drug inhibits the metabolism of mercaptopurine and azathioprine, drugs that are metabolized by xanthine oxidase-->decrease dose of
these drugs.

Front 17

Febuxostat---a. Mechanism of action

Back 17

(1) Irreversible inhibition of xanthine oxidase (the drug is suicide inhibitor).
(2) Inhibition of conversion of hypoxanthine to xanthine and xanthine to uric acid.
(3) Decreased hyperuricemia, which decreases the risk of precipitation of uric acid crystals in joints and tissues.

Front 18

Febuxostat--ADME

Back 18

No dosage adjustment necessary for patients with renal failure–provides an alternative to allopurinol in such patients

Front 19

Febuxostat--Adverse Effects

Back 19

Incr liver enzymes

Front 20

Febuxostat--Drug Interaxn

Back 20

The drug inhibits the metabolism of mercaptopurine and azathioprine, drugs that are metabolized by xanthine oxidase-->decrease dose of
these drugs.

Front 21

Acute attack of gout

Back 21

Pharmacologic interventions consist of inhibiting the inflammatory response, either by inactivating monocytes and neutrophils (glucocorticoids and colchicine) or by decreasing the levels of inflammatory mediators released (glucocorticoids and NSAIDs).

Front 22

Rasburicase

Back 22

In cancer chemotherapy, the rapid lysis of tumor cells can liberate free nucleotides
and greatly increase plasma urate levels. By this mechanism, tumor lysis syndrome
can lead to massive renal injury. Exogenous uricase can be coadministered with cancer chemotherapy to reduce plasma urate levels rapidly, and thereby to prevent renal damage. Allopurinol can also be used to prevent this component of tumor lysis
syndrome. Rasburicase is a recombinant version of the Aspergillus uricase.

Front 23

Prophylactic treatment

Back 23

1. Prophylactic therapy is appropriate for patients with frequent attacks (more than two or three per year) of gouty arthritis, even if the serum uric acid concentration is normal or only minimally elevated.
2. Prophylactic treatment should be instituted immediately after resolution of
the acute episode.
3. Recurrences of acute gouty arthritis may be prevented with continuous
low-dose daily oral colchicine or by uric acid–lowering therapy. Reduction of the serum urate concentration can be accomplished pharmacologically by increasing the renal excretion of uric acid (probenecid) or by decreasing its synthesis (allopurinol or febuxostat). Colchicine is given sometimes to prevent an acute attack of gout which may be precipitated upon initiating uric acid-lowering therapy.