Gout and Uric Acid Metabolism

Gout

• Gout is a familial metabolic disease characterized by recurrent episodes of acute arthritis.
• Monosodium urate crystals deposit in joints and cartilage.
• Uric acid calculi may occur in the kidneys.
• Acute arthritis involves acute inflammation of joint tissue.
• Tophi are deposits of urate in subcutaneous tissues, such as ear lobes and hands.
• Urinary calculi can occur.

Uric Acid Metabolism

• Uric acid results from the breakdown of purines and nucleic acids obtained either through diet or produced in the body.
• Xanthine oxidase converts hypoxanthine to xanthine and xanthine to Uric acid.
• Urate crystals may deposit in joints, leading to gout.
• Uric acid can be reabsorbed or secreted by the tubules into the urine.

Pathophysiology

• In gout, urate crystals accumulate in the synoviocytes.
• This accumulation leads to the production of lysosomal enzymes and interleukin-1 (IL-1).
• IL-1 then leads to the production of prostaglandins (PG)
• These further result in the production of leukotriene B4 (LTB4)
• Colchicine inhibits PMN.
• Indomethacin inhibits MNP.

Uric Acid Solubility

• Uric acid solubility is affected by pH
• Uric acid is more water-soluble at higher pH levels.
• Drinking plenty of water is recommended for managing uric acid levels.

Etiology

• The causes of primary gout include increased uric acid synthesis and/or decreased uric acid excretion.
• Secondary gout results from increased uric acid production due to hematological disorders or decreased excretion caused by drugs like thiazide diuretics and furosemide.

Drug Treatments

• Anti-inflammatory drugs used to treat gout include colchicine, NSAIDs, and adrenal corticosteroids
• Uric acid biosynthesis inhibitors include Allopurinol (Zyloprim) and Febuxostat (Uloric).
• Uricosuric agents include Probenecid and Sulfinpyrazone (Anturane)

Treatment of Acute Gouty Attacks

• Medications used to treat acute gouty attacks include colchicine, indomethacin and other NSAIDs, corticosteroids, and interleukin-1 inhibitors.

Colchicine

• Colchicine is isolated from the autumn crocus.
• Colchicine binds to the protein tubulin, preventing its polymerization into microtubules.
• This inhibits leukocyte chemotaxis, phagocytosis, and degranulation.
• It also inhibits the formation of leukotriene B₄ and can arrest cell division.

Colchicine Pharmacokinetics

• It is rapidly absorbed after oral administration and reaches peak plasma levels within 2 hours.
• It has a higher concentration in the spleen, kidneys, and liver.
• It is metabolized in the liver, and its metabolites are excreted in urine and feces.

Colchicine Clinical Indications

• Management of acute attacks of gouty arthritis.
• It is more specific for gout than other NSAIDs.
• Can be used in Prophylaxis of recurrent gouty arthritis.
• Can be used in Mediterranean fever, an autosomal recessive inherited disease.

Colchicine Adverse Effects

• Inhibits tubulin polymerization and cell mitosis
• Common adverse effects include diarrhea, nausea, vomiting, and abdominal pain.
• Rarely, hair loss or bone marrow depression may occur.
• Acute intoxication can cause burning throat pain, bloody diarrhea, shock, hematuria, oliguria, muscular & CNS depression.
• Treatment for acute intoxication is supportive.

NSAIDs

• Indomethacin (Indocin) is an NSAID frequently used for acute gout.
• NSAIDs inhibit cyclooxygenase (COX I & II) & prostaglandin synthase.
• NSAIDs inhibit urate crystal phagocytosis.
• They are administered orally and are actively secreted by renal tubular cells.
• A smaller dose is required when used with probenecid.

Other NSAIDs

• All NSAIDs except aspirin, salicylates, and tolmetin (Tolectin) are effective treatments.
• Oxaprozin (Daypro) may be preferred due to its mild uricosuric effects.
• Salicylates in low doses block tubular secretion of uric acid.

Adrenal Corticosteroids

• Used for acute attacks when colchicine or NSAIDs are not tolerated or contraindicated.
• Oral prednisone and intraarticular injections are administration options.
• Their toxicity limits their chronic use.

Interleukin-1 Inhibitors

• Anakinra, canakinumab, and rilonacept are Interleukin-1 inhibitors.
• They have limited data but show promise for patients with acute gout who have contraindications or are refractory to traditional therapies like NSAIDs or colchicine.

Chronic Gout Treatments

• Treatments include decreasing uric acid synthesis with allopurinol.
• Other treatments include febuxostat.
• Medications also include uricosuric agents like probenecid.
• Sulfinpyrazone can also be used.
• Pegloticase treats gout by converting uric acid to allantoin.

Allopurinol (Zyloprim)

• Allopurinol is a hypoxanthine analog.
• It competitively inhibits xanthine oxidase, preventing the oxidation of hypoxanthine and xanthine to uric acid.
• This results in decreased plasma uric acid levels because hypoxanthine and xanthine are more water-soluble and have higher renal clearance than uric acid.

Allopurinol Pharmacokinetics

• It is administered orally.
• It metabolizes into alloxanthine via oxidation by xanthine oxidase.
• Alloxanthine is an active metabolite with a T1/2 of 18-30 hours that retains the capacity to inhibit xanthine oxidase.
• It requires QD dosing.

Allopurinol Therapeutic Indications

• Its chronic treatment is used for gout with daily urinary uric acid levels above 600 mg
• It is used for gouty nephropathy, recurrent renal urate stones, and chronic tophaceous gout.
• It is used as a prophylaxis to prevent urate deposition or renal calculi in patients with leukemia and during chemotherapy.
• Allopurinol is the agent of choice for patients with impaired renal function.
• The goal of the drug is to lower serum urate to below 6.5 mg/dL.

Allopurinol Adverse Effects

• Generally well-tolerated
• Common side effects include nausea, vomiting, and diarrhea.
• It can cause allergic skin rashes and occasional hepatotoxicity.
• Acute gouty attacks can be precipitated during initial therapy as urate crystals move from tissue to plasma.
• Preventative measures include using colchicine or NSAIDs with allopurinol for the first 6 months of therapy.

Allopurinol Drug Interactions

• Decreases hepatic drug metabolism of 6-mercaptopurine and azathioprine by xanthine oxidase.
• Decreases hepatic drug metabolism of oral anticoagulants.
• Increases the effect of cyclophosphamide.
• May increase hepatic iron concentration.

Febuxostat (Uloric)

• Febuxostat is a non-purine xanthine oxidase inhibitor and is as effective as allopurinol.
• It has 80% absorption from the GI tract with once-daily dosing.
• It is extensively metabolized by the liver.
• Prophylactic treatment with colchicine or NSAIDs is recommended during the first 6 months of therapy to avoid acute gout.
• Frequent adverse effects include liver function abnormalities, diarrhea, headache, and nausea.

Uricosuric Agents

• Probenecid and sulfinpyrazone are uricosuric agents.
• Uricosuric agents should be avoided in patients with high urate excretion to prevent urate crystals in urine.
• Effects depend on the dose: low doses decrease uric acid excretion by inhibiting active tubular secretion, while high doses increase uric acid excretion by inhibiting tubular reabsorption.

Mechanism of Action

• Uricosuric agents are organic acids that inhibit anionic transport sites in the middle segment of the proximal renal tubule.
• The net reabsorption of uric acid subsequently decreases.

Pharmacokinetics

• Both probenecid and sulfinpyrazone are orally absorbed.
• Probenecid is slowly metabolized, undergoes active tubular secretion, and is completely reabsorbed.
• Sulfinpyrazone is converted to an active uricosuric metabolite and undergoes rapid renal excretion.

Adverse Effects

• Both drugs are generally well-tolerated.
• Common adverse effect is G.I. irritation, which is worse with sulfinpyrazone.
• Rash, allergic dermatitis (more common with probenecid), nephrotic syndrome (more common with probenecid) can occur.
• Aplastic anemia can occur, though it is rare for both.

Therapeutic Indications

• Uricosurics are used after several acute gouty attacks.
• They are also used when there is evidence of tophi.
• Chronic use may decrease acute gouty attacks and prevent renal damage and tophi deposition.
• Uricosurics may be used in low doses to reduce the renal tubular excretion of penicillins to potentiate their therapeutic effect.
• Supportive therapy includes increased fluid intake and alkalinization of urine with sodium bicarbonate to prevent renal calculi.

Drug Interactions

• Uricosurics decrease the renal transport of sulfinpyrazone, indomethacin, penicillin, and sulfonamides.
• Low doses of salicylates (aspirin) inhibit the uricosuric effect.
• Uricosurics increase renal excretion of alloxanthine.
• Contraindicated in patients with renal insufficiency due to the risk of kidney stones.

Pegloticase (Krystexxa)

• Pegloticase is a recombinant mammalian uricase that converts uric acid to soluble allantoin.
• It is covalently attached to methoxypolyethylene glycol (mPEG) to prolong its circulating half-life and reduce immunogenicity.
• Dosing regimen of 8 mg every 2 weeks via intravenous infusion.
• The treatment maintains low urate levels for up to 21 days.

Pegloticase (Krystexxa) Adverse Effects

• Gout flare during the first 3–6 months, requiring prophylaxis with NSAIDs or colchicine.
• Many patients exhibit immune responses, reducing effectiveness.
• Anaphylaxis occurs in more than 6–15% of patients.
• Other adverse effects include nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea.
• Less frequent side effects include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea.
• Avoid in G6PD deficiency due to the risk of hemolytic anemia.
• Useful for treatment refractory chronic gout.

Rasburicase (Elitek)

• Rasburicase is a recombinant urate oxidase.
• Used for prevention and treatment of hyperuricemia in patients receiving chemotherapy.
• Converts uric acid to more soluble allantoin, which is renally excreted.

Rasburicase Indication

• For initial management of plasma uric acid levels in adults and children with leukemia, lymphoma, and solid tumor malignancies receiving anti-cancer therapy that may result in tumor lysis syndrome.
• Administered via intravenous infusion.

Rasburicase Adverse Effects

• In fewer than 1% of patients, anaphylactic shock, hemolysis (avoid in G6PD deficiency), and methemoglobinemia may occur.
• Common adverse effects include vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%).

General Principles of Drug Treatment of Gout

• For acute gouty attacks: use colchicine or indomethacin.

• For chronic therapy: aim to control plasma levels of uric acid and prevent the deposition of urates in joints and renal calculi.

• Selection of agents depends on the patient; uricosuric agents are indicated if the amount of urates in the urine is less than 600 mg daily due to underexcretion.

• For urate amounts exceeding 600 mg daily, allopurinol is preferred, or if renal function is impaired.

• For regression of tophi and renal stones, uricosuric agents should be used concurrently with allopurinol.

• Allopurinol may be indicated for the control of secondary hyperuricemia.

• Other supportive therapy for asymptomatic state includes hydration, use of diuretics, and a low purine diet.

• Initial therapy with uricosuric agents can precipitate acute attacks. A prophylactic small dose of colchicine may be beneficial.

• Alkalinization of urine to increase uric acid excretion may prevent renal calculi.

• Low doses of salicylates are contraindicated as they may antagonize the action of uricosuric agents and increase retention of uric acid.

• Concurrent therapy with allopurinol and a uricosuric agent may decrease the effectiveness of each other, requiring dosage adjustments.

• All treatments provide symptomatic relief only by increasing reabsorption of tophi in tophaceous gouty state preventing the development of nephrolithiasis preventing the progression of chronic gouty arthritis to increase mobility.