Antigout Agents and Uric Acid Metabolism

Antigout Agents

• A gout attack and chronic illness have notable differences
• Medications like colchicine, NSAIDs, corticosteroids, uricosuric drugs, and xanthine oxidase inhibitors have varying mechanisms of action
• Treatments for a gout attack will be covered
• Therapies for chronic illness and prophylactic treatment are outlined

Gout

• Gout is a familial metabolic disease
• It is characterized by recurrent episodes of acute arthritis
• Monosodium urate crystals deposit in the joints and cartilage
• Uric acid calculi can occur in the kidneys
• The site of deposition determines specific manifestations
• Acute arthritis involves acute inflammation of joint tissue
• Tophi define urate deposits in subcutaneous tissues, common in ear lobes and hands
• Urinary calculi may be present

Uric Acid Metabolism

• Xanthine oxidase facilitates the conversion of hypoxanthine to xanthine and xanthine to uric acid
• Plasma uric acid can lead to urate crystal deposition in joints, causing gout
• Uric acid undergoes tubular reabsorption and secretion before excretion in urine

Pathophysiology

• Urate crystals in the joint space trigger local inflammation
• Synoviocytes, PMNs, and MNPs contribute to the inflammatory response
• Colchicine and indomethacin interrupt pathways involved in the inflammatory response

Uric Acid Solubility

• Uric acid solubility depends on pH
• Increased water intake can help with uric acid solubility

Etiology

• Increased uric acid synthesis or decreased excretion causes primary gout
• Secondary gout stems from increased uric acid production due to hematological disorders or from decreased excretion because of drugs, like thiazide diuretics and furosemide

Drug Treatments

• Anti-inflammatory drugs used include colchicine, NSAIDs, and adrenal corticosteroids
• Uric acid biosynthesis inhibitors include allopurinol (Zyloprim) and febuxostat (Uloric)
• Uricosuric agents consist of probenecid and sulfinpyrazone (Anturane)

Treatment of Acute Gouty Attacks

• Medications include colchicine, indomethacine and other NSAIDs, corticosteroids, and interleukin-1 inhibitors

Colchicine

• Colchicine is isolated from the autumn crocus, Colchicum autumnale
• It binds to tubulin to prevent polymerization into microtubules
• This binding inhibits leukocyte chemotaxis, phagocytosis & degranulation
• Colchicine inhibits formation of leukotriene B4 and can arrest cell division

Colchicine Pharmacokinetics

• It is rapidly absorbed after oral administration
• Peak plasma level are reached within 2 hours
• It has a higher concentration in the spleen, kidney & liver
• Colchicine is metabolized in the liver
• Metabolites are excreted in urine & feces

Colchicine Clinical Indications

• Used in acute attacks of gouty arthritis
• More specific for gout than other NSAIDs
• It is used for prophylaxis of recurrent gouty arthritis
• It is also used to treat Mediterranean fever
  • It is an autosomal recessive inherited disease
  • Common in Sephardic (non-Ashkenazi) Jewish, Armenian, Arab and Turkish heritage
  • The mutated pyrin is likely important in keeping inflammation under control
  • Episodes of fever are accompanied with serositis, synovitis or skin rash

Colchicine Adverse Effects

• Colchicine inhibits tubulin polymerization and cell mitosis
• It can cause diarrhea which limits use in acute gout
• It can cause nausea, vomiting, & abdominal pain
• Rarely, it can result in hair loss or bone marrow depression
• Symptoms of acute intoxication: burning throat pain, bloody diarrhea, shock, hematuria, oliguria, muscular & CNS depression
• Supportive treatment is indicated

NSAIDs

• Indomethacin (Indocin) is an NSAID often used as an agent
• Indomethacin provides relief of acute gout
• NSAIDs inhibit cyclooxygenase (COX I & II) and prostaglandin synthase
• NSAIDs inhibit urate crystal phagocytosis
• Pharmacokinetics include oral administration and active secretion by renal tubular cells
• Smaller dose required when used with probenecid

Other NSAIDs

• All except aspirin, salicylates, & tolmetin (Tolectin) have been successful treatments
• Oxaprozin (Daypro) may be best since it has mild uricosuric effects
• Salicylates in low-dose block tubular secretion of uric acid

Adrenal Corticosteroids

• These are used for acute attacks
• Particularly indicated when colchicine or NSAIDs are not tolerated or contraindicated
• Oral prednisone or intraarticular injection are options
• Toxicity limits chronic use

Interleukin-1 Inhibitors

• Anakinra, canakinumab, and rilonacept are examples.
• There is limited data on them
• Offer a promising treatment option for acute gout when patients have contraindications to, or are refractory to, traditional therapies like NSAIDs or colchicine

Chronic Gout Treatments

• Treatments can decrease uric acid synthesis
  • Allopurinol
  • Febuxostat
• Uricosuric Agents
  • Probenecid -Sulfinpyrazone
• Convert Uric Acid to Allantoin
  • Pegloticase

Allopurinol (Zyloprim)

• Allopurinol is a hypoxanthine analog
• It competitively inhibits xanthine oxidase
• Allopurinol prevents oxidation of hypoxanthine & xanthine to uric acid
• It reduces plasma Uric Acid
• Hypoxanthine & xanthine are more H₂O soluble and have a higher renal clearance than uric acid

Allopurinol (Zyloprim) Pharmacokinetics

• Allopurinol is administered orally
• It is oxidized by xanthine oxidase to alloxanthine
• The active metabolite has a T1/2 of 18-30 hrs and retains the capacity to inhibit xanthine oxidase
• Administered QD

Allopurinol (Zyloprim) Therapeutic Indications

• Treats chronic gout, gout with daily urinary uric acid >600 mg, gouty nephropathy, recurrent renal urate stones, and chronic tophaceous gout
• Prophylaxis prevents urate deposition or renal calculi in patients with leukemia & during chemotherapy (cell lysis = ↑ uric acid)
• Used in patients with impaired renal function
• Goal is to lower serum urate to < 6.5 mg/dL

Allopurinol (Zyloprim) Adverse Effects

• Allopurinol is well tolerated
• Side effects include nausea, vomiting, & diarrhea
• It can result in allergic skin rashes and occasional hepatotoxicity
• Acute gouty attacks can be precipitated during initial therapy as urate crystal moves from tissue to plasma, which may be prevented with colchicine or NSAIDs during first 6 months of therapy

Allopurinol (Zyloprim) Drug Interactions

• Allopurinol decreases hepatic drug metabolism
  • For 6-mercaptopurine and azathioprine, it is metabolized by xanthine oxidase
  • For oral anticoagulants
• Allopurinol increases the effect of cyclophosphamide
• May increase hepatic iron concentration

Febuxostat (Uloric)

• It is a non-purine xanthine oxidase inhibitor
• It is as effective as allopurinol
• 80% is absorbed from GI/ with once a day dose
• Extensively metabolized by the liver
• Use prophylactic treatment with colchicine or NSAIDs during first 6 months of therapy to avoid acute gout
• Common adverse effects include liver function abnormalities, diarrhea, headache, and nausea

Uricosuric agents

• Probenecid (Benemid, Probalan)
• Sulfinpyrazone (Anturane)
• Should be avoided in patients with high urate excretion, since this may precipitate crystals in urine
• Effects depend on the dose:
  • Low dose: decreases uric acid excretion by inhibition of active tubular secretion
  • High dose: increases uric acid excretion by inhibition of tubular reabsorption

Uricosuric agents Mechanism of Action

• These agents are organic acids
• They inhibit the anionic transport sites in the middle segment of proximal renal tubule
• The net reabsorption of uric acid is lowered

Uricosuric agents Pharmacokinetics

• Both Probenecid and Sulfinpyrazone are orally absorbed
• Probenecid
  • Slowly metabolized
  • Undergoes active tubular secretion
  • Completely reabsorbed
• Sulfinpyrazone
  • Converted to active uricosuric metabolite
  • Undergoes rapid renal excretion

Uricosuric agents Adverse Effects

• Generally well tolerated by most patients
• Cause G.I. irritation, with sulfinpyrazone being worse
• Rash: both
• Allergic dermatitis: Probenecid
• Nephrotic Syndrome: Probenecid
• Aplastic anemia: rare for both

Uricosuric agents Therapeutic Indications

• Treatment can start After several acute gouty attacks
• Particularly if evidence of tophi appears
• Used Long term, as it may decrease acute gouty attacks, prevent renal damage & tophi deposition.
• Sometimes used in low dose to reduce renal tubular excretion of penicillins to potentiate their therapeutic effect.
• Supportive therapy:
  • Consists of Increase fluid intake
  • Alkalinization of urine (sodium bicarbonate) to prevent renal calculi formation

Uricosuric agents Drug Interactions

• Renal Transport of is impacted:
  • Sulfinpyrazone
  • Indomethacin
  • Penicillin
  • Sulfonamides
• Salicylates (aspirin) : Low doses (analgesic, antipyretic) inhibits uricosuric effect
• Increases renal excretion of alloxanthine
• Contraindication: patients with renal insufficiency (kidney stones)

Pegloticase (Krystexxa)

• This recombinant mammalian uricase (Urate oxidase) converts uric acid to soluble allantoin
• It`s covalently attached to methoxypolyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic response
• Dosed 8 mg every 2 weeks by intravenous infusion which maintains low urate levels for up to 21 days

Pegloticase (Krystexxa) Adverse Effects

• Gout flare during the first 3–6 months. Requires prophylactic treatment with NSAIDs or colchicine
• Immune responses leading to reduced effectiveness are seen in many patients
• Anaphylaxis occurs in more than 6-15% of cases
• Nephrolithiasis, arthralgia, muscle spasm, headache, pneumonia, anemia, and nausea

Pegloticase (Krystexxa) Other Adverse Effects

• Less frequent side effects include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea
• It should be avoided in G6PD deficiency. There is concern for hemolytic anemia because uricase forms hydrogen peroxide
• Treatment of refractory chronic gout

Rasburicase (Elitek)

• This recombinant urate oxidase is used for
• Prevention and treatment of hyperuricemia in patients receiving chemotherapy
• It converts uric acid to more soluble allantoin, which is renally excreted

Rasburicase (Elitek) indication

• It is used to initially manage plasma uric acid levels in adults and children with leukemia, lymphoma, and solid tumor malignancies when are receiving anti-cancer therapy that may result in tumor lysis syndrome and subsequent elevations of plasma uric acid
• Administered via intravenous infusion

Rasburicase (Elitek) Adverse Effects

• Less than 1% of patients get: anaphylactic shock, hemolysis (avoid in G6PD deficiency), and methemoglobinemia
• Most frequent: 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

• Acute gouty attacks may be treated via colchicine or Indomethacin
• Chronic therapy aims at controlling the plasma level of uric acid & preventing the deposition of urates in the joints & renal calculi
• Selection of agents depends on the patient
  • Uricosuric agents are indicated if the amount of urates in the urine is < 600 mg daily (underexcretion)

General Principles of Drug Treatment of Gout more information

• If urate amounts of > 600 mg daily (normal), allopurinol is preferred, or if renal function is impaired
• If there is regression of tophi & renal stones, uricosuric agents should be used concurrently with allopurinol
• For control of secondary hyperuricemia, allopurinol may be indicated. Other supportive therapy for asymptomatic state includes hydration, use of diuretics & low purine diet

Other information for Drug Treatment of Gout

• Initial therapy with uricosuric agents may precipitate acute attacks. Therefore a prophylactic small dose of colchicine may be beneficial
• Alkalinization of urine to ↑ uric acid excretion may prevent renal calculi
• Low doses of salicylates are contraindicated as they may antagonize the action of uricosuric agents & ↑ retention of uric acid
• Concurrent therapy of allopurinol & uricosuric agent may that effectivness of each other. Dosage adjustment may be required
• All treatments provide symptomatic relief only: -↑ reabsorption of tophi in tophaceous gouty state
  • Prevent development of nephrolithiasis
  • Prevent the progression of chronic gouty arthritis to↑ mobility