Gout and Uric Acid Metabolism

Gout

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

Uric Acid Metabolism

• Diet, purines and nucleic acids lead to Hypoxanthine
• Via xanthine oxidase, Hypoxanthine forms xanthine, and xanthine forms plasma uric acid
• Plasma Uric Acid causes urate crystals to be deposited in joints, leading to gout
• Plasma Uric Acid goes through tubular reabsorption and tubular secretion, and is then excreted in urine

Pathophysiology of Gout

• Colchicine inhibits PMN, or polymorphonuclear leukocytes
• Indomethacin inhibits MNP
• Synoviocytes surround urate crystals, causing Lysosomal Enzymes and IL-1 release
• IL-1 release causes the release of PG and LTB₄ leading to PMN

Uric Acid Solubility

• Uric acid solubility increases with higher pH levels
• At a pH of 4.0, none of the uric acid is ionized
• At a pH of 7.6, 90% of the uric acid is ionized
• The pKa is 5.6
• Drinking plenty of water can help increase solubility

Etiology of Gout

• Primary gout occurs due to the increased synthesis and/or decreased excretion of uric acid
• Secondary gout is caused either by increased production of uric acid secondary to hematological disorders or by decreased excretion due to drugs, such as thiazide diuretics and Furosemide

Drug Treatments for Gout

• Anti-inflammatory drugs such as Colchicine, NSAIDs and Adrenal corticosteroids
• Uric Acid Biosynthesis Inhibitors such as Allopurinol (Zyloprim), and Febuxostat (Uloric)
• Uricosuric agents such as Probenecid and Sulfinpyrazone (Anturane)

Treatment of Acute Gouty Attacks involve

• Colchicine
• Indomethacine and other NSAIDs
• Corticosteroids
• Interleukin-1 Inhibitors

Colchicine

• It is isolated from autumn crocus, or Colchicum autumnale
• It binds to the protein tubulin
• Prevents tubulin polymerization into microtubules
• It inhibits leukocyte chemotaxis, phagocytosis, and degranulation
• Formation of leukotriene B₄ is inhibited
• It can arrest cell division

Pharmacokinetics of Colchicine

• Rapid absorption occurs after oral administration
• Peak plasma level is reached within 2 hours
• Higher concentration in the spleen, kidney, and liver
• It is metabolized in the liver
• Metabolites are excreted in urine and feces

Clinical Indications for Colchicine

• It is used in acute attacks of gouty arthritis
• This is more specific for gout than other NSAIDs
• For prophylaxis of recurrent gouty arthritis
• Can be used for Mediterranean fever, which is an autosomal recessive inherited disease
• Mediterranean fever is common in Sephardic (non-Ashkenazi) Jewish, Armenian, Arab and Turkish heritage
• In Mediterranean fever, the mutated pyrin is believed to play a role in keeping inflammation under control
• Episodes of fever are accompanied with serositis, synovitis or skin rash

Adverse Effects of Colchicine

• Tubulin polymerization and cell mitosis is inhibited
• Diarrhea often limits its use in acute gout
• Occasionally causes nausea, vomiting, & abdominal pain
• Rarely causes hair loss or bone marrow depression
• Acute intoxication includes burning throat pain, bloody diarrhea, shock, hematuria, oliguria, muscular & CNS depression
• Acute intoxication warrants supportive treatment

NSAIDs

• Indomethacin (Indocin) is an NSAID used
• It is the agent most often used to provide relief for acute gout
• They inhibit cyclooxygenase (COX I & II)
• They inhibit prostaglandin synthase and urate crystal phagocytosis
• They are taken orally
• Actively secreted by renal tubular cells
• Smaller dose is required when used with probenecid

Other NSAIDs

• All except aspirin, salicylates & tolmetin (Tolectin) have been used as 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

• Used for acute attacks
• Used when colchicine or NSAIDs are not tolerated or contraindicated
• Oral prednisone and intraarticular injection are options
• Toxicity limits their chronic use

Interleukin-1 Inhibitors

• Anakinra, canakinumab, and rilonacept are Interleukin-1 Inhibitors
• Limited data is available regarding the effects of Interleukin-1 Inhibitors
• Interleukin-1 Inhibitors are a promising treatment option for acute gout in patients with contraindications to, or who are refractory to, traditional therapies like NSAIDs or colchicine

Chronic Gout Treatments

• Used to decrease uric acid synthesis
• This can be achieved through the use of Allopurinol, or Febuxostat
• Uricosuric Agents such as Probenecid and Sulfinpyrazone
• Used to covert Uric Acid to Allantoin using Pegloticase

Allopurinol (Zyloprim)

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

Pharmacokinetics of Allopurinol

• Administered orally
• Oxidized by xanthine oxidase to alloxanthine
• Its active metabolite has a T1/2 of 18-30 hrs and retains the capacity to inhibit xanthine oxidase
• Dosed once per day

Therapeutic Indications of Allopurinol

• It is used for chronic treatment of Gout with daily urinary uric acid >600 mg
• It is used for Gouty nephropathy
• Treats recurrent renal urate stones, chronic tophaceous gout
• Is used prophylactically to prevent urate deposition and renal calculi in patients with leukemia & during chemotherapy
• It is the agent of choice in patients with impaired renal function
• It lowers serum urate to < 6.5 mg/dL

Adverse effects

• It is well tolerated
• May produce Nausea, vomiting, & diarrhea and Allergic skin rashes
• Can cause occasional hepatotoxicity
• Acute gouty attacks can be precipitated during initial therapy as urate crystal move from tissue to plasma
• This may be prevented by using colchicine or NSAIDs with allopurinol for first 6 months of therapy

Drug Interactions

• Decreases hepatic drug metabolism of (6-mercaptopurine, azathioprine), oral anticoagulants
• Metabolized by xanthine oxidase
• Increases effect of cyclophosphamide
• May increase hepatic iron concentration

Febuxostat (Uloric)

• It is a non-purine xanthine oxidase inhibitor
• As effective as allopurinol
• 80% absorbed from GI/ once a day dose
• Extensively metabolized by liver
• Requires Prophylactic treatment with colchicine or NSAIDs during first 6 months of therapy to avoid acute gout
• Liver function abnormalities, Diarrhea, Headache, and Nausea can be frequent adverse effects:

Uricosuric agents

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

Mechanism of Action of Uricosuric Agents

• As organic acids, these agents inhibit the anionic transport sites in the middle segment of the proximal renal tubule
• This decreases the net reabsorption of uric acid

Pharmacokinetics of Uricosuric Agents

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

Adverse Effects of Uricosuric Agents

• Well tolerated by most patients
• Can cause G.I. irritation
• Sulfinpyrazone is worse
• Can cause rash, allergic dermatitis, nephrotic syndrome, and aplastic anemia Allergic dermatitis and nephrotic syndrome is likely to be caused by Probenecid
• Aplastic anemia is rare for both Probenecid and Sulfinpyrazone

Therapeutic Indications of Uricosuric Agents

• Used after several acute gouty attacks and when there is evidence of tophi
• Chronic use may decrease acute gouty attacks, prevent renal damage & tophi deposition
• Occasionally used in low dose to reduce renal tubular excretion of penicillins to potentiate their therapeutic effect
• Requires supportive therapy
• Increase fluid intake
• Alkalinization of urine (sodium bicarbonate) to prevent renal calculi formation

Drug Interactions of Uricosuric Agents

• Decreases Renal Transport of:
  • Sulfinpyrazone
  • Indomethacin,
  • Penicillin
  • Sulfonamides
• Salicylates (aspirin) - at low doses (analgesic, antipyretic) inhibits uricosuric effect
• Increase renal excretion of alloxanthine
• Contraindicated for patients with renal insufficiency (kidney stones)

Pegloticase (Krystexxa)

• Recombinant mammalian uricase (Urate oxidase) converts uric acid to soluble allantoin

• Covalently attached to methoxypolyethylene glycol (mPEG) to prolong the circulating halt-life and diminish immunogenic response

• 8 mg is administered every 2 weeks via intravenous infusion

• Maintains low urate levels for up to 21 days

Adverse Effects of Pegloticase

• Gout flare during the first 3–6 months requires prophylaxis with NSAIDs or colchicine

• Many patients show an immune response leading to reduced effectiveness

• Can lead to anaphylaxis in around 6–15% of patients

• Can result in: Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea

• Less frequent side effects noted, include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea

• Avoid in G6PD deficiency concern for hemolytic anemia because uricase forms hydrogen peroxide

• Used for treatment refractory chronic gout

Rasburicase (Elitek)

• A recombinant urate oxidase

• Used for the Prevention and treatment of hyperuricemia in patients receiving chemotherapy

• Converts uric acid to more soluble allantoin, which is renally excreted

Indications of Rasburicase

• It is used for the Initial management of plasma uric acid levels in adults and children with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis syndrome and subsequent elevations of plasma uric acid

It is administered via intravenous infusion

Adverse Effects

• < 1% of Patients may experience: anaphylactic shock, hemolysis (avoid in G6PD deficiency), and methemoglobinemia

• Most Frequent side effects (over 1 percent of patients) 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 involves

• Treating Acute gouty attacks by giving: colchicine or Indomethacin

• Chronic therapy aims to control 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)

• For urate amounts of > 600 mg daily (normalallopurinol is preferred, or if renal function is impaired

• For 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 Initial therapy with uricosuric agents may precipitate acute attacks

• Therefore a prophylactic small dose of colchicine may be beneficial

• Alkalinization of urine increase in uric acid excretion and prevents renal calculi

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

• Concurrent therapy of allopurinol & uricosuric agent may decrease the effectiveness of each other-Dosage adjustment may be required

• All treatments provide symptomatic relief only: increase reabsorption of tophi in tophaceous gouty state, prevent development of nephrolithiasis, and prevents the progression of chronic gouty arthritis to increase mobility