Gout Medications

Gout medications include antiinflammatory and urate-lowering medications. Colchicine is an antiinflammatory medication that can be used for acute gout flares. The urate-lowering drug classes include the xanthine oxidase inhibitors, uricosuric agents, and uricases. These medications are beneficial for the prevention of gout exacerbations and work through a variety of mechanisms. Xanthine oxidase inhibitors are the most commonly used urate-lowering therapy; these work by inhibiting the enzyme necessary for the conversion of purines to uric acid. Uricosuric agents reduce reabsorption of uric acid by the proximal tubule, thereby increasing renal excretion. Lastly, the urases are recombinant enzymes that metabolize uric acid to allantoin. In addition to gout, urate-lowering treatment can also be used for other indications, such as the prevention of tumor lysis syndrome and uric acid nephrolithiasis.

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Overview

Gout pathophysiology

  • Gout is a metabolic disease associated with: 
    • ↑ Serum uric acid levels (> 6.8 mg/dL) 
    • Abnormal deposits of monosodium urate in tissues
  • Uric acid:
    • Produced from purine compounds (synthesized in the body or comes from foods)
    • Excreted mainly through the kidneys
  • Hyperuricemia is due to overproduction and/or underexcretion of uric acid → supersaturation → deposition of monosodium urate crystals in the tissues
  • Monosodium urate crystals:
    • Can erode the bone and damage other tissues, such as tendons and cartilage
    • Cause recurrent monoarticular arthritis and chronic deforming arthritis 
  • The precise relationship between hyperuricemia and gout is unclear:
    • The majority (90%) of people with hyperuricemia do not have gout.
    • Normal or low serum uric acid levels do not rule out gout.
    • All individuals with gout will have hyperuricemia at some point, although levels may fluctuate.

Management options

  • Antiinflammatory therapies:
    • NSAIDs
    • Glucocorticoids
    • Colchicine
  • Urate-lowering therapies:
    • ↓ Uric acid production: xanthine oxidase inhibitors
    • ↑ Uric acid excretion: uricosuric agents
    • ↑ Uric acid metabolism: uricases

Colchicine

Chemistry

Colchicine is an alkaloid extracted from Colchicum autumnale (autumn crocus).

Mechanism of action

  • Antiinflammatory
  • Inhibits microtubule polymerization by binding to tubulin
  • Effects:
    • Inhibits cell mitosis
    • Prevents neutrophil:
      • Migration
      • Activation
      • Degranulation

Pharmacokinetics

Absorption:

  • Rapid oral absorption
  • Food consumption does not affect rate of absorption. 

Distribution: 

  • Concentrates in:
    • Leukocytes
    • Liver
    • Kidneys
    • Spleen
  • Protein binding: approximately 40%

Metabolism: 

  • Hepatic
  • Cytochrome P450 system (CYP3A4)
  • Glucuronidation 

Excretion: 

  • Urine
  • Bile
  • Enterohepatic recirculation is possible.

Indications

Gout:

  • Treatment of acute flares (primarily used by individuals who are unable to take NSAIDs)
  • Prevention of recurrent flares

Other indications include:

  • Calcium pyrophosphate crystal arthritis
  • Acute pericarditis
  • Behçet syndrome
  • Sweet syndrome
  • Familial Mediterranean fever: 
    • ↓ Frequency of attacks
    • ↓ Risk of amyloidosis

Adverse effects

  • GI:
    • Nausea
    • Vomiting
    • Diarrhea 
    • Abdominal cramping/pain
    • Hepatotoxicity
  • Hematologic: 
    • DIC 
    • Leukopenia
    • Granulocytopenia
    • Thrombopenia
    • Aplastic anemia 
  • Neuromuscular: rhabdomyolysis 
  • Genitourinary:
    • Azoospermia
    • Oligospermia
  • Dermatologic: 
    • Alopecia 
    • Maculopapular rash 
  • Nervous system: peripheral neuropathy

Precautions

Caution should be used in individuals with:

  • Severe renal impairment
  • Severe hepatic impairment 
  • Bone marrow suppression

Drug interactions

The following could lead to increased levels of colchicine:

  • P-glycoprotein (efflux transporter) inhibitors:
    • Cyclosporine
    • Ranolazine 
  • CYP3A4 inhibitors:
    • Clarithromycin and erythromycin
    • Itraconazole, fluconazole, and ketoconazole
    • Ritonavir
    • Diltiazem and verapamil
    • Grapefruit juice

Xanthine Oxidase Inhibitors

Chemistry

  • Allopurinol: purine analog (of hypoxanthine, a substrate of xanthine oxidase)
  • Febuxostat: nonpurine

Mechanism of action

  • Normal action of xanthine oxidase:
    • Converts hypoxanthine to xanthine
    • Then converts xanthine to uric acid
  • Allopurinol:
    • Competitive inhibitor of xanthine oxidase
    • Its metabolite, oxypurinol, is a noncompetitive inhibitor. 
  • Febuxostat:
    • Occupies a channel in xanthine oxidase
    • Impairs access to the active site → inhibits enzyme function
  • Overall: both prevent uric acid synthesis → ↓ plasma uric acid concentration → prevent hyperuricemia
Xanthine oxidase inhibitors preventing conversion into uric acid

The xanthine oxidase inhibitors, allopurinol and febuxostat, prevent the conversion of hypoxanthine and xanthine to uric acid.

Image by Lecturio.

Pharmacokinetics

Table: Pharmacokinetics of the xanthine oxidase medications
MedicationAbsorptionDistributionMetabolismExcretion
AllopurinolWell absorbed orallyNegligible protein-binding
  • Hepatic and xanthine oxidase
  • Active metabolites
Urine and feces
FebuxostatHighly protein-bound
  • Hepatic
  • Cytochrome P450 system
  • Active metabolites

Indications

Allopurinol:

  • Gout: 
    • Preferred urate-lowering medication
    • Can be initiated during an acute flare with concurrent antiinflammatory therapy
    • Useful in treating: 
      • Gouty arthritis
      • Skin tophi
      • Uric acid nephropathy
  • Hyperuricemia secondary to malignancy and tumor lysis syndrome
  • Prevention of calcium oxalate or uric acid nephrolithiasis

Febuxostat:

  • Gout: 
    • Used for those who are not able to tolerate allopurinol or who have significant renal impairment
    • Can be initiated during an acute flare with concurrent antiinflammatory therapy.
  • Hyperuricemia
  • Prevention of tumor lysis syndrome

Adverse effects

Allopurinol:

  • Acute gout flare (↓ serum uric acid → mobilization of uric acid crystals from joints and tophi)
  • Hypersensitivity:
    • Pruritus 
    • Fever 
    • Erythematous or maculopapular eruption 
    • Stevens-Johnson syndrome or toxic epidermal necrolysis 
    • Drug reaction with eosinophilia and systemic symptoms (DRESS)
  • GI:
    • Nausea
    • Abdominal pain
    • Anorexia
    • Ageusia
    • Hepatotoxicity
  • Hematologic:
    • Neutropenia
    • Thrombocytopenia
    • Aplastic anemia

Febuxostat:

  • Acute gout flare
  • GI: 
    • Nausea
    • Diarrhea 
    • ↑ Transaminases
  • Dermatology: rash 
  • Neuromuscular:
    • Headache
    • Arthralgia

Contraindications

  • Allopurinol: individuals with HLA-B5801 allele → ↑ risk of severe hypersensitivity reactions
  • Febuxostat: individuals with cardiovascular disease → ↑ risk of heart-related death

Drug interactions

Xanthine oxidase inhibitors can lead to an increased concentration of 6-mercaptopurine and azathioprine (which are metabolized by xanthine oxidase).

Uricosuric Drugs

Mechanism of action

  • Normal physiology:
    • Uric acid is filtered at the glomerulus.
    • 90% is reabsorbed in the proximal tubule.
    • Only a small amount is excreted in the urine.
  • Uricosuric medications: ↑ excretion of uric acid in the urine → ↓ serum uric acid
    • Probenecid:
      • Competitively inhibits the transporter responsible for uric acid reabsorption
      • Probenecid is reabsorbed, not uric acid.
    • Lesinurad: similar mechanism of action

Pharmacokinetics

Table: Pharmacokinetics of the uricosuric medications
MedicationAbsorptionDistributionMetabolismExcretion
ProbenecidRapid, well absorbedHighly protein-boundHepaticUrine
LesinuradHepatic, cytochrome P450Urine and feces

Indications

Uricosuric agents are uncommonly used for the treatment of hyperuricemia and chronic gout.

  • Used in individuals whose conditions have not appropriately responded to monotherapy with xanthine oxidase inhibitors
  • Probenecid: 
    • Can be used as monotherapy
    • May be ineffective in moderate to severe chronic kidney disease
  • Lesinurad is used in combination with a xanthine oxidase inhibitor.

Adverse effects

Probenecid:

  • Acute gout flare (similar to xanthine oxidase inhibitors)
  • GI: 
    • Nausea and vomiting
    • Anorexia
    • Dyspepsia 
  • CNS:
    • Dizziness 
    • Headache 
  • Genitourinary:
    • Polyuria
    • Nephrotic syndrome
  • Hematologic:
    • Hemolytic anemia
    • Aplastic anemia

Lesinurad:

  • Acute gout flare
  • CNS: headache
  • GI: gastroesophageal reflux disease
  • Genitourinary:
    • Acute renal failure 
    • Nephrolithiasis

Contraindications

  • Severe renal impairment
  • Kidney transplantation
  • Probenecid: uric acid nephrolithiasis
  • Lesinurad: tumor lysis syndrome

Drug interactions

The following drug interactions are associated with probenecid:

  • ↓ Urinary excretion of: 
    • Penicillin
    • Cephalosporins
    • Methotrexate 
  • Salicylates → ↓ probenecid effect

Uricases

Medications in this class

  • Pegloticase
  • Rasburicase

Chemistry

These medications are classified as recombinant urate oxidases (uricases).

Mechanism of action

The uricases metabolize uric acid to allantoin, which is: 

  • More soluble than uric acid
  • Unlikely to precipitate

Indications

Pegloticase:

  • Used for advanced or chronic gout that is refractory to other therapies
  • Not used for asymptomatic hyperuricemia
  • Should not to be used in combination with other urate-lowering agents

Rasburicase:

  • Used to treat hyperuricemia related to malignancy and tumor lysis syndrome
  • Not FDA-approved for treatment of gout

Adverse effects

  • GI: 
    • Nausea and vomiting
    • Diarrhea 
    • Constipation
  • Dermatologic: 
    • Rash 
    • Urticaria 
  • Immunologic:
    • Development of antibodies to the medication
    • Anaphylaxis
  • Cardiovascular:
    • Peripheral edema
    • Supraventricular arrhythmia

Contraindications

The uricases should not be used for individuals with glucose-6-phosphatase dehydrogenase (G6PD) deficiency (can precipitate severe hemolysis).

References

  1. Cleveland Clinic. (n.d.). Gout: what is it, symptoms, causes, treatment. Retrieved October 1, 2021, from https://my.clevelandclinic.org/health/diseases/4755-gout
  2. CDC. (2020). Gout, arthritis. https://www.cdc.gov/arthritis/basics/gout.html
  3. Hilal-Dandan, R., et al. (2014). Goodman and Gilman’s Manual of Pharmacology and Therapeutics. Open WorldCat, http://accesspharmacy.mhmedical.com/book.aspx?bookid=1810.
  4. Rang, H.P., Dale, M.M. (Eds.). (2016). Rang and Dale’s Pharmacology, 8th ed. Elsevier, Churchill Livingstone.
  5. Johns Hopkins Arthritis Center. Gout treatment : medications and lifestyle adjustments to lower uric acid. Retrieved October 1, 2021, from https://www.hopkinsarthritis.org/arthritis-info/gout/gout-treatment/
  6. Perez-Ruiz, F. (2020). Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout. UpToDate. Retrieved October 1, 2021, from https://www.uptodate.com/contents/pharmacologic-urate-lowering-therapy-and-treatment-of-tophi-in-patients-with-gout 
  7. Sadiq, N.M., Robinson, K.J., Terrell, J.M. (2021). Colchicine. StatPearls. Retrieved October 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK431102/
  8. Gerriets, V., Jialal, I. (2021). Febuxostat. StatPearls. Retrieved October 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544239/
  9. Qurie, A., Banal, P., Goyal, A., Musa, R. (2021). Allopurinol. StatPearls. Retrieved October 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK499942/
  10. First, D.E., Ulrich, R.W., Prakash, S. (2012). Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, and drugs used in gout. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, pp. 635–657. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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