Allopurinol (Zyloprim®) versus Colchicine (Colcrys®)

Based on "Basic and Clinical Pharmacology"
written by Bertram G. Katzung, MD, PhD

Difference between Allopurinol and Colchicine

Table 1. Comparison of Allopurinol and Colchicine

Allopurinol	Colchicine
Brand names
Zyloprim® Aloprim®	Colcrys® Mitigare®
Drug class
Antigout agents
Antihyperuricemic agent, Xanthine oxidase inhibitor	Colchicum alkaloid
Dose formulations
• tablets • powder for injection	• tablets
Legal status
• Rx only • Not a controlled drug
FDA-approved indications
• Gout (prevention of acute attacks, tophi deposition, joint destruction, uric acid lithiasis, promotion of tophaceous deposits resolution). • Recurrent calcium oxalate kidney stones • Hyperuricemia Notes • Allopurinol is NOT used for asymptomatic gout. • The drug can be used in both over producers and under excretors of uric acid.	• Acute Gout. Colchicine significantly relieves acute attacks of gout. Colchicine is fastest acting drug to control an acute gout attacks 2 • Familial Mediterranean fever (FMF) • Prophylaxis of gout flares (only Mitigare®)
"Off-label" uses
• Lesch-Nyhan syndrome-associated hyperuricemia • Prevention of tissue damage due to free radical formation • Protozoal diseases • Inflammatory bowel disease (as adjuvant medication) 9 • Refractory epilepsy (as adjuvant medication) 10 • Schizophrenia(as adjuvant medication) 11 • Lesch-Nyhan syndrome-associated hyperuricemia • Cardioprotective effect 12	• Prophylaxis of acute flares during initiation of allopurinol for chronic gouty arthritis 3 • Behcet's syndrome • Canker sores (aphthous stomatitis) 6 • Sweet's syndrome • Scleroderma • Liver disease 7 • Osteoarthritis (pain and symptom relieving) 8 • Pericarditis 4 • Artherosclerosis 4 • Acute myocardial infarction (improves cardiac function and survival after MI) 5 • Gout diagnostic aid
Mechanism of action
Allopurinol works as urate-lowering agent through inhibition of the enzyme xanthine oxidase required for the conversion of hypoxanthine and xanthine to uric acid. With allopurinol therapy the blood level of uric acid and its renal excretion are reduced. Allopurinol is an analog of hypoxanthine. Its active metabolite, oxypurinol, an analog of xanthine, also inhibits xanthine oxidase.	Colchicine works as an anti-inflammatory agent. Colchicine modulates many pro- and anti-inflammatory pathways associated with acute inflammation in gouty arthritis and interferes with multiple cell functions. It blocks the assembly and polymerization of microtubules and thereby disrupts inflammasome activation. Colchicine also inhibits activation of innate immune responses. It has anti-fibrotic activities and various effects on endothelial function.
No analgesic action
Onset of action
• Reduction of blood uric acid levels in 1 - 2 days. Maximal reduction of blood uric acid in 7 - 10 days. • Improvement of symptoms is evident in about 6 months.	• Pain relief in about 18 to 24 hours
Half-life
1-2 hours for allopurinol 15 hours for oxipurinol (half-life of allopurinol is dependent on renal function)	27-31 hours
Oral bioavailability
70-90%	45%
Metabolism, Elimination
• Eliminated mainly by glomerular filtration. About 20% of allopurinol is excreted in the feces. Less than 10% of the unchanged drug is excreted in the urine. Oxipurinol is mainly eliminated via the kidneys.	• Colchicine is metabolized in the liver to two main metabolites ( 2-O-demethylcolchicine and 3-O-demethylcolchicine) and one minor metabolite colchiceine. • Eliminated by hepatobiliary excretion. Renal excretion accounts for 10–20% of colchicine.
Contraindications
• Hypersensitivity to allopurinol	• Concomitant use with P-glycoprotein inhibitors or strong CYP3A4 inhibitors (life-threatening toxicity possible).
Warnings
• Hypersensitivity reactions to Allopurinol • Increase in acute attacks of gout following the initiation of Allopurinol therapy	• Renal or hepatic impairment – colchicine clearance is decreased • Bone marrow suppression • Neuromuscular toxicity • In overdose is extremely toxic
Side effects
• Allopurinol usually is well tolerated. • Generally, allopurinol toxicity is attributed to oxipurinol accumulation. So liver or kidney disease increases the risk of side effects. Hypersensitivity • The most common side effects are hypersensitivity reactions, such as pruritic or maculopapular rash, exfoliative dermatitis, malaise, fever. • Allopurinol hypersensitivity may manifest after months of therapy. • Severe hypersensitivity reaction (liver function abnormalities, renal impairment, vasculitis) can possibly progress to toxic epidermal necrolysis & death. • Serious hypersensitivity reactions preclude further use of the drug. • Allergic reactions are more common in people with impaired renal function. Other side effects • diarrhea, nausea, alkaline phosphatase increase • drowsiness • hepatotoxicity	• The most common side effects are gastrointestinal (diarrhoea, nausea, vomiting, and abdominal pain). • Pharyngolaryngeal pain. • Hematologic (leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia). • Elderly are more susceptible to cumulative toxicity of colchicine.
Drug interactions
• ACE Inhibitors (increased risk of hypersensitivity reactions) • Warfarin • Thiazide diuretic • Cytotoxic agents	• P-gp inhibitors (eg. cyclosporine) • Strong CYP3A4 inhibitors (eg. clarithromycin, telithromycin, itraconazole, ketoconazole, nefazodone, and some protease inhibitors) • Grapefruit juice
Pregnancy category
C

Allopurinol advantages over Colchicine

• Allopurinol is the first choice medication for chronic gouty arthritis.
• Allopurinol is particularly effective for severe cases of gout, with tophi or nephrolithiasis.
• Allopurinol may have a beneficial effect on renal function, hypertension and mortality.

• Colchicine is not suitable for chronic therapy.
• Colchicine has a narrow therapeutic window. Overdose can lead to a lethal intoxication.

Colchicine advantages over Allopurinol

• Allopurinol should not be started during acute attack of gout, because the therapy itself, at least during the initial stages, may exacerbate the condition
• Colchicine is very effective for acute attacks of gout. Colchicine rapidly relieves acute pain and inflammation, substantial improvement is achieved within hours.
  

Head-to-head comparative studies

Currently there are no head-to-head comparative trials.

References

• 1. Appelbaum SJ, Mayersohn M, Dorr RT, Perrier D. Allopurinol kinetics and bioavailability. Intravenous, oral and rectal administration. 1982;8(1):93-8.
• 2. Tripathi K. D. Essentials of Medical Pharmacology, 6th edition. New Delhi: Jaypee Brothers Medical Publishers; 2010. p. 214
• 3. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004 Dec;31(12):2429-32.
• 4. Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015 Dec;45(3):341-50
• 5. Fujisue K, Sugamura K, Kurokawa H, et al. Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction. Circ J. 2017 Jul 25;81(8):1174-1182.
• 6. Vaillant L, Samimi M. Aphthous ulcers and oral ulcerations. Presse Med. 2016 Feb;45(2):215-26.
• 7. Nikolaidis N, Kountouras J, Giouleme O, et al. Colchicine treatment of liver fibrosis. Hepatogastroenterology. 2006 Mar-Apr;53(68):281-5.
• 8. Aran S, Malekzadeh S, Seifirad S. A double-blind randomized controlled trial appraising the symptom-modifying effects of colchicine on osteoarthritis of the knee. Clin Exp Rheumatol. 2011 May-Jun;29(3):513-8. PubMed
• 9. Sparrow MP, Hande SA, Friedman S, et al. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol. 2007 Feb;5(2):209-14.
• 10. Togha M, Akhondzadeh S, Motamedi M, et al. Allopurinol as adjunctive therapy in intractable epilepsy: a double-blind and placebo-controlled trial.Arch Med Res. 2007 Apr;38(3):313-6
• 11. Dickerson FB, Stallings CR, Origoni AE, et al. A double-blind trial of adjunctive allopurinol for schizophrenia.Schizophr Res. 2009 Apr;109(1-3):66-9.
• 12. Grimaldi-Bensouda L, Alpérovitch A, Aubrun E, et al. Impact of allopurinol on risk of myocardial infarction.Ann Rheum Dis. 2015 May;74(5):836-42.

Published: September, 2017
Last updated: October 01, 2017