What are some of the therapeutic goals for treating gout?
1. Increase excretion of uric acid 2. Inhibit inflammatory cells 3. Inhibit uric acid biosynthesis 4. Provide symptomatic relief (NSAIDs or steroids -- short-term)
Used within the first 24 hours
What should NOT be used to treat gout?
Aspirin -- inhibits uric acid secretion at low dose
Provides symptomatic relief in patients that can't take NSAIDs
Short term use
Adverse effects with extended use
No effect on uric acid excretion
Antimitotic: arrests cell division n G1 by interfering with microtubule and spindle formation
Binds to microtubles in inflammatory cells = neutrophils: inhibits neutrophil activation and migration
Lessens the symptoms of inflammation
How is colchicine metabolized?
Rapid absorption but variability
Large volume of distribution
Metabolized by CYP450
Substrate for P-glycoprotein (transmembrane protein that eliminates drugs)
What are some adverse effects of colchicine?
Narrow therapeutic-toxicity window
GI: nausea, vomiting, diarrhea, abdominal pain
Usually a latent period before symptoms
Effects rapid proliferating cells of GI
What are some contraindications of colchicine?
Hepatic/renal disease (decrease dose or less frequent dosing)
Especially if also taking CYP3A4 or P-gp inhibitor
Reasion = increase concentration of colchicine
How is colchicine used therapeutically?
Acute gout attacks (within hours)
Prophylactically in patients with chronic gout
Tends not to be the drug of choice because of adverse effects
When is it appropriate to use prophylactical therapy for gout?
Urate nephrolithiasis (uric acid stones)
Tophaceous gout: nodular masses of uric acid crystals (tophi) are deposited in different soft tissue areas of the body
What are some non-pharmacologial measures individuals with gout should take?
Abstain from alcohol
Discontinue medicine that impair uric acid excretion (aspirin, thiazide diuretics)
Inhibits terminal steps in uric acid biosynthesis
Blocks xanthine oxidase
Decreases plasma uric acid concentration, uric acid crystals dissolve
How is allopurinol metabolized?
Structural analog of hypoxanthine
Converted to oxypurinol by aldehyde oxidoreductase
Plasma half-life prolonged:
allopurinol (1-2 hours)
oxypurinol (18-30 hours)
What are some adverse effects of allopurinol?
Hypersensitivity: increases if taken with ACE inhibitors, thiazide diuretics, amoxicillin
Acute gout attack: mobilizes tissue stores of uric acid, give the drug with colchicine or NSAID
What are the therapeutic uses of allopurinol?
Prevention of primary hyperurecemia of chronic gout
Severe forms of gouty nephropathy, tophaceous deposits, renal urate stones
Prophylactic treatment in secondary forms of hyperurecemia due to hematological disorders of anti-neoplastic therapy
Non-purine xanthine oxidase inhibitor
Forms a stable complex with both the reduced and oxidized form of xanthine oxidase and inhibits catalytic function in both states
Comparison of Allopurinol and Febuxostat.
- Febuxostat is more potent than allopurinol
- Febuxostat is more effective than allopurinol in the subset of patients with imparied renal function
- Incidence of adverse events (dizziness, diarrhea, headache, nausea) similar with both drugs
- Incidence of CV side effects (antiplatelet trialists collaboration events) was numerically higher with febuxostat than allopurinol
Converts uric acid to allantoin (an inactive and water soluble metabolite of uric acid)
PEGylated recombinant form of urate oxidase enzyme (uricase -- normally absent in humans)
What are the pharmacokinetics of Pegloticase?
Intravenous administration (every 2 weeks)
What are some adverse effects of Pegloticase?
Infusion site reactions
Gout flare: provide prophylaxis for acute gout flares
Immune response: can form antibodies directed at PEG portion of molecule
What is Pegloticase therapeutically used for?
Refractory chronic gout
What are uricosuric agents?
Give an example.
Something that increases the rate of excretion of uric acid
How does probenecid increase uric acid exretion?
Increases uric acid secretion by competing with the renal tubular acid transporter so that less urate is reabsorbed
What are the pharmacokinetics of Probenecid?
Plasma protein binding
What are some adverse effects of probenecid?
Some GI side effects
Ineffective in patients wtih renal insufficiency
Contraindicated in patient with uric acid kidney stones
What is Probenecid therapeutically used for?
Used for chronic gout but rarely in patients with any kidney disease or overproducers of uric acid...more likely to produce uric acid stones
What are some drug interactions with Probenecid?
Interfere with renal excretion of drugs that undergo active tubular secretion, especially weak acids.
Inhibition of glucuronide conjugation of other drugs.
Methotrexate, Clofibrate, Palatrexate, Penicillin, Salicylates
Other gout drug interactions
Plasma levels of drugs that are metabolized by xanthine oxidase increase -- possibly to toxic levels when administered with allopurinol or febuxostat.
Life-threatening toxicities are associated with administration of concomitant therapy with P-glycoprotein or CYP3A4 inhibitors or colchicine