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Gout Pharmacotherapy
Ryan L. Crass, PharmD
PGY1 Pharmacy Resident
UK HealthCare
[email protected]
Learning Objectives
1. Understand the pathophysiology of and risk factors for the
development of gouty arthritis
2. Recognize clinical and laboratory findings consistent with
the diagnosis of gout and how they are modified by
treatment
3. Explain the different treatment modalities for acute gout
attacks and long-term prophylaxis
4. Discuss the mechanisms, major adverse effects, and key
drug-drug interactions for the primary medications used in
the treatment and prevention of gout
“The Disease of Kings”
Characterizing the Disease
PATHOPHYSIOLOGY, MANIFESTATIONS, AND DIAGNOSIS
Characterizing Gout
• Gout is a spectrum of clinical features
related to an excess total body burden of
uric acid
• One of the most common adulthood
rheumatic diseases
– about 4% of U.S. adults (~ 8.3 million people)
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Pathophysiology
Hyperuricemia
• Uric acid is byproduct of purine metabolism
• Hyperuricemia occurs when there is an
imbalance in uric acid production and
excretion
– Defined as serum uric acid > 7 mg/dL
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Pathophysiology
Hyperuricemia
Overproduction
Xanthine Oxidase
Xanthine Oxidase
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Underexcretion
Pathophysiology
Gouty Arthritis
• Precipitation of monosodium urate (MSU)
crystals and activation of inflammation
Hyperuricemia
(> 7 mg/dL)
• Overproduction
• Underexcretion
Precipitation of
MSU crystals
• Temperature
• pH
• Concentration
Neutrophil
infiltration and
inflammation
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
• Redness
• Swelling
• Pain
• Warmth
Risk Factors
•
•
•
•
•
•
•
Hyperuricemia*
Male sex
High purine diet (red meats, shellfish)
Beer and alcohol
Obesity and the metabolic syndrome
CKD
Solid organ transplantation
*Hyperuricemia ≠ gout
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Risk Factors
• Medications
– Diuretics (thiazides, loops)
– Calcineurin inhibitors
– Low-dose salicylates
– Niacin
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Clinical Manifestations
Acute Gouty Arthritis (“Flare”)
• Symptoms
– Warmth/swelling
– Severe Pain
– Fever, leukocytosis
• Location:
– Usually monoarticular
• Time course
– Onset: Rapid
– Peak: 8-12 hours
– Duration: 3-10 days
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Chronic Gouty Arhritis
• Chronic Gout
– Polyarticular involvement
– Tophi = urate crystal aggregates
– Nephropathy
Summary
Disease Characteristics
• The pathophysiology of gout is a
dysregulation of the production and/or
excretion of uric acid
• Gout commonly manifests as an acutely
painful monoarticular arthritis with or
without tophi formation
• Modifiable risk factors include diet, lifestyle,
medications, and hyperuricemia
Treatment
ACUTE GOUTY ARTHRITIS
General Principles
• Maintenance ULT should be continued
during attacks
• Timing
– Therapy should be initiated within 24 hours
AND
– Continued until resolution of symptoms
*ULT = Urate lowering therapy
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Pharmacotherapy
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
NSAIDs
NSAIDs (naproxen, indomethacin, sulindac)
Mechanism
Inhibition of cyclooxygenase (COX) enzymes reducing
prostaglandin synthesis
Dose
Full antiinflammatory doses
- Naproxen: 750 mg x1, then 250 mg TID
- Indomethacin: 50 mg TID
- Sulindac: 200 mg BID
Administration
Take with food or dairy
Adverse Events
Common: dysepsia, hypetension, fluid retention
Rare/Serious: GI bleeding, acute kidney injury
Drug Interactions Antiplatelets/anticoagulants, antihypertensives, corticosteroids
Pearls
- Generally not used in combination with systemic steroids
- Do not use salicylates as can disrupt uric acid levels
- Antiinflammatory doses of other NSAIDs may be effective
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Systemic Corticosteroids
Corticosteroids (prednisone, prednisolone, methylprednisolone)
Mechanism
Broad range of effects leading to reduced neutrophil
infiltration and cytokine release
Dose
1. Pulse: 0.5 mg/kg/day x 5-10 days
2. Taper: 0.5 mg/kg/day x 2-5 days, then taper over 7-10 days
3. Methyprednisolone dose pack
Administration
Take with food and early in the day
Adverse Events
Common: hyperglycemia, hypertension, edema, insomnia
Rare/Serious: delayed wound healing, osteoporosis
Drug Interactions
NSAIDS*, fluoroquinolones
Pearls
- Generally not used in combination with NSAIDs
- May exacerbate underlying hypertension or diabetes
- Consider adding intraarticular steroids to any modality if
1-2 large joints affected
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Colchicine
Colchicine (Colcrys®)
Mechanism
Inhibits beta-tubulin polymyerization leading to decreased
neutrophil chemotaxis and inflammation
Dose
Acute Gout Attack: 1.2 mg, then 0.6 mg 1-hour later.
Prophylaxis dosing starting 12 hours later
Prophylaxis: 0.6 mg QD – BID
Administration
Take with a full class of water
Adverse Events
Common: GI distress (diarrhea, N&V)
Rare/Serious: myelosuppression, myopathy
Drug Interactions
CYP3A4/P-gp substrate (Avoid strong inducers/inhibitors)
Pearls
- Treatment generally titrated to diarrhea
- Do not repeat treatment courses within 14 days
- Contraindicated with renal or hepatic impairment AND a
strong CYP3A4/P-gp inhibitor
Colcrys®. [package insert]:Philadelphia, PA. AR Scientific, INC;2009.
Evaluating Response
ULT should start 6-8 weeks
after resolution of acute attack
Criteria for Inadequate Response
↓ < 20% in pain score within 24 hours
↓ < 50% in pain score beyond 24 hours
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Summary:
Acute Gouty Arthritis
• Pharmacotherapy is the mainstay of acute
gout treatment
• NSAIDs, systemic cortiocosteroids, and
colchcine are all first line options and choice
of agent should be guided by patientspecific factors
• Combination therapy can be used for severe
attacks
Treatment
MAINTENANCE URATE LOWERING THERAPY
Non-pharmacologic Therapy
• Dietary and lifestyle modifications
– Consume in moderation
• Alcohol, red meat, shellfish, sweets
– Weight loss
– Tobacco cessation
– Appropriate hydration
• Minimize non-essential medications that
may induce hyperuricemia
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Who should receive ULT?
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Which agents are first line?
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Xanthine Oxidase Inhibitors
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Allopurinol
Allopurinol (Zyloprim®)
Mechanism
Xanthine oxidase inhibitor (XOI)
Dose
Initial: 100 mg QD
Titrate: q2-5 weeks until uric acid target achieved
Max Dose: 800 mg/day divided
Administration
Take with or without meals
Adverse Events
Common: Rash, pruritis, transaminitis
Rare/Serious: myelosuppression, hepatotoxicity, SJS/TEN
Drug Interactions
Purine antimetabolites (azathioprine, 6-mercaptopurine),
theophylline, didanosine
Pearls
- Dose is titrated up slowly to avoid acute gout flare
- Dose is reduced by 50% in renal impairment
- Hypersensitivity reaction more common with concurrent
thiazides and in Asian populations (consider HLA-B*5801
screening)
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Febuxostat
Febuxistat (Uloric®)
Mechanism
Xanthine oxidase inhibitor (XOI)
Dose
Initial: 40 mg QD
Titrate: may incease to 80 mg if not at goal in 2 weeks
Max Dose: 120 mg/day
Administration
Take with or without meals
Adverse Events
Common: Rash, gout flare, transaminitis
Rare/Serious: hepatotoxicity, thrombotic events, SJS/TEN
Drug Interactions
Purine antimetabolites (azathioprine, 6-mercaptopurine),
theophylline, didanosine
Pearls
- Consider in patients who do not tolerate allopurinol or
have inadequate response (BRAND only)
- Gout flares more common during initiation of therapy
- Not renally eliminated
Uloric®. [package insert]:Deerfield, IL. Takeda Pharmaceuticals
America, Inc;2013.
CONTRAINDICATION
6-MP
Theophylline
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Uricosurics
fenofibrate
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Probenecid
Probenecid
Mechanism
Inhibits the uric acid – organic anion transport pathway
Dose
Initial: 250 mg BID x 1 week
Titrate: 500 mg/day increments every 4 weeks
Max Dose: 2 g/day
Administration
Take with food and plenty of fluids
Adverse Events
Common: GI intolerance (dyspepsia, reflux), rash, acute gout
Rare/Serious: nephrolithiasis
Drug Interactions
Significant – inhibits secretory elimination of anionic drugs
Pearls
- No benefit if CrCL < 30-50 mL/min
- Can be used therapeutically to boost beta-lactam levels
- Monitor urinary uric acid excretion before and during
therapy
- Contraindicated: history of nephrolithiasis
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Prophylaxis When Initiating ULT
6-8 weeks
after acute
attack
resolution
Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.
Treatment-Resistant Gout
• Referral to a rheumatologist
– Refractory signs and symptoms
– Difficulty reaching serum uric acid target,
particularly with renal impairment and trial of
XOI
– Multiple/serious adverse effects to treatment
Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.
Uricase Enzyme
Rasburicase (Elitek®)
Pegloticase (Krystexxa®)
Teng GG, et al. Drugs. 2006;66(12):1547-1563.
Medicinal
Chemistry
Hot Off the Press
http://www.fda.gov/NewsEvents/Newsroom
/PressAnnouncements/ucm478791.htm
Lesinurad (Zurampic®)
Probenecid
Mechanism
Selective inhibitor of URAT1 and OAT4 (diuretic-induced)
Dose
200 mg QD with a XOI
Administration
Take with food and plenty of fluids (2L/day) at the same
time as XOI
Adverse Events
Common: Headache, reflux, influenza
Rare/Serious: Acute renal failure (monotherapy)
Drug Interactions
CYP2C9 inhibitors/inducers
Pearls
- Contraindicated: monotherapy or with CrCL < 45 mL/min
- Limited experience and yet to define place in therapy
Zurampic®. [package insert]:Wilmington, DE. AstraZeneca
Pharmaceuticals LP;2015.
Summary:
Urate Lowering Therapy
• Maintenance ULT is indicated in significant
disease burden and renal comorbidities
• Xanthine oxidase inhibitors are the mainstay
of therapy to target uric acid levels of at
least < 6 mg/dL
• Uricosuric agents are alternatives to XOIs
and useful adjuncts in resistant disease
Take Away Points
• Gout is a common rheumatic disease that can
be largely “cured” with pharmacotherapy
• Medication selection during acute attacks
should be guided by patient-specific factors
• Maintenance ULT is largely well tolerated by
some significant drug-drug interactions exist
and most medications should be adjusted for
renal dysfunction
Patient Case
• Doran Martell is a 58 YOM with PMHx HTN,
HLD, T2DM, DVT who presents with a chief
complaint of swelling and excruciating pain
in his right foot.
Patient Case
• Doran Martell supplies the following history
– Diet: Eats shellfish frequently due to proximity
to the sea, red meat on weekends
– EtOH: Drinks 3-4 ales/day
– Exercise: Little physical activity
Medications
•
•
•
•
•
•
ASA 325 mg q4-6 PRN pain
Valsartan 160 mg QD
HCTZ 25 mg QD
Niacin OTC capsules QD
Simvastatin 20 mg QHS
Warfarin 5 mg QMWF & 2.5 mg QTuThSaSu
Patient Counseling
• What modifiable risk factors could you
counsel this patient on?
• Which medications may exacerbate gout?
Physical Exam Findings
Erythema, tenderness,
and swelling in the right
great toe
Patient Case
• Labs
– A1c 5.9%
– Scr: 1.4 (CrCL ~ 59 mL/min)
– LFTs: WNL
– Uric Acid: 9 mg/dL
• Vitals
– BP: 150/94 | HR: 87 | RR: 16
Medications
•
•
•
•
•
•
ASA 325 mg q4-6 PRN pain
Valsartan 160 mg QD
HCTZ 25 mg QD
Niacin OTC capsules QD
Simvastatin 20 mg QHS
Warfarin 5 mg QMWF & 2.5 mg QTuThSaSu
Patient Case
• With your neighbor discuss:
– Which laboratory/physical exam findings are
consistent with acute gout?
– Which medication(s) you want initiate for Doran
Martell’s acute gout attack? Why?
Patient Case
• One year later, Prince Doran returns to clinic
for follow up (he was swept away in wars
and intrigue and missed his other follow
ups). This is his physical exam today:
Patient Case
• He is asymptomatic but has tophi on
examination. He has made the dietary and
lifestyle modifications you discussed
previously. What therapy would you like to
initiate?
Questions?