Pharmacotherapy of Gout

07/08/2022 By; Abera J 1

 Learning Objectives
• Upon completion of the chapter, the students will be able to:

– Explain the pathophysiology of gout and hyperuricemia,

– Recognize major RFs for dev’t of gout,

– Identify signs and symptoms of gout,

– Develop a pharmacotherapeutic plan for a Pt.’ with gout,
– Select an appropriate drug for Pt.’s with gout, and

– Outline a plan for monitoring efficacy and toxicity.

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 Gout

– A heterogeneous clinical spectrum of diseases:-

• Elevated serum urate concentration (hyperuricemia)

– > 7 mg/dL for men and > 6 mg/dL for women

• Recurrent attacks of acute arthritis associated with

monosodium urate (MSU) crystals in synovial fluid leukocytes

• Deposits of MSU (tophi) in tissues in and around joints

• Interstitial renal disease, and UA nephrolithiasis

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 Gout…
• Gout can occur from either;
– Overproduction or
– Under excretion of UA (90% of Pt.’s)
• Overproduction of UA;
– Origins of purines in the body;
• Dietary purine
• Conversion of tissue nucleic acid into purine
nucleotides, and
• De novo synthesis of purine bases
– UA may accumulate excessively if production
exceeds excretion

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 Gout…
• Under excretion of UA;
– Hyperuricemia can be caused by;
• A decline in the urinary excretion of UA to a
level below the rate of production
– Drugs that decrease renal clearance of UA;
• Diuretics, Ethanol, Ethambutol, Nicotinic acid,
Pyrazinamide
• Cytotoxic drugs, Cyclosporine, Levodopa,
Salicylates

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 Gout…

• To differentiate overproducers or under excreters;

– Make purine-free diet for 3 to 5 days
– Measure UA excretion in the urine in 24 hours
• If;
– UA excreted is > 600 mg: overproducer
– UA excreted is < 600 mg: under excreter

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 Pathophysiology of Gout
• Gout is caused by an abnormality in UA metabolism.
– UA is a waste product of purine breakdown contained in
the DNA of degraded body cells and dietary protein.
– It is water soluble and excreted primarily by the kidneys.
– UA solubility is dependent on concentration and
temperature.
– At high serum concentrations, lower body temperature
causes the precipitation of MSU crystals.

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 Pathophysiology of Gout…
• When the urate precipitates and deposits in joints as MSU crystals
– Leukocytes are attracted to the synovial space
• In order to phagocytize the urate crystals

– Lysis of cells and a discharge of lysosomal and proteolytic
enzyme  an inflammatory response
– Clinical manifestation of the disease
» such as pain and swelling,
» If left untreated, can lead to cartilage and joint
destruction.

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 Stages of Gout
– Asymptomatic

– Acute

– Intercritical

– Chronic

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 Stages of Gout…
• Asymptomatic
– When Pt.’s have hyperuricemia without any symptoms of
gout
– Gout can only be determined with the measurement of
SUA level or imaging techniques
• Acute
– Severe and sudden onset
– Involve one or a few joints
– Frequently starts nocturnally
– Joint is warm, red, and tender

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 Stages of Gout…
• Gouty Attacks
– Over time, attacks will occur more frequently,
affect more joints, and last longer
– Usually sudden in onset and nocturnal
– As the attacks become repeated and prolonged,
the Pt.’s enters the chronic phase, characterized
by the development of tophi

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 Stages of Gout…
• Intercritical
– The period of time between two gout attacks
– Ongoing deposition of urate crystals in joints
– Treatment during this periods,
• Prevent joint damage and destruction
• This phase is painless and can last indefinitely

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 Stages of Gout…
• Chronic
– Continuous or persistent over a long period of time
– After approximately 10 years of recurrent attacks,
tophi will likely develop
– Accumulations of MSU crystals in subcutaneous
tissue, synovial membranes, tendons, and soft tissues
– Deposits of the crystals in the renal tubules can also
lead to renal calculi and nephropathy

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 Clinical Presentation and Diagnosis

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 Clinical presentation and Diagnosis…
• Laboratory tests
– Elevated SUA levels
• > 7 mg/dL for men and > 6 mg/dL for women
– Leukocytosis
– Aspiration of synovial fluid
• Observation of MSU crystals in synovial fluid or a
tophus-allows definitive diagnosis
– Radiographs: for Pt.’s with long-standing gout
• May show asymmetric swelling within a joint
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 Treatment

• Goals of therapy

– To terminate the acute attack

– To prevent recurrent attacks

– To prevent disease complications

– Avoid treatment-related AEs

– Improve QoL

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 Treatment…

• Two major phases in the management of gout;

– Treatment of the acute inflammatory flare

– Chronic management

• To prevent further episodes by reducing SUA

levels

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 Treatment of Acute Gout
• First-line therapy
– NSAIDs,
– Colchicine, and
– Ccorticosteroids
• Selection of each agent depends;
– On number of joints affected,
– Presence/absence of infection,
– Prior response, and
– Pt factors such as comorbidities and renal function

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 NSAIDs

– Mainstay of therapy for acute attacks of gouty

arthritis

– No NSAID is more effective than the other

– Excellent efficacy and minimal toxicity with short-

term use

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 NSAIDs…
 Timing of pharmacotherapy determines outcome;
– Most effective when given within the first 24
hours of the onset of pain
• Resolution of an acute attack within 5 to 8 days
after initiating therapy
• Only naproxen, indomethacin, and sulindac are FDA
approved for treatment of acute gout.

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 NSAIDs…
• Includes:
– Indomethacin: 50 mg TID
– Naproxen: 250 mg TID
– Ibuprofen: 400 mg TID
– Sulindac: 200 mg BID

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 NSAIDs…
• SEs
– GI system (gastritis, bleeding, perforation)
• Use selective COX-2 inhibitors: etoricoxib and
lumiracoxib
– Kidneys (renal papillary necrosis, reduced CrCL)
– CV system (sodium and fluid retention, increased BP)
– CNS (impaired cognitive function, headache,
dizziness)

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 Colchicine
• Interfere with the function of mitotic spindles in
neutrophils by binding of tubulin dimers;
– This inhibits phagocytic activity.
• Should be started within the first 12-36 hours of an acute
attack
• Cause dose-dependent GI AEs including N/V and diarrhea
• Other AEs include neutropenia and axonal neuromyopathy
• Dose:
– Initial: 1.2 mg followed by 0.6 mg 1 hour later
– Maintenance: 0.6 mg once or twice daily started 12 hours
following the initial dose

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 Corticosteroids

• Used either systemically or by intraarticular injection

– Intraarticular or oral corticosteroids
• If only one or two joints are involved
– Parenteral corticosteroids
• If an attack is polyarticular
• Gradually taper dose when discontinuing steroid
therapy

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 Corticosteroid…
• Dose
– Prednisone or prednisolone (PO)
• 0.5 mg/kg daily for 5 to 10 days followed by abrupt
discontinuation or
• 0.5 mg/kg daily for 2 to 5 days followed by tapering for
7 to 10 days
– Methylprednisolone (IM)
• Start with 24 mg on day 1 and decrease by 4 mg each
day for 6 consecutive days
– Triamcinolone acetonide (intraarticular): 20 -40 mg

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 Pharmacotherapy Regimens for Acute Gout Treatment

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 Management of Chronic Gout
• To prevent further crystal accumulation and recurrent
gouty flares
• Therapy should be initiated 1-2 weeks after an acute attack
has resolved
• Generally started for Pt.’s with;
– Two or more attacks per year
– Tophi
– Nephrolithiasis
– CKD (stage 2 or worse)

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 Management of Chronic Gout…

• Two classes of drugs can achieve long-term reduction of SUA:

• Xanthine oxidase inhibitors
• Uricosurics
• Goal of initiating urate-lowering therapies
– To achieve and maintain a SUA concentration of less
than 6 mg/dL and preferably below 5 mg/dL

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 Xanthine oxidase inhibitors

• Allopurinol
– Reduce UA concentration by;
• Impairing the ability of xanthine oxidase to convert
hypoxanthine to xanthine and xanthine to UA
– Effective in both underexcreters and overproducers of UA
• Dose
– 100-800 mg/day titrated every 2 to 5 weeks according to
serum urate level

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 Xanthine oxidase inhibitors…

Allopurinol…
• AEs
– Mild: skin rash, leukopenia, GI problems, headache, and
urticaria
– Severe: severe rash (TEN, erythema multiforme, or
exfoliative dermatitis), hepatitis, interstitial, and nephritis
• Occur in approximately 1:1,000 Pt.’s
• Associated with a 20% to 25% mortality
• Exacerbated by renal insufficiency and thiazide diuretics

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 Xanthine oxidase inhibitors…

• Febuxostat
– A xanthine oxidase inhibitor
– Similar efficacy as that of allopurinol
– Dose: 40-80 mg/ day
– AEs: nausea, arthralgia, and minor liver
transaminase elevations

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 Xanthine oxidase inhibitors…
• Add a low-dose NSAID and Colchicine with

xanthine oxidase inhibitors until;

– The SUA level is stable at <6 mg/dL and

– Acute attacks have been absent for 3 to 6

months

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 Uricosuric agents

• Increase the renal clearance of UA by;

– Inhibiting postsecretory renal proximal tubular
reabsorption of UA
• Probenecid
– Dose: 250 mg BID for 1 to 2 weeks and then 500 mg BID for 2 weeks
– Max dose: 2g
– May cause stone formation

– CI in Pt.s with;
• CrCl <50 mL/min
• Overproducers of UA

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 Uricosuric agents…

• Pt.’s should be willing to drink at least eight glasses of water

per day to decrease the risk of nephrolithiasis

– Avoid concurrent use of ASA with probenecid; because

ASA will block the effect of probenecid

– Probenecid can block excretion of penicillin, increase

serum concentration of furosemide, and extend heparin

metabolism

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 Pharmacotherapy Regimens for Urate Lowering

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 Life style modifications

– Reduce alcohol intake

– Regular exercise
– Weight loss

– Increase water intake

– Watch diet for food rich in purines
• Organ meats, lentils, peas, yeast, beer

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 Diet

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Thank You.

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