Louise Parent-Stevens, Pharm.D.
Spring 1998
HYPERURICEMIA AND GOUT
Louise Parent-Stevens, Pharm.D.
Spring 1998
HYPERURICEMIA
AND GOUT
To comprehend the pharmacotherapeutic management of hyperuricemia and gout.
Upon completion of the coursework on hyperuricemia and gout the student will be able to:
DiPiro:Pharmacotherapy 3rd Edition--Chapter 86, Hyperuricemia and Gout
I. Definitions:
II. Epidemiology:
III. Pathogenesis and Pathophysiology:
IV. Clinical Presentation:
VI. Prognosis
VII. Treatment of Acute Attack
A. Colchicine
1. Mechanism of action
-decreases inflammatory response through binding of microtubular proteins which interferes with granulocyte mobility
2. Efficacy: somewhat diagnostic for gout because
-90% respond to colchicine if treatment is initiated within a few hours after onset, response rates decline if acute attack is >24hrs old
-colchicine is relatively specific therapy for acute gout
3. Dosing:
-colchicine has a narrow therapeutic index
-doses should be decreased in renal and hepatic dysfunction
but there are no standard guidelines
-PO: 1.2mg stat, then 0.6mg every hour until:
-response is achieved, or
-gastrointestinal toxicity (diarrhea, abd. pain), or
-maximum dose of 12 tablets is taken
-IV: 2mg in 20cc NS infused slowly, may repeat with 1mg in 6hrs
but no more than 4mg in 24hours
-decrease total dose to 2mg/24hrs in elderly patients
or patients who have been on colchicine maintenance
-give only to patients who cannot tolerate the oral tablets
-avoid extravasation because causes soft tissue necrosis
4. Adverse reactions
-gastrointestinal: diarrhea, nausea, vomiting, hemorrhagic
colitis, occurs in 70-80% of patients on oral therapy, less frequent with IV therapy but may see with high doses
-bone marrow depression: cumulative toxicity
-renal dysfunction: toxic side effect seen after large doses,
hematuria, oliguria
-necrosis of soft tissue after extravasation: do not give IM/SQ
B. NSAIDs
1. Mechanism of action:
-anti-inflammatory effects through inhibition of prostaglandin
synthesis and inhibition of motility of PMNs
-not specific for gout—adequate doses will relieve inflammation from any cause
2. Agents and Dosing
-Indomethacin: 75mg stat, 25-50mg q6hr, taper as symptoms resolve (do not use SR dosage form for initial treatment)
-Phenylbutazone: 600mg/day in divided doses, not drug of choice
-very effective but do not use for >one week because of risk of aplastic anemia
-avoid in elderly
-Any non-salicylate NSAIDs should be effective if given in anti-inflammatory doses
-avoid salicylates because of effect on uric acid elimination
C. Intraarticular Steroids:
-effective anti-inflammatory agents
-reserve for patients who cannot tolerate oral colchicine or NSAID therapy and who are not candidates for IV colchicine
-limited to 4 injections per joint per year
-can use:
-methylprednisolone (Depomedrol(r))
-triamcinolone hexocetanide (Aristospan(r))
-dose is dependent on size of joint to be injected
-IM injection of depot corticosteroid product (e.g. DepoMedrolÒ ) or ACTH
-tapering effect of depot product prevents rebound gout attacks
-efficacy comparable to NSAIDs in studies
-limited toxicity due to short term use
VIII. Prophylaxis and Control of Hyperuricemia
-not everyone who has hyperuricemia or an attack of gout needs prophylactic or uric acid lowering therapy. Many hyperuricemic patients will never develop disease and some patients who have an attack of gout will not have a recurrence. In these persons the risk of uric acid lowering therapy may outweigh the benefit
A. When to treat
1. Recurrent attacks: choice of treatment will depend on the frequency of the attacks. Attacks once yearly may be better treated with colchicine/NSAIDs acutely rather than exposing the patient to yearlong therapy. Frequency of attacks >1-2/year are a good indication for prophylactic or uric acid lowering therapy.
2. Tophi: indicator of long-standing disease, will regress/disappear with uric acid lowering therapy, patients with tophi should be treated e even if gout attacks are not frequent
3. Uric acid nephrolithiasis: treatment will prevent further stones (and development of renal dysfunction due to gouty nephropathy?)
B. Goal is to prevent arthritic attacks, gouty arthritis complications and/or decrease uric acid to normal levels
C. Therapy to lower uric acid levels should not be initiated until any acute attack is resolved
D. Initiation of therapy to decrease serum uric acid may precipitate an acute attack, prophylaxis with colchicine or NSAIDs may be given for first 1-2 months of treatment or until uric acid is within normal limits or patients should have acute treatment readily available (e.g. a supply of colchicine or an appropriate NSAID at home.)
E. Dietary restrictions (Table 2)
-generally cannot rely on dietary restrictions to decrease uric acid sufficiently but patients should be made aware of what foods are high in purines
-alcohol intake should be minimized
Table 2: Purine Content of Foodstuffs
| Food
Highest in Purines: (150-825mg/100gm) Sweetbreads Anchovies Sardines Liver Kidneys |
Foods
High in Purines (50-150mg/100gm) Meat, poultry Fish (fresh & saltwater) Lobster, oysters, crabs, eels Dried beans and peas, lentils Spinach Oatmeal, Wheat gem & bran |
| Foods
Lowest in Purines (0-15mg/100gm) Fruits of all kinds Vegetables (unless listed above) Most breads, cereals & cereal products Milk Cheese Eggs Fish roe Nuts of all varieties Fats of all types Sugars, syrups, sweets Gelatin |
|
F. Therapeutic Agents
1. Colchicine and NSAIDs are useful in preventing acute attacks, may be useful for patients with mildly elevated uric acid levels who have 1-3 attacks/year -- possibly safer than uric acid lowering therapy in these patients
a. Colchicine
-low dose (0.5-1.0mg/day) prevents acute arthritic attacks
-does not alter serum uric acid levels
-will not prevent tophi or nephrolithiasis
b. NSAIDs
-any of the agents in therapeutic doses will prevent acute attacks
-like colchicine, will not lower uric acid or prevent tophi or renal stones
-avoid salicylates--at lower doses they will increase uric acid levels
2. Uric Acid Lowering Treatment is indicated for patients with
-frequent recurrent attacks
-tophi
-urate nephropathy or kidney stones
a.Uricosurics:
-inhibit pre and post-secretory components of uric acid resorption
-have greatest efficacy in alkaline urine
-encourage high fluid intake to minimize risk of precipitating uric acid within the kidney and development of stones
-should not be used in patients with history of kidney stones unless stones known not to be uric acid
-are only indicated in patients who underexcrete uric acid
-are ineffective in decreased renal function (CrCl <25ml/min)
i. Probenecid (Benemid(r), others)
-Dosing: 250mg bid up to 3.0gm/day
-Adverse reactions:
-hypersensitivity: rashes +/- fever, anaphylaxis
-gastrointestinal: take with food or milk
-Drug interactions:
-Inhibition of excretion of many drugs through blockage of tubular secretion
-sulfonamides and sulfonylureas
-methotrexate
-rifampin
-penicillin antibiotics
-Salicylates: large doses (>2 gms) inhibit the uricosuric effect of probenecid
ii. Sulfinpyrazone (Anturane(r))
-increased potency vs probenecid
-also has antiplatelet effect at doses of 600-800mg/day
-Dosing: 50mg bid-400mg/day, may go up to 800mg/day
-Adverse reactions
-hypersensitivity reactions (uncommon): rash, may cause bronchoconstriction in patients with ASA intolerance, contraindicated in patients allergic to phenylbutazone/pyrazoles
-gastrointestinal irritation: take with food or milk
-Drug interactions:
-salicylates: doses >2gm/day inhibit the uricosuric effect of sulfinpyrazone
-warfarin: sulfinpyrazone inhibits hepatic metabolism and may cause protein displacement of warfarin
3. Allopurinol (Zyloprim(r), others)
a. Mechanism of action
-blocks uric acid formation through inhibition of xanthine oxidase, decreases excessive rates of purine synthesis
b. Efficacy
-useful in both overproducers and underexcretors
-increases renal elimination of xanthine and hypoxanthine (uric acid precursors), therefore encourage fluid intake and foods that alkalinize urine
c. Dosing
-start at 100mg per day, increase weekly as needed
-70% of patients will be controlled on 300mg/day
-may give up to 1200mg/day if necessary
-may give once daily because of long half life of active metabolite, oxypurinol, but divided doses recommended if total daily dose >300mg
-renal disease requires dose adjustment-recommended initial doses
CrCl ................Dosage
80ml/min 250mg/day 60ml/min 200mg/day 40ml/min 150mg/day 20ml/min 100mg/day 10ml/min 100mg every other day <10ml/min 100mg every third day
(Adapted from: Am J Med 76:55, 1984.)
d. Adverse Reactions
-hypersensitivity rash: maculopapular/purpuric:
-usually occurs within 1st 5 weeks
- with ampicillin treatment
-resolves with drug DC
-rechallenge cautiously—may progress to more severe/fatal reactions
-severe hypersensitivity more common in pts with impaired renal function
-gastrointestinal: nausea, vomiting, abdominal pain -hepatomegaly/nephritis: may be manifestation of a hypersensitivity reaction
e. Drug Interactions
-ampicillin: increased rash
-ACE inhibitors: increased risk of hypersensitivity reactions
-azathioprine: decreased metabolism of azathioprine metabolite, requires dosage adjustment of AZA
-warfarin: increased anticoagulant effect
-cyclophosphamide: enhance bone marrow toxicity of cyclophosphamide
Controversial, no set guidelines, but consider in the following patient groups:
A. Develops symptoms
B. Excretes >900mg of uric acid/24hr: significant risk for kidney stones
C. Serum uric acid >10mg/dl, treatment of asymptomatic uric acid levels <10mg/dl is very controversial
D. Patient with malignancy scheduled for cancer chemotherapy
BF is a 72 year old black male who presents with redness, swelling and pain in his Rt great toe that is unrelieved by ASA or APAP. The pain started early this morning. He denies any trauma but does state that he attended a wedding last evening.
1. What signs and symptoms does BF have that are
consistent with a diagnosis of gout?
2. Could this be drug-induced gout?
3. How would you treat this attack of gout and what
are the advantages and disadvantages of your selected
therapy?
4. What additional information or lab tests would you
want before deciding on long-term therapy?
5. Given the information about this
patient that you currently have, what prophylactic
therapy, if any, would you choose for this patient?
1. What signs and symptoms does BF have that are
consistent with a diagnosis of gout?
The pain, swelling and tenderness were acute in onset.
The Rt great toe is the joint most commonly affected by
gout. The pain was unrelieved by ASA or APAP. He has an
elevated uric acid and a positive family history of gout.
2. Could this be drug-induced gout?
Furosemide can elevate uric acid levels. Unfortunately,
all the loop and thiazide diuretics have similar effects,
so switching to a different diuretic would not be
beneficial. Low dose aspirin (<2gm/day) can cause uric acid levels to rise. More appropriate choice of analgesics would include acetaminophen or non-salicylate NSAIDs since they do not appreciably increase uric acid levels. Alcohol raises uric acid levels and may be responsible for this attack of gout (he attended a wedding the previous evening). He should be counseled to avoid alcohol as much as possible.
3. How would you treat this attack of gout and what
are the advantages and disadvantages of your selected
therapy?
Drug of Choice: Colchicine 1.2mg stat, then 0.6mg qhr
until relief of pain or diarrhea occurs, or 12 tablets
are taken, which ever comes first. Colchicine is
relatively specific for gout, especially when given
within the first 12-24 hours of an attack, so its use
would be somewhat diagnostic. The disadvantage is that it
can cause significant GI distress and in the elderly, the
therapeutic index is probably narrower than in young
patients. NSAIDs, e.g. indomethacin 50mg tid. In this
patient, NSAIDs would not be as desirable as colchicine
because of their sodium retaining effects (pt has CHF)
and their deleterious effects on renal function in
patients on diuretics or who have compromised renal
function (he has both). Also, the elderly are more
sensitive to the CNS effects of the NSAIDs (drowsiness,
dizziness, confusion). However, a short course of NSAID
therapy could be used (<1 wk of treatment) as long as the patient was monitored closely.
4. What additional information or lab tests would you
want before deciding on long-term therapy?
5. What prophylactic therapy, if any, would you choose
for this patient?
This patient needs to be on long-term prophylaxis because
he has long standing hyperuricemia (tophi on the elbow
and ear pinna), has a history of kidney stones that may
be due to hyperuricemia, and his uric acid level is
relatively high (10.1). Although chances are that he is
an underexcretor (90% of patients with hyperuricemia are
underexcretors), based on his estimated creatinine
clearance, he has significant renal impairment and a
history of kidney stones which rule out the use of
uricosurics such as probenecid and sulfinpyrazone.
Therefore, allopurinol would be the drug of choice in
this patient. Once his creatinine clearance has been
calculated from his 24 hour urine collection, the initial
allopurinol dosage can be determined. When the acute
attack has cleared he can be started on allopurinol. At
the same time, he should be given low dose daily
colchicine (0.6mg qd rather than bid because of his age.)
to prevent precipitating an acute attack of gout from
mobilization of his uric acid tissue stores.
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