gout Flashcards
can make dx of gout on
symptoms
serum uric acid levels
colchicine only works for
gout
not other arthritis
Primary gout is a familial disorder that is thought to result from genetically-determined errors of
purine metabolism or uric acid excretion that lead to increased circulating levels of uric acid.
secondary gout from
drugs, diet, disease states
uric acid is the major end product of
purine metabolism (adenine, guanine)-->xanthine-->uric acid (no physio function) try to excrete
??? increase levels and catabolism of purines
-high purine diet, heavy alcohol consumption, surgery, certain drugs, etc–> can increase uric acid formation
90% uric is filtered at the ??
10%
-problem if..
glomerulus (~90%)
(~10%), by active secretion through the organic acid secretory system in the proximal tubule
-drugs may compete for transporter: low-dose ASA, diuretics
decreased function of kidney (hypo perfusion) caused by ??? may cause build up of uric acid
heart failure
about 75-90% of the uric acid/urate ion in the tubular fluid can be
reabsorbed in the proximal tubule by the anion exchange transport system
-if hard time reabsorbing uric acid–>potential gout
Normal values for plasma urate/uric acid
solubility of uric acid in water
pKa?
- 0-7.0 mg/deciliter or 120- 420 μM
- 68 g/L (approach solubility! about 5L blood in body)
pKa of 5.7
more soluble at high pH(alkaline)
factors contrib. to hyperuricemia/gout
Heredity Diet Alcohol (often a major factor) Low fluid intake Cancer Radiation therapy Drugs
hyperuricemia/gout inducing drugs
aspirin (low-moderate doses) diuretics (especially thiazides) sulfonamide antimicrobials antineoplastics (anticancer drugs) l-DOPA
25% of gout pts have attacks even though..
also, many ppl with mild hyperuricemia never…
their uric acid levels are in normal range
develop gout
steps in acute gout attack:
- sodium urate crystals form in joint
- phagocytosis by neutros and macros
- neutro activation and release of inflamm. mediators (PGs, LKs, NO, Superoxide) triggers inflammatory reaction
also the generation of lactic acid and other acidic metabs lower pH–>inc. urate crystal formation
4 stages of gout
Asymptomatic hyperuricemia (may progress to gout)
Acute gouty arthritis
Intercritical (interval) gout
Chronic tophaceous gout (+/- progressive renal failure)
Chronic tophaceous gout dev. from
deposition of urate crystals in the kidney and renal calculi
pharm approach: suppress acute attack
1st: NSAIDs
indomethacin* (traditional)
ibuprofen
ketorolac (emerging!)
(acetaminophin: no anti-inflammatory)
2nd: Colchicine (Colcrys)
3rd: Corticosteroids - prednisone, methylprednisolone
indomethacin has a…
indol ring
can produce CNS effects that other NSAIDS don’t
-behavioral diffs, hallucinations, diff concentrating
-cause ha
toxic to GIT, CV events
don’t use chronically
if chronic problem of high uric acid (>7):
Increase excretion of uric acid
Probenecid (Benemid)
*not effective for tx acute attacks
Colchicine
unique anti-inflamm. classically assoc. w. gout
works in 12-24 hrs
binds to tubulin and prevents it’s polymerization to microtubule–>reduces leukocyte migration, phago. and mitosis
also inhib. prod and rel. of proinflamm GPs from neutrophils
colchicine also used for..
familial Mediterrean fever
Colchicine adverse effects
diarrhea: watery, sloughing of intestinal epi (rice-water)
GI upset: N/V
colchicine dosage
0.5 - 1.0 mg every 2 hours until symptoms are relieved
Lower, less frequent doses are sometimes
used to prevent recurrence of attacks
colchicine removed from market for awhile
too cheap, company not making enough money
now: “Colcryst”: $600/mo!
how to dose corticosteroids
quick onset?
fixed dose then taper for few weeks to avoid ACTH suppression
medrol dose pack
can work w.in 4-6 hrs, 24 hrs symps gone!
tolerated well short-term
may have recurrence when taper–>may have to lengthen dosage: Cushing’s symps
if combo NSAID and corticosteroids
both GI SEs, don’t used in combo
esp. indomethacin
ketorolac (toradol) for gout
injectable NSAID typ. only used pain man. (kidney stones) but can be used for acute gout attacks: analgesics + anti-inflamm.
main prob: GI irritation
Probenecid
Uricosuric Agent
*works bests in pts who do not normally pee out large amounts of uric acid
if chronic problem of high uric acid (>7):
inhibition of formation of uric acid
Allopurinol (Xyloprim)
Febuxostat (Uloric)
*both work best in pts who make too much uric acid (chemo) also good for pts w. existing kidney stones (gouty nephropathy)
target of uric acid levels
if chronic problem of high uric acid (>7):
Facilitate breakdown of uric acid (recombinant uricase enzymes that converts uric acid to allantoin)
Rasburicase (Elitek)
Pegloticase (Krystexxa)
*last resorts for refractory gout
in gout pts, avoid
ASA
inhibits uric acid pump (biphasic effect on uric acid excretion)
allopurinol
used for acute gout attacks?
older, cheaper
inhibits the enzyme xanthine oxidase–>reduces the
formation of uric acid
does not stop an acute gout attack, but over time it can greatly reduce the potential for future attacks
common reaction in early allopurinol therapy
increased frequency of gout attacks
-breakdown of crystals as the uric acid blood levels begin to fall
The acute attacks may necessitate the concomitant use of colchicine, etc
allopurinol SEs
elevation of liver enzymes: monitor every few mos
allergic reactions: skin
Febuxostat (Uloric)
similar to allopurinol, newer, more expensive, more effective according to Proz.
Probenecid (Benemid)
inhibits both the secretion and the reabsorption of organic acids
-more uric acid is reabsorbed (75-90%) than secreted (10%) by the tubule, so therefore: the net effect of probenecid is to increase uric acid excretion (good!)
Probenecid (Benemid) contraindicated in…
pts w. kidney stones (advanced gout: gout nephropathy)–>increased risk of stone formation in kidney as urate conc. in tubular fluid/urine increases
important to hydrate to maintain urine flow and prevent urate crystal formation!
recent surgery pts
put pts on allopurinol/febuxostat pre-op to prevent gout attack
Probenecid intial therapy may have
gout precipitates from breakdown, so may trigger attacks in early tx (like allopurinol)
Pegloticase (Krystexxa)
recombinant urate oxidase, metabolizes urate to allantoin IV infusion advanced gout, refractory, severe 2 hr admin *Does not inhibit formation of uric acid
Pegloticase (Krystexxa) SEs
hypersn (foreign protein)
inf. from IV
Rasburicase (Elitek)
recombinant urate oxidase, metabolizes urate to allantoin
Do not inhibit formation of uric acid
while Pegloticase is used for adults with severe, refractory gout, Rasburicase is for….
pediatric patients with leukemia, lymphoma and solid tumor malignancies receiving anticancer therapy expected to result in tumor lysis and elevation of plasma uric acid
adverse effects of both Rasburicase and Pegloticase
fever, ha, rashes, N/V, bowel disturbs, GI pain, allergic reactions
for pts with severe, chronic gout/hyperuricemia, may be necessary to use ???
combo tx:
allopurinol and probenecid for hyperuricemia
+
cholchicine, NSAIDs, or steroids for acute attacks
