Gout Flashcards
what is gout
- a metabolic disorder
- diorder of uric acid metabolism
- overproduction and/or decreased excretion
enzyme uricase converts
uric acid to allantoin, then further metabolize to urea
-is absent in humans
clinical symptoms of gout
-hyperuricemia and recurrent attacks of severe, acute arthritis which can be mono-or polyarticular
what areas are most affected by gout
- big too
- instep
- ankle and/or heel
- knee
- elbow
- wrist
who does gout mostly affect
- males
- overweight or obese, high blood pressure or diabetes
risk factors for gout
- Reduced clearance: renal insufficiency, lead, low dose aspirin, ethambutol, diuretics, etc
- Diet rich in purines; such as frequently eating sardines and liver,
- Drinking too much beeror spirits – these types of alcoholic drinks contain relatively high levels of purines
inhibitors of uric acid synthesis
- allopurinol
- febuxostat
uricosuric agents
Probenecid
treatment of gout and pain and inflammation
Colchicine
Indomethacin
drugs increasing uric acid degradation
Rasburicase
when does the incidence of gout increase in women
after menopause
rising incidence of gout in the US is attributed to what
- dietary changes
- increasing obesity
- insulin resistance syndrome
what is primary or genetic gout
~80% of cases
-some pts have an unsual shunt mechanism, converting glycine directly to uric acid
what is secondary gout
-disorder (ie. hematological origin) and certain cacners increase the breakdown of cellular nucleoproteins, or from use of drugs that impair the elimination of uric acid: salicylates, alcohol, ethambutol, thiazides and furosemide diuretics
risk factors for gout are related to what
primarily related to extent and duration of hyperuricemia
describe the natural history of gout and how it develops
- asymptomatic hyperuricemia, infrequently progresses to gout
- acute gouty arthritis
- intercritical gout
- chronric tophaceous gout (develops in 30-40% of patients with acute gouty arthritis)
what is the normal amount of uric acid in the body
~600-800 mg uric acid day/urine unrestricted diet
~7 mg uric acid/100mL serum
what are the values of asymptomatic hyperuricemia
~800-1000mg uric acid day/ urine or ~7-10 mg uric acid/ 100mL serum
-diet, exercise
what is synoviocytes
phagocytose urate crystals and then secrete inflammatory mediators which in turn attract and activate macrophages, thus amplifying the ongoing inflammatory process
what is the objective of drug therapy
- end inflammatory process and apin
- prevent phaogcytosis of urate crystals deposited in joints and recurrence of gout attacks
- reduce hyperuricemia, promote tophi resolution and prevent urate crystals deposition
- increase uric acid elimination. Uricosuric agents and/or increasing rate of urine flow
- decrease uric acid production. Drugs, dietary restrictions
are combination drugs better than using drugs separately
combination drugs that inhibit uric acid synthesis and increase its elimination has NOT shown to be better than using drugs separately
what are the chemistry properties of uric acid
pKa = 5.6
weak acid
uric acid is the major end product of
purine metabolism
how is uric acid excreted
renal
what affects uric acid excretion
-urinary pH and urate solubility
how is uric acid filtered
freely filtered at the glomerulus
is uric acid reabsorbed
active reabsorption, proximal tubule. Effect of drugs
where does active secretion of uric acid occur
proximal tubule. Effect of drugs
uricosuric drugs and large doses of aspirin (>3g/dl) results in
a net decreased reabsorption in the proximal tubule
aspirin (<2.6g/dl) results in
net uric acid retention (net inhibition of the secretory transporter)
describe the renal uric acid excretion process
- after glomerular filtration, almost all uric acid is reabsorbed in the proximal tubule (weak acid transport mechanism; uricosurics promote renal excretion of uric acid by inhibiting its reabsorption in the proximal tubule)
- it is then secreted further down in the proximal tubule
- chronic diuretic therapy reduces renal uric acid excretion because of increased uric acid reabsorption in the proximal tubule secondary to volume depletion, and competition between the diuretic and uric acid for the organic acid secretory mechanism
at physiologic pH normal urates concentration range is
below 7.0 mg/dl
normal urate concentration range varies with
-sex, age, weight, blood pressure, renal function, alcohol intake, and purine content of the diet
when do urate levels being to rise
during puberty in males but remain low in females until menopause due to higher excretion attributable to hormonal influences, ie. uricouric effects of estrogen
urate is the catabolic end product of
adenine and guanine, the purine bases essential for nucleic acids and purine nucleotides
although purine nucleotide breakdown occurs in all cells, urate is produced only in tisses that contain
xanthine oxidase
ie. primarily in liver and small intestine
normally 3/4 of urate produced is excreted by the kidneys, the remainder is eliminated through
intestine
after glomerular filtration of the irate, almost all of it is reabsorbed in
the proximal tubule
-it is then secreted in the proximal tubule and again reabsorbed
as pH is low in the urinary tract, urate is excreted in what form in the urine
as uric acid
what drugs increase urate levels
salicylates (low dose <2.6 g/dl)
- nicotinic acid ethambutol
- diuretics, pyrazinamide
- cyclosporine, Vit B12
- lead
- levodopa
- ethanol
what drugs decrease urate levels
salicylates (>3.0 g/day)
- ascorbic acid, fenofibrate
- calcitonic, glucocrticoids
- calcium channel blockers, uricosurics
- dicumarol, ACE inhibitors
- estrogens
what are the most common metabolic defects leading to uric acid overproduction
- deficiency of hypoxanthine guanine phosphoribosyl transferase, an enzyme deficient in children with Lesch Nyhan syndrome
- increased 5’-phosphoribosyl pyrophosphate synthase
- increased uric acid production assocaited with polycythemia Cera, leukemia, psoriasis
- also use of cytotoxic agents increasing breakdown of cellular nucleic acids…may lead to acute uric acid nephropathy
what happens a patient has a deficiency of hypoxanthine guanine phosphoribosyl transferase
- hypoxanthine is not cycled back through inosinic acid
- instead there is an increase in hypoxanthine and uric acid
what is the main mechanism of action for the treatment of gout
- competitive inhibition of xanthine oxidase, the enzyme involved in the conversion of hypoxanthine to xanthine and in the further metabolism of xanthine to uric acid
- in this process, allopurinol is oxidizied by xanthine oxidase to oxipurinol, an active compound which also inhibits this enzyme
what is the minor mechanism of action for the treatment of gout
-depletes tissue srotes of 5’-phosphoribosyl pyrophosphate and inhibits 5’-PRPP aminotransferase, thus reducing de novo purine synthesis
what are the pharmacokinetics of allopurinol
well absorbed after oral administration, metabolized (t1/2-1-2 hr) to oxipurinol, an active long lasting inhibitor of xantine oxidase, this allowing for 1 tablet/d treatment
what are the clinical uses of allopurinol
- often the initial urate-lowering drug used in gout treatment
- effective in hyperuriciemia caused by uric acid overproduction and in chronic tophaceous gout
- especially useful in patients with renal insufficiency or calculi
- reduces serum urate levels usually within few days to 2 weeks
- actions not antagonized by salicylates
- not useful for acute attacks of gouty arthritis
- inhibits appearance of reperfusion injury
what are the side effects of allopurinol
- generally well tolerated
- adverse rxns include: diarrhea, nausea, abnormal liver tests, rash
what is the black box warning of allopurinol
- this is not an imnnocuos drug. It is not recommended for the treatment of asymptomatic hyperuricemia
- allopurinol should be discontinued at first appearance of skin rash or other sign of an allergic rxn
what adverse rxns do elderly individuals with renal insufficiency experience
allopurinol-allergic rxn
what are the rare adverse side effects of allopurinol
- peripheral neuritis and necrotizing vasculitis
- aplastic anemai and hepatic toxicity
- patients develop allergic skin rxn seen as pruritic maculopapular lesion
what drugs interact with allopurinol
-ampicillin and thiazides inhibit oxidation of mercaptopurine to azathioprine, increases toxicity of other cytotoxic drugs (cyclophosphamide)
what is Stevens-Johnson syndrome and Toxic Epidermal necrolysis
- 2 forms of life threatening skin conditions in which cell death causes the epidermis to separate from the dermis
- the syndrome is though to be a hypersensitivity complex that affects the skin and the mucous membranes
- the main known cause is certain medications, followed by infections and rarely, cancers
what was the first nonpurine-like, potent and selective inhibitor of xanthine oxidase
febuxostat
how is febuxostat absorbed and excreted
- rapidly and extensively absorbed following oral administration, peak plasma level reached within 1 hr
- liver metabolized and urine excreted
are dose adjustments of Febuxostat required in patients with impaired renal function
no!
what is Febuxostate used for
effective for the treatment of chronic gout regardless of its pathogenic cause-underexcretion or overproduction
-appears to be well accepted in patients unable to tolerate allopurinol
what drugs should be used at the beginning of febuxostat treatment and why
prophylactic NSAIDs or colchicine should be used to prevent possible gout attack
what are the side effects of Febuoxostat
may produce GI intolerance and hepatic function alternations
what are probenecid and sulfinpyraxone
- uricosuric agents
- weak organic acids, extensively bound to plasma proteins (>90%)
how are probenecid and sulfinpyrazone secreted
- actively secreted by the proximal tubule anionic secretory system
- and then completely reabsorbed by the renal tubules
what is mechanism of action of probenecid and sulfinpyrazone
-inhibit the middle segment of the proximal tubule active reabsorption of filtered urate
what are the pharmacokinetics of Probenecid
-taken orally, rapidly absorbed. Half-life 6-12 hr
what are the pharmacokinetics of Sulfinpyrazone
-taken orally, metabolite of phenylbutazone. Lacks anti-inflammatory, analgesic and sodium retaining properties
how are probenecid and sulfinpyrazone eliminated
mostly unchanged in urine
patients allergic to allopurinol should take
Probenecid if pt has underexcretion hyperuricemia, normal renal function, and not history of nephrolithiasis or massive tophi
probenecid is not useful for patients with
renal insufficiency (glomerular filtration rate 30ml/min) or already secreting large amounts of uric acid
probenecid can initially be given to
- small doses of colchicine as prophylaxis of acute gout episodes
- maintain large urine volume and alkalinie urine (eg. sodium bicarbonate)
what are the adverse reactions of probenecid
- generally well tolerated
- may produce GI intolerance, dermatitis, nephrotic syndrome (rare)
drug interactions with uricosuric agents cause
- decrease renal secretion of acidic compounds:
- penicillin
- aminosalicylic acid
- sulfonylurea
- 17-ketosteroids - increases renal excretion rate of oxupurinol, the main active allopurinol metabolite
what can reverse probenecid uricosuric effects?
small doses of salicylates, including aspiring (<2.6g/d)
large doses of aspiring have what effect
large aspiring dose (>3.0 g/d) produce net uricosuric effects
what is colchicine and what is it used for
- considered second to NSAIDs for the treatment of gout attacks
- effective as prophylactic, adjunct therapy to uricosurics and to inhibitors of uric acid synthesis
what is the MA of colchine
-binds microtubule protein tubulin preventing its polymerization, leading to inhibition of leukocyte migration & further urate crystal phagocytosis
when are oral administartions of colchicine initated
at first sign of attack and continue until symptoms subside…or significant GI distress occurs
what is the maximum dose of colchicine
0.6 mg tablet every 2 hr up to 8mg
how is colchicine administered by IV
2 mg vial in 20 mL saline - slow administration (uncommon; soft skin and tissue necrosis)
-if plus tablets total amount not exceed 4-5 mg
what is the absorbance of colchicine
- rapidly absorbed after oral administration
- rapidly cleared from plasma
- accumulates in leukocytes where it is also stored
- liver deacetylates colchicine
what is indomethacin
an NSAIDs that is effective in the treatment of gout
-preferred over colchine as the initial treatment of gout attacks
how much indomethacin can be administered
50mg/ x3/ day until pain subsides, then 25mg x 3 daily for 7 days
when should Indomethacin not be used
- not to be used in chronic gout or prophylaxis of this condition
- not specific for treatment of gout
- no effect on uric acid excretion rate or synthesis
what is Rasburicase
- produced by a genetically modified Saccharomyces cerevisiae strain
- is a recombinant urate-oxidase, catalyzes uric acid conversion to its soluble metabolite allantoin
- lowers urate levels more effectively than allopurinol
what is Rasburicase used for
recommended for the initial management of hyperuricemia in pediatric patients with cancer chemoterapy-caused increased uric acid production
how much Rasburicase should be administered
IV 0.15 mg/kg/d x 5 days, with chemotherapy initiated a few hrs after first dose
what are the side effects of Rasburicase
- production of antibodies
- acute renal failure
- anaphylaxis
- GI abnormalities
what drugs are inhibitors of uric acid synthesis
- allopurinol
- febuxostat
what are uricosuric agents
probenecid
what drugs are used for the treatment of gout pain and inflammation
- colchicine
- indomethacin
what drugs increase uric acid degradation
Rasburicase
