Hyperuricemia and Gout Flashcards
What is Hyperuricemia?
It is defined as having a plasma concentration of Uric Acid > 7mg/dl
How soluble is Uric Acid? What is the consequence of it’s solubility?
Not very soluble, so [UA] > 9 mg/dl = crystals in acid environment
What are the two causes of Hyperuricemia?
Metabolic (10%) and Renal (90%)
Describe the metabolic cause of hyperuricemia.
These are over producers. Primary from increased PRPP synthetase of decreased HGPRT (in mediterraneans) or Secondary from myelo/lympho proliferative disorders (this is more purine turnover) or chemo/radiation (cells dying release purine)
Describe the renal cause of hyperuricemia.
These are the under secretors. Primary from CKD/renal failure. Secondary from long term diuretic therapy (increased resorption of uric acid) and toxemia of pregnancy
What is gout?
The deposition of uric acid crystals in joint spaces
What is it called if gout is in the great toe?
Podagra
What is acute gouty arthritis?
When uric acid crystals in joint spaces break leading to severe acute pain
What is tophaeceous grout?
A chronic form of gout, tophi are nodules of uric acid
How is uric acid handles in the kidneys?
It is filtered then reabsorbed in the proximal C.T. then secreted and partially reabsorbed again
What is the first attempt at treatment for gout?
Stop eating meat - non pharmaceutical
What are the 5 aims of treatment for gout? (remember these, they will be used when describing the uses of drugs)
1) Terminate an acute attack
2) Prevent recurrence of acute gouty arthritis
3) Revers or prevent complications of deposited ureate crystals
4) Prevent other factors associated with disease (obesity, HTN, hypertrigliceridemia
5) Prevent formation of Uric acid nephroliths
What is Colchicine used for?
1 and 2; effective only against gouty arthritis and prophylaxis against attacks
What is the MOA of Colchicine?
Prevent depolymerization of microtubules in PMNs so they can’t move, inhibits polys from making inflammatory cytokines; This terminates attacks of gout and prevents recurrence of gouty arthritis; useful in Mediterranean fever
How is Colchicine met/elim?
Hepatically metabolized mainly by deacetylation and excreted through biliary system (up to 20% in urine)
What are the acute ADE’s with Colchicine?
GI effects (N/V, diarrhea, anorexia, lactose intolerance); these are dose related
What are the chronic ADEs with Colchicine?
Blood dyscrasias; Bone marrow suppression (associated with later stage of colchicine fox after GI adverse effects)
Why is impaired renal and hepatic function important in Colchicine?
Because it leads to elevated serum drug levels which leads to increase in toxicity; in particular, myopathy, peripheral neuropathy, and rhabdo have all been reported in patients taking colchicine, especially in overdose
Can colchicine be removed with dialysis?
NO
Is there an antidote for Colchicine adverse reactions?
NO
What is Indomethacine used for?
1 and 2; for the treatment of an acute attack
What is the MOA of indomethacine?
It is a COX1 Inh (analgesic and antipyretic and anti-inflammatory); it inhibits leukocyte motility; Many patients who use this acutely switch to a milder NSAID
What are Indomethacine ADEs?
GI = N/V/Ulcers so give with an antacid; CNS (frontal headache); blood dyscrasia
What two drugs does Indomethacine antagonize?
HCTZ and Furosemide
What are Allopurinol therapeutic effects?
3 and 5; Reduction in plasma levels and urinary excretion of UA, increased plasma levels and urinary excretion of oxypurine precursors (Xanthine/Hypoxanthine); Facilitates dissolution of uric acid in joints and kidneys; prevents formation of kidney stones
What patients is Allopurinol not good for?
Patients with renal failure
What is Allopurinol MOA? What is it metabolized to and what does that do?
Inhibit formation of uric acid by competitive inh of X.O.; It is metabolized to oxypurinol, which is a non-competetive inn of X.O. (suicide Inh)
What are Allopurinol therapeutic uses?
Primary hyperuricemia of gout due to enzyme abnormalities (children with familial juvenile hyperuricemid nephropathy) and secondary hyperuricemia due to hematologic disorders or chemo
What are Allopurinol ADEs?
Increased incidence of acute gout, hypersensitivity reaction/exfoliative dermatitis, decreased liver function
What drug does Allopurinol reaction with?
6-mercaptopurine
What is contraindicated for use with Allopurinol?
Ampicillin and related Abx
What is Febuxostat MOA?
It is a potent inn of oxidized and reduced XO, enzyme inhibitor complex is stable; structurally unrelated to allo but it lowers urate concentration by decreasing urate levels like allopurinol
What ix Febuxostat used for and indicated in?
80 mg regular dose = better than aloo with less ADEs; mainly indicated to lower ureate levels in patients who display adverse symptoms to allopurinol (HSRs or renal insufficiency), used for 3 and 5
Can febuxostat be used in patients with mild renal impairment?
Yes
What are the ADEs of Febuxostat?
Mild; 2-3% of patients had transaminase elevation >3x upper limit
What is the MOA of Probenecid?
Increases urinary secretion of uric acid by inhibiting organic acid transporters and competes for UA with UA reabsorption transporter; more UA stays inside renal tubule this way. Also causes UA dissolution in joints
When is Probenecid used/indicated?
In patients that are under secreters (<1g of UA per day) with NORMAL renal function; give with adequate hydration to patients with good renal function
What are Probenecid ADEs?
Salicylates inhibit uricosic action of probenecid so switch to tylenol
What is Urate Oxidase?
It is an enzyme present in almost all mammals, but not humans, that lowers uric acid levels by converting uric acid into Allantoin, which is a benign metabolite which is easily excreted in urine
What is Pegloticase?
A bio-uricolytic agent (urate oxidase agent analog); It is a recombinant, PEGylated formulation of modified mammalian (PIG) urate oxidase
What is the MOA of Pegloticase?
It converts uric acid to Allantoin which is secreted out; It rapidly lowers serum UA and reduces urinary UA while increasing levels of allantoic which is 5x more soluble
What does Pegloticase control?
Severe gout in patients that havent been helped by other treatment/other drugs are CId; it also rapidly dissolves tophi
What are the ADEs of Pegloticase?
Gout flares as tophi dissolve rapidly so give colchicine, NSAID, or glucocorticoids prophylactically
Why is the half life of Pegloticase increased?
It is a Pegylated formulation of urate oxidase to increase its elimination to 10-12 days from 8 hours
How is Pegloticase administered? What’s special about its admin?
IV and it is EXPENSIVE (>30k a year)
What can happen in patients receiving Pegloticase?
89% develop Abs against PEG moiety; clinical manifestations in subjects with high IgG titers
