benjamin franklin.

Zyloprim gen

allopurinol

uloric gen

febuoxstat— same class as allopurinol

Colcrys, Mitigare generic

Colchicine

Elitek generic

Rasburicase

Krytexxa generic

Pegloticase

• 2 x’s bc double the time

Probenecid generic

Probenecid (LOLLL)

what is hyperuricemia

too much uric acid— from breakdown of purines in the blood

• can be kidney issue/too much for kidney to handle, or body produces too much uric acid

does hyperuricemia automatically mean gout?

• NO

what does uric acid become that causes pain when it deposits in joints

monosodium urate crystals

• mediated by xanthine oxidase

sources of excess uric acid (excess purines)

• diet: organ meats/red meat, beer, high-fructose drinks

• DNA/RNA in the body — can be from cell lysis like with chemo

• alcohol use can cause both these mechanisms to occur

what is serum level that is diagnostic for hyperuricemia? what is the level for premenopausal women?

• 7 mg/dL

• >6mg/dL

where do the monosodium urate crystals form

• cartilage

• tendons

• soft tissues

• kidneys— uric-acid stones

mmmmhmm yes the big toe

lower temp body sites for CRYSTAL forming you see

what are tophi

FIRM deposits surronded by chronic inflamatory tissue, appear as firm white-yellow bumps.

• per dr bennett— Deposits of monosodium urate crystals in tissues

what is gouty arthritis

joint inflammation caused by monosodium urate crystals

• immune mediated

what is PRIMARY hyperU and gout

assoicated with BORN with ti error in purine metabolism

what is secondary hyperU and gout?

assoicated with disease/drugs

what are some drugs that cause gout

diuretics, nicotinic acid, salicylates

(<2g/day), ethanol, pyrazinamide, levodopa, ethambutol, cytotoxic drugs,

cyclosporine

can you have a gout attack with a normal uric-acid level

YES

• inflammation temporarily

  • UA moves out of blood into tissues and crystalizes— so you have normally blood levevls but still have gout bc built up in the joints and such

who gets gout?

• mostly old men

• sometimes old women, but more bc of less estrogen that makes it harder to get uric acid

three sources of purines

1. dietary

2. convestion of nucliec acids to nucelotides

3. de novo synth

s/s gout

ever

 Intense pain

 Erythema & warmth

 Swelling

 Inflamed joint(s)

 Podagra

• Acute attack of gout in great toe

 Tophus

• Aggregated deposits of sodium urate

what is podagra

acute attack of gout in great toe

risk factors for gout

• ↑ age

• ▪ Male gender

• ▪ Hypertension

• ▪ Excessive Ethanol

• ▪ Diet high in meat or fish

• ▪ ↑ SCr and BUN

• ▪ Obesity

• ▪ Drugs

• ▪ Various other medical conditions (↑ TGs, DM)

what drugs can be used for acute attacks of gout

• nsaids

• clochicines (colcrys, mitigare)

• intra-articular corticosteriods

what are the drugs used for proph

• Xanthine Oxidase inhibitors (Allopurinol, Febuxostat) : inhibits UA synthesis

• Uricosuric (Lesinurad ®, Probenecid): inhibit reabsorption of UA in the kidneys, increase UA excretion

• Recombinant Uricase (Pegloticase, Rasburicase) : convert UA to allantoin

what are the xanthine oxidase inhibitors

allopurinol, febuxostat

are purines one or two rings

TWOOO

• a’s and g’s

does high or low dose aspirin make gout worse

LOOWWW dose

• high dose is good

why Nsaids used in gout acute

decreases cox acitivty and PG synth== helps with inflammation

why is there inflammation with acute gout attack

urate crystals are phagocytosed by synoviocytes (in la joints)— causes release of PGs, IL-1— causes inflammation

what is top of line for gout NSAID? why not always used?

indomethacin

• more toxic effects than ibuprofen

how long use NSAID for gout attack

cont for 24 hour after attack, then taper quickly 2-3 days

is PRPP high or low in gout? what does it do

HIGH (phosphoribosyl pyrophosphate)

• xanthine precursor that becomes uric acid

is HGPRT high or low in gout? what does it do

LOW

• hypoxanthine-guanine phosphoribosyltransferase

  • recycles purines to MAKE Dna- takes up free purines

when to start NSAID for gout

at onset of symptoms for prevention/treatment

can we turn uric acid into allantoin?

NOOO but birds can

what enzyme turns urate into teh uric acid crystals

uric acid oxidase, or uricase

MOA colchicine

stops WBCs from getting to uric acid crystals in joints— stops inflam response

• (“leukotriene migration”)

why use fenofibrate in gout

decreases hypertriglycerideemia

• may increase uric acid clearance in kidneys

what one arb used in gout

losartan!

does colchicine have pain decreasing effects

NO just prevents more inflammation

CI for colchicine

Avoid in renal or hepatic dysfunctions. Wait 12 hrs before resuming taking prophylaxis drug such as allopurinol

when is colchicine used in gout

• at first sign of attack -onset of pain

• only to be used for a few days most the time

adrs colchicine

NVD, neuropathy due to inhibition of Vit B12 absorption, bone marrow suppression, alopecia, rash,

myopathy, numbness

adrs colchicine

CYP3A4 inhibitor (do NOT use, can be fatal), alcohol, statin (rhabdomyolysis), cyclosporine, pGp

macrolides (CYP3A4 inhibitor→ decrease clearance of colchicine, increase level of colchicine in the body)

what are the two purines

adenosine and guanosine

what are the two PO cor.riods used in gout

methylprednisolone or triamcinolone

when should not use OCS in gout

if joints septic (GROSS!)

OCS adrs

skin atrophy, infection, edema, hyperglycemia, ↑ BP, tendon rupture,

osteonecrosis, hypokalemia

• esp for if using intra-articular injection

which is most selective inhibition of xanthine oxidase

febuxostat

when do you have to adjust febuxo in renal

when crCl is <30

adrs of febux

serious skin reaction, headache, NV, arthralgia

how long can use nsaid for?

20 weeks

what happens if use nsaids more than 30 weeks ? does this affect most gout pts?

temproary fetal blood vessel closure— hurts the baby’s lungs in preg women

• obvy does not affect most gout patients

febuxostat BW!

cardiovascular death, renal, hepatic

• apparently allopurinol does not have that

CI febuxostat

Contraindication: pts taking azathioprine, theophylline

what do you probably have to take for first 3-6 months of xzanthine oxidase inhibitor thearpy

NSAID for the first 3-6 months or colchicine 0.6 mg once or twice daily for pain and flare=ups

• allopruinol takes WEEKS to take affect

does allopurinol help acute

NOOOo no no

what do you have to adjust allopurinol dosing for

renal impairment

adr allopurinol

Skin irritation (maculopapular, Steven Johnson syndrome), GI irritation, diarrhea,

toxic epidermal necrolysis (TEN), peripheral neuritis, cataracts, bone marrow suppression,

aplastic anemia, hypersensitivity Rx

HLA-B*5801 testing prior use in Asian descendent

test for what in allopurinol therapy

HLA-B*5801 in pts with Asian descent

besides lack of coverage of pain in acute, why do patients need low dose colchicine/nsaid or prednisone when started on feb/allo

can initially cause gout flare0

• old crystal deposits become unstable

why allopurinol temporarily trigger or wrosen gout attack

• inhibiting xanthine oxidase, driving equilibruim forward so that since there is less urate crystals in blood, more in tissue broekn down

• the smaller/broken down crystals

• nuetorphils then start immune rxn to this

what are the uricosuric agents

probenecid, Lesinurad

which xan oxi inhib looks like purine

allopurinol

what does Lesinurad and Probenecid do

make the kidneys excrete more uric acid.

• block URAT1 transporter that absorbs urate

  • more urate excreted out

when physiologu can make probenecid not effective and why

crCl , 50 ml/min

• bc you dont have enough renal function to pee out the uric acid

couneling for probenecid

• need to drink plenty of water

adrs probenecid (uricosuric agents)

may precipitate acute attack, GI irritation (take with food), rash, aplastic anemia

what does OH do to allopurinol

decrease

what does allopurinol (zyloprim) do to AZA and 6MP?

increase their toxicity

• these are immunosuppressant drugs for autoimmune diseases; aza the prodrug for 6MP; interfere with DNA synthesis

thiazide effect on allopurinol

increase tox

vitamin C how eff allopurinol

increaes kidney stone formation

ACEi how affect allopurinol

increases allopurinol toxicity

• angioedema— synergistic

what does allopurinol do to cyclosporine

increases cyclosporine levels

what does allopurinol do to half life of warfarin

increases half life

what does allopurinol do to half life of theophylline

increaes half life of theophylline

• DURP bc inhibiting xanthine oxidase so methylxanthines would be elminated quicker

CI for probenesid

use with caution or AVOID with pts that have hemolytic anemia

• G6PD pts — glucose 6-phosphate dehydrogenase is cruucial for RBCs

is urine acidic or basic

its actally acidic normally but bennett says otherwise

recombinant uricase drugs (Pegloticase, Rasburicase) what do they do

gives us the bird enzyme! uricase that turns uric acid in allantoin that is easier to elminate in urine

why do we add the PEG to uricase in Pegloticase

prolongs time in the body! not broken down as quickly

which recom uricase more for tumor lysis syndrome instead of gout

Rasburicase (Elitek)

what is tumor lysis syndrome

when so many cancer cells break open there is too much raw ccell juice that the body can’t elminate

• potassium, phosphate, uric acid from DNA/RNA all too high

• kidney injury

Rasburicase makes it easier to at least get out teh uric acid

BBW for Rasburicase (the tumor lysis one)

anaphylaaxiss, hemolysis

ADR Rasburicase

peripheral edema, HA, anx, rash, nvd, sepsiss

what is source for Pegloticase

porcine

Pegloticase ind

hypersenstivity or resistant to allopurinol

what does refractory mean

stubborn, resist to treatment

can ANY fibrate be used as gout proh

NO just fenofibrate

recall the BW and warnings for losartan

• fetal toxicity

effect of diuertics on uric acid

INCREASE— Renal tubular reabsorption associated with volume depletion,

stimulates URAT1

Cyclosporine, Tacrolimus affect on uric acid level

increase— renal tubular reabsorption

by what mech does low dose salicylate (aspirin) affect UA

DECREASES excretion— causes MORE UA build up

by what mech does high does salicylate work on UA?1

inhibition of URAT1—- increases excretion of UA

what heart med increase Uric acid levels by an unknown mech

beta blockers!