-lose weight (gradually because dramatically can set off an attack)

-decrease alcohol

-eat foods with less purines (urate is the end product of their metabolism)

-avoid drugs that cause hyperuricemia

decrease PGs [image]and decrease analgeis and inflammation via COX inhibib

low dose may inhibit urate excretion

high dose has risk of renal calculli

inhibit some effects of uricosuric agents 

-nulify antihypertensive effects of some drugs

-increase risk of bleeding if another anticoagulant is being administered

-biphosphonates (common bone builders) have reported GI bleeding with NSAIDs

-steroids and aspirin magnify NSAID toxic effects

binding tubulin so polymerization is halted.

-leukocyte migration stalls, stalling phagocytosis and lactic acid production

narrow NI, can lead to diarrhea, vomiting, shock.

can cause BM supression, agranulocytosis

a substrate of CYP3A4 and PGP, therefore anything that inhibits this may cause colchicine toxicity

it is usually excreted unchanged, therefore renal impairment will accumulate inchanged colchicine which is dangerous

Glucocorticoids have widespread effects Þ many side effects.

when there is a chronic gout impairment. (allipurol is one)

XO inhibitors decreases urate overproducers.  the pre-products (xanthine and hypoxanthine; from adenosine and guanosine) to uric acid are more soluble and readily excreted through urine.  even if xanthine and hypxanthine build up, they don't crystallize and have a negative feedback mechanism for the metabolism of other A or G

be careful because XO inhibits may be able to mobilize urate and cause a flare

Febuxostat appears to be well tolerated in patients with history of allopurinol intolerance.

Significant hepatic transaminase elevations have occurred with febuxostat use.

allo is insig. plasma bound, feb is extensively

allo metab:  XO oxidation to oxypurinol

feb metab: CYP450, UGT

Pegloticase [Krystexxa] MOA

for adults with a refractory condition

it is a urate oxidase which converts uric acid to allantoin (a water soluble purine metabolite that is excreted in urine); H2O2 is released in process

contraindicated in pts with G6PD deficiency

Rasburicase [Elitek] MOA

urate metabolism to allantoin, just like pegloticase, however, it is intend for hyperuricemia associated with malignancy

in patients at risk for tumor lysis syndrome

two uricosuric agents

Probenecid and Sulfinpyrazone

inhibit uric acid reabsorption by using organic acid transporters located in the proximal convoluted tubule.  they inhibit URAT1 on the apical side of a tubular cell

renal fxn must be good, urine output must be maintained

gastrointestinal irritation is a concern

they compete at the OATP and therefore, may increase the concentration of some other drugs that may be in the system and needing clearance

salicylates can decrease uricosuric effects and administering probenecid and sulfpyrazone in patients taking high dose aspirin is contraindicated

prolonged application of topical steroids, covering the application area with dressing that occuldes it, or using topical steroids over a very large surface area runs the risks of causing systemic side effects.

this is because the HPA-axis can be disrupted and shut off.  the HPA-axis is a feedback loop involving the hypothalmus, pituitary, and adrenal glands which homeostatically regulates native needs of steroid dispersal in the human body

corticosteroid plasma protein binding:

natural cortisol binding is limited to CBG proteins 90% of the time.  The other 10% of the time it is bound to albumin, which has a low affinity for the binding, but a surprisingly high capacity to do it.

Synthetic coritsol (hydrocortisone) has a selectivity for albumin.  For this reason, more it will be un-bound to plasma and will be available to exert effects.

When steroids compete for binding sites, more is in circulation

prodrugs, they need to be converted to their active forms by the liver

cortisol and prednisolone

readily active drug should be administered if a patient has hepatic insufficiency

through transcription activation or deregulation.

transcription can be enhanced when steroids bind to effector sites in the DNA, or they can be repressed as is the case with COX2 or NOS2 or cytokine genes.

-steroid(S) enters passively through PM

-S binds glucocorticoid receptor (GR) in cytoplasm

-S+GR complexes with other proteins and S+GR complex has conformational change

-S-GR binds DNA and does its thing

GC effects:

carbohydrate and protein metabolism?

lipid metabolism?

fluid and electrolyte balance?

CV?

Skeletal muscle?

CNS?

carbo- tells liver to form glucose from amino acids and clycerol to save brain and heart from starvation; also they signal protein breakdown to provide the building blocks

lipid - redistribute body fat=buffalo hump

fluids - inhibits ion loss= causes swelling

calcium - stores go down

CV - hypertension

skeletal muscle - muscle wasting (protein breakdown)

CNS - euphoria followed by depression

use steroids.  this is known as bridge therapy.  

also, intraarticular injection of steroids is useful if the symptoms are localized to a could joints.  be careful though, because asceptic (painless) necrosis could happen.  

usually large doses have to be given at first, but one should always work down the lowest effective dose

adrenal insufficiency.  the HPA axis has been depressed so the complete absence of GCs will cause this and can be life-threatening

there could also be a flare-up of the underlying disease being depressed

-few non-specific effects

-can be used along with some NSAIDs

-early use in disease can retard bone erosion

-improved serological evidence of disease

a folic acid analog (folic acid is typically  converted into an active form, tetrahydrofolate, which is vital to some biosynthesis rxns)

50% plasma bound with narrow TI

be careful of OATP competitors because MTX relies on these for renal excretion.  competitors will increase serum conc.

MTX enters cell through folate carrier and gets reversibly polyglutamated by FPGS (reversibility possible through GGH and effluxed out of cell through an ABC)

effects take place in inflammatory cells

when MTXpg, the enzymes  ATIC, TYMS, and DHFR cannot metabolize it after it competitively binds

DHFR= important in purine synthesis and ultimately DNA synthesis (lymphocyte and macrophage fxn)

TYMS= vital for converting uracil to thymine, MTXpg competitively binds 

ATIC= converts AICAR to an intermediate necessary for forming IMP (an intermediate necessary for purine metabolism), causes accumulation of adenosine and adenine nucleotides if inhibited

most common SE: naseau, diarrhea, ulcerative somatitis

hepatotoxicity!

-worse if had h/o other hepatotoxic drugs; azathioprine, sulfasalazine, or leftunomide

BM suppression

CONTRAINDICATED in pregnancy

DO NOT give live attenuated virus vaccines

pneumonoitis, lymphoma, phototox, cyclosporine increases conc.

***folate rescue can reverse toxic effects if administered in 24 hours

oral, highly albumin bound, affinity for connective tissue deposition, capable of displacing MTX, eliminated post hepatic acetylation

often used with MTX and hydroxychloroquine, although MTX has to be watch carefully

MOA undefined

approved for juvenile idiopathic arth and ank. spondylosis

may cause G6PD deficiency among other problems (just like uricase drugs)

discontinue at first sign of rash, jaundice, hepatotox

Contraindicated in preg. bc it displaces bilirubin from its binding to albumin and may cause jaundice or encephalopathy

chloroquine and hydroxychloroquine

MOA?

effects?

oral, preferential binding and sequestered to melanin-containing tissues among other tissues plus erythrocytes (for this reason, a high loading dose is needed, however, the erythrocyte accumulation is why it is an antimalarial)

metabolized by CYP2D6 and 3A4

MOA: possible conc inside lysosomes, increasing pH, decreasing T-cell activation

not true DMARDs bc do not slow joint damage

hydroxy is relatively safe and well tolerated, although should not be used in epileptics or if no effect is observed

HOWEVER, ocular toxicity, retinopathy is possible; have optholmalic check-ups

also a G6PD deficiency causing agent

avoid in patients with oprphyria cutanea tarda or psoriasis

CONTRAindicated in pregnancy

immunosupressent

similar results to MTX

HEPATOTOXICITY possible, therefore, only indiciated in patients where the benefits are expected to outweigh the risks

TERATOGEN

not of children

monoclonal Abs administered parentally, very specific

obviously bc they supress the immune system, infectious risk is high (TB, fungal infections, Hep B, lots of bacterials)

THEREFORE, immunizations should be up to date PRIOR to induction of therapy

TNF is vital to inflammatory response  mediation.  it is secreted mainly by macrophages in response to IL-1

inhibitors have been shown to curb inflammatory response and decrease progression of radiologic joint damage

monoclonal antibody

and IgG anti-TNF which binds to soluble and membrane bound TNF preventing cytokine from building on the receptor

watch out for quick hypersensitivity responses

only usually indicated in severe cases of RA

DNA-derived fusion protein.  an TNF receptor bound to a human IgG

supQ injection

mimics natural TNF receptor and therefore binds TNF-alpha and beta thereby preventing cytokines from building on receptors

for moderate to severe to severe RA, also osiruatuc artgm alk spondylosisfor people older than 2

lymphocyte modulator

binds CD80/86 on an APC thus blocking costimulatory interaction between APC and CD28

monoclonal Ab to CD20 (a membrane bound protein) on the surface of B-cells and is either:

-targeted by specialized killer cells

or

-binds complement which leads to direct cellular toxicity (hole in membrane, lysis)

or

-CD20 binding automatically initiates an apoptosis cascade

97% of all CD20+ B-cell are killed in this way

T-cell activation is impaired bc B-cells play an important role in presenting them with Ag

Interluekin Antagonist

It's an IL-1 receptor agonist.  Therefore, it binds IL-1 receptors but does not activate them

Carbamazepine (antiepileptic drug)  Phenobarbital (antiepileptic drug)  Phenytoin (antiepileptic drug)  Rifampin (antibiotic)  St. John’s wort (herbal remedy) 

 Cimetidine (reduces stomach acidity)  Erythromycin and Clarithromycin (macrolide antibiotics)  Ketoconazole and Itraconazole (antifungals)  Ritonavir (protease inhibitor; one of the most potent CYP3A4 inhibitors)  Atazanavir (protease inhibitor); also inhibits UGT1A1  Grapefruit juice 

a lot will be excreted b/c they are soluble.

some will be used to synthesize adensine and guanosine monophosphates, we don't want these being formed, but the fact that they are formed means that they can give negative feedback signals to the enzyme which produces new de novo purines

it is quickly metabolized to M1 which blocks pyrimidine synthesis

known to cause severe liver damage, contraindicated in pregnancy