RA and Gout Flashcards
What two NSAIDs are used to relieve symptoms in long-term treatment of RA?
indomethacine and naproxen; don’t halt disease progression!!
How are glucocorticoids useful in the Tx of RA?
initially before a DMARD has taken effect; intro-articularly to help alleviate symptoms
What are the actions of glucocorticoids?
inhibit PLA2 (inhibiting release of arachidonic acid and prostaglandin formation) inhibition of cytokine production (preventing induction of COX-2)
What was the mechanism of gold salts in the Tx of RA? Are these still used?
antipruritic; repress immune responsiveness, especially by inhibiting proper macrophage function
no longer used - produced serious side effects in 30% of patients
The prolonged use of what drugs can cause serious effects such as hyperglycemia, osteoporosis, and poor wound healing?
glucocorticoids
What antimalarial drugs have been used in the treatment of RA and SLE? Which was better tolerated?
chloroquine and hydroxychloroquine;
hydroxychloroquine better tolerated and fewer adverse effects (long term chloroquine can cause irreversible retinal damage)
Sulfasalazine use for treating RA is increasing. It acts more quickly than antimalarials. What is the proposed mechanism? And what side effects cause a third of patients to discontinue use?
possibly inhibits IL-1 and TNF-alpha release;
side effects: N/V, HA, skin rashes, neutropenia
What immunosuppressive drug is the most commonly used DMARD in RA treatment and is still considered the ‘gold standard’?
methotrexate (MTX)
What’s the MOA of MTX as learned in cancer? What is likely it’s principal MOA in the low doses used in RA Tx?
typically, inhibits DHFR (folate analog!)
in low dose - inhibition of AICAR transformylase and thymidylate synthetase with secondary effects on PMN chemotaxis
AMP accumulates, converted to adenosine, a potent inhibitor of inflammation
What side effects of MTX are seen with the low doses used in RA Tx?
nausea, stomatitis
hepatotoxicity can occur and pts should be monitored for it
What’s the new immunosuppressive drug being used in RA? How does it work?
leflunomide; prodrug
inhibits DHODH, required for de novo pyrimidine synthesis
T-cell response to stimuli inhibited
Significant side effects of leflunomide?
diarrhea, hepatotoxicity
Name the five TNF-alpha antagonists (biologics).
etanercept, infliximab, adalimumab, golimumab, certolizumab
Etanercept is the only TNF-alpha antagonist that isn’t a mAb. What is it?
fusion protein of two TNF receptors fused with Fc portion of IgG; binds TNF and prevents it from binding to receptors
What’s the problem with infliximab?
it’s a chimeric Ab, so it’s antigenic and can cause production of anti-mouse Abs
Adalimumab has more convenient dosing than etanercept. What’s the difference?
etanercept - twice weekly subcu injection
adalimumab - twice monthly subcu
Golimumab is only dose once per month which is great! But what are those pesky side effects?
increased risk of serious infections - TB, fungal, other opportunistic
The metabolism and elimination of certolizumab is delayed by conjugating it to what molecule?
polyethylene glycol
What’s the IL-1 antagonist used for RA treatment? What’s the downside to its use?
anakinra; short half-life necessitates daily high dose treatments
Another RA med that can cause serious infections but works by antagonizing IL-6 receptor is..
tocilizumab
What two drugs that can be used in RA refractory to TNF inhibitors act by inhibiting lymphocytes?
abatacept and rituximab
How does abatacept work? Side effects?
inhibits T-cell activation and induces apoptosis;
HA, infections
We know rituximab is anti-CD20 and reduces B-cells. What side effects do you have to watch out for in RA though?
infections; hypersensitivity reactions (decrease with repeat dosing)
What are the two general causes of hyperuricemia?
high rate of production and low rate of excretion
High rate of urate production might be caused by …
disease states (rapid production and destruction of cells); metabolism (ketosis, acidosis); drug induced (anti-neoplastics, alcohol); diet (high purine intake - animal muscle, seafood, beer)
Low rate of irate excretion might be the result of …
renal problems (might just be because you’re getting old); suboptimal urine volumes; drugs (thiazides inhibit urate secretion!)
What caused your acute gouty arthritis and what should you do about?
can be set off by surgery, overeating, overdrinking, injury
even untreated it will subside in a few days and the joint will return to normal
Can gout be controlled without drugs?
Yes! lifestyle changes (weight loss, diet control, reduced EtOH intake) and altering drug intake will usually be sufficient
Colchicine can dramatically relieve the pain and inflammation of gouty arthritis but doesn’t actually affect urate metabolism or excretion. How does it do it?!
binds tubulin, preventing polymerization (it’s an alkaloid from a plant, after all); this inhibits leukocyte migration, phagocytosis, metabolic activity, and release of pro inflammatory autacoids
What adverse effects are associated with colchicine?
N/V, abd pain, diarrhea
long term use - peripheral neuropathy or neutropenia
low therapeutic index!!
What other things can be helpful in acute gouty arthritis?
NSAIDs (especially indomethacin, naproxen, sulindac, celecoxib)
corticosteroids (intra-articular injection good for monoarticular gout!)
What drugs increase the rate of uric acid excretion? How do they do it?
probenecid and sulfinpyrazone;
they’re organic acids that compete with urate at the anionic transporter in renal tubule and inhibit reabsorption; tophaceous deposits will be reabsorbed in most pts
What side effects might result from probenecid treatment?
GI irritation, nausea
ironically, reducing urate levels might cause urate crystal mobilization and acute gouty arthritis
secretion of some weak acids reduced (penicillin)
What can be used to reduce synthesis of urate?
allopurinol and febuxostat
Mechanism of allopurinol?
inhibits xanthine oxidase competitively (its metabolic product, alloxanthine is a non-competitive inhibitor of XO)
What pts would you use allopurinol in?
those who produce a lot of urate and have a lot of it in their urine;
to prevent a problem in people following chemotherapy
Adverse effects of allopurinol?
maculopapular rash in a couple, rarely hypersensitivity;
actue gouty arthritis as tissue urate is being mobilized
How is febuxostat different from allopurinol?
it’s a non-purine, non-competitive antagonist of XO
Adverse effects of febuxostat?
nausea, rash, arthralgias, expensive!
cardiovascular safety is currently being assessed
If a patient has chronic gout and none of the other drugs are working, what could you use?
pegloticase, a recombinant form of uricase (which metabolizes urate in other species) bound to polyethylene glycol
