Rheumatoid Arthritis and DMARDs Flashcards
How do you treat osteoarthritis?
acetaminophen
describe osteoarthritis:
associated with age, immune system is NOT involved, treatment is acetaminophen, not an NSAID, good for analgesic purposes
T/F. Rheumatoid arthritis is an autoimmune disease.
TRUE, with immune system drug targets.
First approach of treatment for RA:
physical therapy; rest and splitting to prevent muscular atrophy
Second approach for treatment of RA:
drugs; to relieve symptoms, MINIMIZE TISSUE DESTRUCTION CAUSED BY INFLAMMATION
T/F. Aggressive treatment very early to halt disease progression is now common.
TRUE.
What does DMARDs stand for?
Disease-Modifying Anti-Rheumatic Drugs: slowing or stopping disease progression
Third approach to treatment of RA:
surgery if drugs inadequate
Three groups that help treat RA:
NSAIDs and GCs, “Traditional” DMARDs, and Biologic Response Modifies or Biologics
Group of drugs that is generally a broad immune-toxic mechanism:
Traditional DMARDs
What does traditional mean?
oral
Group of drugs that target individual specific signaling molecules:
Biologic Response Modifiers or Biologics
Protein or peptide drugs:
Biologic response modifiers
Small molecule drugs, brand and can do all types of things:
Traditional DMARDs (and oral)
NSAID used for RA:
Naproxen.
Why is NSAID never mono therapy?
It provides just a bandaid, but does not fix problem, not sufficient enough; only provides initial relief
GC stands for:
glucocorticoids
What is a glucocorticoid?
anti-inflammatory steroids
What is the most commonly used GC?
Prednisone
Characteristics of Prednisone:
highly effective, but long term toxicity effects; not used as a mono therapy, rapid acting bridge agent
Traditional DMARDs:
methotrexate, hydroxychloroquine, sulfasalazine, triple drug therapy, leflunomide, minocycline
Biologic DMARDs
ANTI-TNF drugs, etanercept, infliximab
The first choice DMARDs drug for initial therapy of RA and used in early stages of RA (but can be used in late stages too:
Methotrexate, also called MTX
Do we use Methotrexate with other drugs?
Yes, very often. Also use in more than 50% of RA patients
Dose of methotrexate?
once per week, mat take up to 4-6 weeks to see effects
Structure and mechanism of methotrexate:
FOLIC ACID analog; folate transporters.
Does methotrexate have a long half life in the cell than plasma?
Yes, much longer than plasma half-life.
What is mechanism 1 of methotrexate?
acts as anti-metabolite (anti-folate) to inhibit PURINE and PYRIMIDINE synthesis; inhibits DHFR and FH4; anti-cancer mechanism
What is mechanism 2 of methotrexate?
inhibits enzyme AICAR; inhibits purine synthesis; increase anti-inflammatory mediate ADENOSINE outside cells; doesn’t just slow but REVERSES; MAJOR MECHANISM in RA
What is mechanism 3 of methotrexate?
reduce pyrimidine synthesis, inhibits proliferation of inflammatory cells
Overall the mechanisms for methotrexate rely on what?
rapid immune cell proliferation depends on purines and pyramids; methotrexate inhibits both, but increases adenosine (anti-inflammatory)
Side effects of methotrexate:
minor GI problems, rare hepatotoxicity with high doses, elevation of liver enzyme levels at high doses, USE ONCE A WEEK to avoid high doses, avoid alcohol, avoid patients with liver failure
Many side effects of methotrexate or due to what?
induced folate deficiency
How can you reduce folate deficiency?
REPLACEMENT FOLIC ACID DAILY (1-3 mg)
What are CONTRAINDICATIONS of methotrexate?
renal insufficiency; pregnancy or those planning for pregnancy (teratogenic), nursing mothers, abortifacient with misoprostol
What is a less common complication but signs need to be watched when administering MTX?
increased infections, including upper respiratory, TB, fungal
Anti-malarial drug that is anti-inflammatory:
hydroxychloroquine
What drugs do we use hydroxychloroquine with?
MTX, sulfasalazine
How is hydroxychloroquine thought to work?
altering cellular pH
T/F. hydroxychloroquine has a slow onset and very long half-life (45 days). And skin is reservoir.
TRUE.
Side effects of hydroxychloroquine:
Retinal damage (melanin contains tissues such as eye), decreased blood glucose, increased risk of hypoglycemia in diabetics; NO adverse effects in pregnancy/breast feeding
is another traditional DMARD and immune-suppressive drug, it has poorly defined mechanisms but is thought to:
inhibition of multiple immune cells and cytokines
What drugs do we give Sulfasalazine with?
Hydroxychloroquine and/or MTX
Where is Sulfasalazine metabolized and what is it metabolized to?
metabolized in gut; metabolized to salicylate and sulfapyridine
Sulfasalazine is known to have anti-inflammatory effects where?
In the bowel
Common side effects of Sulfasalazine:
GI issues, anorexia, headache, skin irritation
Most significant concerns with Sulfasalazine:
blood dycrasias; reduce folate absorption; do not use in those with sulfa or CELEBREX allergy (cross-reactivity)
Another name for Triple drug therapy:
Nebraska therapy (UNMC)
Process of triple drug therapy:
start with MTX weekly, then try hydroxychloroquine plus Sulfasalazine daily; then try all three in combo; can add NSAIDs or prednisone
Inhibits digydro-orotate dehydrogenase which inhibits pyrite synthesis; also inhibits tyrosine kinases at higher doses:
Leflunomide
What is overall effect of Leflunomide?
INHIBIT T-CELL proliferation, reduces antibody production by B-Cells
T/F. Leflunomide is a pro-drug.
TRUE
Why does Leflunomide have an extremely long effective half-life with significant consequences?
due to repeated entero-heptatic recirculation; active agent can remain in body long after last administration
Side effects of Leflunomide:
diarrhea, and hair loss (alopecia), carcinogenic and teratogenic, CONTRAINDICATED before and during pregnancy, cholestyramine WASHOUT if needed prior to stopping birth control
Well established tetracycline antibiotic that inhibits collagenase; specific action to decrease collagen degradation component of RA:
minocycline
minocycline administration and use:
oral, once or twice a day. use in early disease progression
Side effects of minocycline:
dizziness and hyper pigmentation
Biologic DMARDs:
newer drugs that are peptides or proteins (NOT small molecules)
How to biologic DMARDs act?
all are immuno-suppresive but act by targeting INDIVIDUAL SPECIFIC MEDIATORS; target mediators early in inflammation signaling cascades
What types of drugs prevent auto-antibody production and release and subsequent inflammation?
biologic DMARDs
T/F. Biologic DMARD block signaling molecules.
TRUE, these signaling factors drive inflammation and damage to synovial cells and structures
Difference between murine, chimeric, and humanized:
0%, 65%, 90%
What does “mib” and “nib” stand for?
Mib = protease/proteosome inhibitors; nib = (inhibit) kinase inhibitors
T/F. All of the biologics are more effective when used in combination with methotrexate/
TRUE.
Side effects for biologics:
increased risk of infections, blood dycrasias, increased cancer incidence (non-Hodgkins, non-melanoma skin), GI problems, headache, skin rash, cough
Examples of Anti-Tumore Necrosis Factor drugs (ANTI-TNF):
EtanerCEPT, InflixiMAB
Which of the biologics is most commonly used?
Anti-TNFs
What does TNF-alpha do?
upstream regulator of many other immune and inflammatory cytokines; TNF receptors p55 and p75
One of the first anti-TNF drugs:
Etanercept
The soluble p75 subunit of the TNF reCEPTor used as a drug:
Etanercept
Mechanism by which Etanercept works:
bings to and prevents TNF from binding to its cellular receptor
Administration and use of Etanercept:
given weekly, shortest duration, used in combo with MTX
Side effects of Etanercept:
headaches, sinus issues, allergies, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) (rare untreatable viral infection of CNS); black box warning for lymphomas
T/F. Etanercept is not a protein.
FALSE, it IS a protein.
A Monoclonal AntiBody against TNF (not part of the receptor), a mouse-human chimera (xi), bings to TNF:
InfliXImab
Another anti-TNF drug that is monoclonal antibody against TNF:
InfliXImab
Administration and use of InfliXImab:
IV, every 4-8 weeks, after initial loading dose; ALWAYS COMBINED WITH MTX or other t-DMARDs
Side effects of InfliXImab:
similar to Etanercept; can cause HYPOTENSION (do not use in heart failure patients)
