Duan-DMARDS etc Flashcards
What are the important corticosteroids to keep in mind?
prednisone
prednisolone
dexamethasone
What are some important DMARDs that are anti-TNFalpha?
adalimumab
infliximab
etanercept
anakinra
What are some important DMARDs that are antimetabolites?
azathioprine
methotrexate
cyclophosphamide
cyclosporine
What are the symptoms of RA? How would you describe this disease?
chronic progressive systemic autoimmune disease
Symmetric synovitis
Joint inflammation, pain, swelling, stiffness, progressive erosions of bones, joint misalignment, reduced or lost function
rheumatoid nodules on the extensor surfaces of the elbows, forearms, and hands.
Multisystem extra-articular manifestations
Pulmonary and vascular involvement
Keratoconjunctivitis
Sensory peripheral neuropathy
What are the goals of RA therapy?
Control inflammation
Alleviate pain
Slow progression/rate of joint damage
Reduce disease activity and induce remission
Maintain function for essential daily activities
Maximize quality of life
What are the ways to admin RA meds? Other treatments?
systemic oral meds
intra-articular injections
joint exercises & rest
joint surgery
What are the 2 functional groups that RA medicines fall into?
- drugs that treat pain & inflammation but don’t limit joint damage
- drugs that help control disease & limit joint damage
Where do NSAIDS & Corticosteroids (glucocorticoids) & DMARDS fall into functional categories?
NSAIDS & Corticosteroids–drugs that treat pain & inflammation
DMARDS–limit joint damage
What is combination therapy?
widely used several oral DMARDS OR oral + biological DMARDS OR DMARDS + Corticosteroids (systemic or injection)
Phospholipase A2 turns Membrane phospholipids into eicosanoids. Which 2 enzymes are involved next?
LOX: turns eicosanoids into leukotrienes.
COX: turns them into prostaglandins.
What are some drugs that target Phospholipase A2?
Corticosteroids: prednisone & dexamethasone
What are some drugs that target COX?
NSAIDS
Which drugs target LOX?
5-lox inhibitors
sulfasalazine
leukotriene receptor antagonist
What does the presence of leukotrienes do? Prostaglandins cause inflammation.
phagocyte mobilization
changes in vascular permeability
inflammation
Which enzyme, COX-1 or COX-2 causes inflammation, pain, fever?
COX-2
What are the advantages of using NSAIDs to manage RA?
effective control of inflammation & pain effective reduction in swelling improves mobility, flexibility, ROM QOL up low cost
What are the disadvantages of using NSAIDS to manage RA?
doesn't help disease progression GI toxicity possible renal problems hepatic dysfunction CNS toxicity with high dose
Where are corticosteroids made in the body?
adrenal cortex
including glucocorticoids & mineral corticoids
What is the function of glucocorticoids? WHat is an example?
cortisol
carb, fat, protein metabolism
prevent phospholipid release-anti-inflammatory
decrease eosinophil action
What is the function of mineral corticoids? What is an example?
Aldosterone
electrolyte & water levels
promotes sodium retention in kidney
Describe the hypothalamic-pituitary adrenal axis feedback.
CRH (vasopressin) from hypothalamus stimulates Pituitary gland to release ACTH.
ACTH causes the release of Glucocorticoids from adrenal glands.
Neg feedback to pituitary & hypothalamus.
Pos feedback to hippocampus, which is inhibitor to hypothalamus.
Additionally, stress is stimulatory to hypothalamus.
What is the MOA of corticosteroids?
diffuse into cells via simple diffusion & binds transcription factors. Enter nucleus & regulate synthesis of IFNgamma, GM-CSF & interleukins & TNFalpha
also inhibit COX-2 & phospholipase A2.
How do corticosteroids use lipocortin?
lipocortin inhibits phospholipase A2.
Corticosteroids increase lipocortin.
What are some clinical uses of glucocorticoids?
immunosuppression anti-inflammatory autoimmune diseases (RA) Asthma Anti-cancer Replacement THerapy (addison's disease) Allergic disorders collagen disease nephrotic disease resp distress syndrome
Name some corticosteroids used in RA therapy? Which have short duration? Long duration?
Cortisol: 1.5-3 hrs Cortisone: 0.5 hrs Prednisone: 3-4 hrs Triamcinolone: 36-54 hrs Dexamethasone: 35-54 hrs Fludrocortisone: 24 hrs
How do synthetic corticosteroids compare to endogenous ones?
Synthetic have stronger potency, lower dose, longer duration
How are corticosteroids well absorbed? How do they travel in blood? Where are they metabolized? Excreted?
well absorbed orally
bound to plasma proteins
metabolized in liver (Cyt P450)
excreted in kidney
What are some other important pharmacokinetic features of corticosteroids?
Plasma half-life shorter than biological halflife
Substantial lag time before onset of action
Persistence of effect after disappearance from plasma
What are the adverse effects of using chronic use of glucocorticoids?
Fat redistribution: Cushing's syndrome, Moon face, buffalo hump Diabetes HPA suppression Impaired Wound Healing MSK: osteoporosis Cardio: fluid retention, edema, HTN Gastric Ulcers Infection Growth inhibition
What are the advantages of corticoid therapy?
anti-inflammatory & immunosuppression
helps joint flares if you use intra-articular injections
What are the disadvantages of corticoid therapy?
doesn’t affect disease progression
skin thinning, ecchymoses, Cushing appearance
cause of steroid-induced osteopenia
What are oral DMARDS?
small molecular chemical drugs
What are biologic DMARDS?
genetically engineered antibodies & proteins Ex: TNFalpha blockers
can also target IL-1, IL-6, CD20, CD28
How long does it take for DMARDS to have an observable clinical effect?
takes more than 3 months
What is the MOA of azathioprine?
purine synthesis inhibitor
What is the MOA of cyclosporin A?
calcineurin inhibitor
What is the MOA of leflunomide?
pyrimidine synthesis inhibitor
What is the MOA of methotrexate?
purine metabolism inhibitor
What is the MOA of abatacept?
T cell costimulatory signal inhibitor
What is the MOA of adalimumab?
TNF alpha inhibitor
What is the MOA of chloroquine & hydroxychloroquine? Note: these are antimalarials
suppression of IL-1 & TNFalpha
induce apoptosis of inflammatory cells & decrease chemotaxis
What is the MOA of D-penicillamine?
reducing numbers of T lymphocytes
What is the MOA of etanercept & golimumab? And infliximab
TNFalpha inhibitor
What is the MOA of minocycline?
5-LO inhibitor
What is the MOA of rituximab?
chimeric monoclonal antibody againstCD20on B-cell surface
What is the MOA of sulfasalazine?
Suppression of IL-1 & TNF-alpha, induce apoptosis of inflammatory cells and increase chemotactic factors
What is the MOA of tocilizumab?
anti-IL6
What is the recommended dose for methotrexate in treatment of rheumatoid arthritis?
7.5-20 mg/wk
What are the advantages to DMARDS?
slow disease progression improve functional disability decrease pain interfere with inflammation retard joint erosions
What is the time to benefit for methotrexate?
1-3 mo
What is the potential toxicity for methotrexate?
moderate
on par with gold (parenteral)
What are the toxicities to monitor for DMARDs?
hepatotoxicity
pulmonary
myelosuppression
What is the general & specific MOA for methotrexate?
general: purine metabolism inhibitor
specific: blocks dihydrofolate reductase & thymidylate synthase
What are the pros of using methotrexate?
we know what it does
ok to continue therapy with it
proven efficacy in RA
What are the cons of using methotrexate?
lab monitoring every 1-2 mo
possible liver, lung toxicity, myelosuppresion
What is the MOA of sulfasalazine?
COX & LOX inhibitor as well as IL-1 & TNFalpha inhibitor
What are the pros to sulfasalazine?
effective
mild level of toxicity
What are the cons to using sulfasalazine?
some pts sulfa intolerant
bad for patients with G6pd deficiency
monitor every 3 mo
look for myelosuppression, GI, decreased digoxin absorption
What is the MOA of azathioprine?
immunosuppressive
purine synthesis inhibitor
prevents leukocyte proliferation
What are the pros to azathioprine?
effective in refractory RA
metabolized to 6-mercaptopurine
What are the cons to azathioprine?
risk for severe leukopenia, thrombocytopenia
risk for liver toxicity, cancer, opportunistic infections, macrocytic anemia, bone marrow depression, GI
have to monitor every 2 weeks & then every 1-3 mo.
What shouldn’t you take azathioprine with for risk of myelosuppresion?
ACE-1 inhibitor or allopurinol for gout.
What is the MOA of gold auranofin?
blocks phagocytosis
What are the pros of gold auranofin?
good for refractory RA
can be used orally
accumulates in synovium
What are the cons of gold auranofin?
6 mo before you know if effective
close monitoring
can’t take if you have liver or kidney problems
can’t combine with other immunosuppressants
shouldn’t use with X-rays
What are the some of the toxicities associated with gold auranofin?
skin lesions stomatitis oral ulcers glomerulonephritis nephrosis thrombocytopenia agranulocytosis
What is the MOA of leflunomide aka ARAVA?
inhibits pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase (mitochondrial enzyme)
affects T cells
What are the pros of lefluonomide aka arava?
works in 1 mo
can use long term
prevents expansion of activated lymphocytes
selectively targets autoimmune lymphocytes
What are the cons of lefluonomide?
less clinical experience with it
liver & GI toxicity
expensive
long half life requires loading
Once again, what are biological DMARDS?
genetically engineered antibodies & proteins
block cytokines & signaling molecules
What are the biological TNF alpha blockers?
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
What is the biological DMARD that blocks IL-1?
anakinra (kineret)
What is the biological DMARd that blocks B cells CD20?
Rituximab (Rituxan)
What is the structure of etanercept (enbrel)? Which drug is it sometimes used with? How is it administered?
dimeric fusion protein
extracellular ligand that binds TNFreceptor that is linked to the Fc part of IgG1
used sometimes with methotrexate
administered by injection
What seems to be the main problem with Etanercept?
immunosuppressive
can get bad infections
don’t use in diabetics etc.
WHat is the structure of infliximab aka remicade?
chimeric IgG1 antibody that binds to TNFalpha with high affinity
inhibits binding of TNFa to receptors by bind to it first!
can be used with methotrexate
T/F Methotrexate could potentiate the antirheumatoid activity of infliximab while reducing its immunogenicity
True.
What is the structure of adalimumab aka Humira?
recombinant IgG1 monoclonal antibody specific for TNFalpha
only consists of human peptide sequences
binds TNFalpha & blocks its interaction w/ p55 & p75 on cell surfaces
When would you prescribe a biologic DMARD over an oral DMARD?
for patients with longstanding active RA that need to change their therapy
give a greater symptoms response & remission rate than oral DMARDS
can’t compare effectiveness yet
IS it okay to combine 2 biologic DMARDS?
NO. doesn’t increase effectiveness
increases risks for bad side effects
What are some good DMARD combos?
methotrexate + sulfasalazine + hydroxychloroquine
methotrexate + cyclosporine
methotrexate + leflunomide
methotrexate + biologic DMARD
**only for people with longstanding active RA, not early RA
T/F DMARDS should be initiated early in active RA.
True.
T/F DMARD combo treatment should be X + sulfasalazine.
False. X + methotrexate
T/F Biologic DMARDs are indicated when oral DMARDs are not successful.
True.
T/F Biologic DMARDs + Methotrexate are superior to oral DMARDs + methotrexate.
False.
superior to
oral DMARDS alone…that’s all we know for now.
What is an effective firstline treatment for RA?
Methotrexate (oral DMARD)
For people with longstanding active RA…what do you sometimes want to do with oral DMARDs?
use 2-3 oral DMARDs at once!
