RA 2 - treatment (SD) Flashcards
1st RA treatment
NSAIDs
immediate relief to pain
don’t alter LT progression
How do NSAIDs work?
through COX enzyme inhibition
adverse effects of NSAIDs
gastric
headache
hypertension
NSAID examples and doses (high doses)
diclofenac 150mg max daily dose etodolac 1200mg fenoprofen 3200mg flurbiprofen 300mg ibuprofen 3200mg indomethacin 200mg naproxen 1500mg celecoxib 400mg piroxicam 20mg
2nd treatment for RA
DMARDs
disease modifying anti-rheumatic drugs
What do DMARDs do?
they slow the progression of RA
When do DMARDs have an effect?
take weeks/months to work
traditional DMARDs examples
sulfasalazine leflunomide MTX azathioprine hydroxychloroquine
examples of biologic DMARDs
rituximab abatacept tofacitinib infliximab tocilizumab
What are DMARDs used for (4 reasons in RA)?
decrease activated T cells
target macrophages
target cytokines
stop bone erosion
1st choice DMARD
aminosalicylate
What is aminosalicylate an analogue of?
salicylic acid
oral form of animosalicylate?
sulfasalizine (5ASA)
2 components of sulfasalazine
sulfapyridine
5-ASA (active component)
What links 5ASA and sulpapyridine in sulfasalazine?
a diazo bond
What cleaves the diazo bond in sulfasalazine?
colonic bacteria
How does 5ASA work?
inhibition of leukocyte movement
reduces cytokine levels and TNF
inhibition of inflammatory mediators
What inflammatory mediators does 5ASA inhibit?
prostaglandins
leukotrienes
platelet activating facor
cyclooxygenase
side effects of sulfapyridine
headache
dizziness
fever
allegic reaction
2 immunosuppressants - drug to suppress the immune system
methotrexate
leflunomide
What type of drug is methotrexate?
antifolate
When is methotrexate given?
in RA when intolerant/insufficient response to first line therpapy (aminosalycylate)
How does methotrexate work?
- it blocks pyrimidine and purine bio synthetic pathway
- blocks proliferation of B-cells by interfering with DNA synthesis/repair/replication
What is leflunomide used for?
prevents skin/heart/kidney graft rejection (animals) autoimmune diseases (humans - RA/psoriatic arthritis)
How does leflunomide work?
- inhibits the pyrimide biosynthetic pathway
- dec DNA/RNA nitrogen-containing bases
- stops B /T cell proliferation cycles, production of antibodies
What does leflunomide inhibit?
DHODH
dihydroorotate dehydrogenase
What is leflunomide metabolised to? (active metabolite)
teriflunomide
What does teriflunomide inhibit?
DHODH - dihydroorotate dehydrogenase
What does DHODH convert to?
orotic acid
this converts to uridine (uricil + ribose, uricil is a component of RNA)
What happens when DHODH is blocked and pyrimide pools cannot form?
decreases DNA/RNA synthesis
inhibits lymphocyte proliferation
What is hydroxychloroquine?
4-aminoquinoline
What is hydroxychloroquine used to treat?
RA
lupus erythematous
malaria
How does hydroxychloroquine work?
MA unknown but:
accumulates and stabilises lysosomes
impacts antigen presentation
causes suppression of T cells
examples of biologic DMARDs
rituximab abatacept tofacitinib infliximab tocilizumab
What do biologic DMARDs centre around?
monoclonal antibodies
suffix of biologic DMARDs
-mab (monoclonal antibody)
anti-TNF biologic DMARDs
adalimumab certolizumab etanercept golimumab infliximab
anti- IL1 DMARD
anakinra
anti-IL6 DMARD
tocilizumab
What do TNF alpha biologics target?
TNF
TNFR (receptor)
What are adalimumab and golimumab?
biologic DMARDs - TNF alpha
fully humanised monoclonal antibodies specific for TNF alpha
What is certolizumab?
TNF alpha biologic DMARD
Fab fragment of a humanised monoclonal antibody specific for TNF alpha
What is etanercept?
TNF alpha biologic DMARD
fusion protein consisting of 2 recombinant soluble extracellular portions of the human TNFR2
fused to the constant domain of human IgG1
binds to TNF alpha
What is infliximab?
TNF aplha biologic DMARD
chimaeric monoclonal antibody
neutralises TNF aplha
example of IL1 biologic DMARD
anakinra
How does Anakinra work?
competitively inhibits IL-1 binding to the IL-1 type 1 recepor
What does IL-1 cause?
imflammation
immunological response
example of IL6 biologic DMARD
tocilizumab
What is tocilizumab?
recombinant humanised monoclonal antibody
acts as a competitive inhibitor at the IL-6 receptor
What is IL-6?
proinflammatory cytokine produced by T and B lymphocytes, monocytes and fibroblasts
example of a T-cell co-stimulation modulator
Abatacept
What do T-cell co-stimulation modulators do?
prevent T cell activation
What does the ‘co-stimulatory signal’ involve?
binding of CD80/CD86 molecules on the surface of APC to the CD28 receptor on T-cells
How does abatacept work?
it selectively binds to CD80/CD86 and blocks the co-stimulatory signal
How is abatacept given?
IV infusion
half life of abatacept
long, 14 days
example of an anti-CD20 B-cell depleter
Rituximab
What is CD20?
a cell marker on B cells
How does rituximab work (anti-CD20 B cell depleter)?
depletes CD20+ B cells by bining to the CD20 antigen expressed on the cells surface
blocking CD20 leads to B cell death via apoptosis/lysis
