RA 2 - treatment (SD) Flashcards by Sarah Ramsbottom

1st RA treatment

NSAIDs
immediate relief to pain
don’t alter LT progression

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How do NSAIDs work?

through COX enzyme inhibition

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adverse effects of NSAIDs

gastric
headache
hypertension

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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

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2nd treatment for RA

DMARDs

disease modifying anti-rheumatic drugs

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What do DMARDs do?

they slow the progression of RA

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When do DMARDs have an effect?

take weeks/months to work

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traditional DMARDs examples

sulfasalazine
leflunomide
MTX
azathioprine
hydroxychloroquine

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examples of biologic DMARDs

rituximab
abatacept
tofacitinib
infliximab
tocilizumab

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What are DMARDs used for (4 reasons in RA)?

decrease activated T cells
target macrophages
target cytokines
stop bone erosion

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1st choice DMARD

aminosalicylate

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What is aminosalicylate an analogue of?

salicylic acid

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oral form of animosalicylate?

sulfasalizine (5ASA)

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2 components of sulfasalazine

sulfapyridine

5-ASA (active component)

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What links 5ASA and sulpapyridine in sulfasalazine?

a diazo bond

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What cleaves the diazo bond in sulfasalazine?

colonic bacteria

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How does 5ASA work?

inhibition of leukocyte movement
reduces cytokine levels and TNF
inhibition of inflammatory mediators

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What inflammatory mediators does 5ASA inhibit?

prostaglandins
leukotrienes
platelet activating facor
cyclooxygenase

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side effects of sulfapyridine

headache
dizziness
fever
allegic reaction

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2 immunosuppressants - drug to suppress the immune system

methotrexate

leflunomide

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What type of drug is methotrexate?

antifolate

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When is methotrexate given?

in RA when intolerant/insufficient response to first line therpapy (aminosalycylate)

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How does methotrexate work?

it blocks pyrimidine and purine bio synthetic pathway

- blocks proliferation of B-cells by interfering with DNA synthesis/repair/replication

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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