drug management for rhuematoid arthritis Flashcards
therpeutic goals in RA
prserve function - disease modification
prevent pain
burden of inflammation in RA lies in
the synovium
becomes infiltrated with macrophages, T and B lymphocytes, vessels, fibroblasts, other inflammatory cells
cause destruction of the normal joint cartilage and bone
RA pathogenesis
T-lymphocyte becomes reactive to a self antigen
T cells are reactive to normal tissue - proliferation and activation
macrophage activation
antibody production and joint tissue damage
drugs targetting T-cell proliferation and function
methootrexate
leflunomide
glucocorticoids
drugs targeting macrophage function
TNF-a inhibitors
glucocorticoids
drugs targeting uncertain mode of action
sulfasalazine
hydroxychloroquine
TNF-a is secreted by
macrophages and acts through TNF-receptors
macrophages secrete TNFa when
tiggered by activated T lymphocyte
what does TNFa do
engages on receptors
cells populatng the synovium are activated to facilitate inflammation
synovium cells and their response to TNFa
endothelial cells - adhesion receptors for leukocytes lymphocytes - activation, proliferation macrophages - activation APC - maturation and migration some tumour cells - apoptosis
two engineered anti-TNFa antibodies
infliximab
adalimumab
infliximab
human sequences and mouse sequences, modified to minimise human antigenicity
adalimumab
comletely humanised Fab sequence
adverse effects of TNFa inhibition
immune supression
- increased nfection rate, including some infections only seen in immunosuppression
- particular risk in people with dormant tuberculosis
- increased rate of some malgnancies
3 glucocorticoids
hydrocortisone
prednisolone
dexamethasone
how glucocorticoids interact with the cell
GC binds to circulating corticosteroid binding globulin
steroid binds cytosolic glucocorticoid receptor, which translocated to nucleus
steroid receptor complex binds recognition sequences on promoter of responsive genes, stimulating transcription
effects of glucocorticoids
macrophages - decrease of cytokines including TNFa ans decrease of other proinflammatory functions
t lymphocytes - decrease in recruitment and proliferation
b lymphocytes - decreasse in antibody production
GCs are used in
systemic - autoimmune disease, allograft (transplant) tolerance
local - asthma, dermatitis, ulcerative colitis, inflammatory arthritis and others
adervse effects of GC when used systemically
metabolic and mineralocorticoid adverse effects
commonly used systemically early in treatment
avoid or minimise, to prevent adverse effects
dihydrofolate reductase
turns folic acid into tetrahydrofolate by adding 4 hydrogens
tetrahydrofolate
essential for asssembling purines and pyrimidines
action of methotrexate
antagonist fr dihydrofolate reductase - stops production of dihydrofolate which causes prevention of T cell proliferation
mathotrexate toxicity
antiprolferative actions
- bone marrow
- gut (mouth ulcers, GI upset)
tetragonicity risk (high doses embryotoxic
hepatotoxicity and pulmonary fibrosis
excretion of methotretaxe
mostly renally excreted - check renal function
leflunomide
blocks dihydroorotate dehydrogenase, which is in the pathway for pyrimidine synthesis
- also antiproliferative
- also teratogenic
has a long half life
avoid n young women, or reliable contraception
causes hepatotoxicity
prostaglandins and prostaglandin inhibition in RA
for pain
non-opoiod analgesics
prostaglandins are products of macrophages - sensitise pain receptors and pro-inflammation
inhibiting prostagladnin production
- suppresses sign of inflamation, including pain
- does NOT prevent disease progression
typical drug prescription for RA
- MTX or leflunomide
- add hydrocychloroquine, sulfasalazine
- add biological agent, usually anti-TNFa
- los dose systemic glocucorticoids commonly used in early phase, when pursuing remission
- cyclooxygenase inhibitors (NSAIDs) for analgesia and acute anti-inflammatory action
non-pharmacological management
protection of joints (splints)
management of CV risk
general functional support, to compensate for disability
psychological support
