drug management for rhuematoid arthritis

Question 1

therpeutic goals in RA

Answer 1

prserve function - disease modification

prevent pain

Question 2

burden of inflammation in RA lies in

Answer 2

the synovium
becomes infiltrated with macrophages, T and B lymphocytes, vessels, fibroblasts, other inflammatory cells
cause destruction of the normal joint cartilage and bone

Question 3

RA pathogenesis

Answer 3

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

Question 4

drugs targetting T-cell proliferation and function

Answer 4

methootrexate
leflunomide
glucocorticoids

Question 5

drugs targeting macrophage function

Answer 5

TNF-a inhibitors

glucocorticoids

Question 6

drugs targeting uncertain mode of action

Answer 6

sulfasalazine

hydroxychloroquine

Question 7

TNF-a is secreted by

Answer 7

macrophages and acts through TNF-receptors

Question 8

macrophages secrete TNFa when

Answer 8

tiggered by activated T lymphocyte

Question 9

what does TNFa do

Answer 9

engages on receptors

cells populatng the synovium are activated to facilitate inflammation

Question 10

synovium cells and their response to TNFa

Answer 10

endothelial cells - adhesion receptors for leukocytes 
lymphocytes - activation, proliferation 
macrophages - activation 
APC - maturation and migration 
some tumour cells - apoptosis

Question 11

two engineered anti-TNFa antibodies

Answer 11

infliximab

adalimumab

Question 12

infliximab

Answer 12

human sequences and mouse sequences, modified to minimise human antigenicity

Question 13

adalimumab

Answer 13

comletely humanised Fab sequence

Question 14

adverse effects of TNFa inhibition

Answer 14

immune supression

• increased nfection rate, including some infections only seen in immunosuppression
• particular risk in people with dormant tuberculosis
• increased rate of some malgnancies

Question 15

3 glucocorticoids

Answer 15

hydrocortisone
prednisolone
dexamethasone

Question 16

how glucocorticoids interact with the cell

Answer 16

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

Question 17

effects of glucocorticoids

Answer 17

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

Question 18

GCs are used in

Answer 18

systemic - autoimmune disease, allograft (transplant) tolerance
local - asthma, dermatitis, ulcerative colitis, inflammatory arthritis and others

Question 19

adervse effects of GC when used systemically

Answer 19

metabolic and mineralocorticoid adverse effects
commonly used systemically early in treatment
avoid or minimise, to prevent adverse effects

Question 20

dihydrofolate reductase

Answer 20

turns folic acid into tetrahydrofolate by adding 4 hydrogens

Question 21

tetrahydrofolate

Answer 21

essential for asssembling purines and pyrimidines

Question 22

action of methotrexate

Answer 22

antagonist fr dihydrofolate reductase - stops production of dihydrofolate which causes prevention of T cell proliferation

Question 23

mathotrexate toxicity

Answer 23

antiprolferative actions

• bone marrow
• gut (mouth ulcers, GI upset)

tetragonicity risk (high doses embryotoxic

hepatotoxicity and pulmonary fibrosis

Question 24

excretion of methotretaxe

Answer 24

mostly renally excreted - check renal function

Question 25

leflunomide

Answer 25

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

Question 26

prostaglandins and prostaglandin inhibition in RA

Answer 26

for pain non-opoiod analgesics prostaglandins are products of macrophages - sensitise pain receptors and pro-inflammation

Question 27

inhibiting prostagladnin production

Answer 27

- suppresses sign of inflamation, including pain | - does NOT prevent disease progression

Question 28

typical drug prescription for RA

Answer 28

- 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

Question 29

non-pharmacological management

Answer 29

protection of joints (splints) management of CV risk general functional support, to compensate for disability psychological support