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Flashcards in Arthritis drugs Deck (35):
1

What is arthritis?

causes pain
affects mobility
unpredictable

2

Osteoarthritis definition

affects the bone
primary = wear and tear, ageing
secondary = trauma, disease or obesity
pain through INFLAMMATION

3

Rheumatoid arthritis definition

affects blood
systemic auto-immune disorder that can effect other tissues
pain through INFLAMMATION - release of cytokines

4

Osteoarthritis

disease affecting the synovial joints eg. knee, elbow, wrist
characterised by loss of cartilage and bone from articulating surfaces and alteration in cartilage structure (cartilage is needed to prevent bone friction)

5

Why is cartilage degraded?

? increase in cytokines which are inflammatory chemical causing inflammation
- IL-1B inhibits type 2 collagen synthesis of hyaline cartilage
- destroys environment surrounding cartilage cells = structure change
- increase in matrix metalloproteinase = breakdown of collagen = cartilage degradation

6

How is normal joint structure maintained?

Type 1 collagen = found in the bone, function is osteoblast differentiation from bone marrow
Type 2 collagen = found in cartilage, function is maintaining integrity of cartilage
Aggrecan = found in synovial membrane, function is maintaining integrity of cartilage
Matrix metalloproteinase = found in synovial tissue, function is degrading ECM proteins to enable growth

7

Risk factors of osteoarthritis

obesity, gender (females increased risk post-menopause due to decrease in oestrogen), previous joint injury/disease, metabolic disorders, age (<40) genetics eg collagen gene mutation

8

Prostaglandins

PGD2/PGI2 = vasodilation
PGE2 = vasodilation, pyogenic + anti-inflammatory effects
potentiate effects of histamine + bradykinin
- increased permeability of venules = oedema
- increased sensitivity of C fibres = PAIN
= enables WBC to reach site of injury/infection

9

COX enzyme

3 forms
COX-1 -
> produced all the time
> expressed in most tissues
> 'housekeeping' enzyme
> protects GI mucosa, controls renal blood flow, initiation of labour
COX-2 -
> produced when needed
> inflammatory cells induced by injury, infection, cytokines
> produces inflammatory mediators
> ovulation, uterine contractions
COX-3
ALL catalyse arachidonic acid - PGs and thromboxane
COX enzymes are a target for NSAIDs

10

NSAID examples

aspirin
ibuprofen
diclofenac
meloxicam
indomethacin
available OTC
different formulations

11

Actions of NSAIDs in osteoarthritis treatment

Antipyretic = inhibits actions of PGs on hypothalamus
Analgesic = reduce sensitivity of neurones to bradykinin, effective against pain of muscular/skeletal origin
Anti-inflammatory = reduce vasodilation and decrease permeability of venules
- may scavenge oxygen radicals = decrease tissue damage
pain relief almost immediate

12

Problems with NSAIDs

risk of gastric ulcers
impair coagulation
use with caution in elderly
risk of CV events in patients with cardiac disease/hypertension
may induce asthma attach, rhinitis, angioedema (rapid swelling of dermis, subcutaneous tissues), urticaria – skin rash
why problem ? many inhibit COX1 and COX2
- PGs produced in COX1 have many beneficial processes inc. production of GI mucus blocking increase risk of ulcers

13

Solving problems with NSAIDs

COX1 and COX2 differ in structure = should be possible to produce selective drugs
COX2 inhibits -
Celecoxib, eterocoxib used in patients with high risk of GI side effects
- common SE: headache, skin rash, peripheral oedema

14

Misoprostol

synthetic PG
given along side NSAIDs preserves mucous lining of GI tract and protects against ulceration
SE: vaginal bleeding, diarrhoea

15

Aspirin

rapidly absorbed in the stomach
displaces Warfarin bound to plasma proteins therefore it increases plasma Warfarin and potentiates Warfarin's anticoagulant activity

16

Paracetomol

not an NSAID as has no anti-inflammatory effect
it is an analgesic and antipyretic
supresses PG production
chronic use of large doses = kidney damage
toxic doses (10-15g) = potentially fatal liver damage
can be given along NSAIDs (with proton-pump inhibitor)

17

Other Osteoarthritis treatment options

weight loss
exercise to strengthen core muscles
joint supports/braces
suitable footwear
thermotherapy
intra-articular corticosteroid injection = temporary benefit
joint replacement surgery
bisphosphonates
opioid analgesics eg. Oxycodone
monoclonal antibodies eg Dunosomab

18

Strontium ranelate in treating osteoarthritis

promotes osteoblast differentiation/inhibits osteoclast activity
reduces pain
indicated to prevent fractures in severe osteoporosis
can increase risk of MI and thrombotic events

19

Glucosamine sulphate in treating osteoarthritis

major constituent of ECM
present in cartilage and synovial fluid
possible long term benefits, not reo=commended by NICE

20

Rheumatoid arthritis

causes joint inflammation
leads to proliferation of synovial membrane and erosion of cartilage/bone
autoimmune disorder
symptoms = swollen, stiff and painful joints

21

Treatment and management

NSAIDS/ opioid analgesics
glucocorticoids

immuno-suppressants
disease modifying anti-rheumatoid drugs (DMARDS)
anti-cytokines

managed by diet + complementary therapy, drugs and surgery

22

Glucocorticoids

roduced by the cortex
have metabolic, immunosuppressive and anti-inflammatory effects
> short acting (1-12hrs) eg. Cortisone, Hydrocortisone, twice daily cream/injection
> inter-mediate acting (12-36 hrs) eg Prednisolone, daily oral/injection
> long acting (36-55hrs) eg Dexamethasone, injection every 3-21 days

23

Actions of glucocorticoids

decrease transcription of pro-inflammatory cytokines
decrease circulating lymphocytes
inhibit phospholipase A2 causing a decrease in arachidonic acid
increase synthesis of anti-inflammatory proteins eg. Beclometasone, prednisolonw

24

Long term side effects of glucocorticoids

buffalo hump, hypertension, thinning of skin, increased risk of infection, poor wound healing, osteoporosis, muscle wasting
can reduce SE by not administering orally, or by lowering plasma concentrations
danger of stopping treatment immediately

25

Disease Modifying Anti-Rheumatoid Drugs

drugs with unrelated structures, and diff mechanisms of action

26

Methotrexate (DMARDS)
- immunosupressant

folic acid antagonist - inhibits DNA synthesis
blocks growth and differentiation of rapidly dividing cells
inhibits T cell activation
SE = blood abnormalities, liver cirrhosis, folate deficiency
often prescribed with another DMARD

27

Sulfasalazine (DMARD)

common choice of DMARD
complex of salicylate (NSAID) and sulphonamide (antibiotic)
causes remission in active RA
SE = GI upset, headache and skin reactions, reduced WBC

28

Penicillamine (DMARD)

produced by hydrolysis of penicillin
decrease IL1 generation = decrease fibroblasts = decrease immune response
SE = rashes, stomatitis, anorexia
should not be given with gold compounds

29

Gold compounds (DMARD)

Auranofin (oral) - decrease pain and joint swelling
Sodium auranofin - deep i.m injection
concentrates in synovial cells, liver cells, kidney tubule, adrenal cortex and macrophages
effects develop over 3-4 months
SE = skin rashes, flu like symptoms, mouth ulcers, encephalopathy, hepatitis

30

Anti-malarials (DMARD)

eg. Chloroquine/ hydroxychloroquine
increase pH of intracellular vacuoles = interferes with antigen-presenting
induces apoptosis in T-lymphocytes
used when other treatments fail
therapeutic effects take about a month
SE = nausea and vomiting, blurring of vision

31

Biological agents
- anticytokine drugs

introduced in 1998
decrease disease activity = increase quality of life and decrease need for surgery/mechanical aids
engineered recombinant antibodies
given with Methotrexate
eg. Etenercept, Infliximab, Abatacept, Rituximab
given by s.c or i.v injection
SE = may develop latent disease eg TB, opportunistic infections, nausea etc
new biologics = Janus Kinase Inhibitors

32

Ciclosporin

immunosuppressant
no effect on acute inflammation
inhibits IL2 gene transcription = decreases T cell proliferation
poorly absorbed orally = special formulations
accumulates in high concs in tissues
SE = nephrotoxicity, hapetotoxicity, hypertension, GI problems

33

Azathioprine

immunosuppressant
cytotoxic: interferes with purine metabolism to decrease DNA synthesis
depressed cell-mediated and antibody-mediated immune reactions
main effect is that is supresses bone marrow

34

Leflunomide

immunosuppressant
inhibits pyrimidine synthesis
specific inhibitor of activated T cells
well absorbed orally, long half life
SE = diarrhoea, alopecia, increased liver enzymes = risk of hepatotoxicity

35

Cyclophosphamide

immunosuppressant
only used when other therapies have failed
Inhibits cross-linking of DNA
prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein
Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)