Week 2 - Drugs And Arthritis Flashcards
(83 cards)
1
Q
What is osteoarthritis characterised by?
A
Loss of cartilage and bone from articulating surfaces
2
Q
What do prostaglandins D2 and I2 trigger?
A
Vasodilation
3
Q
What does prostaglandin E2 trigger?
A
Vasodilation, pyrogenic and anti-inflammatory effects
4
Q
What do the products of COX-2 have a role in?
A
Inflammation, fever, pain
5
Q
Name some NSAIDS
A
Ibuprofen, aspirin, diclofenac, meloxicam, indomethacin
6
Q
Why do NSAIDS have antipyretic effects?
A
They inhibit actions of prostaglandins on the hypothalamus
7
Q
Why do NSAIDS have an analgesic effect?
A
- reduce sensitivity of neurones to bradykinin
- pain transmission is blocked by COX inhibition
8
Q
Why do NSAIDS have an anti inflammatory effect?
A
Reduce vasodilation and decrease the permeability of venules
9
Q
What is another action of NSAIDS that hasn’t already been mentioned?
A
May scavenge oxygen radicals - decreases tissue damage
10
Q
What does aspirin inhibit and what is the effect of that?
A
Inhibits NFkB expression
- decreases transcription of genes for inflammatory mediators
11
Q
What does celecoxib, diclofenac and ibuprofen decrease?
A
Decreases IL-6 and TNF-a in SF
12
Q
What are some issues with NSAIDS?
A
- risk of gastric ulcers/GI bleeding
- impair coagulation
- risk of CV events in puts with cardiac disease/hypertension
- may induce asthma attack, angioedema, urticaria (hives) or rhinitis
13
Q
Why are some of the problems to do with NSAIDS caused?
A
May inhibit COX-1 as well as COX-2
PGs produced by COX-1 are involved in many beneficial processes - production of GI mucus, inhibit platelet aggregation (PGI2), also generates TXA2 (promotes platelet aggregation)
14
Q
Give an example of a well tolerated GI drug with some COX2 selectivity
A
Meloxicam
- appears to concentrate in synovial fluid, less GI effects and doesn’t affect platelet function
- CV complications
15
Q
What types of joints does osteoarthritis affect?
A
Synovial joints - where bones meet to form a joint, bones surface are covered with a thin layer of cartilage and synovial fluid separates/lubricates them.
(Wrist, elbow, shoulder, knee etc).
16
Q
Which drugs (NSAIDS) are COX-2 inhibitors?
A
Celecoxib, etoricoxib
17
Q
Whith what patients are celecoxib and etoricoxib mainly used?
A
Used on pts at a high risk of GI side effects but with little CV risk
18
Q
What are common side effects of COX-2 inhibitors?
A
Headache, dizziness, skin rash, peripheral oedema
19
Q
What is given alongside NSAIDS which preserves the mucus lining of the GI tract?
A
Misoprostol
Proton pump inhibitors e.g. Omeprazole
20
Q
What is misoprostol?
A
- synthetic prostaglandin
- PGE1 analogue
21
Q
What are the side effects of misoprostol?
A
Diarrhoea, vaginal bleeding, used to induce abortion (can be a side effect)
22
Q
Where is aspirin absorbed?
A
Rapidly absorbed in the stomach (I.e. Weak acid)
23
Q
What does aspirin displace?
A
Displaces warfarin bound to plasma proteins
- increases plasma warfarin and potentiates warfarins anticoagulant activity (warfarin not active until free from plasma proteins)
24
Q
Is paracetamol an NSAID?
A
No
- analgesic, antipyretic
- does suppress PG production
-used as a safer/long term alternative to NSAIDS/COX-2 inhibitors
25
What are non-drug treatment options for osteoarthritis?
Exercise, weight loss, suitable foot wear, joint supports/braces, thermotherapy/ TENS devices
26
What are drug treatment options for osteoarthritis?
- paracetamol - regular dosing +\- oral NSAID with PPI
- topical NSAID or capsaicin
- opioid analgesic
- intra-articular corticosteroid injection
- joint replacement surgery
27
What are drugs with potential benefit to treat osteoarthritis?
- strontium ranelate - promotes osteoblasts differentiation / inhibits osteoclast activity, reduces pain but found to increase risk of MI and thrombotic events - only used when severe OA
- glucosamine sulphate - present in cartilage and synovial fluid - differing results from clinical trials
28
Why does rheumatoid arthritis occur?
Antibodies are targeted towards normal proteins in the connective tissue of joints, with the result that pro-inflammatory chemicals called cytokines are released
-attacks cartilage and proteins within it
29
Where is joint inflammation especially caused in rheumatoid arthritis?
- synovial membrane
- tendon sheaths
- bursae(filled with synovial fluid, provide a cushion between bones/tendons/muscles around a joint
30
What does RA as an autoimmune disease lead to?
Leads to proliferation of synovial membrane which forms a spur into the articulating surface of the bones and erosion of cartilage/bone as they rub together - inflammation --> pain
31
How is the disease progression for rheumatoid arthritis measured?
Measuring levels of C-reactive protein (CRP) in the blood
32
What are the drug treatment options for rheumatoid arthritis?
- NSAIDS/opioid analgesics - pain
- glucocorticoids- pain and limitation of joint damage
- immunosuppressants - limitation of joint damage
- DMARDS - limitation of joint damage
- anticytokines - limitation of joint damage
33
How do immunosuppressant drugs work?
Reduce the production and activation of T-cells at the start of this process (however T-cells play an important role in the overall function of the immune system)
34
How do glucocorticoids work?
Suppress the function of macrophages, hence reduce secretion of inflammatory cytokines
35
How do anticytokine drugs (anti-IL1 and anti-TNF) work?
Suppress the activation of osteoclasts and fibroblasts
36
How do DMARDS work?
Act directly on the joint to block inflammatory processes
37
Name some corticosteroids
Prednisolone, dexamethasone, fludrocortisone
38
Where are glucocorticoids naturally produced in the body?
Adrenal cortex - hydrocortisone (cortisol)
39
When are glucocorticoids used and how long for?
Short term - to manage flare-ups (rapidly reduce inflammation) in pts with recent onset or established disease
Long term - if other treatment options fail (must discuss complications before administering)
40
What effects to glucocorticoids have on the body?
- metabolic effects - increase breakdown of protein and fatty release glucose (liver/adipose tissue)
- anti-inflammatory - inhibit production of inflammatory mediators
- immunosuppressive - inhibit NFkB which is necessary for activation of B-cells and synthesis or cytokines
41
What are mineralocorticoids mainly used for?
Water and electrolyte balance (e.g. Aldosterone)
42
What is the advantage of using synthetic steroids?
Modification of natural steroids gives:
- different split of activities/potencies
- varying duration of action
- useful to be able to manipulate steroid activity according to therapeutic needs
43
Name the synthetic steroids
- prednisolone/prednisone - mixed gluco/mineralocorticoid activity
- dexamethasone/betamethasone/beclomethasone/budesonide - glucocorticoid activity
- fludrocortisone (treats adrenal insufficiency) - mainly mineralocorticoid activity
44
State the duration of action of the different steroids
- cortisone/hydrocortisone - short acting (1-12 hours) - 2X daily cream or intra-articular injection
- prednisolone - intermediate acting (12-36 hrs) - daily oral or intra-articular injection
- dexamethasone - long acting (36-55 hrs) - intra-articular injection every 3-21 days
45
What must steroids do before they cause a response?
Enter the cell (lipid/fat soluble)
46
What happens to steroids when they cross the cell membrane?
- bind to free rectors in the cytoplasm to form a complex
- 2 complexes join together, enabling them to enter the nucleus
- binds to DNA inside nucleus
- results in genes being either switched on (mRNA produced used to make certain proteins) or off
47
Name the actions that glucocorticoids have in rheumatoid arthritis
- anti-inflammatory and immunosuppressant actions
- decreased transcription of pro-inflammatory cytokines (e.g. IL-2)
- decrease circulating lymphocytes
- inhibit phospholipase A2 (decreases release of arachidonic acid)
- increases synthesis of anti-inflammatory proteins (e.g. Protease inhibitors)
48
Name some glucocorticoids and state their action
Beclomethasone, budesonide, prednisolone
-stabilise mast cells (so decreases histamine release)
49
What are the unwanted effects of oral corticosteroids?
Cushingoid features
-buffalo hump, hypertension, muscle wasting, osteoporosis, poor wound healing, increased risk of infection, thinning of skin, increased abdo fat, moon face, metabolic effects, risk of infection
50
Why is there a danger when stopping steroid treatment abruptly?
- causes suppression of normal steroid synthesis
(Due to excessive negative feedback, may precipitate acute adrenal failure)
-gradual reduction needed
51
Name some disease-modifying anti rheumatoid drugs (DMARDS)
- sulfasalazine
- pencillamine
- gold compounds
- anti-malarials
- anti-cytokines
- immunosuppressants (methotrexate, ciclosporin, azathioprine, leflunomide)
(Unrelated structures and different mechanisms of action)
52
What is the mechanism of action of sulfasalazine?
- scavenging free radicals produced by neutrophils (to kill bacteria but they also damage surrounding tissue
- causes remission in active RA
- given as enteric coated tablets (poorly absorbed orally)
- 1st choice DMARD
- complex of salicylate (NSAID) and sulphonamide (antibiotic)
53
What are the side effects of sulfasalazine?
GI upset, headache, skin reactions, leukopenia
54
What is the mechanism of action and general info for pencillamine?
- produced by hydrolysis of penicillin
- therapeutic effects take weeks
- lowers IL-1 generation and lowers fibroblast proliferation = decreases immune response and reduces pannus formation
- given orally
- peak plasma conc. = 1-2 hours
55
What are the side effects of pencillamine?
Rashes, stomitis
Anorexia, taste disturbance, fever, N+V
56
What should pencillamine not be given with?
Gold compounds (metal chelator)
57
Name some gold compounds and state how long it takes for their effects to develop
Auranofin, sodium auranofin
Effects develop over 3-4 months
58
How is auranofin administered and what is its mechanism of action?
- oral
| - inhibits induction of IL-1 + TNF-a (decreases pain and joint swelling)
59
How is sodium auranofin administered and what is its mechanism of action?
- deep I.m. Injection
| - concentrate in synovial cells, liver cells, kidney tubules, adrenal cortex and macrophages
60
What are the side effects of gold compounds?
Skin rashes, flu like symptoms, mouth ulcers, blood disorders (33%)
Serious side effects:
Encephalopathy, peripheral neuropathy, hepatitis (10%)
61
Name some anti-malarial drugs
Chloroquine
| Hydroxychloroquine
62
State the mechanism of action and other info about anti-malarial drugs
- increases the pH of intracellular vacuoles - interferes with antigen presenting
- induces apoptosis in T-lymphocytes
- usually used when all other treatments fail
- therapeutic effects take a month (50% respond)
63
What are the side effects of anti-malarial drugs?
N+V, dizziness, blurring of vision
64
Name some anticytokines
Adalimumab, etenercept, infliximab, rituximab, abatacept, natalizumab, tocilizumab
65
What are anticytokines and when are they used?
- engineered recombinant antibodies
- use restricted to patients who don't respond well to other DMARDS
- can be given with methotrexate (abatacept)
- some pts don't respond
Given by s.c or I.v injection
66
Which drugs(anticytokines) target TNF?
Adalimumab, etenercept, infliximab
By blocking TNF-a - acts as decoy receptors
67
Which drugs(anticytokines) target Leukocyte receptors?
Rituximab, abatacept, natalizumab
68
Which drug(anticytokine) disrupts immune signalling?
Tocilizumab
-blocks IL-6 receptors
69
What are the side effects of anticytokine drugs?
- may develop a latent disease (e.g. TB, hep b, herpes zoster etc) and opportunistic infection
- N+V
- abdominal pain
- worsening heart failure
- hypersensitivity
70
Name some immunosupressants
Ciclosporin, azothioprine, methotrexate, leflunomide, cyclophosphamide
71
State the mechanism of action and general info for ciclosporin
- potent immunosuppressant but no effect on acute inflammation
- inhibits IL-2 gene transcription --> decreases t-cell proliferation
- poorly absorbed orally - special formulations
- accumulates in high conc. In tissues - remains for some time
- patients who have received transplants
72
What are the side effects of ciclosporin?
Nephrotoxicity, hepatotoxicity, hypertension, N+V, gum hypertrophy, GI problems
73
State the mechanism of action and general info for azathioprine
Main effect - suppression of bone marrow
- cytotoxic: interferes with purine metabolism (purines = bases found in DNA which are necessary for synthesis of DNA during cell proliferation) so decreases DNA synthesis
- depresses cell-mediated + antibody-mediated immune reactions by interfering with production of B-cells and presentation of antigen to t-cells (reduces proliferation of these cells)
74
State the mechanism of action and general info for methotrexate
- folic acid antagonist - inhibits DNA synthesis
- blocks growth and differentiation of rapidly dividing cells
- inhibits T-cell activation
- patients often continue treatment for >5 years
- often prescribed with a DMARD
- quicker acting than other drugs
75
What are the side effects of methotrexate?
- possibility of blood dyscrasias (abnormalities) and liver cirrhosis (requires monitoring)
- folate deficiency - need to make RBC --> anaemia
76
State the mechanism of action and general info for leflunomide
- specific inhibitor or activated T cells
| - well absorbed orally - long half life
77
What are the side effects of leflunomide?
Diarrhoea, alopecia, increased liver enzymes (risk of hepatotoxicity)
78
State the mechanism of action and general info for cyclophosphamide
- only used when other therapies have failed
- prodrug - can be administered orally - activated in liver to phosphoramide mustard and acrolein
- Acrolein - haemorrhagic cystitis
- prevented by administering with large volumes of fluid
79
What is the mechanism of action for NSAIDS?
Inhibit COX enzyme --> decreases prostaglandin production
80
What is the mechanism of action for corticosteroids?
Block gene transcription and synthesis of inflammatory proteins, immunosuppressant
81
What is the mechanism of action for Immunosupressants?
Inhibit DNA synthesis or t-cell activation
82
What is the mechanism of action for DMARDS?
Different mechanisms - scavenge free radicals, lower IL-1 etc.
83
What is the mechanism of action for anticytokines?
Antibodies which bind to specific immune cells cytokines to inhibit immune response
