MSK L16 Pharmacology MSK

Question 1

Drugs used: in RA

Answer 1

NSAIDS

DMARDS

Question 2

DMARDS role

Answer 2

• Aim to halt or slow the inflammatory joint destruction
• Slow onset of actions
• May have little long-term effect on disease

Question 3

Molecular Mechanisms in RA: Highly complex multi-factor mediation of the pathological process

Answer 3

1. Auto-immune response – auto-antibodies and immune complex
2. T-cell mediated antigen-specific responses
3. T-cell independent cytokine networks

Question 4

Molecular Mechanisms in RA: What is certain

Answer 4

1. T cells are a/the major driving force
2. Nuclear factor (NF) –kB is activated in the synovium and regulates genes involved in inflammation e.g. TNF, IL etc iNOS and COX-2
3. MAP kinases are activated in rheumatoid tissues – key regulator of cytokine and metalloproteinase production

Question 5

NSAIDS

role

Answer 5

Symptomatic treatment – block eicosanoid synthese

→ Provides symptomatic relief of pain and stiffness, but do not alter disease progression.

Question 6

DMARDS role

Answer 6

1. To prevent erosive damage
2. If patient intolerance to NSADS
3. Extra-articular manifestations of RA
4. Poor response to NSAIDS

Question 7

DMARDS MOA

Answer 7

Sulphasalazine
Gold (aurothiomalalte and auranofin)
Methotrexate

Question 8

DMARDS example

Answer 8

B and T cell action blocking bt unclear

Question 9

Sulphasalazine: Epi

Answer 9

Cheap and commonly first choice in UK

Question 10

Sulphasalazine: Combination of

Answer 10

Sulphapyridine combind with salicycate

Question 11

Sulphasalazine: Hydrolysed by and to

Answer 11

By gut bacteria to sulphapyrieine and 5-aminosalicylic acid

Question 12

Sulphasalazine: Suphapyridine action

Answer 12

Reduces absorption of antigens from colon that may promote joint inflammation

Question 13

Sulphasalazine: 5-aminosalicyclic acid action

Answer 13

Reduces synthesis of inflammatory mediators e.g. eicosanoids and cytokines

Question 14

Sulphasalazine: Side effects

Answer 14

• GI
• Reversible decrease in sperm count
• Sulphonamide idiosyncratic blood dyscrasias (reducetion in WBC and platelet)
• Analyphylaxis

Question 15

Gold (aurothiomalate and Auranofin: Possible MOA

Answer 15

1. Inhibit lymphocyte proliferation
2. Inhibit release and activity of Lysosomal enzymes
3. Decrease production of toxic O2 metabolites from phagocytes
4. Inhibit chemotaxis of neutrophils
5. Inhibit induction of IL-1 and TNF-alpha

Question 16

Gold (aurothiomalate and Auranofin: Acts where

Answer 16

Binds to tissue proteins and accumulates widely, incuding in synovium of inflamed joints

Question 17

Gold (aurothiomalate and Auranofin: Toxicity

Answer 17

Can be serious: 
1.	blood disorders – agranulocytosis, aplastic anaemia
2.	Skin rashes
3.	Diarrhoea
4.	Glomerulonephritis
Serious toxic effects in 10% of patiens

Question 18

Methotrexate: Action speed

Answer 18

Rapid

Question 19

Methotrexate: Use in

Answer 19

DMARD for RA and Chrohns

Question 20

Methotrexate: MOA

Answer 20

Not via inhibition of dihydrofolatereductase (DHFR) – for DMARD unsure

Question 21

Methotrexate: MOA thoughts

Answer 21

Thought to be via inhibition of enzymes involved in purine metabolism:

1. Accumulation of adenosine
2. Inhibition of T cell activation
3. Suppression of adhesion molecule expression by by T-cell

Question 22

Methotrexate
Time to Benefit
Potential for Toxicity
Toxcities to Monitor

Answer 22

1-2 months	
Moderate	
Myelosuppression
Hepatic fibrosis and cirrhosis
Pulmonary infiltrates

Question 23

Hydroxychloquine
Time to Benefit
Potential for Toxicity
Toxcities to Monitor

Answer 23

2-6 months
Low
Macular Damage

Question 24

Leflunomide
Time to Benefit
Potential for Toxicity
Toxcities to Monitor

Answer 24

4-12 wks
Low	
Diarrhea
Alopecia
Rash
Headache
Risk of immunosuppression infection

Question 25

Sulfasalazine Time to Benefit Potential for Toxicity Toxcities to Monitor

Answer 25

1-3 months Low Myelosuppresion

Question 26

Cyclosporin Time to Benefit Potential for Toxicity Toxcities to Monitor

Answer 26

``` 4-8 wks High Renal insufficiency Anaemia Hypertension ```

Question 27

Gold, oral Time to Benefit Potential for Toxicity Toxcities to Monitor

Answer 27

4-6 months Low Myelosupression Proteinuria

Question 28

Gold, parentral Time to Benefit Potential for Toxicity Toxcities to Monitor

Answer 28

3-6 months Moderate Myelosupression Proteinuria

Question 29

Azathioprine Time to Benefit Potential for Toxicity Toxcities to Monitor

Answer 29

``` 2-3 months Moderate Myelosupression Hepatotoxicity Lymphoproliferative disorders ```

Question 30

Minocycline Time to Benefit Potential for Toxicity Toxcities to Monitor

Answer 30

``` 1-3 months Low Hyperpigmentation Dizzines Vaginal yeast infections ```

Question 31

Corticosteroids and RA: Uses

Answer 31

1. Intra-articular injections of individual joints (e.g. knee) 2. In active disease short causes of oral prednisolone, can produce a rapid onset before other drugs

Question 32

Corticosteroids and RA: Standard therapy

Answer 32

Combination of low-dose glucocorticoids and sulphasalazine/methotrexate

Question 33

Corticosteroids and RA:Mechanisms

Answer 33

* Immunosuppressants (act on cell-mediated immune responses) | * Decrease transcription of IL-2, TNF-alpha, interferon-y

Question 34

Gout →Acute arthritis

Answer 34

Due to deposition of urate crystals in the synovial tissue – very painful

Question 35

Gout →Metabolic disorder

Answer 35

Plasma urate concentration increased due to overproduction of purines and/or impaired excretion of purines → Seen with poor renal degradation → High red meat diet → Mostly genetic

Question 36

Gout →Pathology

Answer 36

1. Crystal deposition leads to kinin release/generation of LTB4 2. Phagocytic neutrophil accumulation 3. Free radical formation 4. Call damage and lysis

Question 37

Gout → Treatment

Answer 37

Inhibit uric acid synthesis Increase uric acid secretion (uricosuric drugs) Inhibit inflammatory cell migration into joints Give anti-inflammation/analgesic drugs (NSAIDs)

Question 38

Gout →Drugs for Gout

Answer 38

Allopurinol → blocks formation of uric acid Colchicine → inhibits leckocyte migration into joints Acute → NSAIDS not Aspirin