Arthritis drugs

Question 1

What are NAIDs (Non-Steroidal Anti-Inflammatory Drugs) actions?

Answer 1

 Antipyretic - inhibit actions of PGs on hypothalamus
 Analgesic - reduce sensitivity of neurons to bradykinin and effective against pain of muscular/ skeletal origin
 Anti-inflammatory- reduce vasodilation and decrease permeability of venules
 May scavenge oxygen radicals → ↓ tissue damage
 only suppress signs + symptoms of inflammation – do not ↓ cytokine rel or ↓ toxins which cause tissue damage in chronic disease

Question 2

What are side effects of NSAIDS?

Answer 2

 Risk of gastric ulcers
 Impair coagulation
 Use with caution in elderly (GI bleeding can be serious/ fatal)
 Risk of CV events in patients with cardiac disease/ hypertension
 May induce asthma attack, angioedema, urticaria or rhinitis

Question 3

What causes the side effects?

Answer 3

 Many inhibit COX1 as well as COX2
 PGs produced by COX1 are involved in many beneficial processes: Production of GI mucus (protective), Blocking ↑ risk of ulcer and Cardiovascular function : PGs (e.g. PGI2) inhibit platelet aggregatio

Question 4

Ibuprofen

Answer 4

NSAIDs

ibuprofen - ↓ IL-6 and TNF-α in SF

Question 5

Aspirin

Answer 5

NSAIDs
Rapidly absorbed in stomach (i.e. weak acid) Displaces warfarin bound to plasma proteins (↑ plasma warfarin + potentiates warfarin’s anticoagulant activity)
Aspirin – inhibits NFκB expression → ↓ transcription of genes for inflammatory mediators

Question 6

Diclofenac

Answer 6

NSAIDs

↓ IL-6 and TNF-α in SF

Question 7

How do you solve the NSAID/ COX problem?

Answer 7

 COX1 and COX2 differ in structure- Should be possible to produce selective drugs
 Observed that best tolerated (GI) drugs had some COX2 selectivity

Meloxicam and Celecoxib

Question 8

Meloxicam

Answer 8

NSAIDs
Function = Appears to concentrate in synovial fluid – free concentration higher than in plasma (due to albumin content). At therapeutic concentrations, less GI effects than other NSAIDs and does not affect platelet function.

Side effects = MI and stroke. Also problems with wound healing, angiogenesis and resolution of inflammation + more expensive than NSAIDs

Question 9

Celecoxib

Answer 9

Mainly used in patients with high GI risk and low CV risk

Side effects = headache, dizziness, skin rash, peripheral oedema

Question 10

Glucocorticoids, what are they? How do they work?

Answer 10

Work by suppressing the function of macrophages; hence reduce secretion of inflammatory cytokines

Used short-term – to manage flare-ups (rapidly reduce inflammation) in patients with recent-onset or established disease
Long-term – if other treatment options failed - must discuss complications. These drugs are also used for asthma and arthritis as they reduce histamine.

Question 11

Actions of Glucocorticoids?

Answer 11

Anti-inflammatory, immunosuppressant actions helping reduce RA symptoms:
 ↓ transcription of pro-inflammatory cytokines ( IL2)
 ↓ circulating lymphocytes
 inhibit phospholipase A2 → ↓ release of arachidonic acid
 ↑ synthesis of anti-inflamm. proteins (e.g. protease inhibitors)

Question 12

Name the modification of natural steroid?

Answer 12

1. Mixed gluco-/ mineralocortiocoid activity
2. Glucocorticoid activity
3. Mainly mineralocorticoid activity

Question 13

Side effects of steroids?

Answer 13

• Moon face
• Buffalo hump
• Hypertension
• Thin skin
• Poor healing
• Osteoporosis
• Increased risk of infection
• Increase abdominal fat

Question 14

Prednisolone

Answer 14

Corticosteroids 
Fuction = Mixed gluco-/ mineralocortiocoid activity
Intermediate acting (12-36 hours) via oral or IA injection

Question 15

Dexamethasone

Answer 15

Corticosteroids
Fuction = Glucocorticoid activity
Long acting (3-21 days)
IA injection

Question 16

Fludrocortisone

Answer 16

Corticosteroids
Fuction = Mainly mineralocorticoid activity
Used for addisons disease

Question 17

What are Disease Modifying Antirheumatoid Drugs (DMARDs)?

Answer 17

Drugs with unrelated structures and diff mechanisms of action, the treatment must start upon definite diagnosis of R.A. → slow onset of disease. They work by scavenge free radicals, ↓ IL-1.

Question 18

Sulfasalazine

Answer 18

DMARD

Function = it consists of a Complex of salicylate (NSAID) + sulphonamide (antibiotic). It works by scavenging free radicals prod by neutrophils, causing a remission in active RA.

Side effects = GI upset, headache, skin reactions, leukopenia

Question 19

Penicillamine

Answer 19

DMARD

Function = Thought to ↓ IL-1 generation + ↓ fibroblast proliferation → ↓ immune response. It is given orally, opeak plasma conc can take 1-2 hours

Side effects = rashes, stomatitis (40% patients); anorexia, taste disturbance, fever, n & v
Should not be given with gold compds – metal chelator!

Question 20

Gold compounds (sodium aurothiomalate/ auranofin

Answer 20

DMARD

Auranofin (oral) → inhibits induction of IL-1 + TNF-α → ↓ pain + joint swelling

Sodium auranofin – deep i.m. injection
Concentrate in synovial cells liver cells, kidney tubules, adrenal cortex & macrophages
Effects develop over 3 – 4 months

Side effects = skin rashes, flu-like symptoms, mouth ulcers, blood disorders (33%)

Serious side effects = encephalopathy, peripheral neuropathy + hepatitis (10%)

Question 21

Anti-malarials (chloroquine/ hydroxychloroquine

Answer 21

DMARD

Function = ↑pH of intracellular vacuoles → interferes with antigen-presenting
Induces apoptosis in T-lymphocytes
Usually used when other treatments fail
Therapeutic effects take a month
50% patients respond

Side effects = n+v, dizziness, blurring of vision – requires screening

Question 22

What are Anticytokine Drugs?

Answer 22

Engineered antibodies that act as decoy receptors
Mop up naturally present TNF-alpha
Stop the release of cytokines and COX2
Well expensive 
Only for patients who cant have DMARDs

Question 23

Infliximab
Etenercept
Adalimumab

Answer 23

Anticytokine Drugs

Target TNF

Question 24

rituximab

abatacept

Answer 24

Anticytokine Drugs

Target leukocyte Rs

Question 25

tocilizumab

Answer 25

Anticytokine Drugs

blocks IL-6 Rs → disrupt immune signaling

Question 26

Anticytokine Drugs side effects?

Answer 26

may develop latent disease (e.g. TB, hep B, herpes zoster, etc) + opportunistic infection; also, nausea, ab pain, worsening heart failure, hypersensitivity

Question 27

Immunosuppressants? Why are they used?

Answer 27

Rheumatoid arthritis is an AUTOIMMUNE disorder, Suppressing the immune system will therefore suppress (but not cure) disease

Question 28

Ciclosporin

Answer 28

immunosuppressants - potent and poorly absorbed orally so need special capsule

Function = Inhibits IL-2 gene transcription → ↓ T cell proliferation

Side effects = Nephrotoxicity Hepatotoxicity Hypertension nausea/ vomiting, gum hypertrophy, GI problems

Question 29

Azathioprine

Answer 29

immunosuppressants

Function = Cytotoxic: interferes with purine metabolism → ↓ DNA synthesis. Depresses cell-mediated + antibody-mediated immune reactions, it targets cells in induction phase of immune response

Side effects = suppression of bone marrow

Question 30

Methotrexate

Answer 30

immunosuppressants

Function = Folic acid antagonist → inhibits DNA synthesis
Blocks growth and differentiation of rapidly dividing cells Inhibits T cell activation

Side effects = possibility of blood dyscrasias (abnormalities) + liver cirrhosis (requires monitoring), folate deficiency – Often prescribed with a DMARD

Question 31

Leflunomide

Answer 31

immunosuppressants

Function = Specific inhibitor of activated T cells
Well absorbed orally; long t½

Side effects = diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity

Question 32

Cyclophosphamide

Answer 32

immunosuppressants - Only used when other therapies have failed

Function = Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein

Side effects = Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)