Drugs and Arthritis Flashcards
Name examples of NSAIDs
- Ibuprofen
- Aspirin
- Diclofenac
- Meloxicam
Name examples of Corticosteroids
- Mixed gluco/minerocorticoid - Prednisolone
- Glucocorticoid - Dexamethasone, betamethasone, bedamethasone, budenoside
- Minerocorticoid - Fludrocortisone
Name examples of Immunosuppressants
- Ciclosporin
- Azothioprine
- Methotrexate
- Leflunomide
- Cyclophosphamide
Name examples of disease-modifying anti-rheumatoid drugs (DMARDS)
- Sulfasalazine
- Pencillamine
- Gold compounds
- Anti-malarials
Name examples of anticytokines
- Eternercept
- Infliximab
- Rituximab
- Abatacept
Methotraxate is a cytotocic drug used to treat rheumatoid arthritis. Its mechanism of action involves a reduction in the synthesis of:
- Folic acid
Celecoxib is a COX-2 selective inhibitor with potentially serious side effects. Compared to non-selective NSAID’s, celecoxib is thought to have a reduced risk of causing:
Gastric ulcers
What is an example of a common side effect of cyclophosphamide treatment?
Haemorrhagic cystitis.
What is the proposed mechanism for the gastric bleeding associated with the use of NSAID’s?
Inhibition of COX-1
What is osteoarthritis?
- Loss of cartilage and bone from articulating surfaces.
- Ends of bones rub together.
- Fragments of cartilage end up in synovial fluid.
- RISK FACTORS - obesity, age, gender (female after menopause), previous joint injury, genetics.
What is the mechanism of NSAIDs
- Block COX - reduces prostaglandins.
- Antipyretic - inhibits actions of PGs on hypothalamus.
- Analgesics - reduce sensitivity of neurons to bradykinin, effective against pain of muscular/skeletal origin.
- Anti-inflammatory - reduce vasodilation and decrease permeability of venules.
- Scavenge oxygen radicals to reduce tissue damage.
What is the mechanism of aspirin? (NSAID)
- Inhibits NFxB expression (a protein complex which causes DNA transcription in response to cytokines and stress etc)
- Reduces transcription of genes for inflammatory mediators.
- Rapidly absorbed in the stomach
- Displaces warfarin bound to plasma proteins = increases plasma warfarin and potentiates warfarin’s anticoagulant activity.
What is the mechanism of celecoxib, diclofenac & ibuprofen? (NSAIDs)
- Reduce interleukin-6 and TNS-a in synovial fluid.
- They only suppress signs and symptoms of inflammation, do not reduce cytokine release or toxins which cause tissue damage.
- Validation in individual responses/tolerance to drugs. - ~60% people respond to any NSAID - pain relief immediate.
What are the problems with NSAIDs?
- Risk of gastric ulcers
- Impairs coagulation - Use with caution in elderly (GI Bleeding)
- Risk of CV events in patients with cardiac disease/hypertension.
- May induce asthma attack, angioedema, urticarial or rhinitis.
What causes the side effects of NSAIDs?
- May inhibit cox-1 as well as cox-2
- Prostaglandins produced by COX-1 are involved are involved in many beneficial processes such as: 1) production of GI mucous and blocking risk of ulcers 2) cardiovascular functions: PGs inhibit platelet aggregation 3) COX also generates TXA2 which promotes platelet aggregation.
How can we solve the problems/side effects of NSAIDs?
- Cox-1 and 2 differ in structure, the best tolerated drugs had some COX-2 selectivity
- Meloxicam - concentrates in synovial fluid where there are no plasma proteins = less side effects.
What are examples of COX-2 inhibitors?
- Celecoxib
- Etoricoxib
- 1) the above are used in patients at high risk of serious GI side effects.
- Misoprostol (synthetic Prostaglandin)
What are the side effects of celecoxib and etoricoxib? (NSAIDs)
- Headache
- Dizziness
- Skin rash
- Peripheral oedema
What is the mechanism of paracetamol?
- NOT AN NSAID.
- Suppresses prostaglandin production - analgesia and antipyretic.
- Stimulates serotanergic pathways involved in inhibition of pain sensation - interferes with how pain is perceived by the brain.
What is the mechanism of misoprostol?
- Given alondisde NSAIDs
- Preserves mucous in GI tract
- Protects against ulceration
- Can be used to induce abortion.
- Side effects - diarrhoea, vaginal bleeding.
What are the side effects of paracetamol?
- Chronic use of large doses - kidney damage
- Toxic doses (10-15g) - fatal liver damage.
What are other drugs with potential benefit in osteoarthritis?
- STRONTIUM RANELATE
- promotes osteoblast differentiation/inhibits osteoclast activity
- reduces breakdown of bone, reduces pain and is indicated for the prevention of fractures in severe OA
- side effects - increases risk of MI and thrombotic events. - GLUCOSAMINE SULPHATE
- major constituent of ECM (Extracellular matrix), present in cartilage and synovial fluid, however no significant benefit but possible long-term side effects.
What is rheumatoid arthritis?
- Autoimmune disorder - causes joint inflammation in synovial membrane, tendon sheaths and bursae. -
- Leads to proliferation of synovial membrane and erosion of cartilage.
- Symptoms - swollen joints, morning stiffness, pain.
What are the treatment options for rheumatoid arthritis?
- NSAID/opioid analgesic
- Glucocorticoids - these are mainly for pain relief
- Immunosuppressants
- DMARDS
- Anticytokines - these are for limitation of joint damage.
What is the use of glucocorticoids?
- Produced in the adrenal cortex
- Short term - to manage flare-ups in patients with recent onset or established disease
- Long term - if other treatment options failed and complications have discussed.
How does cortisone/hydrocortisone work?
- Stops the release of CRH
What is the action of glucocorticoids
- Metabolic effects - increased breakdown of protein and fat to release glucose in liver/adipose tissue
- Anti-inflammatory - inhibit production of inflammatory mediators
- Immunosuppressive - inhibits NFxB which is necessary for activation of immune cells and synthesis of cytokines.
What is the action of minerocorticoids?
- Aldosterone - increased reabsorption of Na+ and H20 in collecting ducts of nephron - increased blood pressure.
What are the duration of action of steroids?
- -SHORT ACTING (1-12 hrs) cortisone/hydrocortisone, twice daily cream or intra-articular injection.
- INTERMEDIATE ACTING (12-36 hrs) prednisolone, daily oral or intra-articular injection
- LONG ACTING (36-55hrs) dexamethasone, intra-articular injection every 3-21 days.
How do steroids work?
- -Steroids are lipid soluble so can cross the cell membrane. - Once in the cytoplasm, steroids bind to free receptors to form a complex, 2 complexes join together enabling them to enter the nucleus.
- The complex binds to DNA - this results in genes being either switched on or off - when genes are switched on; messenger RNA is produced which is used to make a particular protein.
- Many steroids work by switching OFF genes which code for proteins involved in inflammation.
How do glucocorticoids work in rheumatoid arthritis?
- Decrease transcription of pro-inflammatory cytokine
- Decrease circulating lymphocytes
- Inhibits phospholipase A2, - decreases release of arachidonic acid
- Increases the synthesis of anti-inflammatory proteins
How does sulfasalazine work? (DMARD)
- Complex of salicylate (NSAID) and sulphonaime (Antibiotic)
- Acts by scavenging free radicals released by neutrophils to kill bacteria but also damage surrounding tissue.
- Causes remission in ‘active RA’
- SIDE EFFECTS - GI upset, headache, skin reactions and leukopenia.
How does penicillamine work? (DMARD)
- Produced by hydrolysis of penicillin
- Decreases interleukin-1 generation and decreases fibroblast proliferation thereby reducing pannus formation (abnormal growth or tissue over joint surface)
- Decreases immune response.
- SIDE EFFECTS - rash, stomatisis, taste disturbance, fever, N+V
- Do not give with gold compounds.
What are gold compounds? (DMARDS)
- AURANOFIN (oral) - inhibits induction of interleukin-1 and TNF-a = decreased pain and joint swelling.
- SODIUM AURANOFIN (im) - concentrates in synovial cells, liver cells, kidney tubules, adrenal cortex and macrophages.
- SIDE EFFECTS - skin rashes, flu-like symptoms, mouth ulcers, blood disorders.
- SERIOUS SIDE EFFECTS - encephalopathy, peripheral neuropathy and hepatitis.
What are anti-malarials? (DMARDS)
- CHLOROQUINE
- HYDROXYCHLOROQUINE
- increases pH of intracellular vacuoles
- interferes with antigen presenting.
- Induces apoptosis in T-Cells.
- SIDE EFFECTS - N+V, dizziness, blurred vision.
What are anti-cytokine drugs? (DMARDS)
- Engineered recombinant antibodies - expensive and not used often.
- target TNF - adalimumab, eternercept, infliximab
- target leukocyte receptors - rituximab, abatacept, natalizumab.
- Blocks IL-6 receptors and disrupt immune signalling - tocilizumab
- SIDE EFFECTS - may develop latent disease (TB, hep b), opportunistic disease, N+V, heart failure and hypersensitivity.
How are immunosuppressants used in the treatment of RA?
- Rheumatoid arthritis is an immune disorder
- immunosuppressants will suppress the effects but not cure.
How is cyclosporine used to treat RA? (immunosuppressant)
- Inhibits interleukin-2 gene transcription - decreased T-cell proliferation
- Poorly absorbed orally - accumulates in tissues
- SIDE EFFECTS - nephrotoxicity, hepatotoxicity, hypertension, N+V, GI problems.
How is azathioprine used to treat RA? (immunosuppressant)
- Cytotoxic: interferes with purine metabolism and decreases DNA synthesis
- Depresses cell-mediated and antibody-mediated immune reactions (target cells in induction phase of inflammatory response)
- Suppression of bone marrow - decreased WBC and RBC
How is methotrexate used to treat RA? (immunosuppressant)
- Folic acid antagonist - decreased DNA synthesis
- Blocks growth and differentiation
- Inhibits T-cell activation
- SIDE EFFECTS - blood dyscrasias, liver cirrhosis, foliate deficiency (not for pregnancy!)
How is leflunomide used to treat RA? (immunosuppressant)
- Specific inhibitor of activated T-cells
- SIDE EFFECTS - diarrhoea, alopecia, hepatotoxicity
How is cyclophosphamine used to treat RA? (immunosuppressant)
- When other treatments have failed
- Pro-drug (oral) - activated in liver to phosphoramide mustard and acrolein.
- Acrolein - haemorrhagic cystitis :(
- Prevents cross-linking of DNA
