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Applied Pharmacology > Drugs and Arthritis > Flashcards

Drugs and Arthritis Flashcards

1
Q

Name examples of NSAIDs

A
  • Ibuprofen
  • Aspirin
  • Diclofenac
  • Meloxicam
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2
Q

Name examples of Corticosteroids

A
  • Mixed gluco/minerocorticoid - Prednisolone
  • Glucocorticoid - Dexamethasone, betamethasone, bedamethasone, budenoside
  • Minerocorticoid - Fludrocortisone
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3
Q

Name examples of Immunosuppressants

A
  • Ciclosporin
  • Azothioprine
  • Methotrexate
  • Leflunomide
  • Cyclophosphamide
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4
Q

Name examples of disease-modifying anti-rheumatoid drugs (DMARDS)

A
  • Sulfasalazine
  • Pencillamine
  • Gold compounds
  • Anti-malarials
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5
Q

Name examples of anticytokines

A
  • Eternercept
  • Infliximab
  • Rituximab
  • Abatacept
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6
Q

Methotraxate is a cytotocic drug used to treat rheumatoid arthritis. Its mechanism of action involves a reduction in the synthesis of:

A
  • Folic acid
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7
Q

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:

A

Gastric ulcers

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8
Q

What is an example of a common side effect of cyclophosphamide treatment?

A

Haemorrhagic cystitis.

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9
Q

What is the proposed mechanism for the gastric bleeding associated with the use of NSAID’s?

A

Inhibition of COX-1

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10
Q

What is osteoarthritis?

A
  • 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.
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11
Q

What is the mechanism of NSAIDs

A
  • 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.
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12
Q

What is the mechanism of aspirin? (NSAID)

A
  • 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.
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13
Q

What is the mechanism of celecoxib, diclofenac & ibuprofen? (NSAIDs)

A
  • 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.
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14
Q

What are the problems with NSAIDs?

A
  • 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.
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15
Q

What causes the side effects of NSAIDs?

A
  • 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.
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16
Q

How can we solve the problems/side effects of NSAIDs?

A
  • 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.
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17
Q

What are examples of COX-2 inhibitors?

A
  • Celecoxib
  • Etoricoxib
  • 1) the above are used in patients at high risk of serious GI side effects.
  • Misoprostol (synthetic Prostaglandin)
18
Q

What are the side effects of celecoxib and etoricoxib? (NSAIDs)

A
  • Headache
  • Dizziness
  • Skin rash
  • Peripheral oedema
19
Q

What is the mechanism of paracetamol?

A
  • 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.
20
Q

What is the mechanism of misoprostol?

A
  • Given alondisde NSAIDs
  • Preserves mucous in GI tract
  • Protects against ulceration
  • Can be used to induce abortion.
  • Side effects - diarrhoea, vaginal bleeding.
21
Q

What are the side effects of paracetamol?

A
  • Chronic use of large doses - kidney damage
  • Toxic doses (10-15g) - fatal liver damage.
22
Q

What are other drugs with potential benefit in osteoarthritis?

A
  • 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.
23
Q

What is rheumatoid arthritis?

A
  • 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.
24
Q

What are the treatment options for rheumatoid arthritis?

A
  • NSAID/opioid analgesic
  • Glucocorticoids - these are mainly for pain relief
  • Immunosuppressants
  • DMARDS
  • Anticytokines - these are for limitation of joint damage.
25
Q

What is the use of glucocorticoids?

A
  • 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.
26
Q

How does cortisone/hydrocortisone work?

A
  • Stops the release of CRH
27
Q

What is the action of glucocorticoids

A
  • 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.
28
Q

What is the action of minerocorticoids?

A
  • Aldosterone - increased reabsorption of Na+ and H20 in collecting ducts of nephron - increased blood pressure.
29
Q

What are the duration of action of steroids?

A
  • -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.
30
Q

How do steroids work?

A
  • -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.
31
Q

How do glucocorticoids work in rheumatoid arthritis?

A
  • Decrease transcription of pro-inflammatory cytokine
  • Decrease circulating lymphocytes
  • Inhibits phospholipase A2, - decreases release of arachidonic acid
  • Increases the synthesis of anti-inflammatory proteins
32
Q

How does sulfasalazine work? (DMARD)

A
  • 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.
33
Q

How does penicillamine work? (DMARD)

A
  • 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.
34
Q

What are gold compounds? (DMARDS)

A
  • 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.
35
Q

What are anti-malarials? (DMARDS)

A
  • CHLOROQUINE
  • HYDROXYCHLOROQUINE
  • increases pH of intracellular vacuoles
  • interferes with antigen presenting.
  • Induces apoptosis in T-Cells.
  • SIDE EFFECTS - N+V, dizziness, blurred vision.
36
Q

What are anti-cytokine drugs? (DMARDS)

A
  • 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.
37
Q

How are immunosuppressants used in the treatment of RA?

A
  • Rheumatoid arthritis is an immune disorder
  • immunosuppressants will suppress the effects but not cure.
38
Q

How is cyclosporine used to treat RA? (immunosuppressant)

A
  • Inhibits interleukin-2 gene transcription - decreased T-cell proliferation
  • Poorly absorbed orally - accumulates in tissues
  • SIDE EFFECTS - nephrotoxicity, hepatotoxicity, hypertension, N+V, GI problems.
39
Q

How is azathioprine used to treat RA? (immunosuppressant)

A
  • 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
40
Q

How is methotrexate used to treat RA? (immunosuppressant)

A
  • 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!)
41
Q

How is leflunomide used to treat RA? (immunosuppressant)

A
  • Specific inhibitor of activated T-cells
  • SIDE EFFECTS - diarrhoea, alopecia, hepatotoxicity
42
Q

How is cyclophosphamine used to treat RA? (immunosuppressant)

A
  • When other treatments have failed
  • Pro-drug (oral) - activated in liver to phosphoramide mustard and acrolein.
  • Acrolein - haemorrhagic cystitis :(
  • Prevents cross-linking of DNA

Applied Pharmacology (12 decks)

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