- They inhibit COX enzyme, thus inhibiting prostaglandin production from arachidonic acid - Analgesic, anti-inflammatory and anti-pyretic - They don't affect the course of the disease

Anti-Inflammatory Drugs Flashcards by Talia Augustidis

How do NSAIDs work?

They inhibit COX enzyme, thus inhibiting prostaglandin production from arachidonic acid
Analgesic, anti-inflammatory and anti-pyretic
They don’t affect the course of the disease

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What are 4 examples of non selective (inhibit all COX enzymes) NSAIDs?

Ibuprofen
Aspirin
Naproxen
Indomethacin

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What do prostaglandins do?

They are pro-inflammatory, vasodilating and sensitise the pain pathway

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What are side effects of non-selective NSAIDs?

Side effects in gut and kidney

- They stop blood flow and mucus secretion which can lead to ulcer formation and internal bleeding

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What are two examples of COX-2 (enzyme found at inflammatory site) selective inhibitors?

Celecoxib

- Meloxicam

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How do you use oral NSAIDs (COX inhibitors) in patients with a cardiovascular risk?

1) Associated use of PPIs e.g. omeprazole to inhibit GI reflux due to excess acid
2) OR use prostaglandin analogue/agonist e.g. misoprostol which helps with vasodilation and increased mucus production
3) Do a gradual increase in NSAID use via topical application e.g. diclofenac (Voltaren)

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What are 3 examples of anti-inflammatory steroids (glucocorticoids /corticosteroids)?

Hydrocortisone
Dexamethasone
Prednisolone

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How do anti-inflammatory steroids work (why are they beneficial)?

1) Multiple anti-inflammatory actions
- Inhibit arachidonic acid (and therefore prostaglandin) release
- Cytokine inhibition
- Down regulation of adhesion molecules
- Inhibition of enzyme induction (COS, NOS)
2) Effects on immune response
- Inhibition of lymphocyte proliferation
- Induces apoptosis of inflammatory cells

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What are 5 side effects of anti-inflammatory steroids?

Osteoporosis
Diabetes
Glaucoma
Increased risk of infection
Adrenal atrophy

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When are anti-inflammatory steroids given (short term)?

Local flare ups
When waiting for other DMARDs to work
‘Steroid sparing’

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Describe giving steroids locally (intra-articular)?

High effective first time
If given again/multiple times doesn’t have the same effective effect
Decreased side effects

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How do disease modifying anti-rheumatic drugs (DMARDs) work?

They suppress the overactive immune and/or inflammatory systems, to inhibit the damaging process (all work via different mechanisms)
Combat the ongoing and destructive inflammation (via immunosuppression or cytotoxicity) - affects course of disease, doesn’t just treat symptoms

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How long to most DMARDs take to work and therefore how are they often prescribed?

Weeks to months

- They are often prescribed together as combination therapies

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What might you prescribe along with a DMARD until it takes its effect?

NSAID and/or steroid

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What are the 3 subsets of DMARDs?

1) Traditional DMARDs
2) Biologics/biosimilars
3) ‘Targeted’ DMARDs

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Describe traditional DMARDS

Taken orally
Broad immunosuppressants
Adverse effects common with most

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Describe biologics/biosimilars

Taken by self-injection or infusion
Target specific mediators
Well tolerated (immunogenic)
Fewer side effects but still immunosuppressant e.g. more vulnerable to TB

Describe ‘targeted’ DMARDs?

Taken orally
Target specific immune system signalling molecules
Small molecular weight inhibitors

What are 5 examples of traditional DMARDs?

Methotrexate
Hydroxychloroquine
Sulfasalazine
Leflunomide
Azathioprine

Which traditional DMARD is the gold standard for inflammatory arthritis and most widely used DMARD for RA?

Methotrexate

Describe use of methotrexate

Substantial efficacy in RA (30% of patients)
Acceptable safety
Low cost
Steroid sparing
Can be mixed with other anti-inflammatories
Low doses are useful and high doses aren’t any better (low dose associated with good clinical outcome)
Used in young and old

What is the recommended dosage of methotrexate?

7.5-15mg once weekly (low dose compared to its use in chemotherapy)

What is the primary mechanism of action of methotrexate?

Folate antagonist - inhibits dihydrofolate reductase (DHFR)

Affects intracellular metabolic pathways dependant on folinic acid dependent
Decreases purine and pyrimidine (polyamine) production/metabolism and interferes with DNA synthesis (anti-proliferative effect in cancer)

What are the anti-inflammatory effects of methotrexate (via folate antagonist and other mechanisms)?

1) Suppresses NF-kappaB activation - inhibits production of cytokines (+ other effects below)
2) Inhibits T cell and macrophage activation (apoptosis of activated lymphocytes)
3) Decreases pro-inflammatory cytokines
4) Inhibits endothelial adhesion molecule activation (which bring inflammatory cells towards joint) - helps CV protection
5) Increases adenosine release - anti-inflammatory, reduces cell activation

What are the adverse effects of methotrexate and therefore what do you have to do?

- Cytopenia (bone marrow suppression due to anti-proliferative effects) - Nausea - Infection - Intestinal - Hepatotoxicity - problems with liver function - Embryotoxic (not safe in pregnancy) - Acute pneumonitis (rarely, inflammation of lungs where pt presents with SoB + fever) - Need to monitor and administer folate

What do biologics reduce?

The number of surgeries (still happens e.g. knees and hips)

What are the two types of biologic used in RA?

1) Anti-TNF antibodies - infliximab, adalimumab (Humira) | 2) Soluble TNF receptor - etanercept

Describe use of biologics

- Used when other DMARDs have failed - Effective for 30% of cases - Can be less successful in follow up treatments - Expensive - Can be given as co-treatments

How do anti-TNF antibodies work?

- Antibody (MAbs) to TNF (inflammatory cytokine released by inflammatory cells e.g. macrophages) - The antibodies bind to and get rid of TNF, stopping it getting to the receptor and causing its inflammatory effects

What is the effect of preventing TNFalpha in RA (main mediator)?

- Stop cartilage and bone degradation - Decrease inflammation - Quite soon after taking the biologic pts feel better and have less pain

What are 3 types of cytokine biologics (block mediator systems)?

1) IL-1 antibodies/receptor antagonists e.g. canakinumab (effective in juvenile arthritis and atherosclerosis) 2) IL-6 blocker e.g. tocilizumab - used for non-responders to MTX/anti-TNF 3) IL-17 receptor antagonist - used in psoriatic arthritis

What are 2 types of cell based biologics?

1) Rituximab - removes B cells | 2) Abatacept - inhibits action of T cells and reduces damaging effects

What are biosimilars?

- A biologic medical product which is almost identical copy of an original product i.e. biologic - May be manufactured by a different company but has the same effect - Cheaper by ~ 40%

What are two examples of the newer targeted DMARDs?

1) Janus kinase (JAK) inhibitors e.g. baricitinib | 2) Apremilast

Describe JAK inhibitors

- Target intracellular pathways (different from biologics) - When the cytokine is circulating in the blood it binds to a cell via JAK-STAT receptors which cause intracellular effects - JAK inhibitors bind to these receptors that the cytokines work on so they can't bind (don't need to block cytokine) - Target the JAK-STAT inflammation pathway - Inhibits cell signalling e.g. T cells via blocking JAK kinases - Oral daily (small molecule, easier to make) - Cheaper than biologics - Used when other DMARDs are not tolerated in moderately to severely active RA - Effective

Describe apremilast

- Inhibits the activity of phosphodiesterase type 4 (PDE4) - Suppresses pro-inflammatory mediator synthesis and promotes anti-inflammatory mediators - Oral - Good for patients with psoriatic arthritis (w DMARDs or alone) - Good for patients intolerant to DMARDs e.g. MTX

Why is there a problem with adherence to DMARDs?

- Takes weeks to work - Needs monitoring and injections - Complex treatment

How can the bioavailability of methotrexate be enhanced in ⅔ patients who have incomplete response?

- S/C administration | - Introducing combination therapies with other DMARD which has synergistic effect

When can methotrexate possibly cause pulmonary fibrosis?

- In patients with severe disease who may have underlying lung damage - Can use it safely in almost all patients (link overinflated) - Only won't use it in patients who already have lung disease

What is an example of a cytotoxic drug?

Cyclosporin

What are the 5 TNF inhibitors (anti-TNF therapy) which differ slightly in make up but all bind to TNF and stop the effects of TNF driving inflammation in the joints and body?

1) Infliximab 2) Adalimumab 3) Etanercept 4) Golimumab 5) Certolizumab pegol

Risk of which infections can be increased when using biologics and what happens?

1) TB - common in patients on biologics so need to screen for previous exposure and if they have had it, would give medication to prevent TB coming back 2) Shingles