Block E Lecture 2 - Treatments for Rheumatoid Arthritis Flashcards
What are the main 2 classes of drugs which can be used to treat Rheumatoid Arthritis?
Non-steroidal anti-inflammatory drugs (NSAIDs)
Disease modifying anti-rheumatic drugs (DMARDs)
(Slide 3)
What are 4 examples of classes of drugs which can be considered disease modifying anti-rheumatic drugs?
Glucocorticoids
Classical (conventional synthetic) DMARDs
Biologics
JAK inhibitors
(Slide 3)
What are the phase I, II and III treatment regimes used to treat rheumatoid arthritis?
Phase 1: Conventional synthetic DMARDs (csDMARDs) and glucocorticoids
Phase II: Change to a different csDMARD and add in biologic DMARD (bDMARD)
Phase III - replace bDMARD with an alternative, or a JAK inhibitor
(Slide 4)
What are the basic properties of the COX 1 and 2 receptors?
COX 1: Constitutive (always present / expressed) and is involved in normal physiology. E.g early stage of inflammation in the endothelium
COX 2: Inducible (expressed in response to a stimulus) and is upregulated in chronically inflamed tissue
(Slide 6)
What are “Classical NSAIDs”?
Non-selective cox inhibitors, though most show a preference for inhibiting COX 1
(Slide 7)
What are 2 examples of classical NSAIDs?
Answers Include:
Aspirin
Ibuprofen
Naproxen
Indomethacin
Flurbiprofen
(Slide 7)
What is an example of a COX 2 selective inhibitor?
Answers Include:
Celecoxib
Rofecoxib
Eterocoxib
(Slide 7)
As well as inhibiting COX 1 and 2, aspirin promotes the synthesise of resolvins and lipoxins. How does it do this?
It acetylates COX2, making it so it converts arachidonic acid into 15R-HETE instead of prostaglandin precursors.
5-LOX then converts this into aspirin triggered lipoxins (ASLs) such as 15-epi-lipoxin A4.
Acetylated COX 2 also converts eicosapentaenoic acid (EPA) into 18R-HEPE
5-LOX then converts this to resolvin E1.
Note: Aspirin can promote synthesis of different lipoxins and resolvins through COX2 if COX2 receives a different substrate.
(Slide 8)
How do indomethacin and diclofenac increase the amount of resolvins and lipoxins in the body?
They inhibit their degradation
(Slide 8)
What are lipoxins?
A class of anti-inflammatory, lipid mediators that resolve inflammation by acting as “stop signals” for inflammatory cells, promoting tissue repair, and modulating the inflammatory response
(Slide 8)
What are 3 therapeutic effects of NSAIDs?
Answers Include:
Reducing pain (analgesics)
Reducing inflammation (reduce vasodilation, vascular permeability and reduce swelling)
Reducing morning joint stiffness
Antipyretic
(Slide 9)
What is an antipyretic?
A drug which reduces fever
(Slide 9)
What do NSAIDs NOT do?
Modify the underlying disease process. They just help with symptoms by reducing inflammation, pain and swelling
(Slide 9)
What are 3 examples of adverse effects of NSAIDS?
Answers Include:
Peptic ulcer disease
Renal failure (due to low blood flow due to a lack of prostaglandins increasing it)
Asthma or bronchospasm
Increased risk of heart attack or stroke
(Slide 10)
What are 4 factors which dictate which combination of drugs are used to treat rheumatoid arthritis?
Disease progression (severity and rate of joint damage)
How well the patient responds to a chosen DMARD
Patient becoming refractory to a DMARD
Other underlying health conditions
Severity of side effects
Cost of treatment
(Slide 13)
What are some problems with DMARDs?
Adverse reactions, side effects and non-responding patients
(Slide 14)
What are 3 aspects of the inflammatory response which glucocorticoids suppress?
Answers Include:
Reducing vascular permeability
Inhibiting adhesion molecule expression
Inhibiting fibroblast activity
Inhibiting white blood cell accumulation and activity
Inhibiting COX 2 and cytokine production
(Slide 16)
How do glucocorticoids work?
They act intracellularly and modify transcription by inducing or repressing genes, though they have non-genomic effects mediated by membrane bound-receptors as well
(Slide 17)
What is the mechanism of action of annexin-1 (a glucocorticoid)?
Glucocorticoid drug binds to the glucocorticoid receptor, which then migrates to the nucleus, and binds to glucocorticoid response elements (GREs) and activates transcription of annexin-1.
Annexin-1 inhibits PLA2, which inhibits production of arachidonic acid and therefore a large amount of inflammatory mediators
(Slide 19)
Other than inhibiting PLA2 what are 2 other examples of things annexin-1 inhibits?
Answers Include:
Neutrophil Accumulation
Monocyte-macrophage accumulation
Macrophage phagocytosis
Production of cytokines by macrophages
(Slide 20)
What are 3 examples of inflammatory mediators which glucocorticoids prevent the synthesis of?
Answers Include:
Arachidonic acid metabolites
Nitric Oxide
Inflammatory cytokines
Chemokines
Adhesion Molecules
(Slide 21)
