Lecture - Rheumatoid Arthritis Meds Flashcards
General things about RA: 1. What sort of disease is it?
It’s a chronic inflammatory autoimmune disease and is disabling and painful
Why’s the difference between osteoarthritis and RA?
With osteoarthritis - you have mechanical damage which is often associated with historical injury and you get inflammation subsequently With RA - also have inflammation here but it’s autoimmune. You have immune cells attacking particular things in joints. You get swelling, joint destruction and growth of abnormal fibrous scarring tissue. This is painful and debilitating
If your hands look like this, what happens?
V hard to use hands after this
What is the treatment of RA - like what are the three parts to the treatment?
- Control pain/symptoms (use paracetamol, NSAIDS)
- Reduce inflammation (NSAIDS, COX-2 inhibitors and glucocorticoids)
- Treat the disease progression (use DMARDS aka disease modifying anti-rheumatic drugs). These include xenobiotics (chemical agents), immunosuppressants and biological agents (produced by biotech)
How do NSAIDS work?
What are they used for?
What are common examples?
COX enzymes: What are the two types, where are they found and which one do we inhibit and with what?
So like, when we get an injury, we turn the arachidonic acid into prostaglandins using a COX enzyme (this is how I interpret it). So NSAIDs inhibit this COX enzyme, I guess
Common NSAIDS: aspirin bc it irreversibly binds to COXs, ibuprogen bc it is more potent than aspirin and diclofenac is more potent than ibuprofen but with higher risk of GI effects (there are oral and topical formulations)
-Prostaglandins are imp in productiion of mucosal lining in stomach so overuse of NSAID will lead to gastric problems. SO they’re used to help patient in initla stages with pain
NSAIDS used for: All reduce pain and inflmmation but not disease progression. They’re useful in first few weeks during diagnostic workup. They bridge therapy when initiating DMARD treatment - adverse effectd with long term use. Like yeah, use to control pain and reduce inflmmation but not to treat disease
COX enzymes:
- COX-1 is a constituitie isoform and inhibition accounts for gastric and renal side effects
- COX-2 is an indicible (like 50x more produced in inflmmatory processes so target this) isoform and inhibition accounts for anti-inflammatory effects.
- COX-1 is commonly found in the kidney, stomach and platelets whereas COX-2 is located in macrophages, leukocytes and fibroblasts
- Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining
Diclofenac is slightly selective for COX-2 and celebex (a coxib) is highly COX-2 selective (so will reduce GI effects but increase risk of CV events bc thrombus formation and they’re prescription only for symtom control for RA!)
Glucocorticoids - used for reduction of infamaation
- Synthesided by what?
- Powerful what effects?
- Alters what to produce effects?
- Limited effects on what?
- Are they also used to bridge therpay to control symptoms until DMARDs are effective?
- What poissible effects do you get with prolonged use? (aka they aren’t a long term strategy)
Three glucocorticoids - what are they each used for and sid effetcs?
Triamcinolone acetonide = Direct local adminstration so injected - often ppl have. aparticular joint that is giving toruble so an injection can give them releif for like a month. SO this isnt just a bridging therapy but also for like if you’re going over a holiday. But if you’re using this a month in-month out then for the worse. There will be effects on tissue growth and stuff
DMARDS #1
- How do they work?
- How were they discovered?
- Immunosuppression can be due to what?
- Are glucocorticoids DMARDS?
- ALL DMARDs will affect immune system - all suppress it to some degree but in all of them, they affect immune system.
- Targetting bone-marrow progenitor so bring down immmune cells or something else
DMARDS #2
- Are they fast or slow acting?
- What do they do to disease?
- All cause i____ so you should monitor what and several DMARDs are used as immunosuppresants for what?
- Do they have analgesic or direct anti-inflam effects?
- What do you used until effects of DMARDs appear?
- To alter disease = you want to bring down the slope of the graph severity vs time
- Induce remission and maintain it - when remission goes on and on, it’s as good as a cure
- Many of these drugs have effects on platelets and blood clotting etc. Need to look at each drug in turn
1. Not directly hence the slow onset for symptom releif. But the damage does decrease when you are treated - SLow acting so need bridge therapy
Two types of DMARDS - two types, what are examples of each? (2 vs random others)
DMARD: Methotrexate
- Why is it the common first choice DMARD?
- What sort of patients is it used with?
- What is its onset of action like compared to other DMARDS?
- What sort of side effects?
Methotrexate #2
- What’re the mechaisms of action?
- What does it target? (3)
- Synthesis and replication of DNA thrugh reducing production of nucleotides. Folic acid needed for nucleotides and when () works as a competitive antagonist for folate - it is targetting diving cells (bone marrow progenitor cells)
DMARDS that are also used as immunosupprssants
- Suppress the activities of the immune system by targetting what?
- examples?
For cases where eg organ transplant - need a global suppression of immune system so real heavy duty
ALso anti-rheumatic effects and they dont have broad cytotoxc effects - they have more specific mechanism
DMARDS that’re used as immunosuppressants: cyclosporin
- Also used to prevent what?
- Inhibits what?
- Decreases what?
- Side effects?
More targetted effect rather than stopping DNA syntehsis - it’s on a particualr molecule, has a particular role. It doesnt decrease the growth of all cells - not as good as an anti-tumore drug but reduces the proliferation and all
Using biological agents as DMARDs
- What are they
- What do they target?
Drugs which are a feature of age-biotic technology. Produce biological molecules that mimic body’s biological molecules and they have an effect
TNF-alpha inhibitors (it’s a biological agent that can suppress disease) - what are two ways in which it works?
So it has receptors which are membrane bound and it has transmembrane domain and cytostolic signalling pathway and extracellular domain which can be solubilised
Two strategies can bring down the amount of TNF signalling to TNF receptors:
One way is to produce the external fragment and solubilise it and join it to something else and use that as a drug. So it goes around binding TNF therefore there is less TNF available to activate membrane bound receptors so it’s an inactivated recepor and it’s acting as a competitior antagonist to active receptors. So like etanercept
-Has receptors which are membrane bound and they have transmembrane domains and cytosolic signalling pathways
Second way is to produce Ab against TNF - works to reduce unbound TNF which could activate the receptor so like infliximab
-Produce AB against TNF - reduce the amount of unbound TNF so less to go around and do its job
In both cases, they are direct homologues of body’s own molecules
Abatacept (biological agent)
- Interefers with what?
- Is a fusion of what?
- Binds to what?
- What are CTLA3 inhbitiors used in?
Works in another way - soluble receptor as well but works on CTLA-4.
It’s a molecule that involved in an immune check point (immune system has regualtory features and they’re called this) = programme death 1 is an example of a checkpoint and CTLA-4 is another one. If you turn on that checkpoint with an agonist, you’ll suppress immune system and if turn it off (inhibit it) then activating immune system.
In cancer, have immune cell activators by inhibiting check point but they’re used as anti-rheumatic things by activating check point - so you just produce CTLA-4 and use that as a biological agent itself and it will bind to CD80 (surface molecules) etc
Inflximab vs rituximab
