NSAIDS, DMARDS, CORTICOSTEROIDS Flashcards
What is the difference between COX1 and COX2?
COX1 is always present in the body, it is physiological
COX2 is involved in inflammation, active in injury, stress and trauma.
What does COX-1 do?
COX-1 causes arachidonic acid to be converted into prostaglandin H2 which is then converted to thromboxane, this is involved in platelet aggregation. (Thromboxane is a hormone of the prostacyclin type which is released for, blood platelets, induces platelet aggregation and arterial constriction).
Why might you be at greater risk of gastritis if taking NSAIDS?
They inhibit the cpCOX enzymes, COX-1 is important in normal physiological mechanisms like the production of prostaglandins, this is needed for the production of the protective mucus of the stomach.
There are selective COX-1 inhibitors and non selective COX inhibitors for NSAIDS and selective COX-2 inhibitors, give examples for all….
Selective COX-1 inhibitors include low dose aspirin
Non selective cox inhibitors include ibuprofen and naproxen
Selective COX-2 inhibitors
Meloxicam and celecoxib
Why do you need to be careful giving someone with kidney damage NSAIDS?
NSAIDS prevent the vasodilation of the afferent arterioles which is important in autoregulation to maintain the GFR.
Explain the risk of COX-2 inhibitors: etoricoxib and celecoxib on the CVS…
So COX-2 causes there to be more thromboxane to be produced than PGI2, increasing risk of MI and stroke.
Remember that anything ending in COXIB is cox-2.
How do NSAIDS have the anti-pyretic effects and analgesic effects?
Analgesic effects- local peripheral action at the site of pain (greater Efficacy if inflamed)
Also has a central component, linked to a decrease in PHE2 synthesis in the dorsal horn
You get a decrease in neurotransmitter release and a decreased excitability of neurones in the pain relay (efficacious after first dose, but full analgesia after several days dosing)
Anti pyrtic effects:
Inhibition of hypothalamic COX-2 where cytokines induced prostaglandin synthesis elevated
Platelet aggregation inhibition through COX-1, decreased thromboxane synthesis
What is the GI ADRS for NSAIDS?
Dyspepsia (indigestion)
Nausea
Peptic ulceration
Bleeding
Perforation
NSAID use increases the incidence of severe GI haemorrhages
Decreases mucus and bicarbonate and increases acid secretion
Decreases mucosal blood flow so you get enhanced cytotoxicity and hypoxia
Decrease in hydrophobicity of mucus layer due to NSAID nature locally
Exacerbation of IBD
Ŵhat are the renal ADRS for NSAIDS?
NSAIDS produce reversible: Decreased GFR Increased creatinine Decreased renal medullary blood flow More likely in underlying CKD and blood flow compromise Eg: congestive HF
Increase in salt and water retention in an otherwise functioning kidney, you get hypertension and oedema (expression of Na/K/2CL- co transporter)
Decrease in renin secretion, hyperkalaemia
The very young and elderly at greater risk
What is the mechanism behind paracetamol?
Not really known, some COX-2 inhibition in spinal cord And you get a decrease in pain signals to higher centres
How is paracetamol inactivated?
It is predominantly inactivated by conjugation in the liver.
What is the importance of the reactive metabolite NAPQI?
When paracetamol is metabolised, one of the minor oxidation products of paracetamol is NAPQI, this is highly reactive and at normal therapeutic doses the conjugation with glutathione will render it harmless, however in high doses there is a limited amount of hepatic glutathione
It’s highly nucleophilic and oxidises theology groups on key metabolic enzymes, it disrupts cellular processes and leads to cell death.
If somebody had taken a paracetamol overdose, then what would you give them?
You would give 5em acetylcysteine which replaces glutathione, you can’t give direct glutathione because it can’t enter the hepatocytes from the blood.
So what is aspirin used for?
Aspirin is an NSAID, at high doses it acts as anti pyretic, anti inflammatory and analgesic.
However at low dose it acts as an anti platelet.
How does aspirin work?
Aspirin is a COX-1 selective inhibitor, therefore it reduces the amount of prostaglandins, PGI2 as well as the amount of thromboxane produced. It is used in the prevention of arterial and venous thrombosis.
What are the differences between venous and arterial thrombosis?
Arterial- lines of zany, white, more to do with change in vessel wall
Venous- venous stasis, red, grows in direction of blood flow.
When is aspirin used?
It is used in the temporary relief of various forms of pain, inflammation associated with various conditions (including RA, SLE, osteoarthritis) and is also used to reduce the risk of death and/ or non fatal MI in patients with a previous infarction or unstable angina prctoris.
What do you need to consider in terms of aspirin and protein binding?
The amount of aspirin bound to albumin is very high, like 99% therefore you need to take in to account how high the plasma concentration of aspirin would be if there is low albumin levels.
Also need to consider renal function (as it is excreted in the urine) and pregnancy.
Why can paracetamol overdose be so dangerous?
Can lead to major damage of the liver
Can often be asymptomatic for many hours, before nausea and vomiting
What is the first line drug used to treat rheumatoid arthritis and give its mechanism of action…
Methotrexate
So methotrexate is interesting because it can also be used in chemo, the way it works in chemo is is slightly different to the way it works in RA and this is due to the dose.
In chemo it will be in very high doses, whereas in RA it will be in very low doses.
In RA it reduces pyrimidines
How does methotrexate work in terms of chemo?
So it inhibits folic acid reductase, this leads to the inhibition of DNA synthesis and inhibition of cellular replication. The affinity of aspirin for dihydrofolate reductase is 100x that of DHFR
What class is methotrexate?
So methotrexate is a disease modifying anti rheumatic drug
What are the side effects of methotrexate?
Mucositis Marrow suppression Hepatitis Cirrhosis Pneumonitis Infection risk Highly teratogenic.
Why is methotrexate more cytotoxic during the S phase of the cell cycle?
So methotrexate acts during DNA and RNA synthesis, hence cytotoxic S phase of the cell cycle, greater toxic effect on rapidly dividing cells which replicate their DNA more frequently.
How often would you give methotrexate?
Methotrexate is given weekly rather than daily due to its long half life.
What is good about methotrexate compared to NSAIDS?
So NSAIDS just reduce the inflammation rather than actually modifying the disease, as methotrexate is disease modifying it can lead to retardation of joint damage.
What is the best way of administrating methotrexate?
It doesn’t have a great mean oral bioavailability- 33%
Whereas it’s mean intramuscular bioavailability is 76%
If a patient taking PO and it has a partial response or they have nausea then swap to sub cut.
What do you need to consider if methotrexate is being taken with NSAIDS?
50% methotrexate bound
99% NSAIDS bound
Therefore NSAIDS will displace methotrexate.
What else could you give methotrexate for?
Ectopic pregnancy
Chrons
Psoriasis
Malignancy
What is sulfasalazine? How does it work?
Sulfasalazine is a second line drug used in the treatment of rheumatoid arthritis
It is also very good for use in IBD
its mechanism of action is still not really known but is is thought it is to do with its break down product: 5-aminosalicylic acid
It is a 5-aminosalicylic acid donor!
When might you consider giving someone sulfasalazine?
You may consider giving someone this drug if they are trying to get pregnant or if they are at a child bearing age, this is because methotrexate is highly tetarogenic.
What are the side effects of sulfasalazine?
Myelosuppression Hepatitis Rash Nausea Abdo pain Vomiting
What are some of the benefits of using sulfasalazine rather than methotrexate?
It is effective, long term blood monitoring not always needed, very few drug interactions, no carcinogenic effects (methotrexate can cause increased risk of cancer), it is safer in pregnancy and is a non biologic agent and therefore cheaper!
Give examples of some biologics which can be used for rheumatoid arthritis?
Biologics- infliximab and adalimumab
How does infliximab work?
It is a TNF alpha (tumour necrosis factor) blocker, which is a key pro inflammatory cytokines which is involved in chronic inflammatory diseases, it’s hyperactivity and enhanced signalling pathways can be observed in inflammatory diseases where it activates further pro inflammatory diseases.
What are the effects of blocking tumour necrosis factor?
Key player in inflammation, tells the inflammatory response what to do.
It decreases inflammation cytokines cascade, reduces recruitment of leukocytes to joint, reduces the elaboration of adhesion molecules and reduces the production of chemokines.
It reduces angiogenesis and VEGF levels
It reduces joint destruction, MMPs and other destructive enzymes bone resorption and erosion
Cartilage breakdown
What is a risk of giving anti TNF therapy?
TB reactivation is a risk, TNF alpha is normally released by macrophages in response to MTB infection, it is essential for the development and maintenance of granulomas.
Therefore you have to screen for latent TB before anti TNF treatment.
What is cyclophosphamide and when is it used?
It is an anti proliferation immunosuppressant, it is used because it works in about 10 days, compared to the rest which are used over months, it can be used in chemo but can also be used in small doses for lupus.
It suppresses the T and B cell activity in a more targeted way than steroids do.
Cyclophosphamide is a pro drug, how is it activated?
It is activated by CYP450s In the liver.
What are some of the risks associated with cyclophosphamide? (A DMARD)
It can be very damaging, acrolein is very toxic to the bladder epithelium and can cause haemorrhagic cystitis
Can’t give for many months
Can cause infertility, it is highly tetarogenic
Causes significant toxicity, increased risk of bladder cancer, lymphoma, leaukaemia, infertility
Therefore you often give mycophenolate mofetil instead for lupus!
How do calcineurin inhibitors work and give examples…
They are active against T helper cells and prevent the production of IL-2 (stimulates bone marrow) via, calcineurin inhibition (calcineurin is just a protein which stimulates T helper cells)
Ciclosporin and and tacrolimus are examples.
What is important to check when on calcineurin inhibitors and why are they not often used?
They are not often used because they cause renal toxicity.
You have to check the BP and eGFR regularly.
Why does ciclosporin and tacrolimus have many drug interactions?
These drugs are metabolised by CYP450 enzymes in the liver, there are many drugs which induce and inhibit this enzyme.
CYP450 inducers:
Rifampicin
Carbamazepine
Phenytoin
CYP450 inhibitors Ciproflocaxin HIV antivirals Fluoxetine Many antifungals.
So how do ciclosporin and tacrolimus work?
Ciclosporin binds to cyclophilin protein
Tacrolimus binds to tacrolimus binding protein
The drug/protein complexes then bind calcineurin
Calcineurin exerts phosphatase activit of activates T cells then nuclear factor migration starts IL-2 transcription.
What are calcineurin 8nhibitors used for?
Used in transplantation, atopic dermatitis and psoriasis.
When is mycophenolate mofetil used?
It is primarily used in transplantation.
It has good efficacy as induction and maintenance therapy for lupus nephritis/Vasculitis maintenance.
What is the MOA for mycophenolate mofetil?
It is a prodrug derived from a fungus.
It inhibits inosine monophosphate dehydrogenase which is required for guanosine synthesis, it impairs B and T cell proliferation but spar3s other rapidly dividing cells.
What are the side effects of mycophenolate mofetil?
Nausea Vomiting Diarrhoea But most important is myelosuppression (bone marrow suppression) Can get ulcers in the mouth
What iscyclophosphamide and what is it used for?
Cyclophosphamide is a cytotoxic agent, it is an alkylation gages which cross links DNA so it can’t replicate.
It has many immunological effects like suppressing T and B cell activity.
It is used for lymphoma, leukaemia, solid cancers, lupus nephritis, wegeners granulomatosis
When is azathrioprine used and what is its mechanism of action?
It is used in SLE and Vasculitis as maintenance therapy
Rarely used in RA as very weak evidence of it helping
Used in IBD
Used as a steroid sparing drug, it allows the duration the patient is exposed to steroids to be cut short.
Why do you have to check the levels of TPMT of someone on azathrioprine?
6-map the active metabolite of azathrioprine is inactivated by TPMT, therefore if TPMT levels are low you can get too much 6-MP and risk of myelosupression
How do corticosteroids work?
They prevent IL-6 and IL-1 production by macrophages and inhibit all the stages of T cell activation.
give A disease modifying anti rheumatic drug that is a non biologic other than sulphasalazine…
Hydroxychloroquine
How does rituximab work?
It is a biologic disease modifying anti rheumatic drug
It binds specifically to a unique cell surface marker CD20, this is found on a subset of B cells and causes B cell apoptosis, the CD20 is not found on stem cells, pro B cells, plasma cells or any other cell type.
They are very effective in RA.
