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
