NSAIDS and Steroids Flashcards
what are the 2 true NSAIDS?
Aspirin and Ibuprofen
what are the mechanisms of action of ibuprofen?
competitive, reversible inhibitor of COX
what are the mechanisms of aspirin?
irreversible, inhibitor that covalently binds to COX
what is theorised paracetamol method of action?
non-competitive inhibition of COX, it is hypothesised that it may do this via mopping up the free radicals at sites of infection that act as cofactors for COX or by targeting another protein
what are the actions of prostaglandins?
sensitising sensory nerve in response to injury / infection, resulting In exacerbated pain
PG secreted from hypothalamus in response to IL-1 (stimulated by pyrogen’s), resets hypothalamus to maintain a high body temperature and induce fever
vasodilation and increasing the permeability of blood vessel for immune cells,
what it the action of COX?
cyclooxygenase, acts on arachidonic acid to convert it to PG
what effect do PG have on the stomach mucosa?
they stimulate it to divide
How are stomach ulcers caused by NSAIDS?
inhibition of mucosa dividing, results in acid burning through to nerves and BV, leading to bleeding and pain
what is worse for stomach ulcers aspirin or ibuprofen?
aspirin - due to its irreversible inhibition
How is paracetamol better for the stomach?
damage to the stomach lining the inflammation results in an increase in free radical conc. The paracetamol acts on these and becomes saturated (stops working in that area), this means PG conc increases and the stomach lining can divide more rapidly again causing less damage
Describe the action of COX1
COX 1 is a constitutive enzyme (continuously expressed by all cells), ubiquitously expressed, responsible for gut effects and its inhibition is why NSAIDs cause damage
describe the action of COX 2
exhibits induced expression in inflammatory cells
what was the problems with the first COX 2 inhibitor?
Vioxx, caused increased risk of cardiac arrest in those with CV problems
(some of these problems where previously undetected)
what are newly developed COX 2 inhibitors?
what are their side effects?
celecoxib and etoricoxib
risk of CV issues so are very carefully prescribed, side effects of these include some GIT bleeding as they do inhibit COX1 to some extent
what is the initial pathway for paracetamol metabolism at low conc?
glucuronide conjugation the enzyme for this reaction has a low Km so has high affinity however it becomes saturated very quickly at therefore its capacity is limited
what is the dangerous metabolism for paracetamol at high conc?
mixed function oxidase P450, these reaction had a higher Km but a much larger capacity this leads to the formation of N-acetyl-benzoquinone-imine (NAPQI)
what are the effect of NAPQI?
toxic to proteins and nucleic acid and can cause hepatocyte damage and liver failure
how is NAPQI removed?
GSH conjugation to glutathione
how can paracetamol overdose be treated?
acetylcysteine (iv) or methionine can be given which replenish glutathione stores as Glutathione stores being depleted is usually the limiting factor
what is a risk factor for high P450 activity?
drinking and smoking
what are the 3 types of steroid secreted from the adrenal cortex?
mineral corticoids (e.g. aldosterone - regulates body / electrolyte balance), glucocorticoids (regulate metabolism and body’s response to stress e.g. cortisol) and androgens (sex hormones e.g. testosterone)
what are the general structures of steroids?
aromatic rings to make them lipophilic so that they can pass through cell membranes
how is the released of steroids caused?
CRF produced by the hypothalamus in response to stressors
CRF then stimulates the anterior pituitary gland to secrete ACTH in the blood stream, this promotes the release of steroids from the adrenal cortex
how is their negative feedback in the steroid system?
Once steroids have reached a certain level they inhibit release of CRF and ACTH in an negative feedback system
What stages of immune response to steroids act on compared to NSAIDS?
early - redness pain and swelling and late - wound healing and cell proliferation
act on both stages, unlike NSAIDS which act on 1st stage
this leads to unforeseen side effects in wound healing
where to glucocorticoids bind in the nucleus to decrease immune response?
bind to positive or negative GREs (glucocorticoid response element) these are promoters that can increase or decrease the expression of a gene respectively
what genes do steroids increase the transcription of?
antiflammatory proteins such as lipocortin
what does trans repression mean in the context of steroids?
disrupting TF that increase the transcription of proteins such as IL-B
what is the mechanism of lipocortin?
Inhibits phospholipase A2 which is the enzyme which catalyses phospholipid into arachidonic acid (precursor to prostaglandins)
why is lipocortin more effective than nsaids?
By inhibiting the PG pathway earlier it prevents the formation of leukotriene’s from arachidonic acid
NSAIDS dont do this