NSAIDS and Steroids

Question 1

what are the 2 true NSAIDS?

Answer 1

Aspirin and Ibuprofen

Question 1

what are the mechanisms of action of ibuprofen?

Answer 1

competitive, reversible inhibitor of COX

Question 2

what are the mechanisms of aspirin?

Answer 2

irreversible, inhibitor that covalently binds to COX

Question 3

what is theorised paracetamol method of action?

Answer 3

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

Question 4

what are the actions of prostaglandins?

Answer 4

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,

Question 5

what it the action of COX?

Answer 5

cyclooxygenase, acts on arachidonic acid to convert it to PG

Question 6

what effect do PG have on the stomach mucosa?

Answer 6

they stimulate it to divide

Question 7

How are stomach ulcers caused by NSAIDS?

Answer 7

inhibition of mucosa dividing, results in acid burning through to nerves and BV, leading to bleeding and pain

Question 8

what is worse for stomach ulcers aspirin or ibuprofen?

Answer 8

aspirin - due to its irreversible inhibition

Question 9

How is paracetamol better for the stomach?

Answer 9

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

Question 10

Describe the action of COX1

Answer 10

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

Question 11

describe the action of COX 2

Answer 11

exhibits induced expression in inflammatory cells

Question 12

what was the problems with the first COX 2 inhibitor?

Answer 12

Vioxx, caused increased risk of cardiac arrest in those with CV problems
(some of these problems where previously undetected)

Question 13

what are newly developed COX 2 inhibitors?
what are their side effects?

Answer 13

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

Question 14

what is the initial pathway for paracetamol metabolism at low conc?

Answer 14

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

Question 15

what is the dangerous metabolism for paracetamol at high conc?

Answer 15

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)

Question 16

what are the effect of NAPQI?

Answer 16

toxic to proteins and nucleic acid and can cause hepatocyte damage and liver failure

Question 17

how is NAPQI removed?

Answer 17

GSH conjugation to glutathione

Question 18

how can paracetamol overdose be treated?

Answer 18

acetylcysteine (iv) or methionine can be given which replenish glutathione stores as Glutathione stores being depleted is usually the limiting factor

Question 19

what is a risk factor for high P450 activity?

Answer 19

drinking and smoking

Question 20

what are the 3 types of steroid secreted from the adrenal cortex?

Answer 20

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)

Question 21

what are the general structures of steroids?

Answer 21

aromatic rings to make them lipophilic so that they can pass through cell membranes

Question 22

how is the released of steroids caused?

Answer 22

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

Question 23

how is their negative feedback in the steroid system?

Answer 23

Once steroids have reached a certain level they inhibit release of CRF and ACTH in an negative feedback system

Question 24

What stages of immune response to steroids act on compared to NSAIDS?

Answer 24

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

Question 25

where to glucocorticoids bind in the nucleus to decrease immune response?

Answer 25

bind to positive or negative GREs (glucocorticoid response element) these are promoters that can increase or decrease the expression of a gene respectively

Question 26

what genes do steroids increase the transcription of?

Answer 26

antiflammatory proteins such as lipocortin

Question 27

what does trans repression mean in the context of steroids?

Answer 27

disrupting TF that increase the transcription of proteins such as IL-B

Question 28

what is the mechanism of lipocortin?

Answer 28

Inhibits phospholipase A2 which is the enzyme which catalyses phospholipid into arachidonic acid (precursor to prostaglandins)

Question 29

why is lipocortin more effective than nsaids?

Answer 29

By inhibiting the PG pathway earlier it prevents the formation of leukotriene’s from arachidonic acid
NSAIDS dont do this