Anti-inflammatory drugs Flashcards
(36 cards)
What are the types of anti-inflammatory drugs?
Non-steroidal anti-inflammatory drugs (NSAIDs)
Steroids
What are NSAIDs?
Aspirin
Ibuprofen
Paracetamol
What is PG synthesis?
Phospholipid is damaged and leaves the cell
Phospholipid is converted to arachidonic acid by phospholipase A2.
Arachidonic acid is converted to prostaglandins by cyclooxygenase.
NSAIDs inhibit cyclooxygenase so prostaglandins can’t effect.
What are the effects of NSAIDs?
Analgesia
Anti-inflammatory
Anti-pyretic
What are the analgesic effects of NSAIDs?
Help low to moderate intensity pain - throbbing, but not severe.
Can also be in combination with opioids.
Prevent prostaglandin (PG) synthesis - PG sensitise nerve endings.
First injury prostaglandins sensitise sensory nerves, repeated injury causes more pain.
What are the anti-inflammatory effects of NSAIDs?
Prostaglandins promote inflammatory response by recruiting immune cells to inflamed area to increase inflammation.
NSAIDs prevent PG synthesis
What happens when there is raised body temperature?
Hypothalamus thinks a high temperature is normal because macrophages in innate immune system release pyrogens in response to virus.
e.g. Interleukins (IL-6)
Pyrogens release prostaglandin, which reset the hypothalamus, so it doesn’t recognise the temperature as high.
How are NSAIDs anti-pyretic?
NSAIDs inhibit prostaglandins, which can reduce the effect of pyrogens and temperature reduces back to normal.
But NSAIDs only reduce raised temperature, not increase a decreased temperature.
What are the mechanisms of action of NSAIDs?
Irreversible inhibition of cyclooxygenase (COX) e.g. aspirin.
Reversible inhibition of COX e.g. ibuprofen
Reversible non-competitive inhibition of COX e.g. paracetamol.
What is the possible mechanism of action of paracetamol?
Free radicals, which are co-factors for COX, and are released in inflammation.
This promotes cyclooxygenase activity.
By mopping up free radicals, paracetamol inhibits the activity of COX, and reduces prostaglandins and therefore inflammation.
What is the importance of paracetamol not being anti-inflammatory?
Paracetamol does not affect the mucosa lining of the stomach.
When taking other NSAIDs, the stomach should be lined with food to prevent the stomach acid burning through the mucosa.
Because NSAIDs inhibit gastric COX-1, which means the prostaglandins normally synthesised cannot inhibit acid secretion and don’t protect the mucosa.
Why does paracetamol not work well at sites of inflammation?
Inflammation damages tissue.
Inflammation in the stomach generates lots of free radicals, which overcomes the capacity of the paracetamol to mop up free radicals.
What is an alternate theory of how paracetamol works?
Evidence that metabolites of paracetamol have direct action on the brain.
Metabolites impact TRPV channels and VGCaC, which are channels involved in pain reception through the spinal cord.
The modulation of these channels is involved in the analgesic action of paracetamol.
What is COX1?
Constitutive enzyme.
Ubiquitously expressed - expressed by most cells including gut mucosa.
Responsible for gut effects
What Is COX2?
Induced expression by inflammatory cells
Responsible for inflammation
So should inhibit COX2 not COX1 when targeting inflammation.
What is Rofecoxib?
A selective COX2 inhibitor.
Now withdrawn as caused thrombosis in patients predisposed to cardiovascular conditions, which increased the risk of strokes and heart attacks.
What are current COX2 inhibitors?
Celecoxib and etoricoxib
Less likely to cause GIT bleeding and pain as non-selective.
Uses for:
Oesteoarthritis
Rheumatoid arthritis
But needs consideration about compromised CVS.
What are the structures of steroids?
All derived from cholesterol, and have similar structures and pharmacological activity.
Are highly aromatic - can cross the lipid cell membrane to become functionally active.
What are the types of steroids?
Glucocorticoids, mineralocorticoids and androgens.
Progesterone, a sex hormones, produces corticosterone, which is a glucocorticoid steroid.
Aldosterone, is a mineralocorticoid, it retains salt throughout the kidneys.
What are glucocorticoids?
e.g. corticosterone, hydrocortisone, cortisol
Effects:
Metabolism - glucose, protein synthesis, lipid, minerals.
In hyperglycaemia, glucocorticoids break down proteins so lose muscle mass, redistribution of lipids to the face, negative impact on minerals - especially Ca2+.
Ca2+ is absorbed less well and secreted more - brittle bones.
What is the process of steroid secretion?
Secretion of endogenous steroids by the adrenal cortex is controlled by the hypothalamus.
The hypothalamus releases corticotrophic releasing factor (CRF), which goes to the pituitary.
This stimulates the pituitary to secrete adrenocorticotrophic hormone (ACTH), which stimulates the adrenal cortex to release the steroids.
The ACTH also encourages the adrenal cortex to remain healthy and for cells to proliferate.
What is negative feedback of steroids?
The production of steroids causes negative feedback on the pituitary to reduce ACTH.
The steroids also cause negative feedback on the hypothalamus to reduce CRF.
As steroid levels decrease, there is less negative feedback, so more CRF and ACTH is released.
What is the effect of exogenous steroids on the production of endogenous steroids?
The hypothalamus and pituitary cannot distinguish betwen exogenous and endogenous steroids.
The exogenous steroids cause switching off of the pituitary and hypothalamus, so less ACTH and CRF are produced, so there is no stimulus of the adrenal cortex.
This causes atrophy of the adrenal cortex and the capacity to produce endogenous steroids is reduced.
What should be done after chronic use of steroids?
After chronic steroids, cannot just stop steroids, as the adrenal cortex cannot generate enough of its own steroids, so should taper off by reducing dosage so the body’s own steroids come back in to circulation and are stimulated itself.
