Anti-inflammatory drugs

Question 1

What are the types of anti-inflammatory drugs?

Answer 1

Non-steroidal anti-inflammatory drugs (NSAIDs)
Steroids

Question 2

What are NSAIDs?

Answer 2

Aspirin
Ibuprofen
Paracetamol

Question 3

What is PG synthesis?

Answer 3

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.

Question 4

What are the effects of NSAIDs?

Answer 4

Analgesia
Anti-inflammatory
Anti-pyretic

Question 5

What are the analgesic effects of NSAIDs?

Answer 5

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 sensitive sensory nerves, repeated injury causes more pain.

Question 6

What are the anti-inflammatory effects of NSAIDs?

Answer 6

Prostaglandins promote inflammatory response by recruiting immune cells to inflamed area to increase inflammation.
Prevent PG synthesis

Question 7

What happens when there is raised body temperature?

Answer 7

Hypothalamus thinks a high temperature is normal because macrophages in innate immune system release pyrogens in response to virus.
e.g. Interleukins (IL-6)
These reset the hypothalamus, so it doesn’t recognise the temperature as high.
Pyrogens release prostaglandins.

Question 8

How are NSAIDs anti-pyretic?

Answer 8

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.

Question 9

What are the mechanisms of action of NSAIDs?

Answer 9

Irreversible inhibition of cyclooxygenase (COX) e.g. aspirin.
Reversible inhibition of COX e.g. ibuprofen
Reversible non-competitive inhibition of COX e.g. paracetamol.

Question 10

What is the possible mechanism of action of paracetamol?

Answer 10

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.

Question 11

What is the importance of paracetamol not being anti-inflammatory?

Answer 11

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.

Question 12

Why does paracetamol not work well at sites of inflammation?

Answer 12

Inflammation damages tissue.
Inflammation in the stomach generates lots of free radicals, which overcomes the capacity of the paracetamol to mop up free radicals.

Question 13

What is an alternate theory of how paracetamol works?

Answer 13

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.

Question 14

What is COX1?

Answer 14

Constitutive enzyme.
Ubiquitously expressed - expressed by most cells including gut mucosa.
Responsible for gut effects

Question 15

What Is COX2?

Answer 15

Induced expression by inflammatory cells
Inflammatory cells
Responsible for inflammation
So should inhibit COX2 not COX1 when targeting inflammation.

Question 16

What is Rofecoxib?

Answer 16

A selective COX2 inhibitor.
Now withdrawn as caused thrombosis in patients predisposed to cardiovascular conditions, which increased the risk of strokes and heart attacks.

Question 17

What are current COX2 inhibitors?

Answer 17

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.

Question 18

What are the structures of steroids?

Answer 18

All derived from cholesterol, and have similar structures and pharmacological activity.
Are highly aromatic - can cross the lipid cell membrane to become functionally active.

Question 19

What are the types of steroids?

Answer 19

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.

Question 20

What are glucocorticoids?

Answer 20

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.

Question 21

What is the process of steroid secretion?

Answer 21

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.

Question 22

What is negative feedback of steroids?

Answer 22

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.

Question 23

What is the effect of exogenous steroids on the production of endogenous steroids?

Answer 23

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.

Question 24

What should be done after chronic use of steroids?

Answer 24

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.

Question 25

What are the therapeutic uses of steroids?

Answer 25

Anti-inflammatory, has greater efficacy than NSAIDs.
Immunosuppressive, but steroids can cause worse side effects.

Question 26

What is the anti-inflammatory use of steroids?

Answer 26

Early on, steroids cause redness, pain and swelling, which is the removal of the damaged tissues.
Later, there is wound healing and cell proliferation to replenish the damaged tissue.

Question 27

What is the immunosuppressive use of steroids?

Answer 27

The immune system is needed to stop infection and cancer formation.
In long term, steroids can cause the body to become more prone to infections and increased tumour growth.
The beneficial use is in reducing rejection from organ donation.

Question 28

What is the mechanism of action of steroids?

Answer 28

Lipophilic glucocorticoid crosses the cell membrane.
Nuclear receptors for steroids are in the cytoplasm.
Glucocorticoid engagement causes homodimerization - 2 similar proteins come together.
Homodimeric receptor translocated to nucleus.

Question 29

What does the homodimeric receptor do?

Answer 29

Binds to positive or negative glucocorticoid response element.
Causes transactivation - generate lipocortin, causes gene to be expressed.
Transrepression - genes switched off
Disrupts NFKB induced transactivation to suppress inflammation.

Question 30

What is lipocortin?

Answer 30

Lipocortin is a steroid that inhibits phospholipase A, in the reaction of phospholipid to arachidonic acid.
Arachidonic acid produces prostaglandins and leukotrienes.
Leukotrienes also promote inflammation.
So steroids have broader inflammatory activity than NSAIDs.

Question 31

What are the uses of steroids?

Answer 31

Replacement therapy of endogenous steroids by a defective adrenal cortex.
Anti-inflammatory - severe asthma - via inhaler, severe arthritis, skin disorders - eczema.

Question 32

What is salbutamol?

Answer 32

A selective inhibitor of B2 receptor on bronchial walls.
It causes bronchial dilation, which makes it easier to breathe in asthma.
But the B2 receptors can exocytose away from the cell membrane, so salbutamol stops working.
The more severe the asthma, the less salbutamol works.

Question 33

What are inhaler steroids?

Answer 33

This has topical application onto the lung by inhaling, so there are less effects on the rest of the body.
But this is only controlling the symptoms of asthma, not curing.

Question 34

What is the use of steroids in emesis?

Answer 34

Emesis is nausea and vomiting associated with cancer chemotherapy, as it causes inflammatory response which causes vomiting.
Synergy of drugs that are 5-HT3 R antagonists to reduce emesis.

Question 35

What are the steroid drugs?

Answer 35

Cortisone and hydrocortisone, these are endogenous steroids, with mineralocorticoid activity, not very selective.
Prednisolone, is fairly selective.
Dexamethasone, highly selective, glucocorticoid with less side effects.

Question 36

What are the side effects of steroids?

Answer 36

Suppressed response to infection and injury.
Atrophy of adrenal cortex.
Disrupted metabolism - iatrogenic cushings syndrome.
Iatrogenic means drug induced.