Anti-inflammatories (L12-13)

Question 1

What are the features of NSAIDs?

Answer 1

non-steroidal anti-inflammatory drugs. Also known as antipyretic analgesics. The main one is aspirin. They are the most widely used anti-inflammatory for over 50 yrs. They provide relief from fever, pain, swelling in chronic joint diseases and other soft tissuei injuries like sprains and fractures. However, they’re ineffective against that contribute to tissue damage associated with chronic inflammation :(

Question 2

How do NSAIDs work?

Answer 2

They modify the inflammatory reaction so decrease vasodilation and therefore oedema (swelling of the injured area). They’re analgesic (reduce certain types of pain) as they decrease production of prostaglandins in damaged and inflamed tissue which sensitises nociceptors to inflammatory mediators like bradykinin and serotonin (so they don’t actually alter nociceptive conduction). They’re antipyretic (lower a raised temp) because of reduction of prostaglandins (the thermostat in the hypothalamus is activated by IL-1 induced COX2 production of PGE

Question 3

What are coxibs?

Answer 3

A type of NSAIDs that inhibit COX-2 but not COX-1

Question 4

What is the structure of cyclo-oxygenase and what are the different isoforms?

Answer 4

Cyclo-oxygenase is made up of 2 identical subunits, each with 2 catalytic sites. There are 2 isoforms of COX

• COX-1- constitutive expression in platelets, stomach, kidney, colons etc
• COX-2 - Inducible expression in most cells, but especially inflammatory cells after stimulation with cytokines, GFs and tumour promoters (immediate early gene response)

Question 5

Why are some NSAIDs more selective than others?

Answer 5

Most traditional NSAIDs inhibit both COXs, but some are more selective to one of them. The selectivity for each also vary massively. The reason some NSAIDs may block one but not the other is because COX1 is narrower, so some are not small enough to get through so only inhibit COX2. Rofecoxib is so selective for COX2 it can kill.

Question 6

What are the side-effects of NSAIDs?

Answer 6

In the gut, prostaglandins normally inhibit acid secretion and protect mucosa, so when they;’re not being produced, you get dyspepsia, diarroea, nausea, vommiting, gastric bleeding and sometimes ulceration. To protect against this, you can co-administer misoprostol which is a prostaglandin analogue which can help protect and do some of the jobs PGs do. The risk varies with the NSAID - aspirin and fenoprofe are low risk and azapopazone is highPGs also maintain renal blood flow, so can lead to kidney failure. Liver damage if taken with paracetomol (not really known why)
Bronchospasm asthma attacks and skin rashes

Question 7

What are the features of aspirin?

Answer 7

Binds covalently to Ser residue on COX, preventing arachidonic acid from reaching the cyclo-oxygenase site. It has an anti-platelet action and reduces the risk of colonic and rectal cancer. Reduced risk of Alzheimer’s
Its a weak acid (pKa of 3.5)
Rapid and efficient absorption in the ileum
Suicide inhibitor (irreversible)

Question 8

What are the features of paracetomol?

Answer 8

It is analgesic and antipyretic due to its CNS effects. Its a weak anti-inflammatory. Its not really known how it works - possibly a COX2 or COX1/3 inhibitor. Well absorbed and metabolised in the liver. Has less side effects than aspirin with long term use, but large doses may increase kidney damage. Its a competitive inhibitor

Question 9

What are the clinical uses of NSAIDs and COXIBs?

Answer 9

Antithrombotic - aspirin given to patients at high risk of arterial thrombosis (anti platelet)
Analgesia
- Short term - aspirin, ibuprofen, paracetamol
Chronic pain requires longer lasting, more potent drug e.g. naproxen (codeine)
- Reduces the requirment for narcoticanalgesics (morphine)
Antipyretic (paracetomol)

Question 10

What is rheumatoid joint pain/arthritis?

Answer 10

Rhematoid arthritis is an autoimmune disorder which effects the lining of joints, cauing pain, swelling and eventually bone erosion and joint deformity. Cna be caused by osteoclasts, fibroblasts and macrophages releasing things like ILs and TNF.

Question 11

What types of drugs can help stop the progression of rheumatoid arthritis?

Answer 11

Methotrexate is a folic acid antagonist involved in cytotoxic and immunosupresant activity. Sulfasalazine is a sulfa drug also used to chronic inflammatory bowel disease which also helps RA. 5-aminosalicylic acid (mesalazine) may act as a free radical scavenger to decrease damage produced by neutrophils.
Immunosuppresant drugs inhibit the inhibition phase of the inflammatory response. Ciclosporin and glucocorticoids (steroids) inhibit transcription of pro-inflammatory cytokines like IL-2.
New anticytokine/anti-inflammaotyr drugs are being developed fromhuman mABs which have a high affinity and selectivity for target. The neutralise the action of either the soluble or membrane bound pro-inflammatory cytokines. Have a long half life

Question 12

How can anti-inflammatories be used to treat asthma?

Answer 12

Asthma effects 5.4 million people in the UK. Due to bronchial hyper-reactivity (reversible airway obstruction). Anti asthmatic drugs include bronchodilators (salbutomol)
Sometimes polymorphisms in beta-2 adrenoreceptors are associated with reduced efficacy of bronchodilators - so anti inflammatory agents like prednisolone and omalizumab are used.

Question 13

Explain IgE- mediated hypersensitivity

Answer 13

Causes astha, hayfever, eczema, urticaria, food allergies and systemic anaphylaxis (anaphalactic shock)
IgE antibodies bind tightly to IgE Fc receptors on mast cells (in skin, mucous, basophils and eisonophils) Mast cells are key mediators of type 1 hypersinsitivity reactions. The natural role of IgE is to fight parasitic infections. Individuals suceptible to allergies are atopic
Allergens can activate mast cells in the lower respiratory tract. Early phase is inflammation and obstruction and late phase (occurs in about 50% of patients) where cytokines lead to leukocyte infiltration and inflammation - can cause an asthma attack. Chronic inflammation can cause tissue damage. This type of asthma is associated with an overactivity of Th2 cells.

Question 14

What are different factors that lead to a susceptibility to antigens?

Answer 14

Genetic factors

• IgE production
• hyper responsivness
• gender and age related

Environmental

• levels of allergens
• nutrition
• pollutants

Question 15

What happens during an asthma attack?

Answer 15

Occurs 5-10 minutes after exposure to the allergen
Causes cross linking of IgE by allergen on mast cell surface which triggers release of inflammatory mediators. This leads to smooth muscle contraction, increase vascular permeability, mucus secretion, platelet activation, stimulation of nerve endings and recruitment and activation of eosinohils.
Cytokines and chemokines during the intermediate phase set the scene for the late phase of the asthma attack. During inflammation you get dilated blood vessels, thickend basement membranes, hypertrophied smooth musle, infiltration of inflammatory cells and increased mucosa. As well as mucus plugs that contain desquamated epithelial cells

Question 16

What are the unwanted side effects of chronic steriodal use?

Answer 16

Euphoria (sometimes depressive or psychotic sysmptoms)
Buffalo hump
Benign intercranial hypertension
Cataracts
Hypertension
Increased abdominal fat
Thinning of arms
Easy bruising
Poor wound healing (due to lack of platelets)
Muscle wasting

Question 17

What are some new therapies being developed to treat asthma?

Answer 17

humanised antibodies and soluble receptors to IgE, cytokines and chemokines (biopharmaceuticals)
PGD2 antagonists to decrease inflammation(small molecules)
They are all inhibitors of immune cell and mast cell signalling.