Anti-inflammatories Flashcards
What are NSAIDs?
Non Steroidal Anti Inflammatory Drugs
What is the active chemical in willow tree bark?
Salicylic acid
What is ASA?
- Acetylsalicylic acid
- Aspirin
What are examples of NSAIDs? (3)
- Aspirin
- Paracetamol (acetaminophen)
- Ibuprofen
How do NSAIDs work?
Inhibit the production of inflammatory mediators (prostaglandins and thromboxanes) by inhibiting COX enzymes
What kind of signalling do prostaglandins and thromboxanes do?
Paracrine
Which enzymes are found in cells which make lipid inflammatory mediators?
Cyclooxygenases (COX enzymes)
How are lipid inflammatory mediators made?
- Phospholipase A2 acts on plasma membrane lipids and generates the precursor (arachidonate)
- COX enzyme converts arachidonate into inflammatory mediators
What does PGF (prostaglandin F) cause?
Myometrial contraction (initiation of labour)
What does PGD2 (prostaglandin D2) cause? (2)
- Inhibits platelet aggregation
- Vasodilation (swelling and redness)
What does PGE2 (prostaglandin F) cause? (2)
- Vasodilator
- Hyperalgesia (increased pain perception)
What does TXA2 (thromboxane A2) cause? (2)
- Blood clotting
- Vasoconstriction
Why is increased bleeding a side effect of NSAIDs?
- Thromboxane A2 causes blood clotting
- NSAIDs block the production of TXA2
What do prostaglandins do?
Attract immune cells
What are NSAIDs used for? (4)
- Anti-inflammatory
- Analgesic
- Antipyretic
- Antithrombotic
How do NSAIDs relieve headache pain?
Decrease vasodilation of blood vessels on the surface of the skull
What does antipyretic mean?
Lower raised temperature
Are NSAIDs used for chronic conditions?
No because different mediators are associated with chronic inflammatory conditions and NSAIDs are ineffective against them
How many COX enzymes are there?
- COX 1,2 and 3
- 3 is actually a variant of 1
What is the function of COX 1?
Normal constant production of prostaglandins with homeostatic functions in the body
What is the function of COX 2?
- Inducible enzyme
- Made in response to injury and inflammation
What is the function of COX 3?
- Expressed in the brain and the kidneys
- Paracetamol exerts action through COX 3 (headaches)
What is the general structure of COX enzymes? (3)
- Dimer (2 identical subunits)
- Embedded into endoplasmic reticulum membrane
- Pore leading to cyclooxygenase site
How are COX 1 and 2 different? (2)
- Pore of COX 1 has isoleucine but COX 2 has valine (smaller) so COX 2 has a wider channel
- Allows for selectivity of COX 2, bigger drugs can enter COX 2
What is the main side effect issue with NSAIDs?
GI irritation
Why do NSAIDs cause GI irritation?
- Prostaglandins play a role in maintaining the protective mucus in the GI tract
- Ulcers can form in severe cases
What are the homeostatic functions of mediators made by COX 1? (3)
- Production of GI mucus
- Maintenance of blood flow through the kidneys
- Control of blood clot formation (TXA2)
What is a suicide inhibitor?
A drug that covalently binds to its target and causes a permanent inactivation
Why is the duration of aspirin action 3/4 hours? (2)
- Aspirin is a suicide inhibitor so permanently blocks COX enzyme site
- Aspirin must be metabolised and excreted and new COX enzymes synthesised for action to wear off
Which NSAIDs are COX 1 selective? (2)
- Aspirin
- Ibuprofen
Which NSAIDs are COX 2 selective?
Coxibs
What are the unwanted side effects of NSAIDs? (4)
- Gut problems
- Impacts on renal function
- Liver damage
- Allergic reactions (rashes, asthma attacks)
Why doesn’t paracetamol cause gut problems?
Selective for COX 3
How can gut side effects of NSAIDs be reduced?
Co-administer a PG analogue (misoprostol)
Why can paracetamol cause liver damage?
First phase of metabolism of paracetamol generates a dangerous chemical which can kill cells
What are the advantages of COX 1 selective drugs?
Anti-thrombotic effects can be useful for patients at risk of strokes
What are the advantages of COX 2 selective drugs?
Don’t cause gut problems
What are the disadvantages of COX 2 selective drugs?
Role in kidney function means that inhibition of COX 2 causes increase in blood pressure and salt retention
Why was the coxib drug Vioxx withdrawn?
- COX 2 selective
- Caused death of patients with underlying cardiovascular disease due to increase in blood pressure and salt retention
What are the properties of aspirin? (3)
- Anti-platelet action
- Reduces risk of colon/rectal cancer and Alzheimer’s
- Suicide inhibitor
Why might aspirin reduce the risk of Alzheimer’s?
Inflammation in the brain is a contributing factor to neurodegenerative disease
What are the properties of paracetamol? (5)
- Effective analgesic and antipyretic
- Weak anti-inflammatory, not good for swelling
- COX 1/3 selective
- Can cause liver and kidney damage
- Competitive inhibitor (binds reversibly)
What do formulations sometimes combine with NSAIDs in painkillers?
- Opioids e.g. naproxen = ibuprofen + codeine
- Combination reduces the amount of opioid needed to achieve the same level of pain relief by 1/3
What are 2 examples of chronic inflammatory conditions?
- Asthma
- Rheumatoid arthritis
What is rheumatoid arthritis?
An inflammatory autoimmune disease that causes painful swelling in the synovium of joints
What causes the symptoms of rheumatoid arthritis?
- Activation of T cells which activate macrophages which release cytokines (IL-1 and TNF-alpha)
- The cytokines cause inflammation leading to the symptoms
What drugs are used to treat rheumatoid arthritis? (5)
- Methotrexate
- DMARDS (Disease Modifying Anti Rheumatic Drugs) e.g. sulfasalazine
- Cyclosporin
- Glucocorticoids e.g. prednisolone
- Biopharmaceuticals
What are the effects of methotrexate? (2)
- Folic acid antagonist
- Immunosuppressant activity
What other condition is sulfasalazine used to treat?
Chronic inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease)
How do cyclosporin and glucocorticoids work?
Inhibit transcription of proinflammatory cytokines
How does cyclosporin work to treat rheumatoid arthritis? (2)
- Inhibits calcineurin so inhibits activity of NFKB
- Therefore prevents production of cytokines
What is a phosphatase?
Enzyme which removes phosphate groups
What is calcineurin? (2)
- Phosphatase which targets NFKB
- NFKB drives transcription of cytokines
What is NFKB?
Transcription factor which drives production of cytokines (IL-2, IL-1, TNF-alpha)
How do glucocorticoids work to treat rheumatoid arthritis?
Bind to DNA and repress the transcription of cytokines at the level of the DNA
What kind of drug is prednisolone?
Glucocorticoid
What does it mean if a drug name ends in ‘mab’?
It is a monoclonal antibody
What is adalimumab?
Humanised monoclonal antibody drug which targets and neutralises TNF-alpha to treat inflammation
How do soluble receptors work?
Inject soluble receptors to the cytokines in order to ‘mop them up’
Which drugs are used to treat asthma? (3)
- Salbutamol
- Steroids e.g. prednisolone
- Biopharmaceuticals e.g. omalizumab
How does salbutamol work?
- Agonist for beta 2 adrenoreceptors in airway smooth muscle
- Causes bronchodilation
Which G protein do beta 2 adrenoreceptors signal via?
Gs
What are the 2 classes of respiratory allergies?
- Allergic rhinitis
- Allergic asthma
What is the difference between allergic rhinitis and allergic asthma?
Allergic rhinitis is restricted to the upper airways (i.e. nose) but allergic asthma affects the lower airways
What happens in respiratory allergies?
Allergen activates mast cells which release inflammatory mediators
What are the 2 phases of respiratory allergy responses?
- Early/immediate phase
- Late phase
What happens during the early phase of respiratory allergy response?
The allergen activates mast cells which secrete histamine
What is the late phase of respiratory allergy response?
- Doesn’t occur in all patients (genetic component which isn’t understood)
- Involves cytokines causing an inappropriate inflammatory response hours after coming into contact with an allergen
What happens in asthma? (2)
- T cells are activated and cause production of IgE antibodies against the allergen
- The antibodies are bound to mast cells and eosinophils which cause the inflammation
What happens when the IgE antibody receptor on mast cells is activated by the allergen? (2)
- Release of histamine, prostaglandins
- Increased transcription of cytokines and chemokines which cause the late phase response
What are the effects of histamine and prostaglandin release from mast cells in asthma? (4)
- Bronchoconstriction
- Increased vascular permeability (allows immune cells into the lungs)
- Mucous secretion
- Stimulation of nerve endings (coughing)
What drugs are used to treat the late phase of the allergic asthma response?
Glucocorticoids
What is seen in chronic inflammation of the airways from uncontrolled asthma? (3)
- Lots of mucous
- Thickening of the smooth muscle around the airways
- More mucous-secreting cells
What is caused by long term glucocorticoid use?
Cushing’s disease
What are the symptoms of Cushing’s disease? (4)
- Buffalo hump
- Bruising
- Hypertension
- Poor wound healing
How does omalizumab work?
Targets IgE antibodies so prevents inflammatory response
What new therapies are being developed for asthma treatment? (2)
- Humanised monoclonal antibodies
- Prostaglandin receptor antagonists
