31.5 Pharmacology of Inflammation Flashcards
What is the mechanism of action for Aspirin and other NSAIDs?
Cyclooxygenase (COX) inhibitors
*suppress prostanoid synthesis (including prostaglandins)
*Aspirin has non-specific action on COX-1 and COX-2
How do COX inhibitors work as analgesics?
Decrease prostaglandin synthesis which sensitise nocioceptive fibres to bradykinin
How do COX inhibitors work as anti-inflammatories?
Decrease the production of prostaglandin E2 and prostacyclin which reduced vasodilation and indirectly, oedema
How are COX inhibitors useful in the treatment of rheumatoid arthritis? What is this condition?
Chronic inflammatory disease characterised by chronic joint swelling and stiffness
COX inhibitors reduce the vasodilation of blood vessels to reduce the delivery of cytokines and chemokines to the joints
What are the systemic effects of COX inhibitors?
Analgesic
Skin reactions (rashes)
Renal effects due to less prostaglandins which normally are involved in regulating renal flow
Antiplatelet action
Raise blood pressure
GI disturbances
What is the difference in COX1 and COX2?
COX-1 is a constituitive enzyme expressed in most tissues as a ‘housekeeping’ enzyme involved in tissue homeostasis (initiates partuition, platelet aggregation, renal blood flow)
COX-2 is induced in inflammatory cells when they are activated by cytokines (IL-1, TNF alpha)
What is the effect of COX-1 inhibitors on the gastrointestinal system?
GASTROINTESTINAL HAEMORRHAGE
Prostaglandins decrease acid secretion and increase mucus secretion so inhibiting this leads to the development of gastric ulcers and bleeds
What is the function of prostanoids in the immune response?
Prostacyclin (PGI2) and prostaglandin E2 acts on Gs receptors to vasodilate, cause bronchodilation
Sensitise nocioceptors to inflammatory mediators such as bradykinin
Thromboxane stimulates platelet aggregation
What is the mechanism of paracetamol?
Inhibits only a specific COX (localised to the CNS) to produce analgesic and antipyretic effects due to inhibition of prostaglandin synthesis in the CNS
There is an absence of an effect on the inflammatory processes underlying rheumatic disease
What is paracetamol used for?
Acts as an analgesic, not an anti-inflammatory.
It inhibits specific COX to produce analgesic and antipyretic effects only. There is an absence of an effect on inflammatory processes underlying rheumatic disease.
Why do COX inhibitors have the greatest effect on prostaglandin secretion by platelets?
Platelets have NO nucleus
Cannot resynthesise COX
Becomes irreversibly blocked
Which cells produce prostaglandins?
Endothelial cells
Platelets
In degranulation reactions
Name a non-steroidal anti-inflammatory drug?
Cyclooxygenase inhibitors (COX)
How do NSAIDs and corticosteroids work to treat rheumatoid arthritis?
Both reduce production of prostanoids for inflammatory signalling (weakly by NSAIDs, strongly by corticosteroids)
What is the mechanism of action of steroids?
They modulate gene expression and reduce the activity of phospholipase A2 which in turn reduces the production of prostaglandins, leukotrienes and platelet activating factor.
What are steroids used for?
Allergic conditions including asthma
Give examples of corticosteroids
Dexamethasone, hydrocortisone
What are the adverse effects of steroids?
*Immune depression increasing the susceptibility to viral infections
*Hypertension via its effect on fluid and electrolyte balance
*Bone resorption (osteoporosis); diabetes; peptic ulcers; thickening of the skin
How can corticosteroids cause bone resorption (osteoporosis)?
They decrease the function of osteoblasts directly, plus indirectly via inhibiting insulin-like growth factor I expression
–> inhibition of bone formation, osteoporosis
How can corticosteroids cause hypertension?
They can overstimulate the mineralocorticoid receptor –> leading to sodium and thus water retention in the kidney
–> volume expansion, increase in BP
How can corticosteroids cause immune depression?
Following reduction of PLA2 there can be further systematic anti-inflammatory responses that make the individual immunosuppressed
*also upregulate production of TGF-β and IL-1β for further, systemic anti-inflammatory responses
How do corticosteroids treat asthma?
Block negative IL-4/5 signalling to relax inflamed lung tissue and reduce bronchoconstriction, reduce mucus secretion
For histamine, summarise:
- Where it is released from
- How it is stored
- Receptors it acts on
- Actions
- Released from mast cells
- Stored in granules with heparin
- Acts via histamine receptors -> H1-H4
- Actions:
- Increased vascular permeability (H1)
- Smooth muscle cell contraction (H1)
- Vasodilatation (H1)
- Cardiac stimulation (H2)
- Stimulation of gastric secretion (H2)
What is chlorpheniramine?
Anti-histamine
What are the limitations of chlorpheniramine?
Poorly selective for H1
- can affect CNS histamine neurotransmitter, –> drowsiness
- can affect gastric H1 –> decreased stomach acid
Also not useful for non-allergic inflammatory responses
What is chlorpheniramine used to treat?
Allergies, anaphylaxis
What is the mechanism of chlorpheniramine?
H1 antagonist
Reduces histamine inflammatory effects from mast cells
What are two main drugs used to treat anaphylaxis?
Antihistamines - address root cause
Adrenaline - oppose hypotensive shock
What is anaphylaxis?
A severe allergic reaction due to mass mast cell degranulation
What does mass mast cell degranulation lead to in anaphylaxis?
Hypersensitivity reactions:
- Bronchiolar constriction
- Vascular leak
- Blood pressure drop, shock
Which four main therapies are used to treat rheumatoid arthritis?
- Aspirin (/other NSAIDs)
- Corticosteroids
- DMARDs: disease-modifying anti-rheumatic drugs
- Therapeutic antibodies
What are DMARDS?
Disease modifying anti-rheumatic drugs. They are immunosuppressants that depress the production of immune cells. (e.g. methotrexate)
What is the mechanism of DMARDS action?
Diff DMARDs interfere with diff critical pathways in inflammatory cascade
Over time depress immune response - relieve joint inflammation
How long does the full effect of DMARDs take to build up?
Several months
How do NSAIDs and corticosteroids work to treat rheumatoid arthritis?
Both reduce production of prostanoids for inflammatory signalling (weakly by NSAIDs, strongly by corticosteroids)
How do therapeutic antibodies treat rheumatoid arthritis?
They more specifically target the cytokines involved and reduce the persistent joint inflammation
Which cytokines might RA therapeutic antibodies target?
IL-6, TNF, IL-1
What is rheumatoid arthritis?
An autoinflammatory disorder affecting joints
What is Rituximab?
anti-lymphocyte monoclonal antibody causing B lymphocyte lysis used to treat rheumatoid arthritis.
What is abatacept?
An Ig-CTLA-4 fusion protein that interferes with the immune activity of T-cells. Used in the treatment of rheumatoid arthritis.
