When does inflammation occur?
Occurs when immunologically competent cells are activated in response to injurious or noxious stimulus (foreign organisms, antigenic substances, physical injury, etc)
Is inflammation beneficial or deleterious?
BOTH - May be beneficial (healing, essential for survival) or deleterious (asthma, rheumatoid arthritis)
What are the classic inflammatory symptoms?
REDNESS (rubor)
SWELLING (tumor)
HEAT (calor)
PAIN (dolor)
What cellular and molecular changes do we see during inflammation?
- Transient local vasodilation
- Increased capillary permeability with exudation
- Activation of numerous molecular inflammatory mediators
- Increased stimulation of mast cells
- Infiltration of leukocytes
- Activation of phagocytosis
- Tissue degeneration and fibrosis
What molecular inflammatory mediators will we see?
- Kinins (bradykinin)
- Neuropeptides (substance P)
- Vasoactive amines (histamine, 5HT)
- Arachodonic acid metabolites (cyclooxygenase (prostaglandin, thromboxanes, prostacyclin) and lipoxins and leukotrienes)
- Cytokines (TNF-alpha)
- Oxygen free radicals
- Proteases
What is the general therapeutic strategy of inflammation
- Relief of pain
- Delay or arrest of disease process
What are the typical pharmacologic approaches to inflammation?
- NSAIDs***
- Glucocorticoids
- DMARDS
- Opioids and other analgesics
What are the functions of NSAIDs?
- Analgesia (reduce pain)
- Antipyretic (reduce fever)
- Anti-inflammatory
What is the primary target of NSAIDs?
Primary target: Prostaglandin production via cyclooxygenases COX-1 and COX-2
Is acetaminophen an NSAID?
Acetaminophen is NOT an NSAID
- It does have analgesic and antipyretic properties though
What are the “main players” of inflammatory prostaglandins?
- PGE2
- PGI2
What is the function of PGE2 and PGI2 prostaglandins?
- Increased edema and vascular permeability
- Modulation of lymphocyte function
What do the two COX isozymes do?
Convert arachidonic acid to prostaglandins
What are the two COX isozymes?
COX-1 and COX-2
What is the function of COX-1?
- Constitutively active and expressed
- Widely distributed in the body
- “Housekeeping” function such as synthesizing prostaglandins in the stomach mucosa to protect the stomach lining from gastric acid
What is the function of COX-2?
- Inducible in times of inflammation
- Functions to produce inflammatory molecules
- COX-2 is expressed in vascular endothelium (produces PGI2)
- Renal COX-2 is essential for normal functioning
What is the arachidonic acid pathway?
A pathway that begins with injury and exposure of cell membrane phospholipids which activates arachidonic acid and ends in two different inflammatory pathways
What are the two inflammatory pathways?
Pathway 1
- Airway inflammation
- Asthma
- Allergic rhinitis
Pathway 2
- Inflammation
- Pain
- Fever
What pathway do COX-1 and COX-2 work on?
The inflammation, pain and fever pathway
- This is also the pathway that NSAIDs work on
- NSAIDS work by inhibiting COX-1/2 and therefore inhibiting prostaglandin synthesis
Reminder of what COX-1 and COX-2 are responsible for again…
COX-1
- GI tract (gastric mucosa)
- Constitutive
- Protective
COX-2
- Inducible
- Inflammatory
NSAIDs are either non-selective or selective. Which ones are in each category?
Non-selective
- Acetylsalicylic Acid (Aspirin)
- Ibuprofen
- Indomethacin
COX-2 Selective
- Celecoxib
What are the common clinical uses for NSAIDs?
- Pain (analgesic)
- Fever (antipyretic)
- Inflammation (arthritis)
- Antithrombotic
- Miscellaneous uses
Describe the use of NSAIDs for pain (analgesia)
- mild to moderate pain
- alone or in combination (caffeine)
Describe the use of NSAIDs for fever (antipyretic)
- aspirin & other PG synthesis inhibitors NOT recommended as fever reducers in children or in viral diseases (acetaminophen can be used)
- May be used in adults
