Inflammation Flashcards
What was the origin of aspirin? What is its effect?
Willow bark isolate; COX1/2 non-selective inhibitor
What is the target of NSAIDs?
COX 1 and COX 2
How many classes of NSAID are we looking at (there are more)?
Seven
What is the mechanism of aspirin’s action on COX?
Irreversible inhibtion via acetylation
What is the effect of acetylsalicylate’s byproduct following COX inhibition?
The remaining salicylate has a 30 minute half life as a competitive inhibitor
What are the therapeutic effects of acetylsalicylic acid?
Anti-inflammatory, analgesic, antipyretic, and anti-clotting (TxA2 inhibition in platelet aggregation)
What are the adverse effects of aspirin (and most NSAIDs)?
GI irritiation (PGE2 and PGI2 inhibition), Nephrotoxicity (too much use, or older patients), Bleeding/anemia (overuse with systemic or GI bleeding), Hypersensitivity reaction (0.2%), Salicylate toxicity (overdose, repiratory alkylosis, metabolic acidosis, coma, and death)
What is the MOA of diflunisal?
Competitive inhibition of COX1 and COX2
How do tolerability and half life of difluisal and aspirin compare?
Diflunisal is better at both; 3x potency in muscle
What is the MOA of acetaminophen on COX?
Competitive inhibition of COX1 and COX2 EXCEPT in presence of peroxides or within the CNS
How is acetominophen metabolized?
Phase 1 to excrete through the kidney; hepatotoxic by Phase 2 reaction in overdose that depletes glutathione
What is the antiinflammatory action of acetominophen? Why?
None - not yet known
When is acetominophen specifically used?
When a patient is intolerant to aspirin
What are the indole compounds? What class are they in?
Sulindac and Indomethacin; NSAIDs
What was the first use of indomethacin?
Gout
How do indole compounds compare to aspirin in potency and side effects?
10x the potency, but more and more serious side effects in chronic use
What is the most common NSAID?
Ibuprofen
What are the propionic acid derivatives? What class of drug are they in?
Ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin, and flurbiprofen; NSAIDs
How do effectiveness and tolerability of Propionic acid derivatives compare to aspirin?
Both are better
What is the general 1/2 life of propionic acid derivatives? What two differ?
Generally 1-2 hours, Naproxen=13hrs and Oxiprozin=50hrs
What is the major enolic acid compound? What makes it good for MSK disorders?
Piroxicam for RA or OA or other inflammatory disorders; long (45hr) half life
What is the use of ketorolac? What class is it in?
IM injection in post-op or topical for the eye; NSAID Heteroaryl Acetic Acid
What are the coxibs?
COX2 inhibitors: Celecoxib and Etoricoxib
How do the coxibs compare to general COX1/2 inhibitors in terms of efficacy and safety?
The lack of COX1 activity means no cardioprotective effects; some have high risk of MI and stroke and have been withdrawn; fewer GI side effects; Effecacy for anti-inflammatory, antipyretic and analgesic properties are similar to other NSAIDs
What is the structural difference between coxibs and other NSAIDs?
Coxibs are larger to sterically hinder them from acting on the smaller COX1 active site
What pathways (broader than COX1vsCOX2) are affected bt NSAIDs?
Prostaglandin, prostacyclin, and thromboxane synthesis; not leukotriene synthesis
What is the only irrevesible NSAID?
Aspirin
What are the three phases of inflammation?
Acute transient (local vasodilation/permeability), delayed subacute (infiltration by leukocytes), and chronic proliferative (tissue degeneration and necrosis)
What is the effect of histamine?
local capillary dilation, edema due to permeability, and itching due to primary sensory neuron sensitization
What are the effects of kinins?
pain from acute primary sensory neuron excitation and chronic arachidonic acid relase with pcv dilation
When are COX1 and COX2 induced/active?
COX1 is constitutive in gastric/platelet/renal blood flow/parturition initiation and COX2 is inflammatory
Match the prostaglandin/thromboxane with the cell source and major action: PGE2
Macrophages; protection of gastric mucosa, vasodilation, hyperalgesia
What are eicosanoids?
arachidonic acid metabolites
What is the source of arachidonic acid in inflammation? How is this relevant to injury response?
Arachidonic acid is derived from cell membrane phospholipids either during the injury (chemical/physical) process or within the kinin-mediated extracellular milieu
What is the product of lipoxygenase metabolism of arachidonic acid?
leukotrienes
What are the products of cyclooxygenase metabolism of arachidonic acid?
prostaglandins, prostacyclins, and thromboxanes
Match the prostaglandin/thromboxane with the cell source and major action: PGD2
Mast cells; vasodilation and inhibition of platelet activation
Match the prostaglandin/thromboxane with the cell source and major action: PGF2a
Mast cells; bronchoconstriction
Match the prostaglandin/thromboxane with the cell source and major action: PGI2 (prostacyclin)
Endothelial cells; vasodilation and inhibition of platelet activation
Match the prostaglandin/thromboxane with the cell source and major action: TxA2 (thromboxane)
Platelets; vasoconstriction, bronchoconstriction, and platelet aggregation
