Anti-Inflammatories

Question 1

What characterizes each of the following three phases of the inflammatory response? 1. acute, transient; 2. delayed, subacute; 3. chronic proliferative

Answer 1

1. local vasodilation, increased capillary permeability
2. infiltration of leukocytes and phagocytic cells
3. tissue degeneration and necrosis

Question 2

Name the four classes of the major inflammatory mediators.

Answer 2

histamine, kinins, cytokines, eicosanoids

Question 3

Actions of histamine in the inflammatory response?

Answer 3

capillary dilation, increases post-capillary venule permeability, itching from sensitizing primary sensory neurons

Question 4

Effects of the kinins? Are there drugs to counter act these effects?

Answer 4

acute pain from excitation of sensory neurons; chronic effects due to capillary dilation, permeability, stimulation of PLA2 to release arachidonic acid
no drugs!!

Question 5

Effects of IL-1?

Answer 5

produced mostly by macrophages; increases eicosanoid synthesizing enzymes, collagenase, and adhesion molecule expression; regulates B and T cells; induces fever

Question 6

Effects of IL-8 and chemokines?

Answer 6

chemotaxis

Question 7

Effects of TNF?

Answer 7

regulates production of other cytokines; induces fibrosis and tissue catabolism

Question 8

What molecules are derived from arachidonic acid? What types of enzymes mediate this?

Answer 8

lipoxygenase - leukotrienes

cyclooxygenase - prostaglandins, prostacyclins, thromboxanes

Question 9

COX-1 is produced constitutively. What is it involved in?

Answer 9

gastric cytoprotection, platelet aggregation, renal blood flow autoregulation, initiation of parturition

Question 10

When is COX-2 induced?

Answer 10

During inflammation - produce prostaglandins locally

Question 11

Source and actions of PGE2?

Answer 11

macrophages; protection of gastric mucosa, vasodilation, hyperalgesia

Question 12

Source and action of PGD2?

Answer 12

mast cells; vasodilation, inhibition of platelet activation

Question 13

Action of PGF2alpha?

Answer 13

bronchoconstriction

Question 14

Source and action of PGI2 (prostacyclin)?

Answer 14

endothelial cells; vasodilation, inhibitions of platelet activation

Question 15

Source and action of TXA2?

Answer 15

platelets; vasoconstriction, bronchoconstriction, platelet aggregation

Question 16

Is aspirin reversible or irreversible? What enzymes does it act on?

Answer 16

irreversible inhibitor (via acetylation) of COX-1 and COX-2

Question 17

How is aspirin metabolized? What does its major metabolic product do?

Answer 17

metabolized in liver to salicylic acid (and then others that are excreted in urine); salicylic acid cannot acetylate but can reversibly inhibit COX-1&2

Question 18

What are the major four effects of aspirin? Which occurs at the lowest dose?

Answer 18

anti-platelet (lowest dose), anti-inflammatory (highest dose), analgesic, antipyretic

Question 19

How does aspirin act as an analgesic? What is it therefore not helpful with?

Answer 19

inhibits eicosanoid sensitization of pain receptors; not effective in alleviating visceral pain

Question 20

What are the potential adverse effects of aspirin?

Answer 20

GI irritation (lose cytoprotection), nephrotoxicity (decreases renal blood flow), bleeding and anemia (prolongs bleeding time), hepatotoxicity, hypersensitivity reactions, salicylate toxicity

Question 21

Action and use of diflunisal?

Answer 21

competitive COX-1/2 inhibitor; analgesic and weak antipyretic effects, longer half-life, fewer GI side effects and less effect on platelets
OA, cancer bone pain, pain post dental extraction, postepisiotomy pain

Question 22

What are the major effects of acetaminophen?

Answer 22

analgesic and anti-pyretic mainly; weak anti-inflammatory (poor inhibition ability in presence of peroxides at inflammatory site, disproportionate effect in brain?)

Question 23

How is acetaminophen metabolized? What threat does this pose?

Answer 23

major - conjugation with sulfate and glucuronide
minor - P450 with toxic intermediate; this pathway becomes important in setting of overdose - potentially fatal hepatic necrosis

Question 24

What can be used to treat acetaminophen overdose?

Answer 24

acetylcysteine (MUCOMYST)

Question 25

What is indomethacin used to treat? What class does it belong to?

Answer 25

indole; used for RA, ankylosing spondylitis, OA, acute gout, ductus arteriosus closure (only use in children!)

Question 26

Side effects of indomethacin?

Answer 26

usual for NSAIDs, sometimes thrombocytopenia, aplastic anemia, severe frontal HA

Question 27

Name the propionic acid derivatives/analogs.

Answer 27

ibuprofen, fenoprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin

Question 28

What is naproxen useful to treat? How often does it need to be taken?

Answer 28

arthritis, twice a day treatment

Question 29

What are the propionic acid derivatives generally useful for? How do they compare to aspirin?

Answer 29

rheumatic disorders, OA, ankylosing spondylitis, postpartum pain, dysmennorheal pain, oral/ophthalmic surgery
usual side effects, better tolerated than aspirin

Question 30

Class and use of piroxicam.

Answer 30

enolic acid; long-term Tx of RA, OA because very long half-life allows once a day dosing
also used in akylosing spondylitis, acute musculoskeletal and acute gout
similar side effects to other NSAIDs

Question 31

What’s different about ketorolac compared to other NSAIDs?

Answer 31

injectable im; used for post-op pain; single dose efficacy equal to opiods

Question 32

How are the coxibs different than traditional NSAIDs?

Answer 32

selectively inhibit COX-2; less GI toxicity, no impact on platelet aggregation
can’t use in pts with heart problems or pregnancy