Flashcards in 15 Prostanoids & NSAIDS Deck (92):
What are the general reactions catalyzed by phospholipase A2 (PLA-2), cyclooxygenase, and lipoxygenase?
Membrane phospholipids(eg phosphatidylcholine) -> C-20:4 (usually arachidonic acid) by PLA-2
C-20:4 -> prostanoids by cyclooxygenase
C-20:4 -> leukotrienes by lipoxygenase
What are eicosanoids?
prostanoid and leukotriene derivatives of C-20 fatty acids
Generally what is the function & classification of a cyclooxygenase enzyme?
One that has both cyclooxygenase and peroxidase activity - in the class PGH synthase
Convert arachidonic acid to prostaglandin H (PGH2)
Generally, how do the effects of prostacyclin (PGI2) and thromboxane (TXA2) relate to one another?
The are opposite effects.
Prostacyclin has anti-inflammatory effects
Thromboxane has pro-inflammatory effects
Which prostanoid has a longer half life?
In general, what length of half-lives do prostanoids have?
Are their effects local or systemic because of this?
Are they stored?
Short half lives
No, not stored (synthesis-dependent, membrane permeable, and passively released)
What are the sites of synthesis of each type of prostanoid?
PGE2 & PGF2alpha - most tissues
PGI2 - endothelium and vascular smooth muscle
TXA2 - platelets and macrophages
What prostanoid(s) lead(s) to hyperalgesia?
Type 1 & 3 prostanoids are often less/more active that type 2 and are pro/anti-inflammatory?
Eg. diets rich in alternative fatty acids could reduce inflammatory and platelet effects of prostanoids
of COX 1 & COX 2:
Which is inducible? Which is constitutively expressed?
Cox 1 - not inducible, constitutively expressed
Cox 2 - highly inducible
of COX 1 & COX 2:
What is the distribution in tissues?
Cox 1 - all except RBCs
Cox 2 - all except RBCs and platelets
Prostaglindin H (PGH) is the same whether made by COX 1 or COX 2.
Prostanoid products of equimolar levels of COX-1 & COX-2 are equivalent in quantity and quality
of COX 1 & COX 2:
What substrate(s) are they selective for?
Which is narrow spectrum?
Cox 1 is narrow spectrum - arachidonate
Cox 2 is broader spectrum - arachdisonate, linolenic, unsaturated C22 FAs
What effect does prostacyclin (PGI2) have on blood vessels?
dilate blood vessels
What effect does prostacyclin (PGI2) have on smooth muscle (except in vessels)? What specific location(s) of smooth muscle?
relax: bronchial, uterine
What effect does prostacyclin (PGI2) have on platelets?
What effect does prostacyclin (PGI2) have on pain?
What effect does thromboxane (TXA2) have on blood vessels?
constrict blood vessels
What effect does thromboxane (TXA2) have on smooth muscle (except in vessels)? What specific location(s) of smooth muscle?
What effect does thromboxane (TXA2) have on platelets?
What effect does thromboxane (TXA2) have on pain?
What effect does PGE2 have on blood vessels?
Gs -> dilate
Gq -> none
What effect does PGE2 have on smooth muscle (except in vessels)? What specific locations of smooth muscle?
Gs -> relax GI circular & bronchial
Gq -> constrict GI longitudinal & uterine
What receptor does thromboxane (TXA2) bind to?
What receptor does prostacyclin (PGI2) bind to?
What effect does PGE2 have on platelets?
What effect does PGE2 have on pain?
Gs -> hyperalgesia
Gq -> none
At steady state for most cells, which enzyme is more predominate? COX-1 or COX-2?
Is COX-1 or COX-2 responsible for most "house-keeping" levels of prostanoids in tissues? What organ is the exception?
kidney where COX-2 has a role
Elevated prostanoid production associated with inflammation is mostly due to _______? (COX-1 or 2?)
Which enzyme (COX-1 or 2) is responsible for hyperalgesia?
During inflammatory pain, COX-2 is induced in sensory nerve terminals. Hyperalgesic prostaglandins are generated (PGE2 & PGI2).
What drug class targets hyperalgesia (reducing inflammatory pain)?
What process is responsible for fever?
IL-1 & TNF-alpha increase COX-2 expression and PGE2 production in the OVLT (organum vasculosum laminae - part of the pre-optic hypothalamus)
What drug class targets fever?
Which enzyme (COX-1 or 2) is in platelets?
What drug class inhibits platelet COX enzyme?
What specific drug irreversibly inhibits?
What is the outcome for aspirin inhibition in a single platelet?
No TXA2 made for the life of the individual platelet
Inhibitions of which enzyme (COX-1 or 2) may increase platelet aggregation? Mechanism?
COX-2 contributes to PGI2 production in endothelial cells
Which enzyme (COX-1 or 2) and prostanoid (PGE2/PGI2/TXA2) contributes to decreasing acid production and increasing mucus formation in the GI tract?
PGE2 in epithelium
PGI2 in vessels
What does inhibition of COX-1 do to the GI tract?
increases acid production and decreases mucus production; lysis of epithelium -> ulcers
What role does COX-2 play in the GI tract?
GI infections or inflammation induces COX-2
What drug can protect against COX-1 inhibition in the GI tract?
What effect(s) do COX-1 &/or 2 have in the kidney? A patient with what problems would be of concern for COX inhibition?
Both COX-1 & 2 increase renal blood flow
Critical for maintenance of renal blood flow in compromised patients (CHF, diuretic use, volume depletion, renal insufficiency)
Which enzyme(s) (COX-1 or 2) are involved in the uterine cycle?
Both COX-1 & 2 present at various stages of the menstrual cycle and pregnancy
Which prostanoids (PGE2/PGI2/TXA2) contribute to functions of the uterus? What function?
PGE2 & PGF2alpha contract uterine smooth muscle
PGI2 relaxes uterine smooth muscle
What effect do COX inhibitors have on the uterus?
can delay premature labor and can reduce dysmenorrhea (menstrual cramps)
What are the 2 classes of prostaglandin effects?
Prostaglandin class 1 - "house-keeping" physiologic effects
class 2 - inflammation
What are the 3 individual functions of class 2 prostaglandins in relation to inflammation?
pain (hyperalgesia) - analgesic action
fever - pyretic action
cell production of, and their response to, some mediators of inflammation
COX-1 prostaglandin products are largely associated with which class of prostaglandin?
COX-1 prostaglandin products largely associated with class 1
COX-2 prostaglandin products largely associated with class 2
What is the importance of the acetyl group in aspirin?
It is irreversibly transferred to COX-1 & COX-2 (acetylation)
What is the chemical structure name of aspirin?
What is the product after aspirin irreversibly inhibits the COX enzymes?
acetyl salicylic acid -> salicylic acid
Where are the metabolites of aspirin excreted?
At what mg total does elimination of aspirin saturate?
What does this do to the half life of aspirin in the body?
increases from 3-5 hours to 12-16 hours
What is the selectivity of aspirin for COX enzymes?
Selectivity = 4.4
You need a 4x higher concentration to inhibit of COX-2 relative to what you need to inhibit COX-1
What is the formula for COX selectivity?
IC50 COX-2 / IC50 COX-1
IC50 COX-1 = 1.7 micromolar
OC50 COX-2 = 7.5 micromolar
7.5/1.7 micromolar = 4.4
What effect does aspirin have on COX enzymes?
What about its metabolite?
aspirin acetylates and irreversibly inhibits COX-1 & 2
salicylic acid is a reversible inhibitor of COX-1 & 2
What class are these drugs in?
diclofenac with misoprostol
nonselective COX inhibitors (NSAIDs)
What class are these drugs in?
COX-2 selective inhibitors (NSAIDs)
What does a drug with a selectivity of much less than 1 indicate for COX enzyme inhibition?
Selective inhibition of COX-2 and (for the most part) not COX-1
Which NSAID has a drastically high selectivity for COX-1?
What is the common usage for ketorolac?
What is the common usage for indomethacin?
high frequency of intolerance
What is the common usage for aspirin?
What is the common usage for naproxen?
What is the common usage for ibuprofen?
What is the common usage for diclofenac?
What is the mechanism of anti-inflammatory effects of NSAIDs?
block production of prostanoids by inhibition of COX
mainly COX-2 responsible for inflammation
What is the mechanism of antipyretic effects of NSAIDs? When will NSAIDs not influence body temperature?
inhibit PGE2 production in the CNS stimulated by IL-1 & TNF-alpha. reduced peripheral prostanoids may also reduce IL-1 expression from macrophages
will NOT influence body temperature when elevated by non-inflammatory factors
1- What is the mechanism of analgesic effects of NSAIDs?
2- What are NSAIDs not effective against?
1- reduction of PGE2 and PGI2-induced hyperalgesia
general reduced inflammation
2- not effective against non-inflammatory pain
What class of drugs is usually more efficacious than NSAIDs in analgesic effects?
What are the effects of NSAIDs on platelets? What is the result?
inhibition of platelet COX-1 -> increased bleeding time
What effect does aspirin have on platelets? Why?
aspirin acetylation of COX-1 is irreversible, so inhibition lasts the life of the platelet (5-7 days)
What is the mechanism of gastric effects of NSAIDs?
Reduced PGE2 and PGI2 lessens gastric protection -> can induce peptic ulcers
What are the 5 therapeutic applications of NSAIDs?
- analgesia (mild to moderate pain)
- mild to moderate inflammation due to injury/stress
- rheumatoid and osteoarthritis (analgesia and chronic inflammation reduction)
- cardiovascular prophylaxis (aspirin ONLY)
What is Salicylism?
hypersensitivity to aspirin
hyperventilation, tinnitus (ringing ears), vertigo, emesis, sweating
What is Reye's Syndrome?
acute encephalopathy and fatty liver degeneration linked with aspirin use in children with viral illness
associated with viral disease and antiviral vaccines
NSAIDs cause what 3 major adverse GI effects? What percentage of chronic NSAID users may require treatment?
Dyspepsia - upper abdominal pain, bloating, nausea (35% chronic NSAID users may require treatment)
Ulcers - gastric ulcer more frequent than duodenal ulcer (16% chronic NSAID users)
GI bleeding - anemia
What condition is associated with these risk factors?
chronic NSAID use
concomitant steroids, other NSAIDs
H. pylori infection
What 3 drug classes can help prevent the adverse GI effects of NSAIDs?
Proton pump inhibitors
Patients with what problems are at risk for renal complications with NSAID use?
-Patients chronically taking NSAID combinations or an NSAID plus acetaminophen
What are the adverse renal effects from NSAID use?
Renal vasoconstriction, water and salt retention -> edema, hypertension, renal failure
Acute renal failure (0.5-1% of chronic NSAID users)
What are the adverse effects of NSAID platelet effects?
increased surgical bleeding
potentiates GI bleeding resulting from gastric erosion ulceration
What are the effects of COX-2 selective NSAIDs? How are they different from the NSAID class as a whole?
Selectively inhibits COX-2 compared to COX-1 (more than 10-fold)
Retain the COX-2 specific effects:
-renal toxicity effects
Lack the COX-1 specific effects:
-platelet and cardio-protective effects
-GI side effects
COX-2 selective NSAIDs are mainly used to treat what 2 problems?
What are the specific effects of acetaminophen?
-relatively non-selective COX inhibitor
-activity substantially reduced in presence of peroxides (often elevated at sites of inflammation)
-lacks significant effects on platelets, cardiovascular, and GI systems
-analgesic and antipyretic effects equivalent to aspirin
What is acetaminophen used to treat? (analgesic/antipyretic/anti-inflammatory/etc)
Analgesic & antipyretic only
negligible anti-inflammatory activity
What organ toxicity is a concern with acetaminophen overdose?
What is the COX selectivity of celecoxib?
10-20x more selective for COX-2 than 1
What is the COX selectivity of rofecoxib?
200x more selective for COX-2 than 1
What are the results from clinical trials of COX-2 selective NSAIDs:
Still on the market?
increased incidence of cardiovascular events: hypertension, heart attack, stroke (associated with long-term continuous use)
rofecoxib - withdrawn
celecoxib - remains available despite evidence of risk
Data shows that ALL NSAIDs appear to be associated with some level of increased risk of cardiovascular event.
False. all except aspirin