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1 Pharm Unit > 15 Prostanoids & NSAIDS > Flashcards

15 Prostanoids & NSAIDS Flashcards

1
Q

What are the general reactions catalyzed by phospholipase A2 (PLA-2), cyclooxygenase, and lipoxygenase?

A

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

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2
Q

What are eicosanoids?

A

prostanoid and leukotriene derivatives of C-20 fatty acids

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3
Q

Generally what is the function & classification of a cyclooxygenase enzyme?

A 
One that has both cyclooxygenase and peroxidase activity - in the class PGH synthase
Convert arachidonic acid to prostaglandin H (PGH2)
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4
Q

Generally, how do the effects of prostacyclin (PGI2) and thromboxane (TXA2) relate to one another?

A

The are opposite effects.
Prostacyclin has anti-inflammatory effects
Thromboxane has pro-inflammatory effects

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5
Q

Which prostanoid has a longer half life?

A

Prostacyclin (PGI2)

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6
Q

In general, what length of half-lives do prostanoids have?
Are their effects local or systemic because of this?
Are they stored?

A

Short half lives
Local activity
No, not stored (synthesis-dependent, membrane permeable, and passively released)

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7
Q

What are the sites of synthesis of each type of prostanoid?

A

PGE2 & PGF2alpha - most tissues
PGI2 - endothelium and vascular smooth muscle
TXA2 - platelets and macrophages

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8
Q

What prostanoid(s) lead(s) to hyperalgesia?

A

PGI2

PGE2

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9
Q

Type 1 & 3 prostanoids are often less/more active that type 2 and are pro/anti-inflammatory?

A

Less active
Anti-inflammatory
Eg. diets rich in alternative fatty acids could reduce inflammatory and platelet effects of prostanoids

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10
Q

of COX 1 & COX 2:

Which is inducible? Which is constitutively expressed?

A

Cox 1 - not inducible, constitutively expressed

Cox 2 - highly inducible

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11
Q

of COX 1 & COX 2:

What is the distribution in tissues?

A

Cox 1 - all except RBCs

Cox 2 - all except RBCs and platelets

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12
Q 
T/F
Prostaglindin H (PGH) is the same whether made by COX 1 or COX 2.
A

True

Prostanoid products of equimolar levels of COX-1 & COX-2 are equivalent in quantity and quality

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13
Q

of COX 1 & COX 2:
What substrate(s) are they selective for?
Which is narrow spectrum?

A

Cox 1 is narrow spectrum - arachidonate

Cox 2 is broader spectrum - arachdisonate, linolenic, unsaturated C22 FAs

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14
Q

What effect does prostacyclin (PGI2) have on blood vessels?

A

dilate blood vessels

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15
Q

What effect does prostacyclin (PGI2) have on smooth muscle (except in vessels)? What specific location(s) of smooth muscle?

A

relax: bronchial, uterine

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16
Q

What effect does prostacyclin (PGI2) have on platelets?

A

inhibits aggregation

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17
Q

What effect does prostacyclin (PGI2) have on pain?

A

hyperalgesia

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18
Q

What effect does thromboxane (TXA2) have on blood vessels?

A

constrict blood vessels

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19
Q

What effect does thromboxane (TXA2) have on smooth muscle (except in vessels)? What specific location(s) of smooth muscle?

A

constrict: bronchial

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20
Q

What effect does thromboxane (TXA2) have on platelets?

A

stimulates aggregation

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21
Q

What effect does thromboxane (TXA2) have on pain?

A

none

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22
Q

What effect does PGE2 have on blood vessels?

A

Gs -> dilate

Gq -> none

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23
Q

What effect does PGE2 have on smooth muscle (except in vessels)? What specific locations of smooth muscle?

A

Gs -> relax GI circular & bronchial

Gq -> constrict GI longitudinal & uterine

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24
Q

What receptor does thromboxane (TXA2) bind to?

A

Gq

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25
Q

What receptor does prostacyclin (PGI2) bind to?

A

Gs

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26
Q

What effect does PGE2 have on platelets?

A

none

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27
Q

What effect does PGE2 have on pain?

A

Gs -> hyperalgesia

Gq -> none

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28
Q

At steady state for most cells, which enzyme is more predominate? COX-1 or COX-2?

A

COX-1

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29
Q

Is COX-1 or COX-2 responsible for most “house-keeping” levels of prostanoids in tissues? What organ is the exception?

A

COX-1

kidney where COX-2 has a role

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30
Q

Elevated prostanoid production associated with inflammation is mostly due to _______? (COX-1 or 2?)

A

COX-2

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31
Q

Which enzyme (COX-1 or 2) is responsible for hyperalgesia?

A

During inflammatory pain, COX-2 is induced in sensory nerve terminals. Hyperalgesic prostaglandins are generated (PGE2 & PGI2).

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32
Q

What drug class targets hyperalgesia (reducing inflammatory pain)?

A

NSAIDs

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33
Q

What process is responsible for fever?

A

IL-1 & TNF-alpha increase COX-2 expression and PGE2 production in the OVLT (organum vasculosum laminae - part of the pre-optic hypothalamus)

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34
Q

What drug class targets fever?

A

NSAIDs

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35
Q

Which enzyme (COX-1 or 2) is in platelets?

A

COX-1

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36
Q 
What drug class inhibits platelet COX enzyme?
What specific drug irreversibly inhibits?
A

NSAIDs

Aspirin

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37
Q

What is the outcome for aspirin inhibition in a single platelet?

A

No TXA2 made for the life of the individual platelet

38
Q

Inhibitions of which enzyme (COX-1 or 2) may increase platelet aggregation? Mechanism?

A

COX-2 contributes to PGI2 production in endothelial cells

39
Q

Which enzyme (COX-1 or 2) and prostanoid (PGE2/PGI2/TXA2) contributes to decreasing acid production and increasing mucus formation in the GI tract?

A

COX-1
PGE2 in epithelium
PGI2 in vessels

40
Q

What does inhibition of COX-1 do to the GI tract?

A

increases acid production and decreases mucus production; lysis of epithelium -> ulcers

41
Q

What role does COX-2 play in the GI tract?

A

GI infections or inflammation induces COX-2

42
Q

What drug can protect against COX-1 inhibition in the GI tract?

A

misoprostol

43
Q

What effect(s) do COX-1 &/or 2 have in the kidney? A patient with what problems would be of concern for COX inhibition?

A

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)

44
Q

Which enzyme(s) (COX-1 or 2) are involved in the uterine cycle?

A

Both COX-1 & 2 present at various stages of the menstrual cycle and pregnancy

45
Q

Which prostanoids (PGE2/PGI2/TXA2) contribute to functions of the uterus? What function?

A

PGE2 & PGF2alpha contract uterine smooth muscle

PGI2 relaxes uterine smooth muscle

46
Q

What effect do COX inhibitors have on the uterus?

A

can delay premature labor and can reduce dysmenorrhea (menstrual cramps)

47
Q

What are the 2 classes of prostaglandin effects?

A 
Prostaglandin class 1 - "house-keeping" physiologic effects
class 2 - inflammation
48
Q

What are the 3 individual functions of class 2 prostaglandins in relation to inflammation?

A

pain (hyperalgesia) - analgesic action
fever - pyretic action
cell production of, and their response to, some mediators of inflammation

49
Q 
COX-1 prostaglandin products are largely associated with which class of prostaglandin?
COX-2?
A 
COX-1 prostaglandin products largely associated with class 1
COX-2 prostaglandin products largely associated with class 2
50
Q

What is the importance of the acetyl group in aspirin?

A

It is irreversibly transferred to COX-1 & COX-2 (acetylation)

51
Q

What is the chemical structure name of aspirin?

What is the product after aspirin irreversibly inhibits the COX enzymes?

A

acetyl salicylic acid -> salicylic acid

52
Q

Where are the metabolites of aspirin excreted?

A

the urine

53
Q

At what mg total does elimination of aspirin saturate?

What does this do to the half life of aspirin in the body?

A

600mg

increases from 3-5 hours to 12-16 hours

54
Q

What is the selectivity of aspirin for COX enzymes?

A

Selectivity = 4.4

You need a 4x higher concentration to inhibit of COX-2 relative to what you need to inhibit COX-1

55
Q

What is the formula for COX selectivity?

A 
IC50 COX-2 / IC50 COX-1
eg aspirin: 
IC50 COX-1 = 1.7 micromolar
OC50 COX-2 = 7.5 micromolar
7.5/1.7 micromolar = 4.4
56
Q

What effect does aspirin have on COX enzymes?

What about its metabolite?

A

aspirin acetylates and irreversibly inhibits COX-1 & 2

salicylic acid is a reversible inhibitor of COX-1 & 2

57
Q 
What class are these drugs in?
aspirin
ibuprofen
naproxen
acetaminophen
diclofenac
diclofenac with misoprostol
indomethacin
ketorolac
A

nonselective COX inhibitors (NSAIDs)

58
Q

What class are these drugs in?
celecoxib
rofecoxib

A

COX-2 selective inhibitors (NSAIDs)

59
Q

What does a drug with a selectivity of much less than 1 indicate for COX enzyme inhibition?

A

Selective inhibition of COX-2 and (for the most part) not COX-1

60
Q

Which NSAID has a drastically high selectivity for COX-1?

A

ketorolac

61
Q

What is the common usage for ketorolac?

A

post-surgical analgesic

62
Q

What is the common usage for indomethacin?

A

Rx arthritis/anti-inflammatory

high frequency of intolerance

63
Q

What is the common usage for aspirin?

A

OTC analgesic/antipyretic

cardiovascular prophylaxis

64
Q

What is the common usage for naproxen?

A

OTC analgesic/antipyretic

Rx anti-inflammatory

65
Q

What is the common usage for ibuprofen?

A

OTC analgesic/antipyretic

66
Q

What is the common usage for diclofenac?

A

Rx arthritis/anti-inflammatory

67
Q

What is the mechanism of anti-inflammatory effects of NSAIDs?

A

block production of prostanoids by inhibition of COX

mainly COX-2 responsible for inflammation

68
Q

What is the mechanism of antipyretic effects of NSAIDs? When will NSAIDs not influence body temperature?

A

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

69
Q

1- What is the mechanism of analgesic effects of NSAIDs?

2- What are NSAIDs not effective against?

A

1- reduction of PGE2 and PGI2-induced hyperalgesia
general reduced inflammation
2- not effective against non-inflammatory pain

70
Q

What class of drugs is usually more efficacious than NSAIDs in analgesic effects?

A

opioids

71
Q

What are the effects of NSAIDs on platelets? What is the result?

A

inhibition of platelet COX-1 -> increased bleeding time

72
Q

What effect does aspirin have on platelets? Why?

A

aspirin acetylation of COX-1 is irreversible, so inhibition lasts the life of the platelet (5-7 days)

73
Q

What is the mechanism of gastric effects of NSAIDs?

A

Reduced PGE2 and PGI2 lessens gastric protection -> can induce peptic ulcers

74
Q

What are the 5 therapeutic applications of NSAIDs?

A
  • fever
  • 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)
75
Q

What is Salicylism?

Signs/symptoms?

A

hypersensitivity to aspirin

hyperventilation, tinnitus (ringing ears), vertigo, emesis, sweating

76
Q

What is Reye’s Syndrome?

A

acute encephalopathy and fatty liver degeneration linked with aspirin use in children with viral illness
associated with viral disease and antiviral vaccines

77
Q

NSAIDs cause what 3 major adverse GI effects? What percentage of chronic NSAID users may require treatment?

A

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

78
Q 
What condition is associated with these risk factors?
Age >65
chronic NSAID use
concomitant steroids, other NSAIDs
high dose
H. pylori infection
alcohol consumption
A

gastric ulcer

79
Q

What 3 drug classes can help prevent the adverse GI effects of NSAIDs?

A

H2-receptor antagonists
Proton pump inhibitors
Misoprostol

80
Q

Patients with what problems are at risk for renal complications with NSAID use?

A
  • CHF
  • Cirrhosis/ascites
  • Advanced age
  • Patients chronically taking NSAID combinations or an NSAID plus acetaminophen
81
Q

What are the adverse renal effects from NSAID use?

A

Renal vasoconstriction, water and salt retention -> edema, hypertension, renal failure
Acute renal failure (0.5-1% of chronic NSAID users)

82
Q

What are the adverse effects of NSAID platelet effects?

A

increased surgical bleeding

potentiates GI bleeding resulting from gastric erosion ulceration

83
Q

What are the effects of COX-2 selective NSAIDs? How are they different from the NSAID class as a whole?

A 
Selectively inhibits COX-2 compared to COX-1 (more than 10-fold)
Retain the COX-2 specific effects:
-anti-inflammatory effects
-antipyretic effects
-analgesic effects
-renal toxicity effects
Lack the COX-1 specific effects:
-platelet and cardio-protective effects
-GI side effects
84
Q

COX-2 selective NSAIDs are mainly used to treat what 2 problems?

A

osteoarthritis

rheumatoid arthritis

85
Q

What are the specific effects of acetaminophen?

A
  • 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
86
Q

What is acetaminophen used to treat? (analgesic/antipyretic/anti-inflammatory/etc)

A

Analgesic & antipyretic only

negligible anti-inflammatory activity

87
Q

What organ toxicity is a concern with acetaminophen overdose?

A

hepatotoxicity

88
Q

What is the COX selectivity of celecoxib?

A

10-20x more selective for COX-2 than 1

89
Q

What is the COX selectivity of rofecoxib?

A

200x more selective for COX-2 than 1

90
Q

What are the results from clinical trials of COX-2 selective NSAIDs:
Adverse effects?
Still on the market?

A

Adverse effects:
increased incidence of cardiovascular events: hypertension, heart attack, stroke (associated with long-term continuous use)

On market?
rofecoxib - withdrawn
celecoxib - remains available despite evidence of risk

91
Q

T/F

Data shows that ALL NSAIDs appear to be associated with some level of increased risk of cardiovascular event.

A

False. all except aspirin

92
Q

What is the possible mechanism of NSAIDs relating to cardiovascular risk?

A

loss of COX-2 dependant antagonism of platelet activity

1 Pharm Unit (14 decks)

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