Eicosanoids Flashcards
1
Q
descirbes family of PGs, LKTs and other releated compounds
A
Eicosanoids
2
Q
Eicosanoids have 20 carbon ______ with 3, 4, or 5 ________
A
Essential FAs
double bonds
3
Q
Eicosatetraenoic acid: 5, 8, 11, 14-eicosatrienoic acis is
A
Arachidonic acid: 20:4
4
Q
Free AA is very _____ in cells
A
low
5
Q
Release of AA is via_______
and is Ca++ _______
A
Phospholipase A2 and is Ca++ DEPENDENT
6
Q
________ hydrolyzes the sn-2 ester bond of membrane phospholids in synthesis of AA
A
PLA2
7
Q
What enZ is required to make PGs and Leukotriends
A
COX 1 and COX2
8
Q
funx of COX
A
oxygenates and cyclizes free AA to form cyclic endoperoxide = PGG2
***occurs at cyclooxygenase site of enZ
= where NSAIDs bind
9
Q
What is special about COX1 and COX2
A
there are two individual enZs
each ones has two different active sites with distinct activities
10
Q
Perioxidase activity of COX is
A
to reduce PGG2–>PGH2
11
Q
how does AA get to PGH2?
A
AA–COX cylcooxygenase activity–>PGG2
PGG2–COX peroxidase activity–> PGH2
12
Q
COX1 and 2 are encoded on same/different chromosomes
A
different
13
Q
type of proteins cyclooxygenase are
A
heme proteins
14
Q
________ has a bigger, more accesible active site
A
COX 2
15
Q
COX-1 is ______ and expressed in all tissues
COX-2 is _____
A
constituitive
inducible
16
Q
this COX has a promoter region that binds TFs
A
COX-2
17
Q
This cyclooxygenase is commonly seen in inflammation
A
COX-2
18
Q
What is the fate of PGH2?
A
PGD2, PGE2, PGF, PGI2, TxA2~ wide variety of PGs
19
Q
Whats the dif btwn E1 and E2?
A
refers to # of double bonds in the molecule
20
Q
Most common lipoxygenase which it leads to synthesis of leukotrienes
A
5-lipoxygenase
21
Q
what does activation of 5-lipoxygenase require?
A
Ca++ and 5-lipoxygenase activating protein (FLAP)
22
Q
family of cytosolic enZ that catalyze oxygenation of FAs to corresponding lipid hydroperoxides
A
lipoxygenases
23
Q
how are lipoxygenases different from cyclooxygenases
A
differ in specificity for placing hydroperoxy group and tissues differ in lipooxygenase they contain
24
Q
LTA4 pathway splits and leads to….
A
LTB4 for chemotaxis and inflammation
LTE4 for allergies, bronchoconstriction and mucus production
25
5-lipoxygenase inhibitor
Zileuton
26
Zarfirlukast is a
Leukotriene R antagonist
DOESNT inhibit biosynthesis
inhibits the effect of the CYS-containing leukotrienes
27
Pharmacokinetics of Zileuton
Preparation:
Metabolized by:
oral prep
| metabolized by CYP 1A2, 2C9 and 3A4
28
Mechanism of Zileuton
inhibits 5-lipoxygenase, no leukotrienes produced
| no production of any LTs
29
Adverse Effects of Zileuton
few, some increase in liver enZs
30
Use of Zileuton
Prophylaxis and chronic tx of asthma... NOT NOT for acute attack
31
Zafirlukast pharmacokinetics
oral adminstration
| metabolized by CYP2C9
32
Mech. of Zafirlukast
cysteinyl leukotriene R antagonist w/ minimal side effects
33
Therapeutic use of Zafirlukast
Prophylaxis and chronic tx of asthma... NOT for acute attack
34
Catabolism of eicosanoids:
rapidly inactivated~ 95% when you infuse PGE1... in one passage through lung
35
First step of catabolism of eicosanoids
- initial, rapid step;
- -15-OH dehydrogenase: oxidation of 15-OH to ketone
- -PG reductase: 15 keto reduced to 13,14 dihydro derivative
36
Second step of Catabolism is relatively slow:
involves B and w oxidation
37
Leukotriene Rs are
GCPRs
38
LTB4 acts on:
BLT1 and BLT2 and chemotaxis
39
LTC4 and LTD4 are:
leukotriene receptors that cause bronchoconstriction and increases vascular permeability
40
LTC4 and LTD4 result in increase in
intracellular Ca++
41
nonenZ pathway resulting free-radical catalyzed peroxidation of AA and structures are simular to
prostaglandins
42
activated by Ca++, inhibited by drugs that reduce the availability of Ca++
Phospholipase A2
43
Glucocorticoids induce synthesis of a group of proteins called annexins (lipocortin) that inhibit
Phospholipase A2 activity
44
Aspirin/other related NSAIDs inhibit
COX1 and COX 2
45
Glucocorticoid decrease expression of
COX-2, but not COX-1
46
In the periphery, PGE2 and PGI2 will:
sensitize pain Rs to mechanical and chemical stimulation
lower the threshold of nociceptors of C fibs
Hyperalgesia--bc they lower threshold for pain
Potentiate pain-producing activity of other mediators, like bradykinin
47
PGs and Pain in the CNS
COX2 expressed in sp cd
expression increased inflammation
centrally released PGs may contribute to neuropathic pain
48
Do PGs alone cause pain
no... only in high enough concentrations
49
What do PGs do to threshold of pain
PGs decrease threshold for pain so that lower concentration of other mediators activate pain fibers
50
Steps of Fever
1. first step is increased formation of cytokines
2. will increase synthesis of PGE2 in areas of brain associated w/ temperature control
3. PGE2 increases cAMP and triggers hypothalamus to increase body temp
4. Hypothalamus regulates set point at which body temperature is maintained
51
Platelets will activate the platelet membrane _____ and cause release of AA and it's metabolism to thromboxane to ________
PLA2
| COX-1
52
what induces platelet aggregation?
TXA2
53
TXA2 acts on:
TP receptor in VSM
| increases intracellular Ca++
54
Activation of PLA2 on the endothelial membrane causes:
release of AA and it's metabolism to prostacycline (PGI2) by COX1 and COX2
55
PGI2 inhibits:
platelet aggregation
56
how does PGI2 inhibit platelet aggregation?
stimulates IP receptors and increases cAMP
57
PGI2 causes
vasodialtion
58
how does PGI2 cause vasodialation
stimulates IP receptors and increases cAMP
59
In periphery, _____ and ______ sensitive nerve endings to effects of chemical and mechanical stimuli by lowering threshold of nociceptors~~ hyperalgesia
PGE2 and PGI2
60
what is expressed in dorsal horn of sp cd and increases expression during inflammation
COX-2
61
Centrally generated _____ activates spinal neurons and microglia that contributes to neuropathic pain
PGE2
62
Fever results from production of PG's, specifically
PGE2 from endothelial cells via COX2
63
Exogenous _____ and _____ induce fever but don't contribute to pyretic response
PGF2-alpha and PGI2
64
Cell source of PGI2 is
endothelial cell
65
Pregnancy is associated with increase in
COX1 and2
66
What is the role of PGI2 in early pregnancy?
keeps uterus in quiescent state and relaxation via IP and increased cAMP
67
PGE2 role in pregnancy:
initiation and progression of labor induces uterine contractility via EP1/EP3 (mediate increase in Ca++)
mediates cervical ripening when it binds to EP2/EP4 in cAMP
68
What mediates cervical ripening during labor
PGE2 binding to EP2/EP4
69
PGF2-alpha role during labor
contracts uterus during labor with FP mediated increase in Ca++
70
______ Receptor is involved in primary dysmenorrhea and contributes to symtpoms
PGF2-alpha
71
In menstruation, disruption of uterine mmbs causes release of _____ and increase _____ synthesis (COX1 and COX2)
AA
| PG
72
PGF2alpha contributes to what symptoms of primary dysmenorrhea?
contracts uterus
contracts GI smooth msl
sensitive afferent pain fibers
73
Fnx of CV or VSM:
| -PGE2 or PGI2 will cause
vasodialation via the EP2/4 Receptors which result in a fall in BP
74
TXA2 and PGF2-alpha in CV or VSM cause
vasoconstriction....
75
When PGE2 is on the EP1/EP3 receptor in CV or VSM the result is...
vasoconstriction
76
PGD2 is a _______ in CV and ______ in pulmonary circulation
vasodialation
| vasoconstriction
77
Locally, PGs produce:
vasodialation
78
Platelets will activate the platelet membrane _____ and cause release of AA and it's metabolism to thromboxane to ________
PLA2
| COX-1
79
what induces platelet aggregation?
TXA2
80
TXA2 acts on:
TP receptor in VSM
| increases intracellular Ca++
81
Activation of PLA2 on the endothelial membrane causes:
release of AA and it's metabolism to prostacycline (PGI2) by COX1 and COX2
82
PGI2 inhibits:
platelet aggregation
83
how does PGI2 inhibit platelet aggregation?
stimulates IP receptors and increases cAMP
84
PGI2 causes
vasodialtion
85
how does PGI2 cause vasodialation
stimulates IP receptors and increases cAMP
86
In periphery, _____ and ______ sensitive nerve endings to effects of chemical and mechanical stimuli by lowering threshold of nociceptors~~ hyperalgesia
PGE2 and PGI2
87
what is expressed in dorsal horn of sp cd and increases expression during inflammation
COX-2
88
Centrally generated _____ activates spinal neurons and microglia that contributes to neuropathic pain
PGE2
89
Fever results from production of PG's, specifically
PGE2 from endothelial cells via COX2
90
Exogenous _____ and _____ induce fever but don't contribute to pyretic response
PGF2-alpha and PGI2
91
Cell source of PGI2 is
endothelial cell
92
Pregnancy is associated with increase in
COX1 and2
93
What is the role of PGI2 in early pregnancy?
keeps uterus in quiescent state and relaxation via IP and increased cAMP
94
PGE2 role in pregnancy:
initiation and progression of labor induces uterine contractility via EP1/EP3 (mediate increase in Ca++)
mediates cervical ripening when it binds to EP2/EP4 in cAMP
95
What mediates cervical ripening during labor
PGE2 binding to EP2/EP4
96
PGF2-alpha role during labor
contracts uterus during labor with FP mediated increase in Ca++
97
______ Receptor is involved in primary dysmenorrhea and contributes to symtpoms
PGF2-alpha
98
In menstruation, disruption of uterine mmbs causes release of _____ and increase _____ synthesis (COX1 and COX2)
AA
| PG
99
PGF2alpha contributes to what symptoms of primary dysmenorrhea?
contracts uterus
contracts GI smooth msl
sensitive afferent pain fibers
100
Fnx of CV or VSM:
| -PGE2 or PGI2 will cause
vasodialation via the EP2/4 Receptors which result in a fall in BP
101
TXA2 and PGF2-alpha in CV or VSM cause
vasoconstriction....
102
When PGE2 is on the EP1/EP3 receptor in CV or VSM the result is...
vasoconstriction
103
PGD2 is a _______ in CV and ______ in pulmonary circulation
vasodialation
| vasoconstriction
104
Locally, PGs produce:
vasodialation
105
Platelets will activate the platelet membrane _____ and cause release of AA and it's metabolism to thromboxane to ________
PLA2
| COX-1
106
what induces platelet aggregation?
TXA2
107
TXA2 acts on:
TP receptor in VSM
| increases intracellular Ca++
108
Activation of PLA2 on the endothelial membrane causes:
release of AA and it's metabolism to prostacycline (PGI2) by COX1 and COX2
109
PGI2 inhibits:
platelet aggregation
110
how does PGI2 inhibit platelet aggregation?
stimulates IP receptors and increases cAMP
111
PGI2 causes
vasodialtion
112
how does PGI2 cause vasodialation
stimulates IP receptors and increases cAMP
113
In periphery, _____ and ______ sensitive nerve endings to effects of chemical and mechanical stimuli by lowering threshold of nociceptors~~ hyperalgesia
PGE2 and PGI2
114
what is expressed in dorsal horn of sp cd and increases expression during inflammation
COX-2
115
Centrally generated _____ activates spinal neurons and microglia that contributes to neuropathic pain
PGE2
116
Fever results from production of PG's, specifically
PGE2 from endothelial cells via COX2
117
Exogenous _____ and _____ induce fever but don't contribute to pyretic response
PGF2-alpha and PGI2
118
Cell source of PGI2 is
endothelial cell
119
Pregnancy is associated with increase in
COX1 and2
120
What is the role of PGI2 in early pregnancy?
keeps uterus in quiescent state and relaxation via IP and increased cAMP
121
PGE2 role in pregnancy:
initiation and progression of labor induces uterine contractility via EP1/EP3 (mediate increase in Ca++)
mediates cervical ripening when it binds to EP2/EP4 in cAMP
122
What mediates cervical ripening during labor
PGE2 binding to EP2/EP4
123
PGF2-alpha role during labor
contracts uterus during labor with FP mediated increase in Ca++
124
______ Receptor is involved in primary dysmenorrhea and contributes to symtpoms
PGF2-alpha
125
In menstruation, disruption of uterine mmbs causes release of _____ and increase _____ synthesis (COX1 and COX2)
AA
| PG
126
PGF2alpha contributes to what symptoms of primary dysmenorrhea?
contracts uterus
contracts GI smooth msl
sensitive afferent pain fibers
127
Fnx of CV or VSM:
| -PGE2 or PGI2 will cause
vasodialation via the EP2/4 Receptors which result in a fall in BP
128
TXA2 and PGF2-alpha in CV or VSM cause
vasoconstriction....
129
When PGE2 is on the EP1/EP3 receptor in CV or VSM the result is...
vasoconstriction
130
PGD2 is a _______ in CV and ______ in pulmonary circulation
vasodialation
| vasoconstriction
131
Locally, PGs produce:
vasodialation
