Eicosanoids Flashcards
1
Q
What is the relative availability of Arachidonic acid in cells?
A
Low
2
Q
What enzyme releases arachidonic acid from phospholipids?
A
Phospholipase A2
3
Q
Cyclooxygenase converts arachidonic acid to what?
A
PGG2
4
Q
Peroxidase converts PGG2 into what?
A
PGH2
5
Q
Arachidonic acid is converted to PGG2 by what enzyme?
A
Cyclooxygenase
6
Q
PGG2 is converted to PGH2 by what enzyme?
A
Peroxidase
7
Q
Where is COX-1 expressed?
A
In all tissues
8
Q
Where is COX-2 commonly seen?
A
In inflammation
9
Q
To what extent are the structures of COX1 and COX2 similar?
A
60%
10
Q
How is the active site of COX2 different from COX1
A
It is bigger and more accessible
11
Q
What are the various fates of PGH2?
A
- PGE2
- PGD2
- PGF2a
- PGI2
- TxA2
12
Q
What is the structural difference between E1 and E2?
A
The number subscript refers to number of double bonds. E2 has two double bonds.
13
Q
Cyclooxygenases convert Arachidonic acid into what two substances?
A
PGs and Thromboxanes
14
Q
5-lipoxygenases convert Arachidonic acid into what substance?
A
Leukotrienes
15
Q
What is the prototype 5-lipoxygenase inhibitor?
A
Zileuton
16
Q
What effect does Zileuton have and how does it achieve this?
A
Decreased production of Leukotrienes
Achieved by inhibition of 5-LO
17
Q
What is the prototype Leukotriene receptor antagonist for this class?
What is its effect on Leukotriene biosynthesis?
A
Zafirlukast
It has no effect on biosynthesis
18
Q
What specific types of leukotrienes does Zafirlukast inhibit the effects of?
A
CYS-containing Leukotrienes
19
Q
How is Zileuton administered?
A
orally
20
Q
How is Zileuton metabolized?
A
CYP enzymes (CYP1A2, 2C9, 3A4)
21
Q
What is the mechanism of action for Zileuton?
A
It inhibits 5-LO and prevents any production of Leukotrienes
22
Q
What is the only adverse effect of Zileuton?
A
Increases liver enzymes in some
23
Q
What is the therapeutic use of Zileuton?
A
Prophylaxis and chronic treatment of asthma
24
Q
What is the common route of administration for Zafirlukast?
A
Oral
25
What enzyme metabolizes Zafirlukast?
CYP2C9
26
What is the mechanism of action for Zafirlukast?
Cys-Leukotriene receptor antagonism
27
What is the therapeutic use for Zafirlukast?
Prophylaxis and chronic treatment of asthma
28
Describe the inactivation of eicosanoids.
Rapid inactivation. Infusion of PGE1 is 95% inactivated through one pass in lung.
29
There are two steps to the catabolism of eicosanoids. Describe them.
1. Initial step is rapid - 15OH dehydrogenase oxidation and PGdelta13 reductase reduction
2. Second step is relatively slow - beta oxidation of side chains
30
What are the two primary second messengers for prostaglandin and thromboxane receptors?
Ca2+ and cAMP
31
Leukotriene LTB4 affects what receptors and to what effect? What second messenger is used?
BLT1 and BLT2
chemotaxis
Ca2+
32
Leukotrienes LTC4, LTD4, and LTE4 affect what receptors and to what effect?
What second messenger is used?
cysLT1 and cysLT2
bronchoconstriction and increased vascular permeability
Ca2+
33
PGE2 and PGI2 have what effects in the periphery regarding pain? (4 items)
1. Sensitize pain receptors
2. Lower the threshold of nociceptors of C fibers
3. Hyperalgesia
4. Potentiate pain-producing activity of other mediators
34
Where in the CNS is there COX2 expression?
| To what end?
In the spinal cord
| May contribute to neuropathic pain
35
Do PGs alone cause pain?
Only in high concentrations. They mainly lower the threshold for pain for other mediators.
36
How do PGs cause fever?
Cytokine formation increases synthesis of PGE2 which increases cAMP and triggers hypothalamus to elevate body temperature
37
How is TXA2 produced in platelets?
activation of platelet membrane stimulates PLA2 to release arachidonic acid which is metabolized by COX1 into thromboxane
38
What effect does TXA2 have?
Induction of platelet aggregation by acting on TP receptor which increases intracellular calcium
39
How are prostaglandins produced in the endothelium?
Activation of endothelial membrane PLA2 causes release of arachidonic acid and its metabolism to prostacyclin (PGI2) by COX1 and COX2
40
What effect does PGI2 have on the endothelium and how?
Inhibition of platelet aggregation by stimulation of the IP receptors and an increase in cAMP
41
What effect does TXA2 have on blood vessels and how?
Induction of vasoconstriction by acting on the TP receptor in vascular smooth muscle resulting in an increase in intracellular calcium
42
What effect does PGI2 have on blood vessels and how?
PGI2 causes vasodilation by stimulation of IP receptors with an increase in cAMP.
43
Is PGI2 synthesized by platelets or endothelial cells?
Endothelial cells
44
What role does PGI2 have in pregnancy?
| By what mechanism?
Keeps uterus in quiescent state
| Relaxation is via IP and increase in cAMP
45
What role does PGE2 have in pregnancy?
| By what mechanism?
Initiation and progression of labor
Induction of uterine contractility through EP1/EP3 mediated increase in calcium
Mediation of cervical ripening by EP2/EP4 type increase in cAMP
46
What role does PGF2a have in pregnancy?
| By what mechanism?
Contracts uterus during labor through FP mediated increase in calcium
47
Which prostaglandin contributes to the symptoms of primary dysmenorrhea?
PGF2a
48
What is the mechanism for the PG contribution in dysmenorrhea?
Disruption of uterine membranes causes release of AA and increase PG synthesis by COX1 and COX2.
49
What effect does PGF2a have during dysmenorrhea?
1. Contraction of uterus
2. Contraction of GI smooth muscle
3. Sensitization of afferent pain fibers
50
IV administration of PGE2 or PGI2 causes a fall in blood pressure through what receptors?
EP2/EP4
51
What two PGs are vasodilators?
PGE2 and PGI2
52
What two PGs are vasoconstrictors?
TXA2 and PGF2a
53
What is peculiar about PGD2 in its relationship to blood vessels?
It is usually a vasodilator except in pulmonary circulation where it is a constrictor.
54
When thinking about role of PGs in blood pressure regulation what two things should be remembered?
1. Locally produces vasodilator PGs tend to predominate
| 2. They serve to counteract the effect of circulating vasoconstrictor autocoids like ANGII
55
How do PGs relate to the Kidney?
Vasodilator PGs like PGE2 and PGI2 promote increased renal blood flow
56
Which PG maintains the PDA? By what receptor? By which COX enzyme?
PGE4. Via EP4 receptor. By COX2.
57
What causes a reduction in PGE2 in neonates and a closure of the PDA?
1. Loss of placenta (major source of circulating PGE2 invitro)
2. Decrease in PGE2 receptors (EP4/dilator subtype)
3. Increase in pulmonary blood flow at birth (major site of PG catabolism)
58
What are the roles of the different PGs in bronchial smooth muscle?
PGF2a & PGD2 constrict
PGE2 relaxes
TXA2 constricts
PGI2 relaxes
59
What two roles do Leukotrienes have in the lungs?
1. Bronchoconstriction
| 2. Chemotaxis
60
What two effects do PGs have on the kidneys?
1. Modulation of renal blood flow
| 2. Regulation of urine formation via direct effect on renal tubules
61
Is COX1 or COX2 more important in renal disease?
COX2
62
Which two PGs are most active in the kidneys?
| What do they do?
PGE2 and PGI2
| Increase blood flow and promote diuresis and natriuresis
63
Which COX enzyme is most active in GI system?
COX1
64
PGE2 (EP3) and PGI2(IP) do what in the stomach?
Inhibit gastric acid secretion and increase gastric mucosal blood flow
65
What three additional effects does PGE2 have on the GI system?
1. Stimulation of viscous mucucs
2. Stimulation of bicarb secretion
3. Contraction of GI smooth muscle
66
How do PGE2 and PGI2 promote inflammation?
Directly increase blood flow and indirectly enhance edema formation and leukocyte infiltration. This increases other mediators that reach the site of injury.
67
How do Leukotrienes promote inflammation?
1. slow reacting substance of anaphylaxis (SRS-A) released from mast cells
2. LTC4/LTD4 increase vascular permeability
3. LTB4 is a chemoattractant for neutrophils
68
Which cancers are associated with an increased concentration of PGs?
1. Colon cancer
2. Breast cancer
3. Renal cell adenocarcinoma
69
What possible role do PGs have in cancer?
Induction of cellular proliferation
70
What PGE2 agent is used for cervical ripening?
Dinoprostone
71
How is DInoprostone administered for cervical ripening?
Cervical gel 0.5mg
72
What is the mechanism of action for Dinoprostone for cervical ripening?
EP4 receptor increase in cAMP resulting in:
- promotion of cervical ripening
- breakdown of collagen
- activation of collagenase
- relaxation of cervical smooth muscle
73
What adverse effects are related to Dinoprostone?
Nausea/Vomiting/Diarrhea
Fever
Uterine rupture
74
What is the therapeutic use for higher dose Dinoprostone and what is the method of administration?
Termination of early pregnancy
| Vaginal suppository 20mg
75
What is the mechanism of action for higher dose Dinoprostone for termination of pregnancy?
EP1/EP3 receptor mediated calcium release resulting in uterine contraction.
76
What PGF2a related drug is used for the termination of pregnancy or control of postpartum hemorrhage?
Carboprost
77
What is the mechanism of action of Carboprost?
FP mediated calcium release resulting in uterine contraction
78
What PGE1 analog is used as "replacement" therapy for prevention of ulcers caused by NSAIDs
Misoprostol
79
What is the mechanism of action for Misoprostol?
- EP3 mediated reduction in cAMP resulting in decrease in gastric acid secretion, increase in mucin, increase in bicarb
- EP2/4 mediated increase in cAMP resulting in increased mucosal blood flow
80
What are the adverse effects associated with Misoprostol?
Diarrhea, Termination of pregnancy
81
What PGE1 related drug is used for Impotence and erectile dysfunction or temporary maintenance of PDA?
Alprostadil
82
How is Alprostadil administered for impotence?
Intracavernous injection
83
How is Alprostadil administered for maintenance of PDA?
IV infusion
84
What is the mechanism of action of Alprostadil for impotence?
Induction of erection through relaxation of trabecular smooth muscle and dilation of cavernosal arteries via EP2/4 mediated increase in cAMP
85
What is the mechanism of action for Alprostadil for maintenance of PDA?
EP2/4 receptor increase in cAMP resulting in relaxation of ductus arteriosus smooth muscle
86
What adverse effect occurs from Alprostadil in about 10% of neonates < 2kg?
Apnea
87
What PGI2 related medication is used for primary pulmonary hypertension?
Epoprostenol
88
How is Epoprostenol administered?
continuous IV infusion
89
What is the mechanism of action for Epoprostenol?
IP receptor cAMP mediated dilation of pulmonary artery vascular smooth muscle
90
What are the adverse effects of Epoprostenol?
Nausea/Vomiting
Headache
Flushing
91
What PGF2a related medication is used for Glaucoma or Eyelash hypotrichosis?
Bimatoprost
92
What is the mechanism of action Bimatoprost in glaucoma?
EP2/4 mediated increase in cAMP resulting in increased outflow of aqueous humor.
93
What are the adverse effects of ophthalmic Bimatoprost?
Eye redness, itching, change in eye color, increase in eye lashes
94
What is the mechanism of action of Bimatoprost in eyelash hypotrichosis?
Increase in the percent and duration of hairs in the growth phase
