Ecosinoids Flashcards
1
Q
Alprostadil (impotence and erectile dysfunction)
Prostaglandin
A
PGE1
2
Q
Alprostadil (impotence and erectile dysfunction)
Site of action
A
corpus cavernosum smooth muscle
3
Q
Alprostadil (impotence and erectile dysfunction)
Mechanism of Action
A
PGE1 analog thatworks via the EP2/4 receptors to increase cAMP which relaxes trabecular smooth muscle and dilates cavernous arteries leading to entrapment of blood
4
Q
Alprostadil (impotence and erectile dysfunction)
Receptor
A
EP2 Receptor
PGE1 works on EP2 receptor
5
Q
Alprostadil (impotence and erectile dysfunction)
Major adverse effect
A
priapism, erection lasting over 6 hours
6
Q
Two therapuetic uses of Alprostadil
A
- Impotence and Erectile Dysfunction when PGE1 acts on EP2 receptor on corpus cavernosum smooth muscle causing an increase in cAMP
- Temporary Maintenance of patent ductus arteriosus when PGE1 acts on EP2 receptor on ductus arteriosus smooth muscle leading to increase in cAMP
7
Q
Alprostadil (maintenance of patent ductus arteriosus)
Prostaglandin
A
PGE1
8
Q
Alprostadil (maintenance of patent ductus arteriosus)
Site of Action
A
ductus arteriosus smooth muscle
9
Q
Alprostadil (maintenance of patent ductus arteriosus)
Mechanism of Action
A
PGE1 analog that increases cAMP via EP2 receptor which relaxes ductus arteriosus smooth muscle
10
Q
Alprostadil (maintenance of patent ductus arteriosus)
Adverse effect
A
apnea
11
Q
Two therapeutic uses of Bimatoprost
A
- glaucoma
2. Eyelash hypotrichosis
12
Q
Bimatoprost (glaucoma) prostaglandin
A
Prostamide F2a
13
Q
Bimatoprost (glaucoma) Site of action
A
trabecular and uveoscleral aqueous humor outflow pathways
14
Q
Bimatoprost (glaucoma) Mechanism of action
A
stimulation of specific Prostamide F2a receptor resulting in changes in genes that remodel cells to increase drainage
15
Q
Bimatoprost (glaucoma) major adverse effect
A
increase length and number of eyelashes
16
Q
Bimatoprost (eyelash hypotrichosis) Prostaglandin
A
Prostamide F2a
17
Q
Bimatoprost (eyelash hypotrchosis) Site of action
A
hair follicles of eye
18
Q
Bimatoprost (eyelash hypotrichosis) Mechanism of action
A
Stimulation of specific Prostamide F2a receptor causing increase in anagen phase of hair cycle
19
Q
Two therapeutic uses for Carboprost
A
- Pregnancy termination
2. To control postpartum hemorrhage
20
Q
Carboprost (pregnancy termination) Prostaglandin
A
PGF2a
21
Q
Carboprost (pregnancy termination) Site of action
A
uterine smooth muscle
22
Q
Carboprost (pregnancy termination) mechanism of action
A
increase in Ca via FP receptor causing uterine contraction
23
Q
Carboprost (pregnancy termination) Major adverse effect
A
uterine rupture
24
Q
Major adverse effect of bimatoprost (eyelash hypotrichosis)
A
eye redness, itching
25
dinoprostone therapeutic functions
1. cervical ripening in pregnancy
| 2. early pregnancy termination
26
dinoprostone (cervical ripening in pregnancy) prostaglandin
PGE2
27
dinoprostone (cervical ripening in pregnancy) Site of action
cervix
28
dinoprostone (cervical ripening in pregnancy) Mechanism of action
- activation of collagenase via EP4 receptor which increases cAMP
- relaxes cervical smooth muscle
29
dinoprostone (cervical ripening in pregnancy) major adverse effect
uterine rupture
30
dinoprostone (early pregnancy termination) prostaglandin
PGE2
31
dinoprostone (early pregnancy termination) Site of action
uterine smooth muscle
32
dinoprostone (early pregnancy termination) Mechanism of action
EP1 mediated increase in Ca
OR
EP3 mediated decrease in cAMP
causes uterine contractions
33
dinoprostone (early pregnancy termination) Major adverse effect
uterine rupture
34
Epoprostenol protaglandin
PGI2
35
Epoprostenol site of action
Pulmonary artery smooth muscle
36
Epoprostenol Mechanism of action
increase in cAMP via IP receptor which dilates the pulmonary artery vascular smooth muscle
37
Epoprostenol major adverse effect
GI related and potential drug interations with other hypertensive therapy or anti-platelt therapy
38
Epoprostenol therapeutic use
idiopathic pulmonary arterial hypertension
39
misoprostol prostaglandin
PGE1
40
misoprostol site of action
parietal cell
41
misoprostol Mechnaism of action
PGE1 analog that suppresses gastric acid secretion via decrease in cAMP via EP3 receptor
42
misoprostol major adverse effect
diarrhea
| CONTRAINDICATED IN PREGNANCY
43
misoprostol therapeutic use
replacement therapy for prevention of ulcers caused by long term administration with NSAIDs
take 4x a day
44
In humans what is the most abundant precursor of ecosinoids
arachidonic acid
45
Describe the biosynthesis of ecosinoids- release of arachidonic acid
- Arachidonic acid is the precursor and it is found in very low concentration in the blood bc it is bound to a phospholipid
- Phospholipase 2 (PLA2) cleaves the Sn-2 ester bond of membrane phospholipids
- this is Ca dependent
46
How do glucocorticoids suppress PLA2
they induce annexin-1 (lipocortin) which suppresses PLA2 activity
47
How many isoforms exist of COX
2
48
How many functions does each isoform of COX have
2. oxygenase function and peroxidase function
49
SO there are ______- distinct ______ at _______ distinct __________ on both COX proteins
There are two distinct activities at two distinct active sites on BOTH COX proteins
50
2 Actions of COX
1. oxygenates and cyclizes the free arachidonic acid to form
cyclic endoperoxide PGG2
- Occurs at cyclooxygenase active site of enzyme
*Site where NSAIDs bind
2. Peroxidase activity to reduce PGG2
to PGH2
-Occurs at peroxidase active site of enzyme
51
Where do NSAIDs bind
at the cyclooxygenase active site of the COX enzyme
52
What is the main difference between COX1 and COX2
-COX 1 is constitutive it is present in all tissues
- COX 2 is inducible. It has a promoter region that binds transcription factors. it is commonly seen in inflammation
* Nf-κB, C/EBP, ERK1/2, MAPK
53
Name the four prostaglandins
PGE2
PGD2
PGF2a
PGI2
54
Name the Thromboxane
TxA2
55
What are the 3 main things that Arachidonic Acid Can be turned into an what enzyme class makes that happen
1. Leukotrienes when acted upon by 5-lipoxygenases
| 2. Prostaglandins and Thromboxanes when acted upon by Cyclooxygenases (COX)
56
Lipoxygenases
Also which is the most important and why
-family of cytosolic lipoxygenases that catalyze the
oxygenation of fatty acids to corresponding lipid
hydroperoxides
-lipoxygenases differ in specificity for placing the
hydroperoxy group, and tissues differ in the
lipoxygenase(s) they contain
****5-lipoxygenase is the most important because it produces Leukotrienes
57
FLAP
5 lipoxygenase activating protein
58
5-lipoxygenase inhibitor
Zileuton
59
Leukotriene receptor
| antagonist
```
Zafirlukast
-DOES NOT INHIBIT
BIOSYNTHESIS
-Inhibits the effect of the
CYS-containing
Leukotrienes (LTC4, LTD4, LTE4)
meaning all except for LTB4
```
60
Which Leukotrienes increase vascular permeability
LTC4 and LTD4
61
Which Leukotrienes cause bronchoconstriction
LTC4 and LTD4
62
Which Leukotrienes serve as chemoattractant for neutophils
LTB4
63
Which Leukotrienes are increased in allergies and asthma
all
64
Zileuton
Inhibits 5-lipoxygenase
leads to No production of any LTs
-Not appropriate or indicated for the reversal of bronchospasm in acute asthma attacks
65
Zafirlukast
- Cysteinyl leukotriene receptor antagonist
| - No effect on LTB4
66
Describe the catabolism of ecosanoids
rapidly inactivated
-95% of PGE1 is inactivated in one pass through the lungs
67
Prostaglandins/Thromboxane interact with what type of receptors
GPCRs therefore their effects involve secondary messengers
68
Receptor and second messenger
| TXA2
TP and Ca mobilization
69
Receptor and second messenger
| PGF2a
FP and Ca mobilization
70
Receptor and second messenger
| PGE2
EP1/EP3 Ca mobilization
EP2/EP4 increase cAMP
71
Receptor and second messenger
| PGI2
IP increase cAMP
72
Receptor and second messenger
| PGD2
DP1 and DP2 increase cAMP
73
Leukotriene LTB4 causes
chemotaxis
Effector system=Increase intracellular
calcium
74
Leuktorienes LTC4 & LTD4 & LTE4 cause
-Bronchoconstriction
-Increase vascular
permeability
Effector system=Increase intracellular
calcium
75
PGE2 and PGI2 and peripheral pain
- act through specific GPCR
- sensitive pain receptors
- lead to hyperalgesia
76
How do PGs cause pain
they decrease the threshold of pain so that lower levels of other mediators are able to cause pain
sometimes when levels of PGs are high enough they can cause pain alone through a specific GPCR
77
Sequence of events for a fever
1. increased formation of
cytokines
2 increases synthesis of PGE2
in areas of brain associated with temperature control
3 increases cAMP and
triggers hypothalamus to elevate body temperature
4 Hypothalamus regulates the
set point at which body temperature maintained = fever
78
Ecosinoids in Platelets
```
-Activation of platelet
membrane PLA
release of arachidonic
acid and its metabolism
to thromboxane by
COX-1 (platelets make thromboxane specifically TXA2)
```
THEN
-TXA2 induces platelet aggregation
◦ Acts on TP receptor
◦ Increase in intracellular calcium
79
TXA2 induces
platelet aggregation
◦ Acts on TP receptor
◦ Increase in intracellular calcium
80
Activation of endothelial membrane PLA2 causes release of arachidonic acid which is then metabolized by COX1 and COX2 into.....
Prostacyclin PGI2
81
What does PGI2 do?
-PGI2 is formed when endothelial membrane PLA2 releases arachidonic acid which is then metabolized by COX 1 and COX2 into PGI2 (Prostacyclin)
- PGI2 inhibits platelet aggregation
* It stimulates IP receptors and INCREASES cAMP
-PGI2 causes vasodilation via IP receptors and INCREASES cAMP
82
What synthesizes PGI2
endothelial cells (to inhibit platelet aggregation)
83
Role of PGI2 in uterus
- early pregnancy-keeps uterus in quiescent state
| - relaxation via IP receptors and increases cAMP
84
Role of PGE2 in uterus
- initiation and progression of labor
- induces uterine contractility via EP1/EP3 mediated increase in calcium
- Mediates cervical ripening via EP2/Ep4 mediated increase in cAMP
85
Role of PGF2a in uterus
-contracts uterus during labor via FP receptor mediated increase in Ca
86
How does pregnancy influence COX
Pregnancy induces COX1 and COX2 which increase PGI2, PGE2, and PGF2a
87
Effect of PGF2a on the non-pregnant uterus
contributes to symptoms of primary dysmenorrhea (cramps)
disruption of the uterine membrane during mensration releases AA increasing PG synthesis via COX 1 and COX2
88
What two prostaglandins are vasodilators
PGE2 and PGI2
But in some cases PGE2 is a vasoconstrictor when it acts on a different receptor (EP1/EP3) which increases Ca and inhibits cAMP
89
What are two vasoconstrictors
PGF2a and TXA2
90
Prostaglandins in the kidneys
PGE2 and PGI2 increase renal blood flow and promote diuresis and natriuresis
91
Which os the following COX1 or COX2 is more important in disease in the kidney
COX2 (there is constituitive expression of COX2 in the macula densa cells, an there is a relationship between COX2 and PG mediated renin release)
92
Describe the role of PGs in blood pressure regulation
LOCALLY produced vasodilator PGs tend to predominate.
- PGE2 acts through EP4 (and EP2) to increase cAMP
- PGI2 acts through IP to increase cAMP
- they serve to counteract the effect of circulating vasoconstrictor autocoids (like angtiotensinII)
-they work to maintain blood flow to vital organs like the kidney, and increase Na and H2o excretion
93
How do prostaglandins influcence Na and H2 excretion
increase
94
During fetal life, the ductus arteriosus is
a normal structure that
allows most of the blood leaving the right ventricle to bypass the pulmonary circulation and pass into the descending aorta.
95
what maintains patency of the ductus arteriosus during fetal life (keeps it open)
PGs specifically PGE2.
it causes relaxation via the EP4 receptor (cAMP) and COX2
96
Function of Leukotrienes
bronchoconstriction and chemotaxis
97
Which COX is important in synthesis of cytoprotective PGs (PGs that protect lining of GI system)
COX1
98
Which PGs inhibit gastric acid secretion, and via which receptors
PGE2 (EP2/4) and PGI2)
99
Role of PGs in gastric ulceration
they suppress gastric ulceration
100
Name two reasons for why Prostaglandins have limited therapeutic use
1. Significant adverse effects-PGs do so many different things all over the body there is great potential for adverse effects
2. Short Half Lives in circulation-PG analogs that have chemical structures that prevent metabolism by 15-OH dehydrogenase and Delta 13-PG reductase have been developed
101
Carboprost (control postpartum hemorrhage) prostaglandin
PGF2a
102
Carboprost (control of postpartum hemorrhage) Site of Action
uterine smooth muscle
103
Carboprost (control of postpartum hemorrhage) mechanism of Action
increase in Ca via FP receptor causing uterine contraction
104
Carboprost (control of postpartum hemorrhage)
| adverse reaction
uterine rupture
