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Pharm Block 2 > Lecture 2: Eicosanoids > Flashcards

Lecture 2: Eicosanoids Flashcards

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1
Q

What are eicosanoids

A

Derived from 20 carbon essential fatty acids containing 3,4, or 5 double bonds

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2
Q

In humans what is the most abundant precursor eicosanoid

A

Arachidonic acid

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3
Q

How is free arachidonic acid made

A

Freed from esterified membrane phospholipids. Phospholipase A2, a calcium dependent enzyme hydrolyzes the sn-2 ester bond of phospholipid and releases arachidonic acid.

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4
Q

2 activities of Cycloooxygenases

A

1) oxygenates and cyclizes precursor fatty acids. forming PGG2 2) Peroxidase activity that converts PGG2 to PGH2

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5
Q

What are the similarities between the Cyclooxygenases

A

Both are membrane bound, heme proteins.

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6
Q

What are the differences between COX-1 and COX-2

A

Active site is larger in COX-2. COX-2 is inducible whereas COX-1 is constitutive. Encoded on different chromosomes

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7
Q

What enzyme leads to the syntehsis of leukotrienes from arachidonic acid

A

5-lipooxygenase

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8
Q

What is required for activation of 5-lipooxygenase

A

Calcium and FLAP (5-lipooxygenase activating protein)

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9
Q

What enzyme leads to prostaglandins and thromboxanes from arachidonic acid

A

Cyclooxygenase

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10
Q

What enzyme leads to epoxides from arachidonic acid

A

CypP450

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11
Q

Inhibitors fo PLA2

A

1) Drugs the reduce availability of calcium. 2) Glucocorticoids which induce synthesis of annexins/lipocortin that inhibit PLA2 activity.

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12
Q

Inhibitors for Cyclooxygenase

A

Aspirin and other NSAIDS inhibit COX-1 and COX-2. Glucocorticoids decrease expression of COX-2, but not COX-1. There are also COX-2 selective drugs

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13
Q

Zileuton

A

Inhibits 5-lipooxygenase.

Mech: Inhibits cys-LTs (bronchoconstriction and increase vascular permeability and LTB4(chemotaxis).

Therapeutic use: prophylactic treatment of mild asthma.

Pharmacokinetics: Oral administration; half life of 2.5 hours; metabolized by CYP enzymes

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14
Q

Zafirlukast

A

cys-LTs Receptor antagonist

Pharmacokinetics: Oral, 10hr-t1/2, metabolized by 2C9/3A4

Mechanism: inhibits cys-LTs

Uses: prophylactic treatment of asthma

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15
Q

What is the general pathway for eicosanoid catabolism

A

2 steps. first fast second slow.

Fast First step uses 15-OH dehydrogenase followed by PG delta-13 reductase.

Slow Second step uses beta and omega oxidation of side chain giving a polar compound that is excreted

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16
Q

What type of receptors do LT and PG use

A

GPCR

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17
Q

What are the important Leukotriene receptors

Study These Flashcards
A

GPCR
LTB4 for chemotaxis.

LTC/D/E4 for bronchoconstriction and increase vascular permeability. Activation increases intracellular calcium

18
Q

What prostaglandins are important for peripheral pain?

Study These Flashcards
A

PGE2 and PGI2

19
Q

What prostaglandin contributes to neuropathic pain (in the CNS)

20
Q

What is the pathway to generate fever

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A
  1. Increased formation of cytokines
  2. Increased synthesis of PGE2
  3. Increases cAMP, triggering hypothalamus to elevate body temperature.
21
Q

What promotes platelet aggregation and where is it found

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A

TXA2 found in Platelets

Note that TXA2 also induces vasoconstriction by acting on TP receptor in VSM, resulting in an increase in intracellular Ca2+

22
Q

What inhibits platelet aggregation and where is it found

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A

PGI2, source from endothelial cell NOT PLATELET

Note that PGI2 also causes vasodilation, stimulating IP receptors resulting in an increase in cAMP

23
Q

What are the prostaglandins for parturition

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A

PGI2 to keep uterus in quiescent state by relaxation via IP and increase cAMP

PGE2 to initiate and progress labor
Uterine contractility induced by EP1/EP3 mediated increase in calcium
Cervical ripening mediated by EP2/EP4 increase in cAMP

PGF2alpha to contract uterus during labor: through FP mediated increase in calcium

24
Q

What does PGF2-alpha do

Study These Flashcards
A

vasoconstriction,
uterine contraction,
pain (Manifests as primary dysmenorrhea)

25
What prostoglandin causes vasodilation
PGE2 and PGI2
26
What Thromboxane causes vasoconstriction
TXA2
27
What prostoglandin causes vasoconstriction
PGF2alpha
28
What does PGD2 do
vasodilator, except in pulmonary circulation where it is a constrictor
29
What maintains patency of ductus arteriosus
Prostoglandins, particularly PGE2 that affects tone in ductus arteriosus causing relaxation via EP4 receptor. (COX-2) Developmentally regulated, loss of responsiveness in neonate compared to fetus due to 1. Loss of placenta, the major source of circulating PGE2 in fetus 2. Decrease in PGE2 receptors (EP4/dilator subtype) 3. Increase pulmonary blood flow at birth (lungs are major site for PG catabolism)
30
What Ecosanoids cause bronchial/tracheal constriction
PGF2, TXA2, LTC4, LTD4
31
What Ecosanoids cause bronchial/tracheal relaxation
PGEs, PGI2
32
What does PGE2 and PGI2 do in the kidneys
Increase renal blood flow b/c of vasodilation, promoting diuresis and natriuresis
33
What does PGE2 and PGI2 do in the GI
Both: inhibit gastric acid and increase gastric mucosal blood flow. PGE2 also stimulates release of viscous mucus, stimulates bicarbonate secretion, contracts GI smooth muscle
34
Inflammatory and immune responses
PGs contribute to signs and symptoms of inflammation LTC4, LTD4: increase vascular permeability LTB4: chemoattractant for neutrophils
35
Cancer
In certain malignancies, colon, carcinoma of breast, renal cell adenocarcinoma, increased concentrations of PGs PGs induce cellular proliferation COX-2 induced in certain cancers
36
Dinoprostone
Synthetic analog of PGE2 Therapeutic uses: 1. Cervical ripening 2. Terminating early pregnancy/abortion Mechanism: 1. Activation of collagenase also relaxing cervical smooth muscle EP4 receptor subtype (for cervical ripening) 2. Uterine contractions via EP1/3 receptors SE: GI related (nausea, vomiting, diarrhea) Fever Uterine rupture: contraindicated in women having history fo cesarean section or other uterine surgery
37
Carboprost
Analog of PGF2alpha Therapeutic use: 1. Termination of pregnancy in 2nd trimester 2. Control postpartum hemorrhage that is not responding to conventional treatment methods Mechanism: 1. Stimulates uterine contractility by action at FP receptors 2. Postpartum, the drug cause myometrial contractions via FP receptors. This provides hemostasis at the stie of placenta formation ``` SE: GI related (nausea, vomiting, diarrhea) Fever Uterine rupture (contraindicated in women having history of cesarean section or other uterine surgery) Rare case of bronchoconstrictino ```
38
Misoprostol
PGE1 analog Therapeutic use: Replacement therapy for prevention of ulcers caused by long term NSAIDS Mechanism: Suppresses gastric acid secretion by stimulating EP3 receptors on parietal cells; causes decrease in cAMP Increase mucin and bicarbonate secretion Increase mucosal blood flow SE: Diarrhea-common and contraindicated in pregnancy *(Misoprostol used with methotrexate or mifepristone for termination of early pregnancy)
39
Alprostadil
PGE1 Use: 1. Impotence/ED 2. Maintenance of patent ductus arteriosus Mechanism of action 1. Increase in cAMP which relaxes smooth muscle fo corpus cavernosum 2. cAMP mediated relaxation of ductus arteriosus smooth muscle SE: 1. Pain at site of injection (reason for intra-urethral formulation) Priapism: prolonged erection 2. Apnea in 10% of neonates, <2kg weight
40
Epoprostenol
PGI2 agonist Therapeutic use: Primary pulmonary hypertension. Mechanism: cAMP mediated dilation of pulmonary artery vascular smooth muscle SE: Nausea, vomiting, headache, flushing
41
Bimatoprost
Prostaglandin PGF2alpha analog Uses: glaucoma and eyelash hypotrichosis Mechanism: Increases outflow of aqueous humor and Increases the percent and duration of hairs in the growth phase. Pharmacology: administered as opthalmic drops SE: Eye redness, itching, permanent changes in eye color (increased brown pigment), eyelid skin; may increase length and number of eyelashes

Pharm Block 2 (14 decks)

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