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Pharm Block 2 > Lecture 2: Eicosanoids > Flashcards

Lecture 2: Eicosanoids Flashcards

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

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?

A

PGE2 and PGI2

19
Q

What prostaglandin contributes to neuropathic pain (in the CNS)

A

PGE2

20
Q

What is the pathway to generate fever

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

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

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

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

A

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

25
Q

What prostoglandin causes vasodilation

A

PGE2 and PGI2

26
Q

What Thromboxane causes vasoconstriction

A

TXA2

27
Q

What prostoglandin causes vasoconstriction

A

PGF2alpha

28
Q

What does PGD2 do

A

vasodilator, except in pulmonary circulation where it is a constrictor

29
Q

What maintains patency of ductus arteriosus

A

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
Q

What Ecosanoids cause bronchial/tracheal constriction

A

PGF2, TXA2, LTC4, LTD4

31
Q

What Ecosanoids cause bronchial/tracheal relaxation

A

PGEs, PGI2

32
Q

What does PGE2 and PGI2 do in the kidneys

A

Increase renal blood flow b/c of vasodilation, promoting diuresis and natriuresis

33
Q

What does PGE2 and PGI2 do in the GI

A

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
Q

Inflammatory and immune responses

A

PGs contribute to signs and symptoms of inflammation

LTC4, LTD4: increase vascular permeability
LTB4: chemoattractant for neutrophils

35
Q

Cancer

A

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
Q

Dinoprostone

A

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)

  1. 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
Q

Carboprost

A

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
Q

Misoprostol

A

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
Q

Alprostadil

A

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
Q

Epoprostenol

A

PGI2 agonist

Therapeutic use: Primary pulmonary hypertension.

Mechanism: cAMP mediated dilation of pulmonary artery vascular smooth muscle

SE: Nausea, vomiting, headache, flushing

41
Q

Bimatoprost

A

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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