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PDA Block 2 > Eicosanoids > Flashcards

Eicosanoids Flashcards

1
Q

Nomenclature:

A
  • ‘eicosanoids’ describes the families of prostaglandins, leukotrienes and other related compounds
  • 8,11,14-eicosatrienoic acid (di-homo-γ-linolenic acid)
  • 5,8,11,14-eicosatetraenoic acid (arachidonic acid)
    • most abundant precursor of eicosanoids
  • 5,8,11,14,17-eicosapentaenoic acid (found primarily in fish oils)
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2
Q

How is arachidonic acid released into the blood?

A
  • concentration of free AA in cells is very low
  • arachidonic acid is found esterified to membrane phospholipids
  • Phospholipase A2 is a calcium-dependent enzyme that hydrolyzes the sn-2 ester bond of phospholipid and releases arachidonic acid
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3
Q

What are the two cyclooxygenases isoforms? How do they differ?

A
  • COX-1 and COX-2:
    • heme proteins
    • membrane-bound
  • How they differ:
    1. COX-1: constitutive
      • Expressed in all tissues
    2. COX-2: inducible
      • Has a promoter region that
        binds transcription factors
      • bigger, more
        accessible active site
      • commonly seen in
        inflammation
      • Nf-kB, C/EBP, ERK1/2,
        MAPK
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4
Q

What are the two activites of cyclooxygenases?

A
  1. oxygenates and cyclizes the precursor fatty acid to form cyclic endoperoxide, PGG2
  2. peroxidase activity that converts PGG2 ⇒ PGH2
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5
Q

What is the fate of PGH2?

A
  • transformed enzymatically into a variety of products including PGI2, TXA2, PGE2, PGF2α or PGD2
  • PGE2 vs PGE1
    • subscript refers to number of double bonds in molecule
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6
Q

Lipooxygenases:

A
  • catalyze the oxygenation of fatty acids to corresponding lipid hydroperoxides
  • 5-lipoxygenase leads to synthesis of leukotrienes:
    • ​most important
    • activation of 5-lipoxygenase requires calcium and 5-lipoxygenase activating protein (FLAP)
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7
Q

What type drugs inhibit Phospholipase A2?

A
  • drugs that reduce the availability of
    calcium
  • glucocorticoids induce synthesis of a group of proteins called annexins (lipocortin) that inhibit phospholipase A2 activity
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8
Q

What type drugs inhibit cyclooxygenase?

A
  • Aspirin/ other related NSAIDs inhibit COX- 1 and COX-2
  • COX-2 selective drugs
  • Glucocorticoids decrease expression of COX-2, but not COX-1
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9
Q

Which drugs inhibit lipooxygenases (LOXs)?

A
  1. zileuton (Zyflo®)
  2. zafirlukast (Accolate®): cysteinyl leukotriene receptor antagonists
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10
Q

Zileuton (Zyflo®)

  • Pharmacokinetics:
  • Mechanism:
  • Adverse Effects:
  • Therapeutic Use:
A

5-lipoxygenase inhibitor:

  • Pharmacokinetics: oral administration; half-life of 2.5 hrs metabolized by CYP enzymes
  • Mechanism: inhibits cys-LTs (bronchoconstriction and increase vascular permeability and LTB4 (chemotaxis)
  • Adverse Effects: few; increase liver enzymes
  • Therapeutic use: prophylactic treatment of mild asthma
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11
Q

Zafirlukast (Accolate®):

  • Pharmacokinetics:
  • Mechanism:
  • Adverse Effects:
  • Therapeutic Use:
A
  • Pharmacokinetics:
    • Oral administration
    • Metabolized CYP2C9
  • Mechanism:
    • Cysteinyl leukotriene receptor
      antagonist
  • Adverse effects:
    • Minimal
  • Therapeutic use:
    • Prophylaxis and chronic
      treatment of asthma
    • Not appropriate or indicated for the reversal of bronchospasm in acute asthma attacks
  • DOES NOT INHIBIT BIOSYNTHESIS
  • Inhibits the effect of the CYS-containing leukotrienes
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12
Q

Eicosanoid Catabolism:

A
  • Rapidly inactivated
    • infuse PGE1: approximately 95% inactivated during one passage through the pulmonary circulation
  • Two Steps:
  1. initial step; rapid:
    • oxidation of the 15-OH group ⇒ ketone by 15-OH PG dehydrogenase
    • followed by reduction catalyzed by Δ13 PG -reductase
    • most biological activity lost
  2. second step; relatively slow:
    • β and ω oxidation of side chains giving a polar compound that is excreted
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13
Q

Cellular Mechanism of Action:

Prostaglandins

A
  • wide diversity of effects
  • explained by a number of distinct receptors
  • all receptors are coupled to effector mechanisms through G proteins
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14
Q

Cellular Mechanism of Action:

Leukotrienes

A
  • LTB4 receptors:
    • BLT1 and BLT2
    • chemotaxis
  • LTC4, LTD4 & LTE4 recpetors:
    • Cysteinyl leukotriene recpetors
    • cysLT1 and cys LT2
    • Bronchoconstriction
    • Increase vascular permeability
  • activation increases intracellular calcium
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15
Q

EICOSANOIDS CAN BE FORMED BY _________________.

A

VIRTUALLY EVERY CELL

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16
Q

How are PGs involved in pain?

A
  1. Periphery:
    • PGE2, PGI2 sensitize afferent nerve endings to effects of chemical and mechanical stimuli by lowering the threshold of nociceptors
      • “hyperalgesia”
    • PGs potentiate pain-producing activity of bradykinin and other autocoids
  2. CNS:
    • Neuronal sensitization
    • COX-2 is expressed in the dorsal horn of the spinal cord
    • Increases during inflammation
    • Centrally generated PGE2 activates spinal neurons and also microglia that contribute to neuropathic pain
17
Q

Do PGs alone cause pain?

A
  • ONLY in high enough concentrations
  • PGs decrease the threshold for pain so that lower concentrations of other mediators (like histamine, bradykinin, substance P) activate the pain fibers
18
Q

How do eicosanoids contribute to fever?

A
  1. Increased formation of cytokines
  2. This increases synthesis of PGE2 in areas of brain associated with temperature control
  3. PGE2 increases cAMP
  4. Triggers hypothalamus to elevate body temperature
  5. Hypothalamus regulates the set point at which body temperature maintained
19
Q

Which eicosanoids induce fever?

A
  • PGE2 synthesis is stimulated by endogenous (e.g. interleukin-1) or exogenous (e.g. lipopolysaccharide) pyrogens
  • Exogenous PGF2α and PGI2: induce fever but do not contribute to the pyretic response
  • PGD2 and TxA2: do not induce fever
20
Q

How do eicosanoids interact with platelets and endothelium?

A
  • Activation of platelet membrane PLA2 ⇒ release of arachidonic acid ⇒ transformation into TXA2 by COX-1
  • TXA2: promotes platelet aggregation (physiological effect) by stimulating the TP receptor
    • TP receptor is coupled to increase in intracellular calcium (cellular mechanism of action)
  • PGI2: inhibits platelet aggregation & promotes vasodilation (physiological effect) via stimulation of IP receptor that couples to cAMP (cellular mechanism of action)
    • Cellular source of PGI2 is endothelial cell, not platelet
    • Activation of endothelial membrane PLA2 ⇒ release of arachidonic acid ⇒ metabolism by COX-1 and/or COX-2 (inflammation)
21
Q

Reproduction and Parturition:
Uterus

  1. PGI2:
  2. PGE2:
  3. PGF2α:
  4. PGF2α:
A
  1. PGI2:
    • keeps uterus in quiescent state during early pregnancy
    • increase of cAMP
  2. PGE2:
    • initiation and progression of labor
    • induces uterine contractility
      • EP1/EP3 mediated increase in
        calcium
    • mediates ripening of cervix;
      • EP2/EP4 mediated increase in
        cAMP
  3. PGF2α:
    • Contracts uterus during labor
      • FP mediated increase in calcium
    • primary dysmenorrhea: menstrual pain severe enough to limit normal activities
      • non-pregnant uterus
      • concentrations increase in menstrual fluid
      • cause vasoconstriction, uterine contraction, pain
  4. COX-1 and COX-2 involvement
22
Q

How do eicosanoids interact with cardiovascular/vascular smooth muscle tissue?

A
  • Prostaglandins:
    • Systemic blood pressure generally falls in response to PGE2
    • Profound hypotension after iv administration of PGI2
  • PGE2 (EP2 and EP4) and PGI2: predominantly vasodilators
    • In some cases, PGE2 is vasoconstrictor (EP1/EP3 recpetors)
  • TXA2: potent vasoconstrictor
  • PGF2α: vasoconstriction
  • PGD2: predominantly vasodilator except in pulmonary where it causes vasoconstriction
23
Q

How do eicosanoids interact with Bronchial/Tracheal Smooth Muscle?

A
  • when sensitized lung tissue is challenged by antigen; a complex mixture of autocoids is released includes both prostaglandins and leukotrienes
  • leukotrienes are the major bronchoconstrictors
  • PGEs, PGI2: relax
  • PGF2α, PGD2, TXA2: all constrict
  • LTC4, LTD4: constrict
24
Q

How do eicosanoids interact with the kidney?

A
  • prostaglandins modulate RBF
  • regulate urine formation (direct effects on renal tubules)
  • PGE2, PGI2:
    • increase RBF because of vasodilation
    • promote diuresis, natriuresis
25
Q

How eicosanoids interact with the GI tract?

A
  • COX-1 production of cytoprotective prostaglandins
    1. PGE2 (EP3) and PGI2 (IP):
      • inhibit gastric acid secretion
    2. PGE2 (EP2/EP4) and PGI2 (IP):
      • increase gastric mucosal blood flow
    3. PGE2: stimulates release of viscous mucus
    4. PGE2: stimulates bicarbonate secretion
    5. PGE2 (EP1): contracts GI smooth muscle
  • PGs have a **cytoprotective effect: **
    • ​Suppress gastric ulceration
26
Q

How are eicosanoids involved in inflammation?

A
  • **COX-2: **PG production
  • PGs: Minor role
    • Signs and symptoms of inflammation
    • PGE2/PGI2: directly increase blood flow and indirectly enhance edema formation and leukocyte infiltration
      • Increases other mediators that reach the site of injury
  • Leukotrienes: Major role
    • LTC4, LTD4: increase vascular permeability
    • LTB4: chemoattractant for neutrophils
    • Increased in allergies/asthma
27
Q

What are eicosanoids role in cancer?

A
  • increased concentrations of PGs in certain malignancies
  • PGs: induce cellular proliferation
  • COX-2: induced in certain cancers
28
Q

Why is use of PGs therpeutically limited?

A
  • Significant adverse effects
  • Short half-lives in circulation
29
Q

Dinoprostone (Prepidil® or Prostin E2®):

  • Therapeutic Use:
  • Preparation:
  • Mechanism of Action:
  • Adverse Effects:
A

Synthetic analog of PGE2

  1. Therapeutic Use: cervical ripening in pregnancy
    Preparation: cervical gel
    Mechanism of Action: promotes cervical ripening (activation of collagenase [breakdown of collagen])
    also relaxes cervical smooth muscle
    EP4 receptor subtype, increases cAMP
  2. Therapeutic Use: to terminate an early pregnancy/abortion
    Preparation: vaginal suppository
    Mechanism of action: uterine contractions via EP1/3 receptors
  • Adverse effects:
    • GI-Related (nausea, vomiting, diarrhea)
    • fever
    • uterine rupture
30
Q

Carboprost Tromethamine (Hemabate®):

  • Therapeutic Use:
  • Preparation:
  • Mechanism of Action:
  • Adverse Effects:
A

PGF2α analog

  • Therapeutic Use:
    1. Termination of pregnancy during the second trimester between weeks 13 and 20 of gestation
    2. to control postpartum hemorrhage that is not
      responding to conventional treatment methods
  • Preparation: I.M.
  • Mechanism of action:
    1. stimulates uterine contractility by action at FP receptors
      • provides hemostasis at the site of placenta formation
    2. increases Ca2+
  • Adverse Effects:
    • GI-Related (nausea, vomiting, diarrhea)
    • fever
    • uterine rupture
31
Q

Misoprotol (Cytotec®):

  • Therapeutic Use:
  • Preparation:
  • Mechanism of Action:
  • Adverse Effects:
A

PGE1 analog:

  • Therapeutic Use:
    • primarily used as “replacement therapy”
    • prevention of ulcers caused by long-term administration with NSAIDs
  • Preparation: oral administration
  • Mechanism of action:
    • stimulates EP3 receptors ⇒ suppresses gastric acid secretion
      • decrease in cAMP
      • increase mucin and bicarbonate secretion
    • increase mucosal blood flow
      • EP2/4 receptors
      • increases cAMP
  • Adverse effect:
    • diarrhea-common
    • 100% contraindicated in pregnancy
32
Q

Alprostadil (Caverject® or Muse® Pellet; Prostin VR Pediatric®):

  • Therapeutic Use:
  • Preparation:
  • Mechanism of Action:
  • Adverse Effects:
A

PGE1:

  1. Therapeutic Use: Impotence/Erectile Dysfunction
    * *Preparation:** intracavernous injection
    * *Mechanism of action:** increase in cAMP which relaxes smooth muscle of corpus cavernosum
    * *Adverse effect:** pain at the site of injection (reason for intra-urethral formulation)
    * *priapism:** prolonged erection
  2. Therapeutic Use: maintenance of patent ductus arteriosus
    * *Preparation:** infused intravenously
    * *Mechanism of action:** cAMP-mediated relaxation of ductus arteriosus smooth muscle
    * *Adverse effect:** apnea
33
Q

Epoprostenol (Flolan®):

  • Therapeutic Use:
  • Preparation:
  • Mechanism of Action:
  • Adverse Effects:
A

PGI2:

  • Therapeutic effect: primary pulmonary hypertension
  • Preparation: continuous intravenous infusion
  • Mechanism of action: cAMP-mediated dilation of pulmonary artery vascular smooth muscle
  • Adverse effects: nausea, vomiting, headache, flushing
34
Q

Bimatoprost ( Lumigan™; Latisse™):

  • Therapeutic Use:
  • Preparation:
  • Mechanism of Action:
  • Adverse Effects:
A

PGF2α:

  1. Therapeutic Use: glaucoma
    * *Preparation:** ophthalmic solution
    * *Mechanism of action:** increases outflow of aqueous humor
    * *Adverse effects:** eye redness, itching, may cause permanent changes in eye color (increased brown pigment), eyelid skin; may increase length and number of eyelashes
  2. Therapeutic Use: eyelash hypotrichosis
    * *Preparation:** ophthalmic solution
    * *Mechanism of action:** increases the percent and duration of hairs in the growth phase
    * *Adverse effects:** excess, unwanted hair growth, brown iris pigmentation, eye redness, itching

PDA Block 2 (15 decks)

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