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Pharmacology Block 2 > 02 Eicosanoids > Flashcards

02 Eicosanoids Flashcards

1
Q

What is the precursor of eicosanoids?

A

Arachidonic acid

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2
Q

What families fall under eicosanoids?

A

Derived from 20C essential FA with 3, 4, or 5 double bonds

Prostaglandins and Leukotrienes

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3
Q

How is arachidonic acid found in the cell?

A

Free AA in cells is very low; found esterfied to membrane phospholipids.

Phospholipase A2 (Ca2+ dept.) hydrolyzes bond and releases AA

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4
Q

Phospholipase A2

A

(Ca2+ dept.) hydrolyzes bond and releases Arachidonic Acid

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5
Q

What enzyme makes prostaglandin from arachidonic acid?

A

Cyclooxygenases (COX-1 and COX-2)

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6
Q

Cyclooxygenase

A

Oxygenates and cyclizes the precursor FA to form cyclic endoperoxide PGG2

Peroxidase activity reduces PGG2 to PGH2

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7
Q

How are COX-1 and COX-2 similar?

A

Heme protein
Dimer of 70 kDa
Membrane bound: ER and Nuclear envelope

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8
Q

Who has a bigger more accessible active site, COX-1 or COX-2?

A

COX-2

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9
Q

What is the difference between COX-1 and COX-2

A

Encoded on different chromosomes

COX-1: Constitutive
– expressed in all tissues

COX-2: Inducible

    • promoter region that binds transcription factors
    • seen with inflammation: NFkB, MAPK
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10
Q

What is the fate of PGH2?

A

Transformed enzymatically into:

  • TXA2
  • PGF2alpha
  • PGE2 or PGE1 (double bonds)
  • PGI2
  • PGD2
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11
Q

Which is constitutive and Inducible between COX-1 and COX-2?

A

COX-1: Constitutive
– expressed in all tissues

COX-2: Inducible

    • promoter region that binds transcription factors
    • seen with inflammation: NFkB, MAPK
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12
Q

How are Leukotrienes synthesized?

A

5-Lipoxygenase (5-LOX)

Catalyzes oxygenation of FA to lipid hydroperoxides

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13
Q

What is the difference of inhibition of COX-1 and COX-2 between NSAIDs vs Glucocorticoids?

A

NSAIDS inhibit COX-1 and COX-2

Glucocorticoids decrease expression of COX-2 but not COX-1

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14
Q

What decreases the expression of COX-2 but not COX-1?

A

Glucocorticoids

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15
Q

Inhibitor of 5-lipoxygenase

A

Zileuton

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16
Q

Zileuton

A

Pharm: T 1/2 = 2.5 hrs; metab by CYPs

Mech: Inhibitor of 5-lipoxygenase = No LT production

  • cys-LTs (bronchoconstriction and increase vascular permeability)
  • LTB4 (chemotaxis)

AE: some inc liver enzymes

Tx: Prophylactic tx of mild chronic asthma

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17
Q

What can be used for prophylactic treatment of mild chronic asthma?

A

Zileuton (inhibitor of 5-lipoxygenase) or Zafirlukast Iinhibits cys-LTs)

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18
Q

What inhibits cys-LTs for bronchoconstriction and increased vascular permeability as well as LTB4 (chemotaxis)?

A

Zileuton (inhibitor of 5-lipoxygenase)

Zafirlukast (Cysteinyl leukotriene receptor antagonist)

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19
Q

What is a cysteinyl leukotriene receptor antagonist?

A

Zafirlukast

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20
Q

Zafirlukast

A

Pharm: T 1/2 = 10 hrs, metab by CYP2C9

Mech: Cysteinyl leukotriene receptor antagonist

AE: minimal

Tx: Prophylactic tx of mild chronic asthma

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21
Q

Which has a longer duration of action, Zileuton or Zafirlukast?

A

T 1/2:
Zafirlukast = 10 hrs
Zileuton = 2.5 hrs

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22
Q

Where is 95% of PGE1 inactivated?

A

95% inactivated in one passage through pulmonary circulation

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23
Q

Eicosanoid catabolism

A
  1. Oxidation of the 15-OH group to ketone by 15-OH PG dehydrogenase
    followed by reduction catalyzed by Δ13 PG -reductase
    (initial step; rapid; most biological activity lost)
  2. β and ω oxidation of side chains giving a polar compound that is excreted
    (second step; relatively slow)
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24
Q

Cellular Mechanism of Action of Prostaglandins

A

wide diversity of effects explained by a number of distinct receptors coupled to effector mechanisms through G proteins leading to either Ca2+ mobilization or inc cAMP resulting in inflammation, pain, immunoregulation, mitogenesis, plasticity, and cell injury

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25
Cellular Mechanism of Action of Leukotrienes
G protein coupled receptors: – LTB4 • BLT1 and BLT2 • chemotaxis – LTC4 & LTD4 & LTE4 • cysLT1 and cys LT2 • Bronchoconstriction • Increase vascular permeability Effector system: – Increase intracellular calcium
26
What leukotriene receptor results in chemotaxis?
LTB4
27
What leukotriene receptors are associated with cys-LTs, bronchoconstriction, mucus production, and increased vascular permeability?
LTC4, LTD4, LTE4
28
What cells can form eicosanoids?
Virtually every cell in the body
29
PGE2 and PGI2 located in the periphery result in?
- Sensitize pain receptors to mechanical and chemical stimulation - Lower threshold of nociceptors of C fibers - Hyperalgesia - Potentiate pain, producing activity of other mediators like bradykinin
30
PGs located in CNS result in?
Expression of COX-2 in spinal cord increased in inflammation Centrally generated PGE2 may contribute to neuropathic pain
31
Do PGs alone cause pain?
ONLY in high concentrations In injury, PGs decreases the THRESHOLD for pain so that lower concentrations of other mediators (histamine, bradykinin, substance P) can activate the pain fibers
32
What are the steps to fever formation?
1. Increased formation of cytokines (IL-1, TNF-alpha) in circulation 2. Increased synthesis of PGE2 at hypothalamus via COX-2 3. PGE2 increases cAMP, which triggers hypothalamus to elevate body temperature thermorergulatory set point 4. Heat conservation/production => fever Hypothalamus regulates the set point at which body temperature is maintained
33
What controls body temp? What factors result in fever?
Increased PGE2 via COX-2 at hypothalamus increases cAMP which triggers hypothalamus to elevate body temp
34
How is thromboxane synthesized?
Activation of platelet membrane PLA2 causes release of arachidonic acid and converted to thromboxane by COX-1
35
Function of thromboxane
TXA2 induces platelet aggregation Acts of TP receptor Inc in intracellular Ca2+
36
What induces platelet aggregation?
Thromboxane (TXA2)
37
Activation of endothelial membrane PLA2 results in?
Release of arachidonic acid and its metabolism to PGI2 by COX-1 and COX-2 to inhibit platelet aggregation and to also vasodilate
38
Activation of platelet membrane PLA2 results in?
release of arachidonic acid and converted to thromboxane by COX-1
39
How is PGI2 synthesized?
Activation of endothelial membrane PLA2 releases arachidonic acid and its metabolism to PGI2 by COX-1 and COX-2
40
Function of PGI2
ENDOTHELIUM Inhibits platelet aggregation - stimulation of IP receptors - inc in cAMP Vasodilation - stimulation of IP receptors - inc in cAMP
41
What PG inhibits platelet aggregation and causes vasodilation of endothelium?
PGI2
42
Pregnancy induces the increase in what enzymes?
COX-1 and COX-2
43
PGI2 effect on uterus?
Early pregnancy: - keeps uterus in quiescent state - relaxation via IP and increase cAMP
44
What PG is associated with early pregnancy and keeping the uterus in quiescent state?
PGI2
45
PGE2 effect on uterus?
- Initiation and progression of labor - At EP1/EP3 receptors, induces uterine contractility (increases Ca2+) - At EP2/EP4 receptors, mediates cervical ripening (increases cAMP)
46
What PG is associated with the initiation and progression of labor (induces uterine contractility AND cervical ripening)?
PGE2 - At EP1/EP3 receptors, induces uterine contractility (increases Ca2+) - At EP2/EP4 receptors, mediates cervical ripening (increases cAMP)
47
PGF2-alpha effect on pregnant uterus?
Contracts uterus during labor (inc Ca2+)
48
Primary Dysmenorrhea
menstrual pain severe enough to limit normal activities and require medication in the presence of normal pelvic organs In menstruation, disruption of uterine membranes causes release of AA and increase PGF2-alpha syn (COX1 and COX2) - contract uterus - contract GI smooth muscle - sensitize afferent pain fibers
49
Effect of PGF2-alpha on non-pregnant uterus?
Primary Dysmenorrhea-- menstrual pain severe enough to limit normal activities and require medication in the presence of normal pelvic organs concentrations increase in menstrual fluid and cause vasoconstriction, uterine contraction, pain
50
Systemic blood pressure generally falls in response to what PG?
PGE2 at EP2/EP4 receptors | PGI2
51
There is profound hypotension after IV administration of what PG?
PGI2
52
What PGs are predominantly vasodilators?
PGE2 at EP2/EP4 receptors PGI2 PGD2 (except in pulmonary, where it is a constrictor)
53
What PG is a (potent) vasoconstrictor?
TXA2 (potent) PGF2-alpha (not potent) PGD2 (only pulmonary) PGE2 at EP1/EP3 receptors
54
Why is it important to know locally produced vasodilator PGs counteract effects of circulating vasoconstrictor autocoids (angiotensin II)?
To maintain blood flow to vital organs like the kidney
55
What maintains blood flow to vital organs like the kidney?
Locally produced vasodilator PG counteracting the effect of circulating vasoconstrictor autocoids (angiotensin II)
56
What is the role of PGs on the fetal heart?
PGs maintain patency of ductus arteriosus (allows most blood leaving RV to bypass pulmonary circulating and pass into the descending aorta) PGE2 affects tone - relaxation via EP4 receptor
57
What PG plays a major role in maintaining the ductus arteriosus?
PGE2 affects tone | - relaxation via EP4 receptor
58
What causes the loss of fetal ductus arteriosus?
- loss of placenta (major source of PGE2 in fetus) - dec in PGE2 receptors (EP4 = dilator) - inc pulmonary blood flow (major site for PG catabolism)
59
When sensitized lung tissue is challenged by an antigen (allergic reaction), what happens?
Releases of prostaglandins and Leukotrienes PGE2 and PGI2 = relax PGF2-alpha, PGD2, TXA2 = constrict LTC4 and LTD4 = constrict Bronchoconstrictor response to leukotrienes predominates
60
What PGs are associated with bronchial relaxation?
PGE2 and PGI2
61
What chemicals are associated with bronchoconstriction?
PGF2-alpha, PGD2, TXA2 LTC4 and LTD4 - predominates over PGs that relax lung
62
What PGs increase renal blood flow and promote diuresis and natriuresis?
PGE2 and PGI2
63
What is the effect of PGE2 and PGI2 on the kidney?
increase renal blood flow and promote diuresis and natriuresis
64
In the GI, what synthesizes cytoprotective PGs to suppress gastric ulceration?
COX-1
65
What is the effect of PGI2 on GI?
Inhibit gastric acid secretion | Increase gastric mucosal blood flow
66
What PGs inhibit gastric acid secretion and increase gastric mucosal blood flow?
PGE2 at EP3 and PGI2
67
What is the effect of PGE2 on GI?
``` Inhibit gastric acid secretion (EP3) Increase gastric mucosal blood flow (EP2/EP4) Stimulate release of viscous mucus Stimulate bicarbonate secretion Contract GI smooth muscle (EP1) ``` ==> Suppress gastric ulceration
68
What enzyme mediates the inflammatory and immune response?
COX-2 PGs and Leukotrienes released by a number of mechanical, thermal, chemical, bacterial insults
69
What do PGs contribute to the inflammatory/immune response?
Signs and symptoms of inflammation (fever, pain, vasoactive effects) PGE2/PGI2: - directly inc blood flow - indirectly enhance edema formation and leukocyte infiltration
70
What do Leukotrienes contribute to the inflammatory/immune response?
LTC4 and LTD4 = increased vascular permeability | LTB4 = chemoattractant for neutrophils
71
In what cancers would you find an increased concentration of PGs?
Colon, Breast, Renal cell adenocarcinoma - PGs induce cellular proliferation - Induced COX-2
72
Why is the use of PGs as therapeutic agents limited?
Significant AEs | Short t 1/2 in circulation
73
Dinoprostone
Synthetic PGE2 analog 1. Cervical ripening in pregnancy (EP4 receptor) Mech: Collagenase activation and relaxation of cervical smooth muscle 2. Abortion of early pregnancy (EP1/EP3 receptor) Mech: Uterine contractions AE: - GI: n/v/d - fever - uterine rupture (contraindicated w/ hx of C-section or uterine sx)
74
What drug is a synthetic analog of PGE2?
Dinoprostone
75
What drug is used for cervical ripening or termination of early pregnancy?
Dinoprostone (PGE2) 1. Cervical ripening in pregnancy (EP4 receptor) 2. Abortion of early pregnancy (EP1/EP3 receptor)
76
Carboprost Tromethamine
PGF2-alpha analog; longer half life (mins) 1. Pregnancy termination during 2nd trimester Mech: Stimulates uterine contractility by FP receptors 2. Control postpartum hemorrhage Mech: Post partum, causes myometrial contractions via FP receptors. Hemostasis at site of placenta formation. AEs: - GI: n/v/d - fever - uterine rupture (contraindicated w/ hx of C-section or uterine sx) - bronchoconstriction (rare)
77
What drug is a PGF2-alpha analog?
Carboprost Tromethamine | Bimatoprost
78
What drug is used for termination of pregnancy during second trimester?
Carboprost Tromethamine (PGF2-alpha)
79
What drug is used to control postpartum hemorrhage?
Carboprost Tromethamine (PGF2-alpha)
80
Misoprostol
PGE1 analog Replacement therapy for prevention of ulcers due to long term NSAID use (4x/day) Mech: - suppress gastric acid secretion by parietal cells (EP3 receptors) - dec in cAMP - inc mucin and bicarb secretion - inc mucosal blood flow AEs: - diarrhea (common) - contraindicated in pregnancy
81
What drugs are PGE1 analogs?
Misoprostol | Alprostadil
82
What drug is used as replacement therapy for NSAID induced ulcers?
Misoprostol (PGE1 analog)
83
What are the AEs of misoprostol?
Diarrhea (common) | Contraindicated in pregnancy
84
Alprostadil
PGE1 1. Impotence/Erectile Dysfunction (Injection) Mech: inc cAMP relaxes smooth muscle of corpus cavernosum (EP2/EP4 receptors) AE: - pain at site of injection - priapism: prolonged erection 2. Maintenance of patent ductus arteriosus (IV) Mech: cAMP-mediated relaxation of ductus arteriosus smooth muscle (EP2/EP4 receptors) AE: - apnea in 10% neonates; <2 kg
85
What PG drug is used to treat erectile dysfunction? What is potential AE?
Alprostadil (PGE1) Can cause priapism (prolonged erection)
86
What PG drug is used to maintain a patent ductus arteriosus?
Alprostadil (PGE1)
87
Epoprostenol
PGI2 Tx: Primary pulmonary hypertension which leads to right heart failure - rare Female idiopathic disease - continuous IV Mech: cAMP-mediated dilation of pulmonary artery vascular smooth muscle AE: - n/v - headache - flushing - potential drug interactions
88
What drug is PGI2?
Epoprostenol
89
What drug is administered as a continuous IV to treat primary pulmonary hypertension?
Epoprostenol (PGI2)
90
Bimatoprost
PGF2-alpha 1. Glaucoma (OPH) Mech: inc outflow of aqueous humor AE: - eye redness, itching, increased brown pigment - may inc length and number of eyelashes 2. Eyelash hypotrichosis (OPH) Mech: inc percent and duration of hairs in growth phase AE: - excess, unwanted hair growth, brown iris pigmentation, eye redness, itching
91
What therapeutic PG is used to treat glaucoma?
Bimatoprost (PGF2-alpha)
92
What drug is used to treat eyelash hypotrichosis?
Bimatoprost (PGF2-alpha)
93
What drug can result in AEs of excess/unwanted hair growth, brown iris pigmentation, eye redness and itching?
Bimatoprost (PGF2-alpha)

Pharmacology Block 2 (12 decks)

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