Eicosanoids Flashcards
eicosanoids def
describes the families of prostaglandins, leukotrienes
mostly derived from arachidonic acid
biosynthesis of eicosanoids
release of arachidonic acid
release of arachidonic acid (free arachidonic acid is very low, but is usually found esterified to membrane phospholipids. Phospholipase A2 is a Ca-dependent enzyme that hydrolyzes the sn2 ester bond of phospholipid and releases arachidonic acid
biosynthesis of eicosanoids
cyclooxygenase
2 isoforms COX1 and COX2
each isoforms has 2 distinct activities
1. oxygenates and cyclizes the precursor fatty acid to form cyclic endoperoxide, PGG2
2. peroxidase activity that converts PGG2 to PGH2
3. COX 1: heme protein, membrane bound, small active site, different chromosome, constitutive. COX 2: heme protein, membrane bound, large active site, inducible
Fate of PGH2: transformed enzymatically into products (PGI2, TXA2, PGE2, PGF2a) PGE2 : PGE1 :: 2 db : 1 db
biosynthesis of eicosanoids
Lipoxygenase
family of cytosolic enzymes that catalyze the oxygenation of fatty acids to corresponding lipid hydroperoxides
lipoxygenases differ in specificity depending on where they attach the hydroperoxy group and tissues differ in the lipoxygenases that they have
most important lipoxygenase is 5-lipoxygenase bc it leads to the formation of leukotrienes
activation of 5-lipoxygenase requires Ca and 5-lipoxygenase activating protein (FLAP)
biosynthesis of eicosanoids
cyp p450
metabolize arachidonic acid to EETs
inhibitors of eicosanoid biosynthesis
via phospholipase A2
activated by Ca, inhibited by drugs that reduce the availability of Ca
glucocorticoids induce synthesis of annexins that inhibit phospholipase A2 activity
inhibitors of eicosanoid biosynthesis
via cyclooxygenase
aspirin and NSAIDS inhibit COX1 and COX2
glucocorticoids decrease expression of COX 2
inhibitors of eicosanoid biosynthesis
via lipoxygenase
inhibitors of 5-lipoxygenase- zileuton (oral admin, t.5=2.5 hrs, metabolized by CYP enzymes, inhibits cys-LTs for bronchoconsttriction and increases vascular permeability and LTB4 for chemotaxis not many SE, its a prophylactic treatment of mild asthma)
Cysteinyl leukotriene receptor antagonist- zafirlukast (oral admin, t.5=10 hrs, metabolized by CYP2C9/3A4 inhibits Cys-LTs, treats mild asthma)
Eicosanoid catabolism
infuse PGE1 - 99% inactivated during one passage thru the pulmonary circulation
2 steps:
1. oxidation by PG dehydrogenase, follwed by reduction by PG reductase fast
- B and omega oxidation–>polar compound–>excreted Slow
cellular mechanism of eicosanoids
prostaglandins: wide effects by a variety of GPCRs
leukotrienes: receptors identified for LTB4, cyseinyl leukotrienes LTC4 and LTD4 coupled to GPCR activation increases intracellular CA
pain and eicosanoids
in the periphery, PGE2 and PGI1 lower the threshold of nociceptors. hyperalgesia. PGs potentiate pain producing activity of brady kinin and autocoids
in the CNS: COX2 is expressed in the dorsal horn of the sp cd and espression increases during inflammation, central PGE2 activates spinal neurons and microglia that can contribute to neuropathic pain.
fever and eicosanoids
fever results from the production of PG, primarily PGE2 from vascular endothelial cells via COX2. These PGs generate the neuronal signals that activate the thermoregulatory center in anterior hypothalamus. PGE2 synthesis is stimulated by endogenous (IL1) or exogenous (lipopolysaccharide) pyrogens
PGF2a and PGI2 induce feve but do not contribute to the pyretic response. TXA2 does not induce fever.
platelets and eicosanoids
activation of platelet membrane PLA2 causes release of arachidonic acid and its transformation into TXA2 by COX1
TXA2: promotes platelet aggregation by stimulating the TP receptor. TP receptor is coupled to increase in intracellular Ca
PGI2: inhibits platelet aggregation via stimulation of IP receptor that couples to cAMP. cell source of PGI2 is endothelial cells (PLA)–> release of arachidonic acid and metabolism by COX1 and/or COX2 (inflammation)
Repro and eicosanoids
uterus/pregnancy: associated increase in COX1 and COX2
PGI2: contributes to quiescent state of uterine activity during early pregnany, relaxation of uterine tone via increase of cAMP
PGE2: initiation and progression of labor by inducing uterine contractility, cervical ripening,
PGF2a: mediates uterine contractility during labor, conc increase in menstrual fluid and cause vasoconstriction, uterine contraction, pain
1’ dysmenorrhea: menstrual pain
CV smooth muscle and eicosanoids
prostaglandins: systemic BP falls in response to PGE2, and hypotension after IV PGI2
PGE2: and PGI2: predominantly vasodilators
TXA2: potent vasoconstrictor
PGF2a: vasocontriction
locally produced PGs counteract the effects of circulating vasoconstrictor autocoids. TO MAINTAIN blood flow to vital organs
PGs maintain patency of ductus arteriosus during fatal life. allows right blood to bypass the pulm system
PGE2: major PG that affects tone of ductus, relaxation via EP4 receptor, COX 2
bronchial tracheal smooth muscle and eicosanoids
when lung get antigen, autocoids are produced (prostaglandins and leukotrienes)
PGEs, PGI2 relax
PGF2a, TXA2 all constrict
LTC4, LTD4 constrict
bronconstriction to leukotrienes predominates
Kidney and eicosanoid
PGs modulate renal blood flow
COX1 and 2
PGE2 and PGI2 increase RBF bc of vasodilation promote diuresis and natriuresis
GI and eicosanoids
COX-1: production of cytoprotective PGs
PGE2 and PGI2: inhibit gastric acid secretion, increase gastric mucosal blood flow
PGE2: stimulates release of viscous mucos, bicarb secretion, contracts GI smooth muscle
inflammatory and immune response eicosanoids
COX2 mediated: PGs and leukotrienes released by a number of mechanical/thermal chemical and bacterial insults
PGs: signs and symptoms of inflammation
LTC4 and LTD4: increase vascular permeability
LTB4: chemoattractant for neutrophils
Cancer and eicosanoids
in certain malignancies increased concentration of PGs, which induce cell proliferation
COX-2 induced in certain cancers
therapeutic uses of prostaglandins
limited bc significant adverse side effects and short half lives in circulation
dinoprostone therapeutic use, preparation, MOA Therapeutic use: Preparation: MOA: Side effects: Therapeutic use: Preparation: MOA: Side effects:
analog of PGE2
Therapeutic use: cervical ripening in pregnancy
Preparation: cervical gel 240 mg
MOA: promotes cervical ripening (via activation of collagenase) & relaxes cervix increases cAMP
Therapeutic use: termination of preg
Preparation:vaginal suppository
MOA: uterine contractions via EP1/3 receptors increase Ca
Side effects: GI releated fever uterine rupture, CX in F w/Hx of C-section/uterine SgX
Carboprost Therapeutic use: Preparation: MOA: Side effects: Therapeutic use: Preparation: MOA: Side effects:
PGF2a analog (analog is t.5=8 min reg PGF2a=15 s)
Therapeutic use: 2nd trimester abortion (13 to 20 wks)
Preparation: im shot 250 mg
MOA: stimulates uterine contractions by FP receptors
Therapeutic use:controls post partum hemorrhage
Preparation: im 250
MOA: myometrial contractions via fP R hemostasis at placenta site
Side effects: GI, fever, uterine rupture Cx in women w/Hx of C-sec/Uterine SgX, sometimes bronchoconstrictions
misoprostal Therapeutic use: Preparation: MOA: Side effects:
(PGE1 analog)
Therapeutic use: replacement therapy for ulcers dutu NSAIDs
Preparation: oral admin 4x/day
MOA: supresses gasstric acid secretion by stimulating EP3 receptors on parietal cells, dec cAMP increases mucin and bicarb and mucosals blood flow
Side effects: diarrhea and CX in pregnancy
use misoprostal and methotrexate to early abortion
Alprostadil Therapeutic use: Preparation: MOA: Side effects:
PGE1 analog
Therapeutic use: impotence
Preparation: intracavernous injection/ intraurethral injection
MOA: EP2/EP4 increase in cAMP which relaxes smooth muscle of corpus cavernosum
Side effects: pain at site of injection, priapism (prolonged erection)
Therapeutic use: maintenance of patent ductus arteriosus
Preparation:IV
MOA: EP2/EP4 cAMP-mediated relaxtion of ductus arteriosus
Side effects: apnea in neonates
Epoprostenol Therapeutic use: Preparation: MOA: Side effects:
PGI2
Therapeutic use: 1’ pulm HTN, rare disease in female
Preparation: continuous IV
MOA: IP:cAMP-mediated dilation pulmonary artery vascular smooth muscle
Side effects: nausea, vomiting, headache flushing
Bimatoprost Therapeutic use: Preparation: MOA: Side effects: Therapeutic use: Preparation: MOA: Side effects:
synthetic PGF2a Therapeutic use:glaucoma Preparation: ophthalmic MOA: increases outflow of aqueous humor, target receptor Side effects:redness itching eye color
Therapeutic use:
Preparation:
MOA:
Side effects:eyelash extention
