autacoids eicosanoids Flashcards
what are the lipid derived eicosanoids
prostaglandins
thromboxanes
leukotrienes
eicosanoid basic facts
lipid mediators from 20 carbon essential polyunsaturated fatty acids
cant make de novo
most come from arachidonic acid (not free, esterified to SN2 position)
cell membrane phospholipids to arachidonic acid via what enzyme
phospholipases (PLA2)
arachidonic acid to isoprostanes via what enzyme
non-enzymatic oxidation
three things from arachidonic acids
cyclooxygenases
lipoxygenases
cytochrome p450
what are the two cyclooxygenases
COX-1 and 2
COX1 and 2 go to
PGG2 then to PGH2
PGH2 forms
prostaglandins (PGD2, PGE2, PGF2a)
prostacyclins (PG12)
thromboxanes (TXA2, TXB2)
3 lipoxygenases
5-LO, 12-LO, 15-LO
5-LO forms
5-GETEs then LTA4
LTA4 forms
CysLTs,LTC4,D4,E4
LTB4
Lipoxins,LXA4,LXB4
12-LO forms
12-HPETEs
12-HPETEs forms
12-HETEs
15-LO forms
15-HPETEs which forms 15-HETEs
15-HETEs forms
lipoxins, LXA4, LXB4
cytochrome P450 forms
HETEs, epoxides
cytochrome P450 via what enzymes
epoxygenase and omega-hydroxylase
how is arachidonic acid released
physical, hormonal and chemical stimuli cause an influx of Ca by pertubing the cell membrane and activating phospholipase A2
rate limiting step in eicosanoid generation
how many reactions do COX-1 and COX-2 also called prostaglandin H synthases catalyze
2
what are the two reactions
oxygen-dependent cyclization of AA to PGG2
peroxidase reduction of PGG2 to PGH2
PGG2 and PGH2 are both what
potent vasoconstrictors and platelet aggregators
PGH2 is converted to what
different eicosanoid products (prostanoids) in a tissue-specific manner
what are the PGH2 derived prostanoids
PGD2, PGF2a, PGE2, TxA2, PGI2
PGH2 in what tissue and what ezyme form PGD2
in brain and mast cells, and PGD2 isomerase
function of PGD2
smooth muscle contraction
inhibits platelet aggregation
PGH2 forms PGF2a in what tissue and what enzyme
in uterus and lung
PGF2a reductase
function of PGF2a
smooth muscle contraction
bronchochonstriction
abortion
PGH2 forms PGE2 in what tissue and what enzyme
macrophages and mast cells
PGE2 isomerase
PGE2 forms what
EP1,2,3,4
function of PGE2
vasodilation hyperalgesia fever diuresis immunomodulation
roles of PGE2
vasodilator and is responsible for cellular homeostasis
mediates vasodilatory effect of bradykinin
essential for regulation of gastric acid production
PGH2 forms PGI2 in what tissue and what enzyme
endothelium and prostacyclin synthase
function of PGI2
vasodilation
inhibits platelet aggregation
PGH2 forms TxA2 in what tissue and what enzyme
platelets and thromboxanse synthase
function of TxA2
vasoconstriction
platelet activation
PGI2 and TxA2 can form
6-keto-PGF1a
TxB2
incative form
formation and degradation of prostanoids
all are formed on demand
perform action in short time
degraded by 15-hydroxyl-PG dehydrogenases (15-OH to 15=O)
what are the two PGE1 analogs
misoprostol and alprostadil
misoprostol
prophylactic for NSAID-induced gastric ulcers
low dose-cytoprotection
high dose-inhibits gastric acid production
abortion or induce labor
alprostadil
maintain patency of ductus arteriosus
2nd line for erectile dysfunction by relaxing smooth muscle of corpora cavernosa
PGF2a analog
latanoprost
latanoprost
treatment of ocular hypertension and open-angle glaucoma by increasing outflow of aqueous humor
arachidonic acid forms 5-HPETE via what
5-lipoxygenase/FLAP
5-HPETE forms LTA4 via what
5-lipoxygenase/FLAP
LTA4 forms LTB4 via
LTA4 hydroxylase
LTA4 forms LTC4 via
LTC4 synthase
LTC4 forms LTD4 via
gamma glutamyl transpetidase
LTD4 forms LTE4 via
dipeptidase
LTC4,D4,E4 go to
cysteinyl leukotriene receptor
LTC4,D4,E4
slow reacting substances of anaphylaxis
during anaphylactic reaction, secreted by mast cells to casue prolonged slow smooth muscle contraction and plays major bronchoconstrictor role in asthma
major source of LTB4 and function
neutrophils (BLT1)
activation of neutrophils, margination, migration, degranulation, superoxide anion generation, eicosanoid synthesis
plasma exudation
major source of LTC4,D4,E4 and function
mast cells, basophils, eosinophils
bronchoconstriction, vasoconstriction, decreased coronary blood flow, decreased cardiac contractility, plasma exudation
arachidonic acid forms 5-HPETE via
5-lipoxygenase
5-HPETE forms 5HETE which does
chemotaxis
5-HPETE forms lipoxin A4 and B4 (LXA4,LXB4) via
12-lipoxygenase
function of LXA4 and LXB4
inhibit neutrophil adhesion and chemotaxis
selective eicosanoid inhibitors
COX inhibitors, LOX inhibitors, LT receptor antagonists
COX inhibitors
called NSAIDs (non-steroidal anti-inflammatory drugs)
non-selective ( irreversible inhibitors (salicylates) competetive inhibitors)
COX-2 selective (-coxibs)
all except aspirin are reversible
block hydrophobic channel of COX protein where AA binds, prevents AA to PGG2
no effect on peroxidase enzyme activity
irreversible COX inhibitors
salicylates include aspirin (acetylsalicycli acid) and its derivatives
aspirin acetylates serine residue of COX covalently and irreversibly inactives COX-1
aspirin switches catalytic activity of COX-2 to produce anti-inflammatory mediators
what is aspirin used for
rarely for anti-inflammatory. more commonly for anti platelet aggregration
platelets express high levels of what
thromboxanse synthase but not prostacyclin synthase
vascular endothelium expresses what
prostacyclin synthase but no thromboxane synthase
what does eating omega-3 fatty acids (DHA, EPA) do?
shifts balance towards generation of COX- and LOX-mediated anti inflammatory molecules
DHA can use LOX to form
resolvin, D1,D2,D3,D4,protectin D1, maresin 1
all are anti inflammatory, promote resolution
EPA can use LOX and COX to form
resolvin, E1, E2
anti-inflammatory and promote resolution
EPA can use COX to form
PGG3
PGG3 can use LOX to form
PGH3
PGH3 can lead to
PGI3 (active)
PGE3 (less)
TXA3 (inactive)
antiinflammatory and reduce aggregation
AA via lox forms
LTB4,C4,D4,E4
inflammatory, chemotaxis, bronchoconstriction
AA via cox forms
PGG2
PGG2 via cox forms
PGH2
PGH2 forms
PGI2 (active)
PGE
TXA2(active)
inflammatory, platelet aggregation
aspirin starts as a pro-drug and need to be biotrasnformed into what, where
to salicylates in the liver
80-90% are bound to plasma protein
salicyclates are excreted where
through the kidney
depends on dose, and urine pH since they are organic acids (pka 3-3.5)
low dose half time salicyclates
2-3hrs 1st order
high does half time of salicyclates
15-30 hrs 0 order
at high doses the liver fails to transform salicylates into what
salicycluric acid and phenolic glucuronide which account for 80% of excretion by the kidney
where do metabolites of salicyclates increase
increase in GFP and proximal tubule secretion via reduction
adverse effects of aspirin
gastroitestinal ulceration and hemorrhage
nephrotoxicity
tinnitus (ringing in the ears)
aspirin induced airway hyerpactivity
why is there aspirin induced airway hyperactivity
shift in reaction from cycloocygenase to lippoxygenase pathway
what is reye’s syndrome
swelling and damage to liver and brain in young children and tennagers recovering from viral infection
how to do you treat salicyclate toxicity
alkaline diuresis
clinical indications for aspirin
mild to moderate pain (headache, myalgia, arthalgia)
phrophylaxsis of stroke and mycocardial infarction
contraindiccations of aspirin
aspirin hypersensitivity
aspirin triggered asthma
children and teenagers with chicken pox of flu due to risk if reye’s
what to use for children and teens instead of apsirin
acetaminophen
acetaminophen classification
as an NSAID but is not technically one
high levels of what can render acetaminophen ineffective in inhibiting COX?
peroxides
where can acetaminophen inhibit COX
centrally (in the brain) where peroxide levels are low
what can acetaminophen be used for
analgesic and antipyretic like aspirin but not anti-inflammatory
problems with acetaminophen
liver toxicity and death due to saturation of glucuronidation, sulfation, and GSH conjugation reactions, yielding toxic NAPQI
treatment of acetaminophen posioning
N-acetylcysteine
non selective reversible NSAIDS
inhibit cox-mediated generation of proinflammatory eicosaniods
anti-inflammatory, antipyretic, analgesic
how to antipyretics work
most likely related to ability to decrease PGE2 levels in regions of the brain surrounding the hypothalamus
how doe PGEs, PGI2, and LTB4 lower threshold of nociceptors
sensitizing afferent nerve endings to effects of chemical or emchanical stimuli
inhibition will raise threshold of nociception
clinical indications for non-selective reversible NSAIDs
mild to moderate pain dysmenorrhea fever gout osteoarthritis, rheumatoid arthritis patent ductus arteriosus closure
non-selective reversible NSAIDs
increase incidence of stomach or intestinal ulcers especially in elderly
bleeding
fluid retention, kidney failure
hypertension
basics of non-selective reversible NSAIDs
pharmacodynamics not kinetics predict response
indication and efficacy vary
in one is not effective, substitute
each attempt with a dose to reach maximum anti-inflammatory range is about 2 weeks
what are the acetic acid derivatives
indomethacin, diclofenac, ketorolac
inhibit COX, promotes incorporation of unesterified AA into triglycerides to reduce availability
indomethacin
can directly inhibit neutrophil motility
no longer first choice NSAID due to GI toxicity
diclofenac
can alter FA transport and reduce intracellular AA
more potent anti-inflammatory agent than indomethacin
ketorolac
primarily used for its strong analgesic properties
only NSAID approved for parenteral use, uses short term due to more side effects
what are the propionic acid derivatives
ibuprofen, naproxen
ibuprofen
relatively potent analgesic used in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, primary dysmenorrhea
better than indomethacin
naproxen
has long plasma half life
more potent than aspirin
directly inhibits leukocytes function and causes less severe GI adverse effects than aspirin
indications for naproxen
for patients resistant to other propionic acid derivatives
it is presented in pur active isomer while others need to be activated
oxicam derivatives and others
piroxicam
piroxicam
efficacious as aspirin, naproxen and ibuprofen in treatment of rheumatoid arthiris and osteoarthritis but better tolerated
inhibits collagenase, proteoglycanase and oxidative burst to modulate neutrophil function
long half life-57 hrs, give daily
problem with COX-2 inhibitors
COX-2 is essential for kidney function and major enzyme for PGI2 produciton which opposes TXA2 in platelets
COX-2 selective inhibitors
celecoxib
celecoxib
anti-inflammatory, antipyretic, and analgesic similar to other non-selective cox inhibitors
no anti-platetlet
clinical indications for celecoxib
acute pain primary dysmenorrhea nakylosing spondylitis osteoarthritis rheumatoid arthritis
adverse effects for celecoxib
increased incidence of MI, stroke, heart failure
peripheral edema
exacerbation of asthma
GI bleeding (less than non-selective NSAIDs)
selective eicosanoid inhibitors
LOX inhibitors
LT receptor antagonists
LOX inhibitors info
leukotriene mediated pathophysiology includes
asthma, inflammatory bowl disease, rheumatoid arthritis, current pharmacoloic agents only target asthma
what is a LOX inhibitor
zileuton
zileuton
selective 5-LOX inhibitor
chelates nonheme iron on 5-LOX to inhibit LTB4,C4,D4 and E4 formation
indicated for asthma, not use due to low bioavailability, low potency, and liver toxicity
LT receptor antagonists
montelukast
zariflukast
montelukast, zafirlukast
LTD4 receptor antagonist
LTC4 and LTE4 also bind to LTD4 recetor with less affinity
both are indicated for asthma
montelukast is also indicated for seasonal allergic rhinitis
non-selective eicosanoid inhibitors
cytokine inhibitor
glucocorticoids
what causes upregulation of COX-2 mRNA and increased PG synthesis
cytokines (IL TNFa) released from damaged cells or immune cells
anti-TNFa or anit-IL agents bind where and do what
binds to cytokines and prevent them from activating the eicosanoid pathways involved in inflammation
aspirin-triggered lipoxins also block TNFa
glucocorticoids
inhibit phospholipase A2 and prevent AA release
limit inflammation by limiting AA inflammatory mediators
glucocorticoids are what kind of anti-inflammatory drugs
steroidal, in contrast with NSAIDS
chronic uses of glucocorticoids
associated with osteoporosis, muscle wasting, and abnormal carbohydrate metabolism
glucocorticoids actions
not limited to inhibition of PLA2
not direct inhibitors of PLA2
4 things glucocorticoids do
induce lipocortins that inhibits PLA2
induce lipocortins on leukocytes to inhibits pro-inflammatory response by activiating lipoxin A4 receptor
repress COX-2 gene and ezyme expression
respress cytokine expression that activates COX-2
