prostaglandins - lecture

Question 1

arachidonic acid

Answer 1

omega 6 FA that eicosinoids are made from

Question 2

things that stimulate eicosinoid release

Answer 2

injury (exposed collagen, thrombin, damaged cells)
heat (thermal injury)
hormones (bradykinin, angiotensin, vasopressin,cytokines)
Ag-Ab complex, activated complement
bacteria, LPS

all activate phospholipase that act on phospholipid that act on arachidonic acid

Question 3

PG synthesis and action in platelets

Answer 3

TxA2 is released from platelets via COX-1
TxS makes TxA2
leaves via PGT channel
acts on VSMC TPbeta receptor => vasoconstriction
acts on platelets TPalpha receptor => aggregation

Question 4

PG synthesis and action in endothelium

Answer 4

PGalphaS makes PGI2
leaves via transporter?
acts on vascular SMC via IP receptor => vasodilation
acts on platelets via IP receptor => clumping

Question 5

PG synthesis and action in uterus

Answer 5

• PGF2 and PGE2
• Production stimulated by LH
• Stimulate follicle release, cervical ripening, uterine contractions, and penile erection
• So, NSAIDs can be used to prolong gestation and may block premature birth

PGFS makes PGF2alpha
transported out by PGT
acts on uterine smooth muscle by FP receptor => contraction and parturition

Question 6

PG synthesis and action in mast cells

Answer 6

PGDS makes PGD2
leaves via PGT
acts on Th2 lymphocyte via DP2 receptor => chemotaxis
acts on lung epithelial cells via DP1 receptor => allergic asthma

Question 7

PG synthesis and action in most cells

Answer 7

PGES make PGE2
transported through PGT
acts on osteoclasts via EP4 receptor => bone resorption
acts on neurons of OVLT in POA via EP3 receptor => fever generation
acts on ovarian CO cells via EP2 receptor => maturation for ovulation and fertilization
acts on spinal neurons via EP1 receptor => pain response

Question 8

nsaids

Answer 8

• inhibit release of arachinoic acid and also cox1 and cox2 - make it more available to leukotriene pathway?
• They IRREVERSIBLY block COX-1 and COX-2. Since platelets (COX-1) are anucleate, that means no more COX-1 until new platelets are made, versus endothelial cells which can make new COX-2 later.
• They do not block and may even stimulate leukotriene synthesis
• They cause GI damage due to blockage of PG E2 production by COX-1
• They are anti-thrombotic by blocking COX-1, which blocks thromboxane production
• They also reduce risk of colon polyp and adenoma (possibly related to COX-1 blockage)

Question 9

why need cox2 specific inhibitors?

Answer 9

selectively inhibit pg production at inflamatory sites via cox2 but don’t inhibit cytoprotective e pg that are produced by gut epi cells via cox 1

Question 10

aspirin

Answer 10

irreversibly inhibits cox1
acetylates PG synthase => inactivation
given to patients after coronary bypass surgery
can reduce colorectal cancer death because of mutant PI3-kinase in cancer patients

Question 11

vioxx

Answer 11

• very selective for cox 2
• so it’s less GI-damaging than NSAIDs because it doesn’t block COX-1 and its product, PG E2 (gut protective)
• However, this also means selectively blocking prostacyclin production in endothelium (via cox 2) but not blocking thromboxane A2 production via cox 1 - get clots

Question 12

COX1

Answer 12

• Platelets (so NSAID inhibition is long lasting as platelets cannot synthesize new COX-1)
• Blocked by NSAIDs, but not Coxibs or GCs
• Produces PGE2 (gut protective), thromboxane A2 (bad – promotes atherogenesis and vasoconstriction), and PG I (opposite of TxA2)
• Its lack of inhibition by Coxibs is why they promoted vascular diseases

Question 13

COX-2

Answer 13

• Endothelial cells (so NSAID inhibition is is removed once the cells synthesize new COX-2)
• Blocked by NSAIDs, GCs and Coxibs (specific)
• Produces inflammation, , and PG I2 (opposite of TxA2)