02-27 Eicosanoids PHARM

Question 1

OBJECTIVE: Know what prostaglandins and leukotrienes do

Answer 1

Eicosa = 20 in Greek
—synthesize by myriad tissues on demand (i.e. no stores?)
—via arachadonic acid pathway
—Involved in inflammation, muscle tone, thrombosis, parturition and GI secretion

Question 2

OBJECTIVE: Know the counterbalance of thromboxane and prostacyclin in the vascular system

Answer 2

COX1 in platelets makes TXA2 (thromboxane A2) which causes vasoconstriction and platelet aggregation
—COX2 (and COX1) in enedothelial cells makes PGI2 (prostacyclin) which causes vasoDILATION and STOPS platelet aggregation
—ASA irrerversibly inhibits platelet COX1, and platelets don’t have a nucleus and therefore can not synthesis a new COX1 to replace it; other NSAIDs reversibly inhibit COXs
—COX2-selective inhibitors block only the production of prostacyclin leaving TXA2 unopposed and predisposing the patient to thrombosis

Question 3

OBJECTIVE: Know how NSAIDs and ant-inflammatory drugs target prostaglandins and leukotrienes

Answer 3

NSAIDs - (aside from ASA) reversibly inhibit both COX1 and COX2

Question 4

OBJECTIVE: misoprostol [BOLD ON DRUG LIST]
—Indication
—Analog of
—Receptor
—ADRs
—Contraindications

Answer 4

INDICATION: ulcer prevention during long-term NSAID therapy, abortion, inhibition of gastric acid secretion
ANALOG OF: prostaglandin E1 (PGE1)
RECEPTOR: EP1
ADRs: diarrhea and occasional abdominal discomfort
Contraindications: pregnancy

Question 5

OBJECTIVE: Alprostadil is an analog of? [NOT BOLD ON DRUG LIST]

Answer 5

Alprostadil (PGE1 analog)

Trade Names:Caverject, Caverject Impulse ®

Drug Class:Prostaglandlin, PGE1 analog.

Mechanism of Action:Vasodilator

Indications:
Treatment of Erectile Dysfunction that does not respond to PDE-5 inhibitors (e.g. sildenafil)
Success rate of ~65%

Pharmacokinetics:
Can be injected directly into the cavernosa, used as a topical cream, or placed in the urethra as a minisuppository, from which it diffuses into the cavernosal tissue

Side Effects:
penile pain (29-49% of users)
urethral bleeding (5%)
hypotension within 1 hour of use (3.3%)

Question 6

OBJECTIVE: Epoprostenol is an analog of? [BOLD ON DRUG LIST]

Answer 6

prostacyclin (PGI2)

Question 7

OBJECTIVE: Iloprost is an analog of? [NOT BOLD ON DRUG LIST]

Answer 7

prostacyclin (PGI2)

Question 8

OBJECTIVE: Dinoprostone is an analog of? [NOT ON DRUG LIST, JUST IN SLIDES]
—Uses?
—Recptor

Answer 8

ANALOG OF:
prostaglandin E2 (PGE2)

USES:
Uterine contract, abortifacient (v.s.), Cervical ripening (gel)

RECEPTOR:
EP1 (same as PGE1)

Question 9

OBJECTIVE: Latanoprost is an analog of? [NOT BOLD ON DRUG LIST]

Answer 9

prostaglandin F2α (PGF2a)

Question 10

What’s the target of the drug montelukast? [NOT ON DRUG LIST, JUST IN SLIDES]

Answer 10

It is a leukotriene-receptor antagonist

Question 11

What’s the target of the drug zileuton? [NOT BOLD ON DRUG LIST]

Answer 11

zileuton = Lipoxygenase inhibitor (i.e. prevents the synthesis of the leukotriene precuros LTA4

Question 12

What’s the target of the drug zafirlukast? [NOT BOLD ON DRUG LIST]

Answer 12

It is a leukotriene-receptor antagonist

Question 13

BOARD Q: Rate limiting step in eicosanoid formation?

—Next step(s)?

Answer 13

Phospholipid from membran —Phospholipase A2 → arachadonic acid
—A.A. can now go to cyclooxygenase (1 or 2) OR to lipoxygenase

Question 14

What’s the target of corticsteroids?

Answer 14

Phospholipase A2 and cyclooxygenase, therefore they stop production of arachadonic acid

Question 15

BOARD Q: Which prostaglandin has cytoprotective effects on the gastric mucosa?

Answer 15

PGI1 - misoprostol

His slides say PGE2, and its synthetic analogs like dinoprostone

Question 16

BOARD Q: Which prostaglandins are major mediators of asthma?

Answer 16

leukotrienes

Question 17

BOARD Q: Which prostaglandin is a major mediator of pain and fever?

Answer 17

PAIN PGE2 (PGI2 and LTB4)
Sensitize nerve endings to painful stimuli
—Edema, hotness, inc. vascular permeability by PGE2, PGI2 and LTs

FEVER
PGE2 has been implicated as being pyretic with high levels detected in the hypothalamus. May be responsible for elevating hypothalamic set-point for temperature control in fever

Question 18

BOARD Q: Which prostaglandins mediate dysmenorrhea?

Answer 18

-PGE2 and PGF2 (released causes uterine contraction and pain) in dysmenorrhea

Question 19

BOARD Q: Which prostaglandin lowers intraocular pressure?

Answer 19

PGF2 Mechanism unknown

Question 20

Second messenger of both classes of leukotriene receptors?

Answer 20

the second messenger is IP3 with a subsequent increase in [Ca2+] in the cytosol.

Question 21

Most potent contractor of bronchiolar smooth muscle?

Answer 21

leukotrienes (esp LTC4 and LTD3

Question 22

Mechanism of ASA hypersensitive asthma

Answer 22

arachadonic acid is shunted towards leukotriene pathway

—excess LTC4 and LTD4 causes inflammation, muscle contraction, vasopermeability, etc.

Question 23

BOARD Q: Which drugs act on a patent ductus arteriosus?

Answer 23

Know that PGE2 and analogs (dinoprostone) are used to keep patent ductus open in infants with heart defects (e.g. transposition of the great vessels).
—Know that NSAIDs (Ibuprofen, indomethacin) are used to close ductus in otherwise healthy infant. (thus contraindicated in preg)

Question 24

BOARD Q: Which prostaglandins are used for pulmonary HTN?

Answer 24

prostacyclin (PGI2) and derivatives:
—iloprost (longer t1/2)
—epoprostenol (3-5 min t1/2)