Eicosanoids & Prostaglandin-based Drugs

1. Eicosanoids include prostaglandins (PGs), leukotrienes (LTs), and epoxygenase products of cytochromes P450 (CYPs).

2. They are synthesized from membrane lipids, primarily from ____

• every nucleated cells is capable of synthesizing these eiscosanoids

arachidonic acid (AA).

______ is formed enzymatically from membrane glycerophosphocholine derivatives by leukocytes, platelets, and endothelial cells.

Platelet-Activating Factor (PAF)

Eicosanoids and PAF act as signaling molecules affecting vascular tone, renal function, hemostasis, inflammation, and immunity.

1. inflammation and pain are mediated by ____

prostaglandin

Eicosanoids and PAF act as signaling molecules affecting vascular tone, renal function, hemostasis, inflammation, and immunity.

• inflammation in lung mediated by ______

leukotrienes

____ is the enzyme in the first step in the synthesis of eicosanoids → helps membrane phospholipid make arachidonic acid

Phospholipase A2

AA is acted on by ____to form prostanoids (PFE2, PGF2a, PGI2 aka prostacyclin, TXAs)

COX 1 and CO2

- ____ always expressed (always being made, not upregulated when theres inflammation

COX 1

- ______ is made in response (is upregulated in response to inflammation, injury, illness etc

COX 2

- AA is also acted on by ______→ forms leukotrienes

• we can also inhibit the synthesis of leukotrienes by inhibiting ______

5-lipooxygenase (5-LOX)

binds to PGE2 → ⬆ Ca2+, ⬇ cAMP

EP1/EP3 (prostaglandin E receptor 1/3)

binds to PGE2 → ⬆cAMP

EP2/EP4 (prostaglandin E receptor 2/4)

which prostagandins is dominant in dominant tissue: GI, uterine smooth muscle to be used for contraction, cytoprotection

EP1/EP3 (prostaglandin E receptor 1/3)

which prostaglandin dominant tissue is cervix, vessels, immune cells for the effects of relaxation, cervical ripening (soften the cervix so labor comes easier)

EP2/EP4 (prostaglandin E receptor 2/4)

EP1/EP3 (prostaglandin E receptor 1/3) drug that is CI in pregnant women bc it can lead to miscarriage by causing uterine contractions

misoprostol

binds to PGF2a → ⬆ Ca2+

FP (Prostaglandin F receptor)

dominant tissue: uterus, cilliary muscle, effect = uterine contraction, ⬆ uveoscleral outflow (used for glaucoma because helps drain aqueous humor)

FP (Prostaglandin F receptor)

binds to PGI2 (prostacyclin) → ⬆cAMP

IP Prostacyclin receptor

2. primary tissue: pulmonary vessels, platelets

3. effect: vasodilation, ⬇ platelet aggregation

1. used in pt with pulmonary HTN (where pulmonary vessels are constricted and has an increased risk in throwing clots

IP Prostacyclin receptor

binds to TXA2 → ⬆ Ca2+

TP (thromboxane A2 receptor)

2. dominant tissue: platelets, vessels

3. effect: aggregation + vasoconstriction (OPPOSITE OF PROSTACYCLIN)

TP (thromboxane A2 receptor)

1. Regulation of vascular tone:

1. Vasodilation:_____

PGI, PGE, and PGD

1. Regulation of vascular tone:

2. Vasoconstriction: ____

TxA2 and PGF

2. Fetal circulation: Maintenance of patent ductus arteriosus by_____

1. fetus doesnt breathe in womb → they get blood from mother ⇒ ductus arteriosus is the conduit that bypass lung

2. if fetus born with congenitive heart defects, doctors keep it open on purpose → prostaglandin keeps this vessel open

3. if fetus born with patent ductus arteriosus → want to close it like it normally does → used NSAIDs to inhibit COX (which then inhibits prostaglandins that keeps it open

PGE2

3. Cardiac effects: ______ protect against oxidative injury

1. decrease free radical damage → good guys

PGI and PGE

4. Renal function regulation: COX-2 derived_____ increase renal blood flow and renin release.

1. prostaglandins (_________) keep renal vasculature open → allow proper circulation = increase blood flow and increase glomerulus filtration

1. pt on NSAIDs (which block clots and production of the prostacyclins) can result in renal damage (via decrease prostanoids production and causing vasoconstriction, decreasing glomerular filtration

PGE and PGI

Gastrointestinal functions: _____ protect mucosa, reduce acid, and stimulate mucus

PGE and PGI

Reproductive effects: _______ regulate uterine contraction and parturition.

PGF and PGE

7. CNS regulation: _____ induces fever and modulates pain perception

1. _____ induce fever → fever is beneficial = suppress growth of pathogenic organisms

2. NSAIDs and COXi will ⬇ fever because it decrease the production of ______

3. PGD= sleep; no analog as of rn

PGE and PGF

List the PGE₁ Analog

misoprostol and aprostadil

MOA: EP₃-mediated reduction of gastric acid secretion plus mucosal protection

misoprostol

USE: Prevent NSAID-induced gastric ulcers → approved GI use; evacuate uterus in miscarriage or abortions

misoprostol

Misoprostol CI

pregnant

two same molecule to different tissue causes different effects (GI=Acts as a protectant by increasing the thickness of the protective gastric mucus layer and reducing stomach acid secretion; uterus= Stimulates strong uterine smooth muscle contractions)

misoprostol

USE: keeps ductus arteriosus open (babies born with congenital heart defects are brought more time until their cardiac surgury) AND erectile dysfunction/impotence

or

ED: intracavernosal smooth muscle injection (Caverjet); or urethral suppositories (Muse)

alprostadil

List the PGE2 Analog

Dinoprostone

1. EP-receptor agonism softens and dilates the cervix and stimulates myometrial contraction.

2. USE: ripen cervix before labor induction (relaxing smooth muscle of cervix leads to myometrial contraction of uterus)

dinoprostone

ADRs: uterine tachysystole (5+ contractions in 10 mins or less), fetal heart rate changes, nausea, vomiting, diarrhea

dinoprostone

Prostaglandin F Receptor: list the PGF2a analog

carboprost

MOA: FP-receptor agonism drives strong myometrial contraction when oxytocin and uterine massage fail

carboprost

USE: Stop refractory postpartum hemorrhage → causes vessel to contrict= stop bleeding

• Also labeled: second-trimester pregnancy termination

carboprost

carboprost CI

asthma

carboprost ADR

bronchoconstriction due to FP receptors in lungs

Ocular FP agonist

Latanoprost (Xalatan), Travoprost (Travatan Z), Bimatoprost (Lumigan), Tafluprost (Zioptan), Latanoprostene bunod (Vyzulta)

MOA: FP-receptor agonism help increase uveoscleral outflow → decrease intraocular pressure

Latanoprost (Xalatan), Travoprost (Travatan Z), Bimatoprost (Lumigan), Tafluprost (Zioptan), Latanoprostene bunod (Vyzulta)

Latanoprost (Xalatan), Travoprost (Travatan Z), Bimatoprost (Lumigan), Tafluprost (Zioptan), Latanoprostene bunod (Vyzulta) ADRs

iris pigmentation

list the prostacyclin: PGI2 Analog

epoprostenol, iloprost, treprostinil, selexipag

MOA: IP signlaing: increased cAMP = pulmonary vasodilation and platelet inhibition

PGI2 Analog: epoprostenol, iloprost, treprostinil, selexipag

PGI2 Analog use

hyperpulmonary hypertension

selexipag DDI

• because selexipag is metabolized by cyp 2c8

gemfibrozil