Eicosanoid Drugs and their Signaling

List Prostaglandins That Signal the Reproductive Tract

Misoprostol

Dinoprostol

Alprostadil

Carboprost thromethamine

List Prostaglandins That Signal the Glaucoma

Lantanoprost (Xalantan)

Bimatoprost (Lumigan)

Travoprost

Unoprostone

List Prostaglandins That Signal GI cytoprotection

Misoprostol

List Prostaglandins That Signal the Pulmonary Hypertension

Iloprost

Treprostinil

Epoprostenol

List Prostaglandins That Signal the Ductus Arteriosus

Alprostidil

List NSAIDs and their indications

Ibuprofen, Naproxen, ASA, and indomethacin

Indications;

Anti- inflammatory

Analgesic

Antipyretic

List Leukotrienene antagonist and their indications

Montelukast (Singulair)

Zafirlukast

Indication: Asthma

What’s an eicosanoid? What does it derive from? What is it’s main therapeutic function.

Lipid autocoid mediator ( or “ signaling Molecule”)derived from arachidonic acid.

Their main function is in the VASCULAR SYSTEM, regulating;

• Vasoconstriction

• Platelet Function

• Capillary Permeability

• Renal Function

Of course, Eicosanoids are also contributed to INFLAMMATORY RESPONSES

• Chemotaxis

• Immune Cell Actvation

• GI Secretion

• EYE Secretion

And our NERVOUS SYSTEM;

• Fever ( CNS)

• Pain Sensitivity. ( Both in central and peripheral)

List some pathological involvements eicosanoid can intervene with.

Asthma

Arthritis

Artherosclerosis

Thrombosis

Fever

Cancer

Chronic Inflammation

Etc.

What is the pathway of eicosanoid synthesis we DO NOT manipulate? Why?

P450 pathway; Cytochrome P450’s metabolize almost everything, so if we were t manipulate that pathway, we would be interfering with so many other processing that may not have favorable outcomes.

Describe the pathway of eicosanoid synthesis to produce specific Prostaglandins.

Arachidonic Acid is pulling from the cellular membrane to mediate an inflammatory Respinonse; the Enzyme to initiate this “ pulling” is phospholipase A2 or PL-A2.

Once the Acid is released, it can undergo the prostaglandin pathway or the Leukotriene pathway.

The Prostaglandin Pathways is Triggered by the Cyclooxyrgenase enzymes ( COX1/2) to produce Prostaglandin H2 or “PgH2”

The function of PgH2 now depends on the location:

If it’s effected directly on the platelets entering the hepatic portal vein, it will produce Thromboxane or "TxA2" to promote platelet aggregation and VC.

If PgH2 acts in the endothelium, it promotes prostacyclin which is the exact opposite of Thromboxane, promoting VD and platelet anti-coagulation.

If PgH2 acts in the gastric mucosa, it supports mucus production and cytoprotection.

T/F ASA is an irreversible inhibitor to TXA.

T

Describe the pathway of eicosanoid synthesis to produce specific Leukotrienes

Arachidonic Acid is pulling from the cellular membrane to mediate an inflammatory Response; the Enzyme to initiate this “ pulling” is phospholipase A2 or PL-A2.

Once the Acid is released, it can undergo the prostaglandin pathway or the Leukotriene pathway.

For the Lueukotriene pathway, the released Arachidonic Acid is metabolized by Lipoxygenase enzymes (LOX) to produce Leukotriene A4 (LTA4), which can further be converted into other leukotrienes like LTC4, LTD4, and LTE4, all of which are involved in mediating inflammatory responses that promote bronchoconstriction.

Dramamine is the _____ of Benadryl

Salt ( Diphenhydramate); Benadryl ( Diphenhyramine)

What is the only antihistamine drug that undergoes extensive metabolism in the liver?

Claritin

What enzyme degrades TxB2?

Prostaglandin (“11-hydro-TXB2”) dehydrogenase

What is the mechanism that Phospholipase A2 does to Arachidonic Acid?

Hydrolysis

List the degradation steps for PGE2

1. Prostaglandin Dehydrogenase

2. Reduction/ Beta-Oxidation/ Oxidation ( depends on the location)

What’s the enzyme that mediates the degradation for PGD2?

11- keto reductase

What does DP1-2 mean?

Prostaglandin D receptors 1 & 2

What does EP1-4 mean?

Prostaglandin E receptors 1-4

What does IP mean?

Prostaglandin I receptors or Prostacyclin

What does TPa,b mean?

Thromboxane receptor

What does BLT1-2 mean?

B Leukotriene receptors 1-2

What does CysLT mean?

Cysteinyl Leukotriene receptors 1 & 2

List the prostaglandin receptors that initiate a relaxant response.

IP- Prostacyclin Receptor ( I2)

EP2 - Prostaglandin E receptors 2

EP4 - Prostaglandin E receptor 4

DP1 - Prostaglandin D receptors 1

List the prostaglandin receptors that initiate a Contractile response

TP - Thromboxane receptors 1
EP1 - Prostaglandin E receptor 1

List the prostaglandin receptors that initiate an inhibitory response?

EP3 - Prostaglandin Receptor E 3

Name the Vascular Effects of the indicated Eicosanoid: TXA2

VC

Inducing platelets aggregation at low doses

Name the Vascular Effects of the indicated Eicosanoid: PGF2a

VC

Name the Vascular Effects of the indicated Eicosanoid: PGI2

VD

Inhibit platelet aggregation at high doses ( bind to IP)

Name the Vascular Effects of the indicated Eicosanoid: PGE2

VD

Induce platelet aggregation at low doses (EP3)

Inhibit platelet aggregation at high doses. (IP)

Name the Vascular Effects of the indicated Eicosanoid: PGD2

VD

Name the indicated Eicosanoid that mediates niacin-induced flushing

PGD2

Name the Vascular Effects of the indicated Eicosanoid:

Name the Vascular Effects of the indicated Eicosanoid: LTC4

Slow Hypotensive Effects:

• decreased plasma volume

• increased capillary permeability

• Plasma exudation ( leakage)

What roles would each eicosanoid play?

PGI2:

• Pulmonary Function

• Uterine Contraction

• Renal Perfusion ( GFR)

What roles would each eicosanoid play?

TXA2

• Pulmonary Function

• Uterine Contraction

• Renal Perfusion ( GFR)

What roles would each eicosanoid play?

PGF2a:

• Pulmonary Function

• Uterine Contraction

• Renal Perfusion ( GFR)

• Decreased Pulmonary Function; Brochoconstriction

• Increase Uterine Contraction

What roles would each eicosanoid play?

LTB4:

• Pulmonary Function

• Uterine Contraction

• Renal Perfusion ( GFR)

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List the Eicosanoids that will cause brochoconstricton

• PGF2a

• TXA2

• CysLT

List the Eicosanoids that will cause Bronchorelaxation

PGI2

PGE2

List the Eicosanoids that will cause uterine contraction

• PGF2a

• TXA2

• PGE2 @ low doses

List the Eicosanoids that will cause Uterine relaxation

• PGE2 @ a high doses

• PGI2

List the Eicosanoids that will cause increase GI motility

Prostanoids and Leukotrienes

List the Eicosanoids that will cause Chemotaxis

Leukotrienes, especially LTB4

List the Eicosanoids that will increase edema and leukocyte infiltration

• PGE2

• PGI2

List the Eicosanoids that will increase renal blood flow and cause renin excretion

• PGE2

• PGI2

List the Eicosanoids that will decrease renal blood flow and renin excretion

TXA1

List the Eicosanoids that will cause decrease intra-ocular pressure

• PGF2a

List the Eicosanoids that will mediates pyrogenesis

PGE2

List the Eicosanoids that will sensitize peripheral nerve to pain sensation

PGE2 and PGI2 and LTB4

Glucocorticoids inhibit ______ activity, and block ___________

PLA2; prostaglandin synthesis

What;s a dietary modification to prostaglandin synthesis?

Replacing Arachidonic with Omega 3 Fatty Acids

Outline special populations for ASA

Those with asthma

Liver dysfunction

Under the age of 20

What’s an upside and downside to COX-2 selective drug

Decreases GI bleeding, increases cardiovascular issues like Myocardial Infarction, Angina, and Stroke

Prostanoids help maintain vasodilation of the _______ arteriole

afferent

What’s the lifetime of a platelet?

8 -12 days

The only direct antagonist for eicosanoids are_________

Leukotriene inhibitors

NSAID inhibit _________synthesis

Prostaglandin Synthesis

LOX inhibitors inhibit _______ synthesis

Leukotrienes