Prostaglandins & Leukotrienes

Eicosanoids

• structurally simple but highly biologically ______, ______ substances

• all structurally similar —> ____-carbon molecules

• derived from ______ of lipids (fatty acids)

• all are ______ (stable/unstable)

• diverse, endogenous

• 20

• oxidation

• unstable

Eicosanoids are derived from:

Oxidation of lipids (fatty acids)

Which of the following is TRUE about eicosanoids?

They are structurally simple but biologically diverse

What is the carbon chain length characteristic of eicosanoids?

20 carbons

What do ALL eicosanoids have in common?

They are unstable

Each eicosanoid has own specific functions:

1. inflammation =

2. blood clotting/platelet aggregation =

3. inhibit platelet aggregation =

4. asthmatic + allergic rxns =

• PG

• TX

• PGI

• LT

Eicosanoids are the most important mediators of which process?

Inflammation

Eicosanoids exert their effects primarily through:

GPCRs

Prostaglandins (PGs) activate GPCRs that may be:

Either inhibitory or stimulatory

A single prostaglandin can:

Bind multiple receptor subtypes

Why can the same prostaglandin have different effects in different tissues?

Different receptors are expressed in different tissues

Which enzyme initiates prostaglandin metabolism by oxidizing the 15-OH group?

PG 15-OH dehydrogenase

Which statement best describes eicosanoids?

Eicosanoids = Local, short-lived signals → unstable → rapid breakdown → drugs = agonists OR antagonists

Which reaction type is used by phospholipases to cleave membrane phospholipids and release arachidonic acid?

Hydrolysis

1. add a Ph group —>

1. reduce double bond —>

2. prodrug (iPr ester) —>

• block oxidation

• increase selectivity, slightly decrease potency

• increase lipophilicity —> higher corneal permeability

1. add methyl —>

• in place of H —> block oxidation at carbon 15 by dehydrogenase

What is the major limitation of natural prostaglandins as drugs?

Instability and off-target effects

The therapeutic goal when using prostaglandin agonists is to:

Increase stability and selectivity

Latanoprost is primarily used to treat:

Glaucoma

PGF₂α (dinoprost) induces which physiological effect?

Uterine contractions

PGF₂α is used clinically to:

Induce labor and abortion

Carboprost’s major clinical use is:

Postpartum hemorrhage treatment

Bimatoprost is used for glaucoma and also for:

Eyelash lengthening & darkening

Which prostaglandin analog has the longest plasma half-life listed in the slide?

Bimatoprost (45 min)

What is the effect on stability?

increase

Which has a higher corneal permeability?

B

What is the effect on stability?

no effect

What is the effect on stability?

increase

what does this mechanism increase?

stability

what does this mechanism increase?

selectivity

The modification in bimatoprost that increases both efficacy and stability is:

Ester → amide

Why is local delivery often required for eicosanoid-based therapeutics?

Receptor expression is tissue-specific

The term “local hormones” refers to eicosanoids because they:

Act near the site where they are produced

Which delivery route is commonly preferred for eicosanoid-based drugs?

Local/topical application

Eicosanoids are derived from fatty acids that are:

20-carbon polyunsaturated fatty acids

The double bonds in essential fatty acids that form eicosanoids are typically:

Cis

Which essential fatty acid is the primary precursor for most eicosanoids?

AA (Arachidonic acid)

Omega-3 and omega-6 fatty acids must be obtained:

From dietary sources

Which fatty acid listed is an omega-3 precursor for eicosanoids?

α-Linolenic acid

Which of the following is an omega-6 fatty acid that forms eicosanoids?

Arachidonic acid