NOCAT Prostaglandins

Prostaglandins

Group of lipids made at tissue damage or infection sites

Controls inflammation, blood flow, formation of blood clots, induction of labor

Decreases stomach acid production

Hormone like effects but not secreted from a gland

They are eicosanoids and 20 carbons units in length

Clinical Conditions Involving Prostaglandins

Painful menstruation, arthritis, heavy menstrual bleeding and some types of cancer are all connected to excessive prostaglandins levels

Conditions that can result from too few prostaglandins include glaucoma and stomach ulcers

Production

Following injury enzyme phospholipase A2 is released

Membrane phospholipids are acted upon by phospholipase A2 to liberate arachidonic acid

Arachidonic acid released from membrane phospholipids

Arachidonic acid is acted on by a number of enzymes like COX and LOX that generate large number of active compounds forming enzymes (lipoxygenases (LOX) and cyclooxygenases (COX))

Arachidonic Acid --- LOX or COX---> Prostaglandins

Cyclooxygenases

Has a cyclooxygenase site and a peroxidase site

COX Isoforms

Importance of difference stems from the ability to design drugs that selectively inhibit one or the other type of isoform

COX-1

Constantly expressed/constitutively active

Primarily responsible for production of thromboxane and prostaglandins

Stimulates normal body functions

>>>>Secretion of protective gastric mucus, regulation of gastric acid, promotion of platelet aggregation and maintenance of renal blood flow

COX-2

Induced by inflammatory stimuli

Produces prostaglandins

>>>>>Mainly mediate inflammation, pain and fever

Newer drugs like celebrex and Vioxx are COX-2 selective which most NSAIDS such as ibuprofen (advil), acetylsalicylic acid (aspirin), acetaminophen (tylenol) inhibit both COX-1 and COX-2

Production gone wrong

Any COX inhibitor would stop the production of prostaglandins

Any inhibitor of phospholipase A2 would stop release of arachidonic acid

>>>>Steroids inhibit the mobilization of AA\\

Vioxx and celebrex are COX-2 inhibitors

Storage/Packaging

they are lipophilic and not stored

Release

Many stimuli mobilize AA generated production of prostaglandins

Exit the cell through lipophilic transport pathways

Act extracellularly on GPCRs

Release gone wrong

Inhibitors of the lipophilic transport pathways releasing prostaglandins from the cell would cause a shortage of prostaglandins

Response

Cells have receptors for 1 or more prostanoids

>>>>Usually GPCRs

Each prostaglandin has a preferred receptor with a higher affinity but it can go to other receptors as well (promiscuous)

Makes it difficult to design selective antagonists due to issue of promiscuous prostaglandins

Response gone wrong

Physiological antagonism would reduce the effect of prostaglandins as they are not able to bind to receptors. Other PGs might antagonize the binding of another PG to the receptor.

Difficult to design drugs that are selective agonist/antagonists for prostaglandins (therefore unlikely)

There are receptor agonists which enhance the beneficial effects of prostaglandins

Prostaglandin analogs work by increasing the outflow of intraocular fluid from the eye

>>>Bimatoprost

>>>Side effects is growth of eyelashes and now marketed for that by Latisse

Effects of Prostaglandins

Pyrogenic (fever inducing)

Platelet aggregation

Vasodilation (widening of blood vessels)

Uterine contraction

Gastric mucus production

Sleep inducing

Neurotransmission

Lower intraocular pressure (IOP) (Fluid pressure in eye)

Effects of Too Much Prostaglandin

High levels of prostaglandins are produced in response to injury or infection and cause inflammation, which is associated with the symptoms of redness, swelling, pain and fever.

Arthritis and menstrual cramping

Effects of Too Little Prostaglandin

Pain, fever, inflammation, blood clots possibly from platelet aggregation

Glaucoma and stomach ulcers

Termination

Intracellular transport/uptake into the cell

Prostaglandin specific enzymatic degradation

Go Wrong

Inhibitor of the uptake mechanism/intracellular transport of prostaglandin

Inhibitor of the enzyme involved in enzymatic degradation of prostaglandin

Lingering PGs cause effects due to products being metabolically active