PROSTAGLANDINS

LEUKOTRIENES
ACTIONS, AGONISTS AND
ANTAGONISTS

ARTHUR PRANCAN, PH.D.

 Learning Objectives

 Discovery – Prostaglandins (PG) and Cyclo-

oxygenase (COX).
 Understand synthesis of PGs and Leukotrienes
(LT). How do you block synthesis?
 Know PGs, LTs and their actions. Why do we
block their synthesis or actions?
 Identify drugs which imitate PGs and which
block synthesis or action of PGs and LTs.
Discovery – U.S. von Euler
 Prostaglandin Discovery

 Isolated Guinea Pig ileum

 A – Unknown substance added to the prep.
 B – Atropine (anticholinergic) pre-treatment
followed by unknown substance.
 Not acetylcholine-mediated event. This action
is new and must be explored.
 The Name - Prostaglandin

 1934 – Professor Ulf von Euler, Karolinska

Institute, Sweden, named Prostaglandin.
 He found biological activity in ram seminal
vessicle extracts and believed he had
discovered a sex-accessory hormone.
 Prosta– is related to sex-specific glands
–glandin is hormone in Swedish.
 Global activity of PGs was revealed in 1960s,
too late to make a definitive name change.
 The Basics – Chemical Origin

 Essential fatty acids released from the cell

membrane are cyclo-oxygenated to form this
primary structure.
 20-carbon carboxylic acid. Letter (e.g. E, F)
designates ring; number (E2), double bonds.
The Basics - Synthesis
 Prostaglandin Synthesis by
Cyclooxygenases COX-1 and -2
Basics - Arachidonic Acid Pathways
 COX = Cyclooxygenase

 Enzyme essential for the synthesis of

prostaglandins (PGs)
 PGs are chemical mediators with cellular
protective (COX-1) and healing/destructive
properties (COX-2)
 Aspirin and Non-Steroidal Antiinflammatory
Drugs (NSAIDs) block COX-1 and COX-2
 COX-2 Inhibitors control inflammation and
avoid loss of protection at COX-1 sites
 COX Site, Product, Action
COX-1 COX-2
GI Tract – PGE2 Inflammed Tissue
Cytoprotection PGE2
Anti-acid Pain, Swelling, Redness
Platelet Blood Vessel Wall
Thromboxane A2 Prostacyclin
Initiates Thrombosis Antithrombotic
Kidney, Arterioles
PGE2, Prostacyclin
Antihypertensive
 Thromboxane A2 (TXA2)

 Vasoconstrictor
 Bronchoconstrictor
 Synthesized by platelets, key in aggregation.
 Announced in 1974 by Bergstrom, Hamberg
and Samuelsson, Karolinska Institute.
Found it by superfusing active platelets over
rabbit aorta. It was recognized as a
prostaglandin.
 Cardiologists began eating aspirin. “An
aspirin a day keeps the heart attack away”
 Thromboxane Synthesis

Platelet
Membrane-bound fatty acids

Free fatty acid Aspirin

irreversible
COX acetylation

Thromboxane A2

Platelet Aggregation, release response, arterial constriction

 Prostacyclin (PGI2)

 Vasodilator
 Bronchodilator
 Stabilizes platelets, disaggregates platelets
 Produced by vascular endothelium
 Autoregulates local blood flow and platelets
 Reported by Salvador Moncada at the
Interscience Conference in Santa Monica,
December 1976. He called it PGX.
 Prostacyclin Synthesis

Endothelial Cell (blood vessel wall)

Membrane-bound fatty acids

Fatty acid, COX and Aspirin

Prostacyclin

Inhibit Platelet Aggregation, Relax Blood Vessels

 Prostaglandin E2 (PGE2)

 Vasodilator
 Bronchodilator
 Cytoprotective in GI tract
 Regulates renal blood flow, probably is a
local vascular autoregulator of flow
 Proinflammatory: Pain, swelling, redness
 Contracts uterine smooth muscle, active in
labor and delivery
 In research and as a drug, is used as PGE1,
which has the same properties.
Prostaglandin E2 and Pain
Vasodilation by PGE2
 Prostaglandin F2α (PGF2α)

 Vasoconstrictor
 Bronchoconstrictor
 Pathogenic in asthma
 Prostaglandin-Related Drugs

 Alprostadil (PGE1) – vasodilator in

peripheral vascular disease. Maintains an
open (Patent) Ductus Arteriosus.
 Misoprostol (16,16 CH3 PGE1) – GI protective.
 Latanoprost (PG F2α) – topical for glaucoma.
 Epoprostenol (PGI2) – Reversal of pulmonary
hypertension. Also Treprostinil.
 Dinoprostone (PGE2) – Induction of labor,
2nd trimester abortion.
 Carboprost (PG F2α) – Induction of labor
 PG Synthesis Inhibitors

 Aspirin irreversibly blocks COX 1 and 2

Analgesic, antipyretic, antiinflammatory.
 NSAIDS are non-selective, reversible COX
inhibitors (ibuprofen). Analgesic,
antipyretic, antiinflammatory.
 COX-2 selective inhibitors (celecoxib) are
antiinflammatory.
 Acetaminophen is analgesic, antipyretic, but
not antiinflammatory.
The Low Dose Aspirin
Story

ARTHUR PRANCAN, PH.D.

 Vascular Pathology I

CUT

collagen
Vessel Lumen
no plug

Prostacyclin

yes
 Vascular Pathology II

Prostacyclin
no
yes
ruptured atheroma

Vessel occlusion or a downstream thrombus and occlusion

 Platelet - Platelet Interactions

collagen Prostacyclin
vessel damage
inhibits
fibrinogen
GP 1a bridging PI
GP
TXA2 IIb/IIIa GP IIb/IIIa
ADP
5-HT
Receptors

More Products
activate
 Low Dose Aspirin Allows PGI2
Recovery
Cells have a nucleus
Platelets have no nucleus
Can replace COX
and cannot make more COX.
AA No TXA2 for life of platelet
ASA XX COX AA aggregation
ASA XX COX
PGH2 TXA2
PGH2
healthy
cell will
repel
TXA2
Prostacyclin
platelets

Will make more platelets

stops
prostacyclin aggregation
and adhesion
 COX-2 Inhibition – Stroke, MI
COX-2 is
Platelets are not stopped
Blocked
by COX-2 block.
AA
Opposite to effect of aspirin.
XX

PGH2 aggregation
TXA2
Will
not
repel TXA2
No Prostacyclin
platelets
COX-1
aggregation
and adhesion are unopposed
 Follow-up To COX-2 Toxicity

 COX-2 selective drugs block synthesis of

Prostacyclin
 COX-2 selective drugs do not block
Thromboxane synthesis by platelets.
 Therefore, a potential for platelet-mediated
cardiovascular events may be promoted by
selective COX-2 therapy alone.
 Current thinking is that low dose aspirin
should be continued with COX-2 blockers.
Leukotriene Synthesis
 Leukotrienes C4, D4

 Bronchoconstrictors
 Chemoattractants
 Chemokinetic modulators of leucocyte
activity and extravasation in inflammation.
 Local edema
 Asthma
 Inflammation
Inflammatory Tissue Swelling
 Leukotriene Modifiers
All drugs are used orally for asthma,
including aspirin sensitive asthma.

 Zileuton blocks lipoxygenase, inhibits LT

synthesis.
 Zafirlukast is a receptor antagonist.
Toxicity is Churg Strauss Syndrome,
systemic eosinophilic vasculitis when
steroid dose is decreased.
 Montelukast (Singulair) is a receptor
antagonist. Named for Montreal by Merck.
Side effects are GI distress, bleeding and
hypersensitivity.
 Postview of Objectives

 Where in the synthesis can a drug stop PGs and

LTs?
 Which drugs block lipase, COX and LO?
 Which drugs block LT receptors?
 What is the concept which makes low dose aspirin
more effective than high dose aspirin in preventing
thrombosis?
 MOA, usefulness: Alprostadil, Misoprostol,
Latanoprost, Epoprostenol, Dinoprostone,
Celecoxib.
 MOA, usefulness: Aspirin, NSAIDS,
Acetaminophen.
 The End
WHATEVER YOU DO, PRESERVE
PROSTACYCLIN.