Cell Membrane Phospholipids Phospholipase A2
Li po
xy
C yc lo
ox y
ge
na se
Arachidonic Acid
Prostaglandins Thromboxanes Prostacyclins
Others
Isoprostanes Cyt. P450 products
ge na
se
Leukotrienes
Cell Membrane Phospholipids Phospholipase A2
Arachidonic Acid Cyclooxygenase I&II
Prostaglandin H2 Thromboxane A2
TXA2 synthase isomerase
PGI2 synthase
Prostacyclin (PGI2)
reductase
Prostaglandin D2
Prostaglandin F2Îą Prostaglandin E2
Cell Membrane Phospholipids Phospholipase A2
HPETE-12
12-LO
Arachidonic Acid
15-LO
5-Lipoxygenase
Leukotriene B4
HETE-15 Lipoxins
5- HPETE
Hydrolase
Leukotriene A4
Dehydrase
5-HETE
Glutathione S-transferase
Leukotriene C4
Leukotriene D4 Peptidase
Leukotriene E4 Peptidase
Cell Membrane Phospholipids Phospholipase A2
C yt .P
45
0
Arachidonic Acid
Compounds with activity on vascular & renal tissue. Role in physiology/patho= Physiology uncertain
N on -e
nz ym
at
ic
Isoprostanes (free radiacal-induced peroxidation of AA. Not blocked by NSAID’s
Endothelium, brain, spinal cord COX-2 also in •• Kidney (Macula densa), ovaries, uterus
Cyclooxygenases I and II Cyclooxygenase I • • • •
Constitutive mRNA: 2.7 kb Protein: 602 AA mRNA induced by: Serum ↑ cAMP ↑ IL-1 ↑ LPS ↓ Corticosteroids --
Cyclooxygenase II • • • •
Inducible mRNA 4.8 kb Protein: 604 AA mRNA induced by: Serum ↑↑↑↑ cAMP ↑↑↑ IL-1 ↑↑↑↑ LPS ↑↑↑ Corticosteroids ↓ ↓ ↓
Modulators of the pathways • NSAID’s and Corticosteroids (COX Inhibitors) • Lipoxygenase Inhibitors (Zileuton) • TXA2 Synthase Inhibitors • Receptor Antagonists (TXA2) • LTD4 Receptor Antagonist (Montelukast) • Analogues (PGE2, PGI2, Archidonic Acid)
Pharmacological/Physiological Effects 1. 2. 3. 4. 5.
I. Cardiovascular System TXA2: vasoconstrictor. PGE2 and PGI2: vasodilators. LTC4 and D4: increased vascular permeability. ↓Cardiac contractility. ↓ blood pressure. Protective effect of vasodilator prostaglandins especially in kidney. Renin release by MD and baroreceptor mechanisms.
Pharmacological/Physiological Effects II. Platelets ARACHIDONIC ACID COX -1
Platelet TXA2
Vasoconstriction Platelet Aggregation
_
_
ASPIRIN
COX -2
Endothelial PGI2
Vasodilation Anti-Platelet Aggregation
Pharmacological/Physiological Effects III. Pulmonary 1.
2.
LTC4 and D4: Bronchoconstriction + ↑mucus secretion + ↑vascular permeability PGE2 , PGI2: bronchodilators.
1. 2.
3.
IV. GI Tract PGE2 + LT’s contract smooth muscle PGE2: watery diarrhea, vomiting and cramps (↑cAMP) PGE2+ PGI2: inhibit gastric acid secretion; Cytoprotective effect (↑ mucosal blood flow; ↑cAMP; ↑ mucus secretion; ↑ protein synthesis). Misoprostol: used to treat peptic ulcers.
Pharmacological/Physiological Effects 1. 2. 3. 4.
V. Reproductive Organs PGE2: relaxes and PGF2: contracts, non pregnant uterus. Both contract pregnant uterus. Role in promoting labor; in miscarriages (premature labor); inducing abortions. Role in maintaining patent ductus arteriosus. Increased concentration in semen: (?) Role in facilitating conception.
Pharmacological/Physiological Effects VI. Pain and Inflammation 1. PGE2, PGI2, LTB4: sensitize nerve endings to painful stimuli. 2. Hyperemia, Edema, Hotness due to increased eicosanoids at inflammation sites. 3. LTB4: chemotactic factor for neutrophils and mononuclear cells. Promotes aggregation and degranulation of PMN’s, adhesion to vessel wall and migration
Therapeutic Uses of Eicosanoids • • • • •
Induction of midtrimester abortion Treatment of peptic ulcer Maintain patency of ductus arteriosus (?) Ischemic disease (Iloprost) Impotence (intracavernous injection of PGE2)
Therapeutic Uses of Modulators • NSAID’s and Corticosteroids: antiinflammatory, analgesic, antipyretic. • Zileuton: for ulcerative colitis, asthma and allergic rhinits: limited success • Montelukast in asthma • TXA2 antagonists in diseases related to platelet aggregation (poor-limited success)
Mean % of Days
33%
32%
19%
Placebo Montelukast .Beclometh
% of patients without asthma attacks
Montelukast in Asthma Mean % days patients experienced sustained asthma control
Beclomethasone
NS Montelukast Placebo Time after randomization (days)
Time to first asthma attack