Lecture notes on Eicosanoids Rajesh Kotha : rajesh4pharmacology@gmail.com
EICOSANOIDS These are the chemical mediators act as autocoids, derived from 20 member fatty acids. So, these are termed as eicosa which means twenty noids. Eg: prostaglandins, thromboxanes and leukotrienes Mostly these eicosanoids are derived from arachidonic acid (eicosatetraenoic acid). Eicosanoids are denoted as PG, TX and LTs for prostaglandins, thromboxanes and leukotrienes respectively. This denotation is followed by alphabets A,B,C etc, which indicates their order of discovery and alphabets will have a numerical like 1,2 etc which indicates the no. of double bonds. ARACHIDONIC ACID RELEASE: In body fatty acids are like arachidonic acid are incorporated in membrane phospholipids in any of the three forms like phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol. By the action of enzymes like phospholipases, membranes get breakdown into various products and these end products depends on enzyme subtype. 
Phospholipase C involved in production of 2nd messengers IP3 and DAG
 Phospholipase D and Phospholipase A2 are involved in production of arachidonic acid. The formed arachidonic acid will undergo metabolism and forms different types of eicosanoids. ARACHIDONIC ACID METABOLISM:
Cyclooxygenase pathway yields prostaglandins, prostacyclin and thromboxanes.
Lipoxygenase pathway yields lipoxins and leukotrienes.
Anandamide pathway yields anandamide, an endogenous ligand for cannabinoid receptors.
Cyclooxygenase pathway: Arachidonic acid undergo metabolism by cyclooxygenase pathway and forms cyclic endoperoxides (PGG2 and PGH2). These undergo metabolic conversions by respective enzymes and forms prostacyclin, prostaglandins and thromboxanes. This cyclooxygenase pathway is mediated by cyclooxygenase enzyme (COX) and this enzyme exhibits in three isoforms in different locations.
COX1 is a constitutive enzyme located in stomach, kidney and thrombocytes.
COX2 is an inducible enzyme which is synthesized in fibroblasts, macrophages, chondrocytes and uterus in response to induction of these cells by cytokines.
COX3 is a constitutive enzyme located in brain. Products of COX pathway are as follows
PG s type PGD2
Receptor
Distribution
DP1
Platelets
DP2
Awakening
Small intestine
Increases peristalsis
uterus
Uterus contraction
Eosinophils,
EP1
Kidney
Agonists
Inhibit platelet aggregation
Nervous tissue
basophils and Th2 cells. PGE2
Function
Increases
recruitment
into
inflammation site. Renal perfusion improvement
Skeletal muscle EP2
Lung and placenta
EP3
Gastro intestinal tract
Decreases gastric acid secretion Increases gastric mucus secretion
Uterus Smooth muscle
Pregnant uterus contraction GI smooth muscle contraction
EP4 PGF2Îą
FP
Corpus luteum Stomach Eye Uterus Kidney
PGI2
IP
Platelets Vascular smooth muscle Bronchi
TXA2
TP
Inhibits platelet aggregation Vasodilation Bronchodilation
Platelets, vascular smooth muscle, spleen, uterus
PHARMACOLOGICAL APPLICATIONS OF PROSTAGLANDINS AND ITS ANALOGUES:
Prostaglandinomimetics: alprostadil etc Prostaglandinolytics
: COX inhibitors
Prostaglandinomimetics: Prostacyclin (epoprostenol) – Primitive pulmonary arterial hypertension Iloprost (PGI2 analogue) – Pulmonary arterial hypertension Peripheral vascular diseases
Alprostadil(PGE1 analogue) – During open heart surgery in neonates Erectile dysfunction
Misoprostal(PGE1 analogue) – Antisecretory, cytoprotector gastric effects Gemoprost(PGE1 analogue) – Cervical dilation during diagnosis and abortion Dinoprostone(PGE2analogue) – Inducing labour in late pregnancy and abortifacient
Sulprostone(PGE2 analogue) – I.M/I.V perfusion for abortion Latanoprost(PGF2 analogue) – Open angle glaucoma, but causes eye coloration, darkening of eye lids and eye lashes.
THROMBOXANES: The two major thromboxanes are thromboxane A2 and thromboxane B2. Thromboxane is named for its role in clot formation. Thromboxanes involved in platelet aggregation, vasoconstriction and pathogenesis of asthma. Thromboxane-A synthase, an enzyme found in platelets, converts the arachidonic acid derivative prostaglandin H2 to thromboxane. It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. The mechanism of secretion of thromboxanes from platelets is still unclear. Role of A2 in platelet aggregation Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation. Drugs acting on thromboxane levels: Platelet aggregation is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxaneA2 release provoked acutely, with the prostaglandinI2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.
LEUKOTRIENES: Leukotrienes are fatty molecules of the immune system that contribute to inflammation in asthma and bronchitis. Leukotrienes produced within a cell convey signals that either act on the cell producing them (autocrine signalling) or on neighboring cells (paracrine signalling) to regulate the immune response. Types: Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4. LTC4, LTD4 and LTE4 are often called cysteinyl leukotrienes due to the presence of the amino acid in their structure. Together, the cysteinyl leukotrienes make up the slow-reacting substance of anaphylaxis (SRS-A). Synthesis: Leukotrienes are synthesized in the cell from arachidonic acid by 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. These will be produced only when leukocytes get stimulated i.e. specifically at the time of inflammatory response. Functions: Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions. Recent research states about the role of 5-lipoxygenase products in cardiovascular and neuropsychiatric illnesses. Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in bronchoconstriction and increase vascular permeability. Leukotrienes in asthma Leukotrienes assist in the pathophysiology of asthma, causing or potentiating the following symptoms:
* airflow obstruction * increased secretion of mucus * mucosal accumulation * bronchoconstriction * infiltration of inflammatory cells in the airway wall.
In excess leukotrienes may cause anaphylactic shock. Leukotrienes modulators are used in treatment of asthma