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Subjective Questions

Q.1- What are ω6 and ω3 fatty acid ? Give examples in support of your answer and discuss their biological significance.

Q.2- Explain the terms-

a) Saponification

b)  Rancidity

c) Lipid Peroxidation

Q.3- Give example of each of the following

a)  Cyclic fatty acid

b) Branched chain fatty acid

c) Trans fatty acid

d) Pentaenoic acid

e) Saturated fatty acid with 20 carbon atoms

Q.4- What is the relationship of melting point with the degree of unsaturation of fatty acids? What is its biological significance?

Q.5- What are essential fatty acids, discuss the functions and the clinical consequences of their deficiencies?

Q.6- Discuss the structure, functions and clinical significance of cholesterol.

Q.7- Give a brief account of the chemistry and functions of phospholipids.

Q.8- Differentiate between Cerebrosides and Gangliosides, in reference to chemistry, functions and clinical significance of each of them.

Q.9- Give a brief account of biochemical defect, clinical symptoms, laboratory diagnosis and treatment of the following diseases-

a) Tay- sach’s disease

b) Gaucher disease

c) Niemann Pick’s disease

Q.10- What is the clinical significance of Lecithin/ Sphingomyelin (L/S) ratio?

Q.11- Discuss in brief about the sources, functions and significance of glycerol.

Q.12- Draw a well labeled diagram of a liposome, discuss its structure and functions.

Q.13- Enumerate the derived lipids and give a detailed account of any two of them.

Q.14- Why do saturated fatty acids have a higher boiling point than the unsaturated fatty acids with the same number of carbon atoms?

Q.15- Give a brief account of esterification of cholesterol by Acyl transferases, differentiate between the activities of each of them.

Q.16- What are phospholipases? Mention the site of action and the biological significance of each of them.

Q.17-Give the components and the biological function of each of the following

a) Triglycerides

b) Phosphatidyl Choline

c) Sphingomyelin

d) GM1- Ganglioside

Q.18- Give an account of lipid storage diseases in a tabular manner, mentioning the biochemical defect and clinical manifestations.

Q.19- Write the significance of-

a) Acid number

b) Acetyl number

c) Saponification number

d) Iodine number.

Q.20- Give a brief account of the steps of Prostaglandin synthesis, mention the role of COX inhibitors.

Q.21- What is the biological and clinical significance of prostaglandins?

Q.22- What is the biochemical basis of low dose Aspirin in antithrombotic prophylaxis?

Q.23-Discuss the synthesis of biologically important Leukotrienes and Lipoxins from Arachidonic acid

Q.24-What is the relationship of COX inhibition and gastric ulceration?

Q.25-What is the role played by Prostaglandins in pregnancy?

Q.26-What is the drawback of usage of prostaglandins as conventional drugs ?

Q.27-What is the reason of Aspirin induced asthma?

Q.28- Differentiate between prostacyclin and Thromboxane.

Q.29- What is the clinical significance of Leukotrienes ?

Q.30- What is SRSA ? Explain briefly.

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Q.1- What are Eicosanoids? Discuss in brief about the chemistry and biological importance of Eicosanoids.

Answer- Prostaglandins and related compounds are collectively known as Eicosanoids. Most are produced from Arachidonic acid, a 20-carbon polyunsaturated fatty acid  (5,8,11,14-eicosatetraenoic acid).(Figure-1)

Figure-1- showing the structure of Arachidonic acid

Dihomo-gamma-linolenic acid (DGLA) and eicosapentaenoic acid (EPA, timnodonic acid) also serve as eicosanoid precursors.

Eicosanoids are basically classified in to two main groups-

a)      Prostanoids

b)     Leukotrienes and Lipoxins.

Prostanoids are further sub classified in to three groups-

1)     Prostaglandins(PGs)

2)     Prostacyclins(PGIs)

3)     Thromboxanes (TXs)

 a) Prostanoids- All prostanoids are considered to be derivatives of a cyclic saturated fatty acid called Prostanoic acid.

1) Chemistry of Prostaglandins- According to structure PGs can be divided into  four major groups.-  PG-E, PG-F, PG-A and PG-B groups. Besides these PG-C and PG-D groups have also been recognized (Figure-2).

PG- G and PG-H considered as Primary PGs, are intermediates in the synthesis of other prostaglandins. Difference in the four main groups is due to the difference in the structure of cyclpentane ring.

Figure-2 –showing the structure of different prostaglandins. R1 and R2 represent the side chain which is same in all members of a series.

Depending upon the number of double bonds in the side chain they are denoted by a subscript- PGE-1, PGE-2, PGE-3 etc.

Series-1 contain one double bond at 13-14 position (Trans)

Series-2 have two double bonds at 13-14 (trans) and 5-6 (Cis)

Series-3 – have three double bonds at13-14 (trans) , 5-6 (Cis) and 17-18 (Cis) positions

2) Chemistry of Prostacyclins- contain another ring between 6 th and 9th carbon atoms (Figure-3).

There are three series of Prostacyclins same as PGs i.e. PI-1,PI-2 and PI-3 etc.


Figure-3- showing the structure of Prostacyclin

3) Chemistry of Thromboxanes-  Thromboxanes have a six membered Oxane ring (Figure-4).  

There are three series for Thromboxanes.

Figure-4- showing the structure of Thromboxanes

Series- 2 Prostanoids are the most important Prostanoids in the biological system.

b) Leukotrienes and Lipoxins- Unlike the prostaglandins and the thromboxanes, which are products of the cyclooxygenase pathway, leukotrienes and lipoxins are products of the 5- and 15- lipoxygenase pathways, respectively. The name “leukotrienes” refers to the leukocyte origin of these molecules, and to the conjugated double bonds in their structure.

The lipoxins are derived from the 15-lipoxygenase pathway and have a fully conjugated tetraene structure.

Leukotrienes of series-1 are denoted by subscript 3 and there are different types of leukotrienes varying from A to E which are represented by LT-A 3, LT-B3 etc.

Series -2 is represented by suffix-4- LT-A4, LTB-4 and seies-3 is represented by suffix-5, LT-A5, LT-B5, LT-C5 s etc.

Biological importance- Eicosanoids are not stored within cells; rather they are synthesized as required in response to hormonal signals. They are considered “local hormones. They are not transported to distal sites within the body.” They function close to the site of synthesis (autocrine, paracrine), where they are rapidly deactivated before they enter circulation as inactive metabolites.

They have various roles in inflammation, fever, regulation of blood pressure, blood clotting, immune system modulation, control of reproductive processes, tissue growth, and regulation of the sleep/wake cycle. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. The lipoxins are anti-inflammatory eicosanoids synthesized through lipoxygenase interactions.

Q.2- Give a brief account of the synthesis of Prostanoids. Highlight the clinical significance if any of this pathway.


Synthesis of Prostanoids- The principal precursor of prostanoids is Arachidonic acid. Additionally, biologically significant prostanoids are derived from dihomo-γ-linolenic acid (DGLA) which is produced in the reaction pathway leading to arachidonic acid from Linoleic acid (see Figure-5 below) ; and also from Eicosa pentaenoic acid which is produced from dietary Alpha Linolenic acid.

Figure-5 showing the formation of Arachidonic acid from dietary Linoleic acid and synthesis of Eicosa pentaenoic acid from Alpha Linolenic acid

Series -1 Eicosanoids are synthesized from dihomo-γ-linolenic acid (DGLA)

Series-2 from Arachidonic acid and

Series-3 are synthesized from Eicosa pentaenoic acid.

The major source of arachidonic acid is through its release from cellular stores. Within the cell, it resides predominantly at the C–2 position of membrane phospholipids and is released from there upon the activation of PLA2 (Phospholipase A2)

Steps of synthesis of Prostanoids- This pathway is also called Cyclo-oxygenase pathway or cyclic pathway.

The prostanoid signaling cascade begins with an external stimulus, most often the binding of a ligand to a cell surface receptor that activates one or more phospholipase A2. The latter are enzymes that release Arachidonic acid from its esterified form in membrane phospholipids such as phosphatidylethanolamine and phosphatidyl Inositol.

Figure-6 – showing the release of Arachidonic acid from Membrane phospholipid

Arachidonate is converted to PGH2 by one of the isoforms of PGH synthase (PGHS-1 or -2), enzymes localized to the endoplasmic reticulum membrane and the nuclear envelope.

PGH2 is in turn metabolized to the prostanoid lipid signals (PGD2, PGE2, PGF2α, PGH2, PGI2, or TXA2) by one of the secondary enzymes that are named for the individual prostanoid produced. The type of prostanoid produced is determined by which downstream enzyme is present; usually one downstream enzyme predominates in a given cell. For example, the prominent secondary enzyme in platelets is thromboxane synthase, whereas vascular endothelial cells feature prostacyclin (PGI) synthase.

Conversion of Arachidonate to PGH2 is a key regulatory step in prostanoid biosynthesis. (Figure )

Each PGHS isoform catalyzes two separate reactions.

The first reaction (Arachidonate to PGG2) involves insertion of two molecules of oxygen and cyclization of the fatty acid backbone. This step is catalyzed by the cyclo-oxygenase activity of PGHS-1 or -2; it is these cyclo-oxygenase activities (also called COX-1 and COX-2) that are inhibited by nonsteroidal antiinflammatory drugs (NSAIDs).

The second step (PGG2 to PGH2) involves the reduction of the hydro peroxide on C15 to an alcohol and is catalyzed by the peroxidase activity of PGHS-1 or -2.

Clinical significance

Although both PGHS isoforms have cyclooxygenase and peroxidase activities and are structurally similar proteins, they have very distinct pathophysiological functions.

  • Many cells, including platelets and gastric mucosal cells, have moderate levels of the “basal” isoform, PGHS-1. Functions attributed to PGHS-1 include regulating hemostasis and vascular tone, renal function, and maintaining gastric mucosal integrity.
  • A smaller number of cells, such as macrophages, vascular endothelial cells, and fibroblasts, dramatically upregulate levels of the “inducible” isoform, PGHS-2, in response to cytokines or mitogens. PGHS-2 has been implicated in cell proliferation, inflammation, carcinogenesis, and parturition.
  • Many cyclooxygenase inhibitors have been developed and their structures are quite varied substrate for binding to the cyclooxygenase site on the enzyme. Aspirin was one of the earliest NSAIDs discovered and is now widely used as an analgesic and antiinflammatory agent. More recently, aspirin has emerged as a very useful antithrombotic agent because of its action against platelet cyclooxygenase activity. Aspirin brings about inhibition of the enzyme by covalent modification making the transition irreversible.
  • Flurbiprofen and indomethacin are able to inhibit both PGHS-1 and -2, although they do not covalently modify either protein. Ibuprofen forms only transient complexes with both PGHS isoforms.


Figure -7– showing the steps of formation of Eicosanoids

  • The recently developed coxibs (such as celecoxib and rofecoxib) derive their exquisitely selective inhibition of PGHS-2 cyclooxygenase from their ability to  bring about noncovalent modification of PGHS-2 and not of PGHS-1. This selectivity has made the coxibs very useful for antiinflammatory and antiproliferative therapy with reduced gastrointestinal side effects, but it also makes them ineffective as antiplatelet agents and consequently can increase cardiovascular risks.

Low-dose aspirin is often used in antithrombotic prophylaxis

Thromboxane produced by platelet COX-1 in concert with a downstream enzyme is prothrombotic, so aspirin and other NSAIDs cause platelet dysfunction and increase bleeding time. Aspirin is unusual in that it causes covalent, irreversible inhibition of the COX protein, whereas other NSAIDs have noncovalent, reversible actions. Thus, platelets, because they cannot synthesize more COX protein, are irreversibly affected by aspirin but only temporarily affected by other NSAIDs. Due to this reason only Low-dose aspirin is often used in antithrombotic prophylaxis as in the prevention of stroke, I.H.D.etc.

Figure-8- showing the activities of COX-1 and COX-2 enzymes

The prothrombotic and vasoconstrictive actions of COX-1-derived Thromboxane in the vasculature are opposed by an antithrombotic and vasodilative  prostaglandin, prostacyclin, that originates from COX-2 in vascular endothelial cells. The COX-2 selective coxibs thus tend to decrease prostacyclin levels in the vasculature without reducing the thromboxane levels. This tendency is thought to explain the small but significant increase in cardiovascular risk that recently led to withdrawal of two coxibs from theU.S. market. Moreover COX protein, are irreversibly affected by aspirin but only temporarily affected by other NSAIDs.

 Q.3- How are prostaglandins catabolized in the body?

Answer-All Arachidonic acid derivatives are quickly, in less than a few minutes, inactivated in the body by several complex reactions. “Switching off” of prostaglandin activity is partly achieved by a remarkable property of cyclooxygenase—that of self-catalyzed destruction; ie, it is a “suicide enzyme.” Furthermore, the inactivation of prostaglandins by 15-hydroxyprostaglandin dehydrogenase is rapid.(OH group preset at 15 th position  is changed to a keto group).Blocking the action of this enzyme with Sulfasalazine or indomethacin can prolong the half-life of prostaglandins in the body. After the action of this enzyme the resultant fatty acids are completely oxidized by beta oxidation.

Q.4- Discus the synthesis of clinically relevant Leukotrienes and Lipoxins from Arachidonic acid .


The leukotrienes are identified as LTs. They are a family of conjugated trienes formed from eicosanoic acids in leukocytes, mastocytoma cells, platelets, and macrophages by the lipoxygenase pathway in response to both immunologic and nonimmunologic stimuli.

Three different lipoxygenases (dioxygenases) insert oxygen into the 5, 12, and 15 positions of arachidonic acid, giving rise to hydroperoxides (HPETE).

Only 5-lipoxygenase forms leukotrienes.(Figure-9)

Lipoxins are a family of conjugated tetraenes also arising in leukocytes. They are formed by the combined action of more than one lipoxygenase.

Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from membrane phospholipids. The enzyme 5-lipoxygenase (5-LOX) in association with the protein, 5-LOX activating protein (FLAP), catalyzes the conversion of arachidonic acid, first to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). LTA4 is synthesized by the action of dehydrase on 5HPETE.

LTA4 is unstable and is converted to LTB4 in neutrophils and monocytes harboring LTA4 hydrolase. In mast cells and eosinophils, which harbor LTC4 synthase, LTA4 is converted to LTC4. The leukotrienes LTC4, LTD4, LTE4 and LTF4 are known as the peptidoleukotrienes or the cysteinyl leukotrienes because of the presence of amino acids.

The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA).

The subscript 4 in each molecule refers to the number of carbon-carbon double bonds present.

Lipoxins-Three pathways exist for the synthesis of the lipoxins. The “classic” pathway involves 5-LOX activity in leukocytes followed by 12-LOX action in platelets. The action of 15-LOX in epithelial cell (such as in the airway) followed by 5-LOX action in leukocytes is the second major lipoxin synthesis pathway. The action of aspirin on COX-2 in epithelial, or endothelial cells as wells as in monocytes results in the eventual production of the 15 epi-lipoxins (also referred to as aspirin triggered lipoxins, ATLs  

Figure-9- Showing the steps of formation of  Leukotrienes and lipoxins

Clinical significance-Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4, D4, and E4. This mixture of leukotrienes is a potent constrictor of the bronchial airway musculature. These leukotrienes together with leukotriene B4 also cause vascular permeability and attraction and activation of leukocytes and are important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions, such as asthma. Leukotrienes are vasoactive, and 5-lipoxygenase has been found in arterial walls.

Q. 5- Discuss the  mechanism of action  and  the details of biological activities associated with Eicosanoids.

Answer-Each of the eicosanoids function via interactions with cell-surface receptors that are members of the G-protein coupled receptor (GPCR) family. There are at least 9 characterized prostaglandin receptors. Receptors that bind the prostaglandin D family of lipids are called the PGD receptors and those that bind E family prostaglandins are called the PGE receptors. The PGD receptors are coupled to the production of cAMP and activation of PKA. The PGE receptors couple to the activation of PLCγ (Phospholipase C) and as a consequence the production of Diacylglycerol (DAG) and  Inositol triphosphate (IP3) from membrane phospholipids. The receptor for prostacyclin (PGI2) is called the PC receptor and it couples to production of cAMP. There are 2 receptors that bind LTB4 called BLT1 and BLT2. The peptidoleukotrienes (cysteinyl leukotrienes) bind to receptors called CysLT1 and CysLT2. The thromboxane receptor is coupled to the activation of PLCγ. Thus  majority of the prostaglandins act by increasing the c AMP level in the cell. Prostaglandins may also bind to nuclear receptors and alter gene transcription.

The major biological activities associated with Eicosanoids are as follows-

Eicosanoid Site of synthesis  Biological Activities
Prostaglandins Almost all cells of the body
PGD2 mast cells Inhibits platelet and leukocyte aggregation, decreases T-cell proliferation, lymphocyte migration  and secretion of IL-1α and IL-2; induces vasodilation and production of cAMP
PGE2 kidney, spleen, heart Increases vasodilation and cAMP production, enhancement of the effects of bradykinin and histamine, induction of uterine contractions and of platelet aggregation, maintaining the open passageway of the fetal ductus arteriosus; decreases T-cell proliferation , lymphocyte migration and secretion of IL-1α and IL-2
PGF2α kidney, spleen, heart Increases vasoconstriction, Bronchoconstriction and smooth muscle contraction
PGH2   Precursor to thromboxanes A2, induction of platelet aggregation and vasoconstriction
PGI2 heart, vascular endothelial cells Inhibits platelet and leukocyte aggregation, decreases T-cell proliferation and lymphocyte migration and secretion of IL-1α and IL-2; induces vasodilation and production of cAMP
TXA2 platelets Induces platelet aggregation, vasoconstriction, lymphocyte proliferation and Bronchoconstriction
TXB2 platelets Vasoconstriction
LTB4 monocytes, basophils, neutrophils, eosinophils, mast cells, epithelial cells powerful inducer of leukocyte chemotaxis and aggregation, vascular permeability, T-cell proliferation and secretion of INF-γ, IL-1 and IL-2


monocytes and alveolar macrophages, basophils, eosinophils, mast cells, epithelial cells component of SRS-A, microvascular vasoconstrictor, vascular permeability and bronchoconstriction and secretion of INF-γ, recruitment of leukocytes to sites of inflammation, enhance mucus secretions in gut and airway


monocytes and alveolar macrophages, eosinophils, mast cells, epithelial cells

same as LTC4


mast cells and basophils

same as LTC4



LXA4 platelets, endothelial cells, mucosal epithelial cells and other leukocytes via inteactions with PMNs Reduce PMN and eosinophil infiltration to sites of inflammation, stimulate nonphlogistic (non-inflammatory-inducing) monocyte recruitment, stimulate macrophage phagocytosis of apoptotic PMNs, block IL-8 (chemokine) expression, block TNF-α release and actions, stimulate TGF-β action
LXB4 platelets, endothelial cells, mucosal epithelial cells and other leukocytes via inteactions with PMNs same as for LXA4


Q . 6- Discuss the physiological functions of Prostaglandins in various tissues

Answer-  The functions of Prostaglandin are incompletely understood.

Known actions include-

S. N. Tissue Physiological function
1) Inflammatory Response i) Fever- PGs induce fever by stimulating the thermoregulatory center in the brain. There is increased body temperature as a result of it.ii) Pain- PGs sensitize pain receptors to stimulation, as a result increase pain perception.iii) Swelling-There is vasodilatation and increased capillary permeability induced by PGS which is responsible for swelling of the inflammed tissue.

iv Erythema, wheal and Flare is also induced by PGs like PGE and PGD2.

v) PGD2 is considered an important mediator of anaphylaxis


2) Intestinal smooth muscles PGE and PGF produce contraction of the longitudinal smooth muscles producing diarrhea, cramps and reflux of bile.
3) Bronchial smooth Muscles PGFs contract and PGE s relax  bronchial smooth muscles.PGE1 and PGE2 are therapeutically used as bronchodilators
4) Vascular Smooth Muscles PGEs and PGI2 cause vasodilatation. PGF2 α and Thromboxane A2 cause vasoconstriction. Systemic blood pressure falls in response to PGEs and PGAs
5) Uterine Muscles PGE1, PGE1 and PGF2α cause uterine contractions.PGE2 has been used for the induction of labor at or near term. In higher dosage PGEs are used as abortificients in first and second trimester of pregnancy. They are also responsible for causing dysmenorrhea.
6) Platelets PGE1 and PGI2 cause inhibition of platelet aggregation, while TXA2 promotes platelet aggregation. PGE1 has been used for harvesting and storage of blood platelets for therapeutic transfusion.
7) Kidney PGEs cause in renal plasma flow, GFR, diuresis, Natriuresis. and kaliuresis is also induced by the action of PGE2
8) Gastrointestinal Secretions PGE1and E2 inhibit gastric secretions and are required for maintaining the integrity of gastric mucosa. The effect is opposite on the pancreatic and intestinal secretions. There is increase in the volume, enzyme and electrolyte content of the pancreatic and intestinal secretions in response to PGE1. Watery diarrhea results in response to administration of PGE1.
9) Endocrine glands i) PGEs have insulin like effects, They inhibit lipolysis and the effects on carbohydrate metabolism are same as insulinii) PTH(Parathormone) like effects are also seen on bone metabolism by PGs. They mobilize calcium from bones producing hypercalcemia.iii)Thyrotropin like effects-are seen on thyroid gland.

iv)Steroidogenic effects are seen on the adrenal tissues

10) Immunological Response PGEs secreted by macrophages may modulate or decrease the functions of T and B lymphocytes .


Q.7- What is the relationship of COX inhibition and Gastric ulceration?


Prostaglandins play a critical role in maintaining gastro duodenal mucosal integrity and repair. The gastric mucosa contains abundant levels of prostaglandins that regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution.  It therefore follows that interruption of prostaglandin synthesis can impair mucosal defense and repair, thus facilitating mucosal injury via a systemic mechanism.  

Humans, and most other mammals have two genes for cyclooxygenase. The products of the genes, COX-1 and COX-2, are structurally quite similar, with only subtle differences. The catalyze the same reactions, although COX-2 works with a wider range of substrates. COX-1 is constitutively expressed in nearly all tissues. In contrast, COX-2 is inducible, especially by inflammatory stimuli. Some evidence suggests that COX-1 is responsible for generating the prostaglandins required for protection of the gastrointestinal tract, while COX-2 is responsible for the increased prostaglandin synthesis associated with inflammation, fever, and pain responses.

Indomethacin, a high affinity inhibitor of COX (and in some individuals, aspirin, and to a lesser extent ibuprofen) induces ulceration; some anti-ulcer drugs appear to function by increasing prostaglandin synthesis. The recently developed coxibs (such as celecoxib and rofecoxib)  cause selective inhibition of COX-2 and not of COX-1. This selectivity has made the coxibs very useful for antiinflammatory and antiproliferative therapy with reduced gastrointestinal side effects.

In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues have been developed for the treatment of peptic ulcers. Primary prevention of NSAID-induced ulceration can be accomplished by misoprostol, which is a Prostaglandin Analogue.

Q. 8- What is the role played by prostaglandins in pregnancy ?

Answer- Prostaglandins are required for normal implantation of the fertilized oocyte. In addition, prostaglandins are involved in initiation of labor. Prostaglandins are used for labor induction (and for induction of  abortions); COX-inhibitors (probably via COX-2) delay onset of labor. COX-2 seems to be required for ovulation.

Q.9- Why are COX inhibitors used as antipyretic agents ?

Answer- Prostaglandins appear to form a major part of the signaling pathway in fever induction. COX inhibitors are thought to exert their anti-pyretic actions by interrupting this pathway. Prostaglandins appear to be involved in some pain pathways; inhibition of COX (probably COX-2) is thus analgesic.

Q. 10-What is the role of COX inhibitors in cancers and Alzheimer’s disease?

Answer- Colon cancer is a major life-threatening cancer. Aspirin has been shown to have an apparent protective effect against colon cancer; some evidence suggests that inhibition of colon tumor induction is due to inhibition of COX-2. Breast and stomach cancer growth may also be inhibited by COX inhibitors.

The brain damage associated with Alzheimer’s disease appears to be largely mediated by inflammatory responses; some epidemiological data have suggested a reduced incidence of Alzheimer’s disease in individuals taking COX inhibitors.

Q.11- What is the reason for Aspirin induced Asthma ?

Answer- Aspirin inhibits the COX pathway and consequently diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of PGE2, the anti-inflammatory PG. LTC4 synthase overexpression further increases the number of cysteinyl LTs, tilting the balance toward inflammation.(Figure-10)

Q.12- What is the biochemical basis of PG induced of dysmenorrhea  ?

Answer- Primary dysmenorrhea results from increased stores of prostaglandin precursors, which are generated by sequential stimulation of the uterus by estrogen and progesterone. During menstruation these precursors are converted to prostaglandins, which cause intense uterine contractions, decreased blood flow, and increased peripheral nerve hypersensitivity, resulting in pain.

Q.13- Discuss the pharmacological applications of Eicosanoids.

Answer- In practice, when eicosanoids have beneficial effects, they are used as drugs called prostaglandinomimetics; when they have adverse effects, one tries to inhibit their biosynthesis or their effects. The pharmacological applications of Prostaglandins can be summarized as follows-

1)     Cardiovascular uses- PGI2 or prostacyclin, called now epoprostenol has several properties: pulmonary and systemic arterial vasodilator, platelet anti-aggregating, gastric protective effects. In sustained continuous intravenous infusion it induces appreciable results in the treatment of primitive pulmonary arterial hypertension. Iloprost, a stable analog of PGI2, is used for the treatment of severe peripheral vascular disease. Alprostadil (PGE1) is indicated for keeping the ductus arteriosus open until surgery in neonates carrying certain cardiac malformations. Because of its vasodilator effect, Alprostadil is also used for the treatment of erectile dysfunction.

2)     Digestive Uses- Misoprostol, an analog of PGE1, has antisecretory and cytoprotector gastric effects. It decreases acid secretion and increases pepsin, mucin and bicarbonate secretion and improves microcirculation. It is indicated in the treatment of gastro duodenal ulcer and for the prevention of NSAID-induced ulcers. Its principal secondary effect is diarrhea. It is contra-indicated for pregnant women. 

3)     Gynecological and obstetrical uses – The derivatives used in gynecology and obstetrics have an activity which resembles that of the prostaglandins E1 and E2.  They induce cervical dilatation and uterine contractions, particularly in late pregnancy. E1 type are used for cervical dilatation for exploring uterus or for abortion. E2 type in low dosage are used for induction of labor and in high dosage are used for medical termination of pregnancy or to illicit abortion.

4)     Ophthalmologic Use- Latanoprost, a prodrug analog of F2 alpha prostaglandin, administered in ophthalmic solution, lowers intraocular pressure by increasing aqueous humor outflow.

5)     Anti- inflammatory use- Inhibitors of cyclo-oxygenases have antiinflammatory properties and include nonsteroidal antiinflammatory drugs or NSAID. The useful effects in therapeutics are-

  • anti-inflammatory effect
  • analgesic effect
  • antipyretic effect
  • inhibition of platelet aggregation and decrease of thromboembolic risk (well-known with aspirin at low doses)
  • Hypocalcemic effect (during hypercalcemia.)
  • inhibition of colic tumor development

Adverse effects:

  • Gastro duodenal ulcerations and digestive bleeding due primarily to COX-1 inhibition
  • Prolongation of pregnancy (if the NSAID is taken by the pregnant woman in late pregnancy)
  • Premature closure of the ductus arteriosus
  • Aggravation of renal impairment by insufficient vasodilator prostaglandin synthesis to counter the vasoconstrictive effect of catecholamines and angiotensin, retention of salt and water and increase of blood pressure  
  • Aggravation of a heart failure.

6)     Ulcerative Colitis- Mesalamine also called mesalazine or 5 aminosalicyclic acid has antiinflammatory properties in the colon and is used in the treatment of ulcerative colitis (Crohn’s disease). Its mechanism of action is complex and as yet incompletely known: in addition to cyclo-oxygenases, it also inhibits lipoxygenases.

7)     Bronchial Asthma- PGE2 agonists and leukotrienes receptor antagonists are used for the treatment of bronchial asthma.

Figure-10- showing the biochemical basis of Aspirin induced bronchial asthma 

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