Prostaglandins, Thromboxane and Leukotrienes, Angiotensin, Bradykinin and Substance P

1. Prostaglandins, Leukotrienes, Angiotensin, Bradykinin & Substance P| Pratishtha Sharma
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Prostaglandins, Thromboxane and Leukotrienes, Angiotensin, Bradykinin and
Substance P
 PROSTAGLANDINS AND LEUKOTRIENES (Eicosanoids)
 Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active derivatives of 20
carbon atom polyunsaturated essential fatty acids that are released from cell membrane
phospholipids. They are the major lipid derived autacoids.
 They were named so because of their presumed origin from the prostate gland. Human
seminal fluid is the richest known source, but they are also present in various tissues.
 The enzyme involved in the formation of PGs from arachidonic acid is cyclooxygenase
(COX). The main PGs are PGE2, PGF2α and PGI2 . And by the action of lipoxygenase is
leukotrienes.
 There are two forms of COX called COX-1 and COX-2. COX-1 is constitutive and is
widely distributed. It participates in various physiological functions such as protection of
gastric mucosa, homeostasis and regulation of cell division. COX-2 is induced during
inflammation by cytokines and endotoxins.

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Pharmacological Action
1. GI Tract- reduce acid secretion and increase the secretion of mucus in the stomach
(cytoprotective action).
2. Cardiovascular system- PGD2 , PGE2, and PGI2 cause vasodilation. PGF2α constricts
pulmonary veins and arteries. TXA2 is a vasoconstrictor.
3. Platelets- PGI2 inhibits platelets aggregation.
4. Eye- PGF2α decreases intraocular pressure.
5. Uterus- PGs are mainly used in mid trimester abortion and in hydatidiform.
Induction of labour, cervical priming, postpartum haemorrhage
6. Male reproductive system- useful in treatment of erectile dysfunction.
Some examples are- Dinoprostone, Dinoprost, Alprostadil, Misoprostol, Latanoprost,
Carboprost
Adverse Effect- Nausea, vomiting, diarrhoea, fever, flushing, hypotension and uterine
contraction.
LEUKOTRIENES (LTS)

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 The leukotrienes are a family of biologically active molecules, formed by leukocytes,
mastocytoma cells, macrophages, and other tissues and cells in response to
immunological and nonimmunological stimuli.
 Leukotrienes are metabolites of arachidonic acid produced by a C-5 lipoxygenase.
 leukotriene A4, is the precursor, which could either be hydrolysed to form leukotriene
B4 or combine with glutathione to form leukotriene C4.
Pharmacological Actions
1. Plays an important role in the induction of neutrophile-endothelial-cell adhesion.
2. Causes the release of some quantities of glucuronidase and lysozyme from the
neutrophiles.
3. Stimulates proliferation of T lymphocytes.
4. Important mediator of inflammatory pain.
LTC4 , LTD4 , and LTE4 are also called sulphidedopeptides or cysteinyl LTs. They play
an important role in the inflammatory process. They cause:
 Vigorous and sustained contraction of smooth muscle (Bronchoconstriction).
 Vasodilation and modulation of vascular permeability, leading to development of
oedema, constrict cutaneous and small coronary blood vessels.
 Increased mucus secretion in the airway.
CYTOKINIES
Inflammation is an integral part of the body’s defence mechanisms against foreign
substance, and natural as well as acquired (specific) immunity play an important role in
human defence. Several polypeptides act as mediators of the inflammatory process. The
effector phases of both natural and acquired immunity are in large part mediated by
protein hormones called cytokines, which are released from a variety of cell types in
response to a number of stimuli.
Properties of Cytokines
1. Low molecular weight proteins.
2. Produced during the effector phase of natural and acquired immunity.
3. They are not stored as performed molecules.
4. A given cytokine has different biological effects on different cell types.

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5. Cytokines act as regulators of cell division.
Classification
1. Haematopoietin family- GM-CSF, erythropoietin, IL-2, IL-4
2. Interferon family- alpha, beta and gamma, IL-10
3. Chemokine family- monocyte chemotactic protein, neutrophil activating protein,
platelet factor-4
4. Tumour necrosis factor (TNF) family- TNFα, TNFβ
ANGIOTENSINS
 Angiotensin are peptide hormones derived from a protein precursor angiotensinogen.
 Angiotensinogen, synthesised from liver, is converted by the circulating renin from the
kidney into Angiotensin I, a decapeptide. It is converted by angiotensin converting
enzyme (ACE) located in the plasma and the capillary endothelial cells, mainly in the
lungs into the angiotensin II.
 Angiotensin II is a potent angiotensinogen
 They act through AT1 and AT2 receptor. (Signal transduction through G-protein coupled
receptor).
Actions
1. It causes rapid regulation of arterial BP in response to an acute fall in BP by constricting
the arterioles, and to some extent veins.
2. Promotes renal Na+
reabsorption in PCT and also causes Na+
retention through the
release of aldosterone.
3. Causes hypertrophy of the heart and thickening of blood vessels
4. Stimulates Vasopressin and ACTH release. It increases the thirst.
KININS
The kinins are vasoactive polypeptide released from an α2 globulin fraction of the
plasma, termed as kininogens by the action of enzymes termed kallikreins.
Kininogens are present in two forms:
1. Low molecular weight kininogens (LMWK)- in blood stream
2. High molecular weight kininogens (HMWK)- blood and tissues.

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 Bradykinin
Plasma kallikreins + Substrate
Binds to receptor on endothelial cell membrane
Gets activated to kallikrein
Activates Clotting factor XII and cleave HMWK
Bradykinin
 Bradykinin acts on two receptors:
1. B1 receptors are induced by inflammation and are absent in normal tissues.
2. B2 receptors
 Pharmacological action
1. CVS- strong vasodilator activity, also have positive chronotropic and inotropic actions.
2. Smooth muscles- contraction of uterus, bronchi and GIT. Promote epithelial ion transport
and fluid secretion in the airways and GI tract leading to cough or angioedema in starting
and later diarrhoea.
3. Produces pain and itching on the blisters.
4. Increase vascular permeability.
5. Release of Prostaglandins and Platelet activating factor
SUBSTANCE P
Substance P is an undecapeptide (a peptide composed of a chain of 11 amino
acid residues) member of the tachykinin neuropeptide family. It is a neuropeptide, acting
as a neurotransmitter and as a neuromodulator.[1][2]
Substance P and its closely
related neurokinin A (NKA) are produced from a polyprotein precursor after differential
splicing of the preprotachykinin A gene.
The endogenous receptor for substance P is neurokinin 1 receptor. It belongs to
the tachykinin receptor sub-family of GPCRs.
Functions:

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1. Vasodilation- Substance P is a potent vasodilator. Substance P-induced vasodilation is
dependent on nitric oxide release. Substance P is involved in the axon reflex-mediated
vasodilation to local heating and wheal and flare reaction.
2. Inflammation
3. Pain
4. Mood, anxiety, learning
5. Vomiting
6. Cell growth, proliferation, angiogenesis and migration