Autacoids.pptx They have also been called’ local hormones’. However, they differ from 'hormones' in two important ways-hormones are produced by specific cells, and are transported through circulation to act on distant target tissues.

Autacoids
Prepared by
Mr. Girish Kashid
Asst. Prof.
Sanjivani College of Pharmaceutical
Education & Research
Prepared by Dr. Girish Kashid

Autacoid:
This term is derived from Greek: autos-self, akos-healing substance or remedy.
These are diverse substances produced by a wide Variety of cells in the body,
having intense biological activity, but generally act locally (e.g. within inflammatory
pockets) at the site of synthesis and release.
They have also been called’ local hormones’.
However, they differ from 'hormones' in two important ways-hormones are
produced by specific cells, and are transported through circulation to act on distant
target tissues.

Autacoids are involved in a number of physiological and pathological processes
(especially reaction to injury and immunological insult) and even serve as
transmitters or modulators in the nervous system, but their role at many sites is not
precisely known.
A number of useful drugs act by modifying their action or metabolism.
Classification:
1. Amine autacoids: Histamine, 5-Hydroxytryptamine (Serotonin)
2. Lipid derived autacoids: Prostaglandins (Eicosanoid), Leukotrienes, Platelet
activating factor
3. Peptide autacoids: Plasma kinins (Bradykinin, Kallidin), Angiotensin
In addition, cytokines (interleukins, TNFα, GM-CSF etc.) and several peptides like
gastrin, somatostatin, vasoactive intestinal peptide and many others may be
considered as autacoids.

1. Amine autacoids: Histamine, 5-Hydroxytryptamine (Serotonin)
5-Hydroxytryptamine (Serotonin)
INTRODUCTION:
• A monoamine neurotransmitter biochemically derived from tryptophan.
• Structurally it contains an indole ring, hydroxyl group and ethyl amine group
attached to the ring.

Structures rich in 5-HT
• GIT (chromaffin cells and enteric neurons)
• Platelets
• CNS
Approximately 90% of the human body's total serotonin is located in the
enterochromaffin cells in the alimentary canal (gut), used to regulate
intestinal movements. Hence also called enteramine.

Important actions of 5-HT
 Increased GI motility
 Increased platelet aggregation
 Increased microvascular permeability
 Stimulation of nociceptive nerve endings
 Control of appetite, sleep, mood, hallucinations, stereotyped
behavior, pain perception, and vomiting

2. Lipid derived autacoids: Prostaglandins (Eicosanoid), Leukotrienes, Platelet
activating factor
Specifically identified, highly fat-soluble materials found naturally in
the human body, is a subset of metabolomics, whose goal is to establish
patterns of occurrence or change of intermediary metabolites that might help
characterize conditions of health or disease.
Prostaglandins, leukotrienes, and essential fatty acids are just
three of the many fat soluble, naturally occurring “targets” or “markers” for
such investigations.
Other lipids of high interest include cholesterol, steroid hormones,
triglycerides, sphingolipids, phospholipids, glycolipids, the fat-soluble vitamins
(A, D, E, K, Q), and the myriad derivatives of these compounds.
Essential fatty acids are those polyunsaturated fatty acids (PUFA) that must be
included in the human diet to maintain health.

Various omega-3 and omega-6 fatty acids are included in this group.
The prostaglandins (PGA through PGJ) are one group of naturally occurring
20-carbon fatty acid derivatives produced by the oxidative metabolism of 5,8,11,14-
eicosatetraenoic acid, an omega-6 fatty acid, which is also called arachidonic acid.
Other so-called eicosanoids produced in the complex biologic oxidation scheme
called the arachidonic acid cascade are thromboxane A2 (TXA2), the leukotrienes
(LKT A–F), and the highly potent antithrombotic agent prostacyclin (PGI2).
In fact, much of the pain, fever, swelling, nausea, and vomiting associated with “illness,”
in general is probably a result of excessive prostaglandin production in damaged tissues.

ESSENTIAL FATTY ACIDS:
The fatty acids that are absolutely necessary to maintain the health of humans
are generally polyunsaturated, even numbered organic acids derived from plants
or marine animals.
For example, the essential fatty acids linoleic acid (18:2) and alpha-linolenic
acid (ALA,18:3) are respectively omega-6 and omega-3 18-carbon fatty acids, which
occur naturally in olive oil as well as other oil-rich plants and seeds.
Other PUFA, such as eicosapentaenoic acid (EPA; 20:5) and
docasahexaenoic acid (DHA; 22:6) are omega-3 fatty acids that occur in the oils of
cold-water ocean fish and have been found to be beneficial to the cardiovascular
health of humans.

Biological Activities Observed with the Eicosanoids

Continued……

EICOSANOID BIOSYNTHESIS
Prostaglandins and other eicosanoids are produced by the oxidative
metabolism of free arachidonic acid.
Under normal circumstances, arachidonic acid is not available for
metabolism as it is present as a conjugated component of the phospholipid
matrix of most cellular membranes.
Release of free arachidonic acid, which subsequently may be
oxidatively metabolized, occurs by stimulation of phospholipase (PLA2)
enzyme activity in response to some traumatic event (e.g., tissue damage,
toxin exposure, or hormonal stimulation)..

It is believed that the clinical anti-inflammatory effect of glucocortical
steroids (i.e., hydrocortisone) is a result of their ability to suppress PLA2
activity via lipocortins and thus prevent the release of free arachidonic acid.
Although it was initially believed that the inflammatory response (swelling,
redness, pain) was principally a result of PGE2, recent interest has focused
on the interrelationships of PGE-type eicosanoids with the cytokines, such as
interleukins-1 and -2, in the modulation of inflammatory reactions.

Two different routes for oxygenation of arachidonic acid have been
identified:
1. The cyclooxygenase pathway
2. The lipoxygenase pathway
The cyclooxygenase pathway, so named because of the unusual bicyclic
endoperoxide (PGG2) produced in the first step of the sequence, involves
the highly stereospecific addition of two molecules of oxygen to the
arachidonic acid substrate, followed by subsequent enzyme-controlled
rearrangements to produce an array of oxygenated eicosanoids with diverse
biologic activities

1. The cyclooxygenase pathway

The lipoxygenase pathway of arachidonic acid metabolism produces
various acyclic lipid peroxides (hydroperoxyeicosatetraenoic acids
[HPETEs]) and derived alcohols (hydroxyeicosatetraenoic acids
[HETEs]).
Although the specific biologic function of each of these lipoxygenase-
derived products is not completely known, they are believed to play a major
role as chemotactic factors that promote cellular mobilization toward sites of
tissue injury.
In addition, the glutathione (GSH) conjugates LKT-C4 and LKT-D4 are
potent, long-acting bronchoconstrictors that are released in the lungs during
severe hypersensitivity episodes (leading to their initial designation as the
“slow reacting substances of anaphylaxis” [SRSAs])
2. The lipoxygenase pathway

Prostanoids are a subclass of eicosanoids consisting of the prostaglandins
(mediators of inflammatory and anaphylactic reactions), the thromboxanes
(mediators of vasoconstriction), and the prostacyclins (active in the resolution
phase of inflammation.)

Prostanoid Receptor

EICOSANOIDS APPROVED FOR HUMAN CLINICAL USE
Prostaglandin E2.
It is a naturally occurring prostaglandin that is administered in a single dose of
10 mg by controlled-release (0.3 mg/hr) vaginal insert to induce cervical
ripening. Use of this agent will potentiate the effects of oxytocin.

Carboprost Tromethamine.
It is a prostaglandin derivative that has been modified to prevent metabolic
oxidation of the 15-position alcohol function. This derivative may be
administered in a hospital setting only in a dose of 250 g by deep intramuscular
injection to induce abortion or to ameliorate severe postpartum
hemorrhage.

Prostaglandin E1, United States Pharmacopeia (USP).
PGE1, Alprostadil (Prostin VR Pediatric), is a naturally occurring prostaglandin
that has found particular use in maintaining a patent (opened) ductus
arteriosus in infants with congenital defects that restrict pulmonary or
systemic blood flow.
Alprostadil must be administered intravenously continually at a rate of
approximately 0.1 g/kg/min to temporarily maintain the patency of the ductus
arteriosus until corrective surgery can be performed.

Prostaglandin E1 Cyclodextrin.
This cyclic polysaccharide complex of PGE1 (Vasoprost) is available as
an orphan drug for the treatment of severe peripheral arterial occlusive disease
when grafts or angioplasty are not indicated.
Cyclodextrin complexation is used to enhance water solubility and reduce rapid
metabolic inactivation.
Misoprostol
Misoprostol, is a modified prostaglandin analog that shows potent
gastric antisecretory and gastroprotective effects when administered orally.
Misoprostol is administered orally in tablet form in a dose of 100 to 200 g
4 times a day to prevent gastric ulceration in susceptible individuals who are
taking NSAIDs. Misoprostol is combined with the NSAID diclofenac (Voltaren)
in an analgesic product (Arthrotec by Pharmacia), which is potentially safe for
longterm antiarthritic therapy.

Lubiprostone
This product is used to relieve chronic idiopathic constipation in adults.
The recommended oral dosage is 24 g 2 times a day with food. Precautions and
side effects are similar to those for other prostaglandin-derived products.
Prostacyclin (PGI2)
Marketed as the sodium salt (epoprostenol; Flolan by GlaxoSmithKline),
this product is administered by continuous infusion of a recently prepared solution
(within 48 hours) for the treatment of primary pulmonary hypertension (PPH).
The chemical stability of this compound in aqueous solution is limited, and the
biological half-life is less than 6 minutes.
The potent vasodilatory, platelet antiaggregatory effect, and vascular
smooth muscle antiproliferatory effect of this naturally occurring eicosanoid
produce a dramatic but short-lived therapeutic effect in PPH patients.

Iloprost
This more chemically and biologically stable derivative of
prostacyclin is available as a solution (10 g/mL) for nasal inhalation
(Ventavis by Actelion) via a precisely calibrated inhalation device for the
treatment of pulmonary arterial hypertension (PAH). Patients inhale 6 to
8 puffs of aerosolized iloprost every 2 to 3 hours to produce a direct
vasodilatory effect on pulmonary blood vessels, thereby decreasing vascular
resistance.

PROSTAGLANDINS FOR OPHTHALMIC USE:
Several prostaglandin analogs have recently come to market for the treatment
of open-angle glaucoma or ocular hypertension in patients who have not
benefited from other available therapies.
Bimatoprost (Lumigan)
It is supplied as a sterile 0.03% ophthalmic solution in 2.5- and 5.0-mL sizes.
The recommended dosage of bimatoprost is limited to one drop into the
affected eye once daily in the evening.

Latanoprost (Xalatan)
It is available as a 0.005% sterile ophthalmic solution in a 2.5-mL dispenser
bottle. Latanoprost is also marketed as a combination ophthalmic product
with the β-adrenergic blocking agent, timolol, which apparently enhances
IOP-lowering by decreasing the production of aqueous humor.

Unoprostone (Rescula)
It is supplied as a 0.15% sterile ophthalmic solution. Unoprostone is
somewhat unusual in that it is a docosanoid (22-carbon atom) PGF2 analog
marketed as the isopropyl ester.

Leukotriene antagonists:
Also known as antileukotrienes, are drugs that inhibit leukotrienes.
They include:
•Leukotriene receptor antagonists: montelukast, zafirlukast, and pranlukast
•Leukotriene synthesis inhibitors: zileuton.

What are leukotrienes?
Leukotrienes (LTs) are potent biological proinflammatory mediators. They are
produced in the body from arachidonic acid by the enzyme 5-lipoxygenase and are
divided into groups according to their chemical structure.
Eosinophils, basophils and mast cells are important sources of cysteinyl-LTs
(LTC4, LTD4 and LTE4).
Cysteinyl-LTs play a role promoting and
maintaining chronic inflammatory responses in allergic respiratory and skin disease
through their effects on chemotaxis (attrating immune
cells), vasodilation (widening blood vessels) and oedema (swelling as fluid leaks through
the blood vessels).
Leukotrienes exert their actions by binding to two receptors, cysteinyl-LT1
receptor and cysteinyl-LT2 receptor, which are found in smooth muscle cells
and macrophages in the airway and on other pro-inflammatory cells (including
eosinophils).

How do leukotriene antagonists work?
Antileukotriene drugs block the actions of cysteinyl-LTs.
•Leukotriene receptor antagonists bind strongly to the cysteinyl-LT1 receptors on target
cells.
•Leukotriene synthesis inhibitors block the enzyme 5-lipoxygenase to prevent the
production of leukotrienes.

 Montelukast is used to control and prevent symptoms caused by asthma (such as
wheezing and shortness of breath).
 It is also used before exercise to prevent breathing problems during exercise
(bronchospasm).
 This medication can help decrease the number of times you need to use your quick
relief inhaler.
 Montelukast is also used to relieve symptoms of hay fever and allergic rhinitis
(such as sneezing, stuffy/runny/itchy nose).
 This drug works by blocking certain natural substances (leukotrienes) that may
cause or worsen asthma and allergies.
 It helps make breathing easier by reducing swelling (inflammation) in the airways.
Montelukast

 Zafirlukast is used to control and prevent symptoms (such as wheezing and
shortness of breath) caused by asthma.
 Controlling symptoms of asthma helps you maintain your normal activities and
cuts down on time lost from work or school.
 It does not work right away and should not be used to relieve sudden asthma
attacks.
Zafirlukast

Pranlukast
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. It
antagonizes or reduces bronchospasm caused, principally in
asthmatics, by an allergic reaction to accidentally or inadvertently
encountered allergens.

Leukotriene synthesis inhibitors:
Zileuton
Zileuton is a synthetic derivative of hydroxyurea with antiasthmatic properties.
The leukotriene inhibitor zileuton blocks 5-lipoxygenase, which catalyzes the
formation of leukotrienes from arachidonic acid; causes bronchodilation;
decreases bronchial mucous secretion and edema; and may prevent or decrease
the symptoms of asthma.

Autacoids.pptx They have also been called’ local hormones’. However, they differ from 'hormones' in two important ways-hormones are produced by specific cells, and are transported through circulation to act on distant target tissues.

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Autacoids.pptx They have also been called’ local hormones’. However, they differ from 'hormones' in two important ways-hormones are produced by specific cells, and are transported through circulation to act on distant target tissues.