LECTURE 10

• Autacoids

• Pherohormones
 Definition of Autacoids
These are heterogeneous group of chemical
substances with wide spectrum of biological
effects , synthesized by different tissues and
exerting local effect with no or very minute serum
level

Autacoids' include histamine , serotonin ,

prostaglandins , leukotriens , vaso-active intestinal
polypeptides (VIPs), kinins, Angiotensin , Nitric
oxide (NO), endothelin,…………etc.
 Features of Autacoids

1. Not released or stored in glands

2. Not circulated in blood
3. Have very short half-life (t1/2)
4. Are formed at the site of action
5. Produce localized action

3
 Classification of Autacoids

1. Naturally occurring biogenic amines: Histamine

and Serotonin (5‐hydroxytryptamine; 5‐HT).

2. Endogenous polypeptides.

3. Lipid‐derived autacoids.

4
Few examples of Autacoids
• Histamine
• Serotonin
• GABA
• Dopamine
• Epinephrine/ Norepinephrine
• Nitric oxide
• Prostaglandins
• Thromboxanes
• Leukotrienes
5
1. HISTAMINE
• Histamine : is a bioactive amine , widely
distributed in animal and plant tissues

• In human body, histamine present in skin , GIT ,

lungs , CNS , CVS, basophiles

• It is stored in granules in mast cell, it is released

in response to many physical and chemical agents
that lead to de-granulation of the mast cells
 Synthesis:
Histamine is synthesized by 2 enzymes:
1- Histidine de-carboxylase that converts histidine to
histamine. This enzyme is inhibited by methyl
histidine

2- Aromatic amino acid de-carboxylase which is non

specific enzyme and inhibited by methyl-dopamine
8
Metabolism :
By 2 routes

1- By histaminase or di-amine oxidase

2- By histamine methylating enzymes

The synthesis and breakdown of histamine
(2 major routes)
 Release:
Histamine is released by the process of de-
granulation in response to:
1- Immunological reactions : Ag-Ab complex
stimulates mast cell de-granulation

2- Chemical and mechanical reactions like histamine

release by drugs -morphine codeine , Vancomycin ,
polymexin,……….etc
Physiological role of histamine:
1. Neurotransmitter in CNS
2. Micro-circulatory regulation
3. Control sleep and alertness
4. Correlates with fetal development
5. Wounds healing
6. Has a role in thermal and body weight regulation.
7. White blood cells chemotaxis
8. Gastric acid secretion
 Mechanism of action of histamine:

Histamine acts by binding to 4 subclasses of

receptors [ H1 , H2 , H3 , H4] which are distributed
in different tissues.
Histamine antagonists :
The action of histamine can be antagonized by :
1- Physiological antagonist : by epinephrine
2- Competitive pharmacological antagonists :
we have H1 and H2 blockers
3- Mast cells stabilizers (drugs that prevent
mast cell de-granulation ) like chromolyin and
nedocromil
 2. Serotonin

(5-Hydroxytryptamine: 5-HT)

HO CH2 H2C NH 2
Indol derivative
NH
Rang et al. Pharmacology – 5st Ed. (2003)
Serotonin synthesis
Synthesis of serotonin from tryptophan involve two reactions:
1) Hydroxylation:
Tryptophan 5- Hydroxytryptophan
• The enzyme catalyzes this reaction is Tryptophan Hydroxylase
• The Co- factor is Tetrahydrobiopterin, which is converted in this
reaction to Dihydrobiopterin
2) Decarboxylation:
5- hydroxytryptophan Serotonin
The enzyme is hydroxytryptophan decarboxylase.
• Serotonin is synthesized in CNS, & Chromaffin cells

16
17
 Serotonin is degraded in two reactions

1) Oxidation:
Monoamine oxidase
5-hydroxytryptamine + O2 + H2O 5- Hydroxyinodole-3-
acetaldehyde

2) Dehydrogenation Aldehyde dehydrogenase

5- Hydroxyinodole-3-acetaldehyde 5-hydroxindole-3-acetate

(Anion of
5-hydroxyindoleacetic acid)

18
 Structures rich in 5-HT

• GIT (chromaffin cells and enteric neurons)

• Platelets
• CNS
 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
 Serotonergic Projections

Sleep, mood

Arousal, mood
Clinical conditions in which
5-HT plays a role include:
• Migraine
• Mood disorders (depressive illnesses)
• Anxiety
• Vomiting
• Carcinoid syndrome (malignant
tumors of enterochromaffin cells in
intestines)
 5-HT1-receptors:
• 5-HT1A - 5-HT1F
• All subtypes occur in CNS and cause neural
inhibition
• Act by inhibiting adenylate cyclase
3. Gamma aminobutyric acid (GABA)

Whereas glutamate is the

principal excitatory
neurotransmitter, GABA is
the principal inhibitory
neurotransmitter in the
brain
GABA Biosynthesis
1. GABA undergoes reconversion to glutamate (amine group is
transferred to -ketoglutarate, generating glutamate and succinic
semialdehyde)
2. Glutamate is transported back into nerve terminal, where it serves
as precursor for new GABA synthesis
 4. Dopamine and Epinephrine

Synthesized in the body mainly by

• Nervous tissue
• Adrenal glands
Biosynthesis of Dopamine and Epinephrine
Effects of Epinephrine
• Gets you ready to fight or run

• Heightens your senses, tenses your muscles,

opens breathing passages, etc.

• In response to stress

• Take less than 30 seconds to kick in and last

several minutes
 Dopaminergic Projections

Thought-Schizophrenia
Mesolimbic pathway motor

Mesocortical pathway

motor

hormones
Reward/pleasure
 5. Nitric Oxide
• First described in 1979 as a potent relaxant of
peripheral vascular smooth muscle.

• Used by the body as a signaling molecule.

• Serves different functions depending on body

system. i.e. neurotransmitter, vasodilator,
bactericide.

• First gas known to act as a biological messenger

• Short lived, usually degraded or reacted within a
few seconds
Conversion of arginine to NO via
nitric oxide synthase
•Nitroglycerin is converted to NO and
dilates coronary arteries in treating
angina pectoris
 6. Eicosanoids
• The eicоsanoids are important
mediators of inflammation
and allergy

• The main source of

eicosanoids is arachidonic acid
It is a 20-carbon unsaturated fatty acid
 Eicosanoids…

• Eicosanoids are specialized fatty acids

• Eicosanoids have strong hormone-like actions in

the tissues where they are produced

• Eicosanoids are not stored and are very unstable

 In general, eicosanoids mediate:

• Inflammatory response, - involves the joints (rheumatoid

arthritis), skin (psoriasis), and eyes

• Production of pain and fever

• Regulation of blood pressure

• Regulation of blood clotting

• Regulation of renal function

• Control of several reproductive functions, such as the

induction of labour
 Main
actions
of the
eicosanoids

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

 Eicosanoid biosynthesis
• In polyunsaturated fatty acid metabolism, especially
metabolism of linoleic and arachidonic acid:
• In humans, arachidonic
acid is formed from
linoleic acid:

• In humans, the double

bonds cannot be
introduced beyond the ∆9
position  linoleic and
linolenic acids are
essential: must be
supplied in food (plant
oils, peanut, soybean,
corn)
 Main sites of eicosanoid biosynthesis

• Endothelial cells
• Leukocytes
• Platelets
• Kidney

• Unlike histamine, eicosanoids are NOT synthesized

in advance and stored in granules – when needed,
they can be produced very quickly from
arachidonate released from membranes
Prostaglandins
Thromboxanes

47
Function of Thromboxanes

• Thromboxanes are synthesized in platelets and

upon release cause vasoconstriction and platelet
aggregation

• It stimulates steroid production by adrenal cortex

• Exerts PTH like effects on bone, it causes increased

mobilization of calcium from bones
Leukotrienes

50
 Leukotrienes (LTs)
• They are a family of conjugated trienes formed
from eicosanoic acids in leukocytes, mast cells and
macrophages by lipoxygenase pathway in response
to immunologic and non inflammatory stimuli

• They have no ring in their structure but have three

conjugated double bonds
 Functions of Leukotrienes

• LTs act as mediators of inflammation and

anaphylaxis

• Inhalation of LTs causes bronchospasm

• LTs-C4 and D4 are potent stimulators of mucus

secretion

• LTs-B4 stimulate chemotaxis of neutrophils and

eosinophils which are found at the site of
inflammation
A look at Pheromones

54
 What are Pheromones?

Pheromones are species specific sensory

input from the social environment that
influence “…a definite behavior or a
developmental process.”
Karlson & Luscher (1959) Pheromones': a new term for a class of biologically active substances. Nature. 1959 Jan 3;183(4653):55-6.

[e.g., by causing changes in levels of hormones]

 Pherohormones

Pheromone - from Greek word pherein (to

transfer) and hormone (to excite) :
• Semiochemical exchange between
individuals of the same species.
• Induces specific reaction such as special
behaviour or developmental process.

56
57
58
 Pheromones Reception

Three parts involved

i. Exocrine glands
ii. Medium (Air or Water)
iii. Pheromone receptors

Receptors should be
• Olfactory
or
• Gustatory (taste)
59
How Pheromones work in Humans

60
http://hartch25.weebly.com/pheromones-in-humans.html
 Neuron. Volume 95, Issue 1, p123–137.e8, 5 July 2017
Top: When male mice detect the ESP1 sex pheromone, they display enhanced aggressive
behavior toward other male mice.
Middle: ESP1 enhances sexual behaviors in female mice.
Bottom: ESP1 and a predator cue (snake skin)- elicits defensive behaviors.
Pup-derived pheromones The same neural
activate the vomeronasal pathway is suppressed
neural pathway in virgin in fathers, resulting in
males, leading to parental behavior.
aggressive behavior
toward pups.
62
http://www.riken.jp/en/research/rikenresearch/highlights/7337/
63
Controlling vector-
borne diseases

Ovitraps baited with the

oviposition pheromone
attract females to lay
their eggs