autacoids

A. Histamine
B. Other biogenic amines
1) Serotonin
2) Bradykinin
C. Eicosanoids
1) Leukotrienes
2) Prostanoids
Hormone (Bayliss & Starling): a chemical
substance that was secreted, without benefit of
a duct, directly into the bloodstream and which
acted at long range, often slowly on distant
organs or tissues
Neurotransmitters: released by neurons, not
endocrine glands, and acted briefly and at short
range on adjacent neurons or target cells
However, these definitions are not as straightforward as they
were historically classified; new evidence shows that:

1. Some non-neurotransmitter, non-traditional hormone

(e.g. glucocorticoids, testosterone) substances can have
local actions that affect a cells self (autocrine) and its
adjacent neighbor cells (paracrine); these are called
local hormones (e.g. histamine, cytokines).

2. Neurotransmitters (e.g. serotonin) have been found to be

able to operate outside of nerve tissue.
Our knowledge of important endogenous substances is
moving from orderly inexactitude (i.e. the old
classification system that says a hormone must act at a
long range and must be released into blood w/o use of a
duct; no category overlapping is allowed)towards a
confused precision (i.e. a new classification based on
labeling substances by their functions; it is a
neurotransmitter because it works as a messenger in
nerves, but it can also be considered a hormone if it
acts at a long range and slowly on targets; overlapping
of categories is allowed).
On the above spectrum between predominant
neurotransmitters and predominant hormones,
the mediators of inflammation fall in the middle
since they both can act as neurotransmitters
and hormones.
Definition of autacoid
A varied group of endogenous substances
occurring in a minute amounts and possessing
distinct chemical structure with distinct biologic/
pharmacologic activity.

Autos=self; akos=medicinal agent or remedy

(Greek)
Naturally occurring substances

Localized in tissues

Does not normally circulate

Diverse physiological and pharmacological

activities area
Differs from hormones and neurotransmitter

Short duration of action

Usually involved in responses to injury

Sites of action restricted to the synthesis

Examples of autacoid
1. Amines: histamine, serotonin (5HT)
2. Polypeptides: kinins, oxytocin, angiotensin II,
vasopressin, ANF (atrial natriuretic factor),
endothelins
3. Fatty acids: prostaglandins, leukotrienes,
thromboxanes, platelet activating factor
4. Others: endothelium-derived relaxing factor (NO),
cytokines (proteins)
Definition of HISTAMINE
Signal for local immune responses, also a
neurotransmitter
A biogenic amine synthesized by the decarboxylation
of histidine
Either stored or quickly inactivated by histamine N
methyltransferaseand diamine oxidase
Release from mast cells is stimulated by IgE
antibodies in response to foreign antigens
Nervous system : H1 & presynaptic H3 receptors

CVS: H1 & H2 receptors

Bronchiles: H1 receptors

Gastric mucosa: H2 receptors

H1 : increased IP3 (inositol triphosphat) & DAG
(diacylglycerol)

H2 : increased cAMP

H3 : decreased cAMP & Cai (intracellular free

calcium)

H4 : decreased cAMP & Cai

Histamine is released as a neurotransmitter. The
cell bodies of histamine neurons are found in the
posterior hypothalamus , in the
tuberomammillary nuclei. From here, these
neurons project throughout the brain, including
to the cortex, through the medial forebrain
bundle. Histamine neurons increase
wakefulness and prevent sleep
Pathophysiological Action of Histamine

Involved in allergic reactions

Mediates type 1 hypersensitivity reactions: hives

and hay fever.

Emesis: mediation of motion sickness.

Histamine shock (hypotension): systemic

anaphylaxis.
Hives (urticaria)
BIOGENIC AMINES

SEROTONIN
Sources: plants (e.g. banana, pineapple, plums)
and animals (e.g.mollusks, arthropods,
mammals, [unlike humans, can be found inthese
animals platelets and not in their mast cells])
Biosynthesis: hydroxylation of tryptophan then
decarboxylation to serotionin (5-hydroxy
tryptamine; 5-HT). Rapidly absorbed
intosecretory granules. Accumulated in
platelets, degradation by oxidative deamination.

Uses: No therapeutic use. Antagonists are highly

useful
Serotonin actions
Neurotransmitter in the CNS
Precursor of melatonin
Induces sleep, intestinal motility
Involved in temperature regulation
Affects mood, behavior (humans)
Deficiency causes depression
Hemostasis: platelet aggregation and vasoconstriction
Serotonin and Body Systems

Respiratory system: bronchoconstriction if

asthmatic; stimulation of aortic and carotid
chemoreceptors RR and minute vol.
GI tract: small intestine very sensitive to
serotonin intense rhythmic contractions due
to direct & indirect (ganglia in wall) effects.
Also stimulates vomiting (5-HT3 receptors on
vagalafferents and centrally)
Cardiovascular system (added info)

Direct vasoconstriction (large arteries) and indirect

vasodilation (NO and PGI2 mediated)
Heart: direct ionotropic & chronotropic effects
Reflex mechanisms due to change in BP
Stimulation of sensory nerve endings in baroreceptors
and in vagal afferents in coronary circulation (Bezold
Jarrisch reflex) bradycardia and hypotension
CNS:

pain perception
Sleep/Wakefulness
Various behaviors normal/abnormal: depression,
schizophrenia, obsessive compulsive behavior, etc.
Neuroendocrine regulation controls hypothalamic
cells involved in release of several anterior pituitary
hormones.
BRADYKININ
A non a peptide formed after tissue damage,
viral and allergic response.

Activate B1 and B2 receptors; t .=15s

Vasodilation (direct or vbia NO, Pgs) inc

capillary pressure.

Increases venous permeability edema.

Contract smooth muscles: intestine, uterus, veins,
bronchioles.
Inceases ion transport and fluid secretion in airways
and GIT allergic rhinitis, diarrhea, pancreatitis
Role in chronic inflammation (i,e, hereditary
angioedema, gout, Rheumatoid Arthritis,
inflammatory bowel disease)
Pain at site of injection stimulate nociceptive
afferents.
ENDOTHELIUM-DERIVED AGENTS

examples are NO and endothelin

EICOSANOIDS
Unlike histamine, they are not found preformed
in tissues,but are generated de novo from
phospholipids.

Control of many physiological processes.

Most important mediators and modulators of the

inflammatory reaction.
Membrane-derived Agents
Derived from AA , a 20 C EFA (essential fatty acid)
Arachidonic Acid (AA) is esterified to phospholipids
of cell membranes
Biosynthesis depends on enzyme availability
Synthesis is regulated and initiated by physical &
chemical stimuli
These stimuli cause release of AA from the cellular
stores
Examples of Eicosanoids
1. Prostaglandins

2. Thromboxanes

3. Leukotrienes

4. Epoxyeicosatrienoic acids
Functions of Eicosanoids:
1. Inflammation
2. Fever
3. Regulation of BP
4. Blood clotting
5. Immune system modulation
6. Control of reproductive processes and tissue growth
7. Regulation of Sleep wake cycle
Biosynthesis of Eicosanoids

Physical & chemical stimuli interact with membrane-bound G protein

receptors activates phopholipase C and/or phospholipase A2 which
increases concentration of intracellular Ca2+.

Phospholipase A2 hydrolyzes ester bond of phopholipids (AA

release).

Phospholipase C cleaves the bond and forms diglyceride

Diglyceride lipase releases diglyceride arachidonate from

diglycerides.

The released arachidonate is oxygenated by several enzymes: major

enzymes are cyclooxygenase and lipoxygenase.