Autacoid

Term derived from greek: autos-self, akos-

healing substance or remedy.
There are divers substance produced by wide
variety of cells in the body, having intense biological
activity, but generally act locally(e.g. within
inflammatory packets) 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
The classical autacoids are-
Amine autacoids: Histamine
Lipid derived autacoids: prostaglandins
peptide autacoids: angiotensin
Unwanted inflammatory reaction
and immune responses.
Unwanted immune responses are
termed allergic or hypersensitivity
reaction and have been classified into
four types .
Unwanted inflammatory reaction
and immune responses.
Type I: immediate or anaphylactic
hypersensitivity --- Type I hypersensitivity
occurs in individual who have a
predominantly ThI response to antigen .
Unwanted inflammatory reaction
and immune responses.
In this individuals , antigenic material that
is not in itself noxious evokes the
production of antibodies of the IgE type ,
which fix to mask cells and ,in the lung, to
eosinophils . Subsequent contact with the
material causes the release of histamine,
PAF , eicosanoids and cytokines from mast
cells .
 Role in allergic response

The principal target cells of

immediate hypersensitivity reactions
are mast cells and basophils. As part
of the allergic response to an antigen,
reaginic antibodies IgE are generated
and bind to the surface of mast cells
and basophils. The IgE molecules
functions as receptor for antigens
Unwanted inflammatory reaction
and immune responses.
The effects may be localized to the nose ,
the bronchial tree , the skin or the
gastrointestinal tract . In some cases the
reaction is more generalized and produces
anaphylactic shock .
Unwanted inflammatory reaction
and immune responses.
In essence , inappropriately deployed Tcell
activity underlies types of hypersensitivy ,
being initiating factor in types I and III and
being involved in both the initiation and
effect phase in type IV .
Unwanted inflammatory reaction
and immune responses.
The hypersensitivity reactions given above
are the basis of the clinically important
group of autoimmune diseases . Examples
of autoimmine conditions have been given ;
other examples held to have a marked
component of cell –mediat hypersensitivity
are rheumatoid arthritis multiple sclerosis
and type I diabetes .
Synthesis and storage of histamine

Histamine is a basic amine formed from

histidine by histidine decrboxylase. It is
found in most tissues of the body but is
present in high concentration in the lungs
and the skins and in particularly high
concentration in the GI tract .
Synthesis and storage of histamine

At the cellular level it is found largely in

mast cells and basophils, associated with
heparin , but non-mast-cell histamin occurs
in histaminocytes in the stomach and in
histaminergic neurons in the brain .
Synthesis and storage of histamine

In mast cells and basophils , histamine is

held in intercellular granules in a complex
with an acidic protein
 Histamine release
Histamine is released from mast cells by
exocytosis during inflammatory or allergic
reactions. Stimuli include the inter action of
complement component C3a and C5a with
specific receptors on the cell surface or the
interaction of antigen cell – fixed IgE
antibodies .
 Histamine release
Secretion is initiated by a rise in cytosolic
Ca2+.
Agents the increase cAMP formation inhibit
histamine secretion .
 Histamine release
Replenishnent of the histamine content of
mast cell or basophil after secretion is a
slow process , which may take days or
weeks , where as turnover of histamine in
the gastric histaminocyte is vary rapid .
 Histamine receptor
Histamine produces its action by an effect
on specific histamine receptors, which are
of three main types H1 ,H2 ,and H3 .
Distinguished by means of selective
antagonist drugs . Some details of the actins
of antagonist and agonist drugs used to
investigate and define the three types of
histamine receptor are given in table .
 Histamine receptor
Selective antagonists at H1 -,H2- and H3-
receptors are mepyramine , cimetidine and
thioperamide , repectively. Selective agonist
for H2- and H3- rerceptors are dimaprit and
(R) –methylhistamine .
 Histamine receptor
Histamine H1 antagonist have clinical uses
as do histamine H2 antagonist , H3 –
receptors antagonist have been developed
and may have a role in CNS pharmacology .
 Actions
Gastric secretion – Histamine stimulates the
secretion of gastric acid by action on H2 –
receptors . In clinical terms , this is the most
important action of histamine since it is
implicated in the pathgenesis of peptic ulcer
.
 Actions
Smooth muscle effects : Histamine acting
on H1 –receptors , causes contractions of
the smooth muscle of the ileum , the
bronchi and bronchioles an the uterus .
The effect on the ileum is not as marked in
humans as it in the guinea –pig .
 Actions
Histamine is one of the main mediators
causing reduction of the air flow in the first
phase of bronchial asthma . Uterine muscle
in most species is contracted .
 Actions
Cardiovascular effects : Histamine dilates
blood vessels in humans by an action on h1-
receoptors , the effect being partly
endothelium dependent in some vascular
beds .it increases the rate and output of the
heart by action on cardiac H2- receptor.
 Itching
• Itching occurs if histamine is injected into
the skin or applied to a blister base ; it is
caused by stimulation of sensory nerve
ending.
 CNS effects
• Histamine is a transmitter in the CNS. It
will be clear from the above that histamine
is released in inflammation and is capable
of producing many of the effects of
inflammation and hypersensitivity :
vasodilatation, increased vascular
permeability and the spasm of smooth
muscle.
 CNS effects
• However, histamine H1 antagonists do not
have mach effect on the acute inflammatory
response. Histamine has a significant role
only in some sorts of type I hypersensitivity
reaction, such as allergic rhinitis and
urticaria .
Histamine is present in almost all
mammalian tissue ranging from
1mcg/g to 100mcg/g. The mast cell is
the predominant storage site for
histamine. The concentration of
histamine is particularly high in the
tissues that contain number of mast
cells, e.g. skin, the mucosa of the
bronchial tree and intestinal mucosa.
 Pathophysiological roles

1. Gastric secretion: Histamine has

dominating physiological role in
mediating secretionof HCl acid in the
stomach. Nonmast cells histamine
occurs in gastric mucosa. It is
released locally under the influences
of all stimuli that evoke gastric
secretion.
 Pathophysiological roles

H2 blockers block acid secretion

induced by histamine and also
diminish the action of Ach and
gastrin.
2. Allergic phenomena: Mediation of
hypersensitivity reactions is the first
role of histamine, but it is only one of
the mediators of such phenomena.
 Pathophysiological roles
Releasing from mast cells following
Antigen antibody reaction on their
surface in immediate hypersensitivity
reaction, histamine is causative in
urticaria, angioedema,
bronchoconstriction, and anaphylactic
shock. The H1 antagonists are
effective in controlling these
manifestations except asthma.
 Pathophysiological roles
3. As transmitter: Histamine is believed
to be the afferent transmitter which
initiates the sensation of itch and pain at
sensory nerve endings.
Nonmast cell histamine occurs in brain,
especially hypothalamus and midbrain. It
is involved in maintaining wakefulness.
H1 antagonists owe their sedative action
due to blockage of these functions.
 Pathophysiological roles

4. Inflammation: Histamine has been

implicated as a mediator of vasodilatation
and other changes that occur during
inflammation. It promotes adhesion of
leukocytes to vascular endothelium by
expressing adhesion molecule P-selectin
on endothelial cell surface.
 Histamine releasers:

A variety of mechanical, chemical and

immunological stimuli are capable of
releasing histamine from mast cells.
1. Tissue damage- trauma, stings, venoms
2. Antigen antibody reaction involving
IgE antibodies
3. Polymer e.g. dextran,
polyvinylpovidone(PVP)
 H1 Antagonists
Antiallergic action: Many manifestations
of Type 1 reactions are suppressed .
Urticaria, itching, angioedema are well
controlled, Anaphyactic fall in BP is
partially prevented. Asthma in man is
practically unaffected by these
antagonists because it is now well
established that leukotrienes and PAF are
more important mediators in human
 H1 Antagonists
CNS: the older antihistamines produce
variable degree of CNS depression. Some
individuals also experience stimulant effects
like restlessness and insomnia. This actually
happens in toxic doses. The second
generation antihistamines are practically
nonsedating.
Certain H1 antihistamines are effective in
preventing motion sickness. Promethazine
controls vomiting of pregnancy and other
 H1 Antagonists
Anticholinergic actions: Many H1 blockers
antagonise the muscarinic actions of Ach.
BP: Most antihistamines cause fall in BP on
iv injection. However, this is not evident on
oral administration.
Pharmacokinetics: the classical or first
generation antihistamines are well absorbed
from oral and parenteral routes, metabolized
in the liver and in urine. They are widely
distributed in the body and enter brain.
 H1 Antagonists

Side effects: with first generation

antihistamines are frequent but are generally
mild. Sedation, diminished alertness and
concentration, light headedness, fatigue and
tendency to fall asleep are the most common.
Patients are cautioned not to operate motor
vehicles or machinery requiring constant
attention.
 Second generation H1 Antagonists
These comparatively newer drugs have the
advantage of not impairing psychomotor
performance, sleepiness etc. However they
have a narrow spectrum of therapeutic
usefulness which is limited by the extent of
involvement of histamine.They are indicated
in -
1. Allergic rhinitis
2. Urticaria
3.Acute allergic reactions to drugs and foods.
 Second generation H1 Antagonists

Example: Terfenadine, Astemizole,

Loratadine, Cetrizine.
Antivertigo: Cinnarizine
 Second generation
The second generation antihistaminics (SGAs)
may be defined as those H1 receptor blockers
marketed after 1980 which have one or more of
the following properties:
higher H1 selectively: no anticholinergic side
effects.
Absence of CNS depressant property.
Additional antiallergic mechanisms apatt
form histamine blockade : some also inhibit late
phase allergic reaction by acting on leukotrienes or
by anti-platelet activation factor effect.
 These newer drugs have the advantage of
not impairing psycomotor performance , produce
no subjective effect, no sleepiness, do not
potentiate alcohol or benzodiadepines. Some
patient do complain of sedation, but incidence is
similar to placebo.
However, they have a narrow spectrum of
therapeutic usefullness which is limited by the
extent of involvement of histamine (acting
through through H1 receptors) in the disease state.
Their principal inindication are:
1. Allergic rhinitis and conjunctivitis, hay fever,
pollinosis– control sneezing, runny but not
blocked nose, and red, watering, itchy eyes.
2. Urticaria, dermographism, atopic eczema.
3. Acute allergic reactions to drug and food.
They have poor antipruritic, antiemetic and
antitussive actions.
 Terfenadine
• It is the first SGA, highly H1 selective, with a
rapid onset(1-2 hour) and moderate
duration(12-24 hour) of action—good for short
term and intermittent use. It produces an active
carboxy metabolite (t ½ 15 hour) which
extends the duration of action. Terfenadine,
but not it its carboxy metabolite(the active H1
blocker), blocks cardiac K+ channels in
overdose and has occasionally produced
polymorphic ventricular tachycardia (torsades
de pointes)
 Loratadine
Another long acting selective peripheral
H1 antagonist which lacks CNS depressant
effects and is faster acting then astemizole. It
is partly metabolized by CYP3A4 to an active
metabolites with a longer t1/2 of 17 hour, but
in contrast to terfenadine/ astemizole, it has
not produced cardiac arrhythmia in overdose.
No interaction with macrolides or antifungals
has been noted. Good efficacy has been
reported in urticaria and atopic dermatitis.
 Dosloratadine
• It is the major active metabolite of loratadine
effective at half the dose. Non-interference
with phychomotor performance and cardiac
safety are decumented.
 Cetirizine
• It is a metabolite of hydroxyzine with marked
affinity for peripheral H1 rectptor; penetrates
brain poorly, but subjective somnolence has
been experienced at higher dose. It is not
metabolized; dose not prolong cardiac action
potential or proguce arrhythmias when given
with erythromycin/ ketoconazolel.
Cetirizine also inhibit release of histamine and of
cytotoxic mediators from platelets as well as
eosinophil chemotaxis during the secondary
phase of the allergic response. Thus, it may
benefit allergic disorders by other actions as
well. It attains high and longer lasting
concentration in skin, when may be responsible
for superior efficacy in urticaria/ atopic
dermatitis, as well as for once daily dosing
despite elimination t ½ of 7-10 hour. It is
indicated in upper respirarory allergics;
pollinosis, urticaria and atopic dermatitis; also
used as adjuvant in seasonal asthma.
 Ebastine
• Another newer SGA that rapidly gets
converted to the active metabolite carbastine
having a t ½ of 10-16 hour. It is non sedating
and active in nasal and skin allergics. Animal
studies have found it to prolong Q- Tc interval
which makes it liable to arrhythmic potential
and CYP3A4 interaction, but actual reports are
still few.