Histamine and Antihistaminics
HISTAMINE
It means ‘tissue amine’ (histos—tissue)
is almost universally present in animal tissues
and in certain plants, e.g. stinging nettle. It is studied in detail by Dale in
the beginning of the 20th century when close
parallelism was noted between its actions and
the manifestations of certain allergic reactions.
It was involved as a mediator of hypersensitivity
phenomena and tissue injury reactions. It is now
known to play important physiological roles.
Histamine is present mostly within storage
granules of mast cells. Skin, gastric and intestinal mucosa, lungs, liver
and placenta are rich in histamine. Non-mast cell histamine occurs in
brain, epidermis, gastric mucosa and growing
regions.
Synthesis, storage and destruction
Histamine ( β imidazolylethylamine) is
synthesized locally from the amino acid histidine
and degraded rapidly by oxidation and methylation . In mast cells, histamine (positively
charged) is held by an acidic protein and heparin
(negatively charged) within intracellular granules.
When the granules are extruded by exocytosis,
Na+ ions in E.C.F. exchange with histamine to
release it free. Increase in intracellular
cAMP (caused by β adrenergic agonists and
methylxanthines) inhibits histamine release. It is inactive orally because liver degrades
all histamine that is absorbed from the gut.
Histamine receptors
There are four types of histaminergic receptors .
| Receptor Type | Major Tissue Locations |
|---|---|
| H1 | smooth muscle, endothelial cells |
| H2 | gastric parietal cells |
| H3 | central nervous system(Autoreceptor) |
| H4 | mast cells, eosinophils, T cells, dentritic cells |
PHARMACOLOGICAL ACTIONS
1. Blood vessels
It causes marked
dilatation of smaller blood vessels, including arterioles, capillaries and venules.
On s.c. injection: flushing appears especially in the blush area, heat,
increased heart rate and cardiac output, with little
or no fall in BP are produced.
Rapid i.v. injection: With low doses of hitamine only the H1 component is manifestsince H1 receptors have higher affinity whereas fall in
BP due to large doses is completely blocked only
by a combination of H1 and H2 antagonists. Pulsatile
headache may occurs due to dilation of cranial vessel.
Vasodilatation caused by histamine is partly (H1 component) indirect, mediated through ‘endothelium
dependent relaxing factor’ (EDRF), i.e. NO; the
receptor being located on the endothelial cells whereas H2 receptors mediating vasodilatation are located
directly on the vascular smooth muscle.
Larger arteries and veins are constricted by
histamine: mediated by H1 receptor on vascular
smooth muscle. Histamine also causes increased
capillary permeability due to separation of
endothelial cells → exudation of plasma. ( H1 response).
Injected intradermally: It produce the triple response
consisting of:
Red spot: due to intense capillary dilatation.
Wheal: due to exudation of fluid from
capillaries and venules.
Flare: Redness in the surrounding area
due to arteriolar dilatation.
2. Heart Direct effects
On in situ heart are not prominent, but the isolated heart, especially of guinea pig, is stimulated—rate as well as force of contraction is increased.
3. Visceral smooth muscle:
Causes bronchoconstriction. Abdominal cramps and colic by increasing
intestinal contractions due to large dose. Smooth muscle contraction is a H1 response.
4. Glands
Histamine causes marked increase
in gastric secretion—primarily of acid but also
of pepsin due to direct action
exerted on parietal cells through H2 receptors and is mediated by increased cAMP generation, which
in turn activates the membrane proton pump (H+
K+
ATPase)
5. Sensory nerve endings:
Itching occurs
when histamine is injected i.v. or intracutaneously.
6. Autonomic ganglia and adrenal medulla
These are stimulated and release of
Adr occurs, which can cause a secondary rise
in BP.
7. CNS
It does not penetrate bloodbrain barrier—no central effects are seen on i.v.
Intracerebroventricular administration :
Produces rise in BP, cardiac stimulation,
behavioural arousal, hypothermia, vomiting and
ADH release mediated through
both H1 and H2 receptors.
PATHOPHYSIOLOGICAL ROLES
1. Gastric secretion
Histamine has dominant
physiological role in mediating secretion of
HCl in the stomach. Nonmast cell
histamine occurs in gastric mucosa, possibly in
cells called ‘histaminocytes’ situated close to the
parietal cells. It is released locally under the influence
of all stimuli that evoke gastric secretion (feeding,
vagal stimulation, cholinergic drugs and gastrin)
and activates the proton pump (H+
K+ ATPase)
through H2 receptors.
H2 blockers not only suppress acid secretion
induced by histamine but also markedly diminish
that in response to ACh and gastrin.
2. Allergic phenomena
Released from
mast cells following AG : AB reaction on their
surface (involving IgE type of reaginic antibodies) Type 1 hypersensitivity
reactions, histamine is causative in urticaria,
angioedema, bronchoconstriction and anaphylactic
shock. The H1 antagonists are effective in
controlling these manifestations to a considerable
extent, except asthma and to a lesser extent
anaphylactic fall in BP in which leukotrienes
(especially LTD4) and PAF appear to be more
important.
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 antihistaminics
owe their sedative action to blockade of this function.)
4. Inflammation
It is a mediator of
vasodilatation and other changes that occur during
inflammation, promotes adhesion of leukocytes
to vascular endothelium by expressing adhesion
molecule P-selectin on endothelial cell surface,
sequestrating leukocytes at the inflammatory site.
5. Tissue growth and repair
Because growing and
regenerating tissues contain high concentrations of histamine.
6. Headache
It has been implicated in certain
vascular headaches.
USES
It has no therapeutic use.
Betahistine
Orally active,H1 selective histamine analogue. It is used
to control vertigo in patients of Meniéré’s disease:
possibly acts by causing vasodilatation in the
internal ear. It is contraindicated in asthmatics
and ulcer patients.
HISTAMINE RELEASERS
Different mechanical, chemical and immunological stimuli are capable of releasing histamine from mast cells.1. Tissue damage: stings and venoms, trauma, proteolytic enzymes, phospholipase A.
2. Antigen: antibody reaction involving IgE antibodies.
3. Polymers: dextran, polyvinyl pyrrolidone (PVP).
4. Some basic drugs: tubocurarine, morphine, atropine, pentamidine, polymyxin B, vancomycin and even some antihistaminics directly release histamine without an immunological reaction.
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