Transcript Pharmacolecture 12 - pharmacology1lecnotes

Histamine
Histamine is an endogenous compound synthesized, stored,
and released primarily by mast cells and after release exerts
profound effects on many tissues and organ.
It is a cellular mediator of the immediate hypersensitivity
reaction and acute inflammatory response and also a primary
stimulant of gastric acid secretion.
It has a central neurotransmitter role
Histamine importance in medicine and pharmacology lies in
its pathophysiological actions and in the therapeutic
usefulness of drugs that block the receptors that mediate its
actions.
The actions of histamine are mediated by at least three
distinct receptors: H1, H2, and H3. Of these, the H1 and H2
receptors are the best characterized and mediated welldefined response in humans that have been used as the basis
for drug development.
Response such as bronchoconstriction are mediated by H1
receptors and are selectively antagonized by classic
antihistamines such as diphenhydramine, mepyramine.
Responses such as facial cutaneous vasodilation and gastric
acid secretion are mediated by H2 receptors and are
antagonized by agents such as cimetidine and ranitidine.
The H3 receptors has been studied mainly in experimental
animals. This receptor is found on the nerve endings and
mediate the inhibition of neurotransmitter release.
This includes the inhibition of the release of histamine from
the histaminergic neurons in the central nervous system (
CNS) and other transmitter in the CNS and of the release of
transmitter from peripheral nerves in the autonomic nervous
system and the myenteric plexus.
Mechanism of action
Action of histamine
The mechanism of signal transduction by histamine at H1, H2,
and H3 receptors differs.
The contractile actions on smooth muscle and neuronal
actions mediated by H1 receptor result from stimulation of the
breakdown of inositol phospholipids.
The stimulus – response mechanism for the H1 receptormediated relaxation of vascular smooth muscle involves the
synthesis and release of nitric oxide, an endothelium-derived
relaxant factor.
The actions of histamine mediated by H2 receptors may stem
from the activation of adenylate cyclase. This occurs in H2
receptor systems that mediate acid secretion, the relaxation
of vascular smooth muscle, neuronal excitation, the inhibition
of basophil degranulation, and increase in myocardial
contractility.
The inhibition of transmitter release mediated by H3 receptors
is thought to involve a modulation of Ca2+ entry into nerve
endings
Synthesis and metabolism of histamine
Histamine is synthesized in vivo by decarboxylation of the
amino acid L- histidine, which is catalyzed by the L-histadine
decarboxylase.
Two primary pathways exist for the catabolism of histamine:
The first is the oxidative deamination pathway, which is
catalyzed by diamine oxidase and leads to the formation of
imidazole acetic acid.
The second pathway involves the methylation of the tele
nitrogen in the imidazole ring, which is catalyzed by
histamine –N- methyltransferase and results in the formation
of T-N- methlhistamine
Storage and release of histamine
Histamine is found in most tissues of the body but present in
high concentrations in the lungs and the skin and in
particularly high concentrations in the gastrointestinal tract.
At cellular level, it is found largely in mast cells and basophils,
associated with heparin, but non-mast-cell histamine occurs
in ‘histaminocytes’ in the stomach and in histaminergic
neurons in the brain.
The basophil content of the tissues is negligible – except in
certain parasitic infections and hypersensitivity reactions and
basophils form only 0.5% of circulating white blood cells.
In mast cells and basophils, histamine is held in intracellular
granules in complex with an acidic protein and heparin of
high molecular weight, termed macroheparin.
Together these comprise the matrix of the granules in which
the basic molecule histamine is held by ionic forces, the
histamine content being approximately 0.1 – 0.2 pmol per
mast cell, and 0.01 pmol per basopil.
Histamine release
Histamine is released from mast cells and basophils by two
general processes of degranulation: noncytolytic and
cytolytic.
Cytolytic release of histamine from mast cells occurs when
the plasma membrane is damaged. This type of release is
energy- independent, does not require intracellular Ca2+, and
is accompanied by the leakage of cytoplasmic content.
Cytolytic release can be induced by variety of substances,
including the phenothiazines, H1-antagonist, and some
narcotics analgesics.
Noncytolytic release can be induced by variety of compounds,
release of histamine through this process is suspected to be
as a result of specific binding of a ligand to a receptor in the
plasma membrane of the mast cell or basophil
In contrast to cytolytic release, noncytolytic release requires
adenosine triphosphate for energy, depends on the changes
in the concentration of intracellular Ca2+, and is not
accompanied by the leakage of cytoplasmic content.
Noncytolytic release is characterized by exocytosis.
Agents that increase cAMP formation (e.g. β- adrenoceptor
agonists) inhibit histamine secretion. Replenishment of the
histamine content of mast cell or basophil after secretion is
a slow process, which may take days or weeks
Whereas turnover of histamine in the gastric histaminocyte
is very rapid.
Actions of histamine:
Gastric secretion: Histamine stimulates the secretion of
gastric acid by action on H2 – receptor. In clinical terms, this
is the most important action of histamine, since it is
implicated in the pathogenesis of peptic ulcer.
Smooth muscle effects: Histamine, acting through H1-
receptors, causes contractions of the smooth muscle of the
ileum, bronchi, and bronchioles, and the uterus. Histamine is
one of the main mediators causing reduction of air flow in
the phase of bronchial asthma. Uterine muscle in most
species is contracted.
Cardiovascular effects: Histamine dilates blood vessels in
humans by action on H1-receptors, the effect being partly
endothelium – dependent in some vascular beds.
It increases the rate and the output of the heart by action
on cardiac H2 – receptors.
Injection intradermally, histamine causes a reddening of the
skin and a wheal with a surrounding flare
The reddening results from vasodilation of the small
arterioles and precapillary sphincters, and the wheal is
caused by the increased permeability of the postcapillary
venules. These effect is mainly mediated through the
activation of H1- receptors.
The flare is an axon reflex that involves stimulation of
sensory nerve fibers and the passage of antidromic impulses
through neighboring branches of the same nerve with
release of a vasodilator mediator.
Itching : itching occurs if histamine is injected into the skin
or applied to a blister base; it is caused by stimulation of
sensory nerve endings.
CNS effect: Histamine is present in the brain in much smaller
amounts than in other tissues, such as skin, and lungs,
undoubtedly serves as neurotransmitter. H1 receptors are
mainly located in postsynaptically and cause excitation; H2 –
and H3 – receptor are inhibitory, respectively post- and
presynaptic, H3 – receptor being inhibitory autoreceptors on
histamine – releasing neurons.