DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

914 Regulation of Mediator Release. The wide variety of
mediators released during the allergic response can
explain the ineffectiveness of drug therapy focused on a
single mediator. Agents that act at muscarinic or α-
adrenergic receptors increase the release of mediators,
an effect of little clinical significance. Epinephrine and
related drugs that act through β 2
adrenergic receptors
increase cellular cyclic AMP and thereby inhibit the
secretory activities of mast cells. However, the beneficial
effects of β adrenergic agonists in allergic states such
as asthma are due mainly to relaxing bronchial smooth
muscle (Chapters 12 and 36).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Release and Functions
of Endogenous Histamine
Histamine has important physiological roles. After its
release from storage granules as a result of the interaction
of antigen with immunoglobulin E (IgE) antibodies
on the mast cell surface, histamine plays a central
role in immediate hypersensitivity and allergic responses.
The actions of histamine on bronchial smooth muscle
and blood vessels account for many of the symptoms
of the allergic response. In addition, some drugs act
directly on mast cells to release histamine, causing
untoward effects. Histamine has a major role in regulating
gastric acid secretion and also modulates neurotransmitter
release.
Role in Allergic Responses. The principal target cells
of immediate hypersensitivity reactions are mast cells
and basophils (Schwartz, 1994). As part of the allergic
response to an antigen, IgE antibodies are generated
and bind to the surfaces of mast cells and basophils via
specific high-affinity F c
receptors. This receptor,
FcεRI, consists of α, β, and two γ chains (Chapter 35).
Atopic individuals develop IgE antibodies to commonly
inhaled antigens. This is a heritable trait, conferring
a predilection to rhinitis, asthma, and atopic
dermatitis.
Antigen bridges the IgE molecules and via FcεRI activates
signaling pathways in mast cells or basophils involving tyrosine
kinases and subsequent phosphorylation of multiple protein substrates
within 5-15 seconds of contact with antigen. Protein kinases
implicated include the Src-related kinases Lyn and Syk. Prominent
among the phosphorylated proteins are the β and γ subunits of FcεRI,
itself, and phospholipase C (PLC)γ 1
and PLCγ 2
, with consequent
production of inositol trisphosphate (IP 3
) and mobilization of intracellular
Ca 2+ (Chapter 3). These events trigger the exocytosis of the
contents of secretory granules.
Release of Other Autacoids. The release of histamine
only partially explains the biological effects that ensue
from immediate hypersensitivity reactions because a
broad spectrum of other inflammatory mediators is
released on mast cell activation.
Stimulation of IgE receptors also activates phospholipase
A 2
(PLA 2
), leading to the production of a host
of mediators, including platelet-activating factor (PAF)
and metabolites of arachidonic acid such as leukotrienes
C 4
and D 4
, which contract the smooth muscles of the
bronchial tree ( Chapters 33 and 36). Kinins also are generated
during some allergic responses. Thus, the mast
cell secretes a variety of inflammatory mediators in addition
to histamine, each contributing to the major symptoms
of the allergic response (see below).
Histamine Release by Drugs, Peptides, Venoms, and
Other Agents. Many compounds, including a large
number of therapeutic agents, stimulate the release of
histamine from mast cells directly and without prior
sensitization. Responses of this sort are most likely to
occur following intravenous injections of certain categories
of substances, particularly organic bases such as
amides, amidines, quaternary ammonium compounds,
pyridinium compounds, piperidines, and alkaloids
(Rothschild, 1966). Tubocurarine, succinylcholine,
morphine, some antibiotics, radiocontrast media, and
certain carbohydrate plasma expanders also may elicit
the response. The phenomenon is one of clinical concern,
and may account for unexpected anaphylactoid
reactions. For example, vancomycin-induced red-man
syndrome, involving hypotension and flushing in the
upper body and face, may be mediated through histamine
release.
In addition to therapeutic agents, certain experimental compounds
stimulate the release of histamine as their dominant pharmacological
characteristic. The archetype is the polybasic substance
known as compound 48/80. This is a mixture of low-molecularweight
polymers of p-methoxy-N-methylphenethylamine, of which
the hexamer is most active.
Basic polypeptides often are effective histamine releasers,
and over a limited range, their potency generally increases with the
number of basic groups. For example, bradykinin is a poor histamine
releaser, whereas kallidin (Lys-bradykinin) and substance P,
with more positively charged amino acids, are more active. Some
venoms, such as that of the wasp, contain potent histamine-releasing
peptides (Johnson and Erdös, 1973). Polymyxin B also is very active.
Basic polypeptides released upon tissue injury constitute pathophysiological
stimuli to secretion for mast cells and basophils.
Within seconds of the intravenous injection of a histamine
liberator, human subjects experience a burning, itching sensation.
This effect, most marked in the palms of the hand and in the face,
scalp, and ears, is soon followed by a feeling of intense warmth. The
skin reddens, and the color rapidly spreads over the trunk. Blood
pressure falls, the heart rate accelerates, and the subject usually complains
of headache. After a few minutes, blood pressure recovers, and
crops of hives usually appear on the skin. Colic, nausea, hypersecretion