Download Histamine receptor antagonists

PHARMACOLOGY
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Autacoids
Prostaglandins, histamine, and serotonin belong to a group of compounds called
autacoids. These heterogeneous substances have widely differing structures and
pharmacologic activities. They all have the common feature of being formed by the
tissues on which they act; thus, they function as local hormones.
The autacoids also differ from circulating hormones in that they are produced by
many tissues rather than in specific endocrine glands.
HISTAMINE
Histamine is a chemical messenger mostly generated in mast cells. Histamine, via
multiple receptor systems, mediates a wide range of cellular responses, including
allergic and inflammatory reactions, gastric acid secretion, and neurotransmission
in parts of the brain. Histamine has no clinical applications, but agents that inhibit
the action of histamine (antihistamines or histamine receptor blockers) have
important therapeutic applications
Location, synthesis, and release of histamine
1. Location: Histamine is present in practically all tissues, with significant
amounts in the lungs, skin, blood vessels, and GI tract. It is found at high
concentration in mast cells and basophils. Histamine functions as a
neurotransmitter in the brain. It also occurs as a component of venoms and in
secretions from insect stings.
2. Synthesis: Histamine is an amine formed by the decarboxylation of the amino
acid histidine by the enzyme histidine decarboxylase, which is expressed in cells
throughout the body, including neurons, gastric parietal cells, mast cells, and
basophils.
3. Release of histamine: Most often, histamine is just one of several chemical
mediators released in response to stimuli. The stimuli for release of histamine from
tissues may include destruction of cells as a result of cold, toxins from organisms,
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venoms from insects and spiders, and trauma. Allergies and anaphylaxis can also
trigger significant release of histamine.
Mechanism of action
Histamine released in response to certain stimuli exerts its effects by binding to
various types of histamine receptors (H1, H2, H3, and H4).
Tissue and Organ System Effects of Histamine
Nervous system—Histamine is a powerful stimulant of sensory nerve endings,
especially those mediating pain and itching. This H1-mediated effect is an
important component of the urticarial response and reactions to insect and nettle
stings. H1 and H3 receptors play important roles in appetite and satiety;
antipsychotic drugs that block these receptors cause significant weight gain
Cardiovascular system— In humans, injection or infusion of histamine causes a
decrease in systolic and diastolic blood pressure and an increase in heart rate.
Flushing, a sense of warmth, and headache may also occur during histamine
administration, consistent with the vasodilation. Histamine-induced edema results
from the action of the amine on H1 receptors in the vessels of the microcirculation,
especially the postcapillary vessels
Bronchiolar smooth muscle— histamine causes bronchoconstriction mediated by
H1 receptors. Patients with asthma are very sensitive to histamine. The
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bronchoconstriction induced in these patients probably represents a hyperactive
neural response, since such patients also respond excessively to many other
stimuli, and the response to histamine can be blocked by autonomic blocking drugs
such as ganglion blocking agents as well as by H1-receptor antagonists
Gastrointestinal tract smooth muscle—Histamine causes contraction of intestinal
smooth muscle, large doses of histamine may cause diarrhea, partly as a result of
this effect. This action of histamine is mediated by H1 receptors.
Other smooth muscle organs—In humans, histamine generally has insignificant
effects on the smooth muscle of the eye and genitourinary tract. However, pregnant
women suffering anaphylactic reactions may abort as a result of histamineinduced
contractions
Secretory tissue—Histamine has long been recognized as a powerful stimulant of
gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor
production
The “triple response”—Intradermal injection of histamine causes a
characteristic red spot, edema, and flare response. The effect involves three
separate cell types: smooth muscle in the microcirculation, capillary or venular
endothelium, and sensory nerve endings
HISTAMINE ANTAGONISTS
The effects of histamine released in the body can be reduced in several ways.
1. Physiologic antagonists, especially epinephrine, have smooth muscle
actions opposite to those of histamine, but they act at different receptors.
2. Release inhibitors reduce the degranulation of mast cells that results from
immunologic triggering by antigen-IgE interaction. Cromolyn and
nedocromil appear to have this effect. Beta2-adrenoceptor agonists also
appear capable of reducing histamine release.
3. Histamine receptor antagonists represent a third approach to the reduction
of histamine-mediated responses
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Histamine receptor antagonists
Compounds that competitively block histamine or act as inverse agonists at H1
receptors have been used in the treatment of allergic conditions for many years,
and in the discussion that follows are referred to as antagonists
Pharmacokinetics
 The H1 antagonists are conveniently divided into first-generation and
second-generation agents. These groups are distinguished by the relatively
strong sedative effects of most of the first-generation drugs.
 The first-generation agents are also more likely to block autonomic
receptors.
 Second-generation H1 blockers are less sedating, owing in part to reduced
distribution into the central nervous system.
 These agents are rapidly absorbed after oral administration, with peak blood
concentrations occurring in 1–2 hours.
 They are widely distributed throughout the body, and the first-generation
drugs enter the central nervous system readily.
 Several of the second-generation agents are metabolized by the CYP3A4
system
 Most of the drugs have an effective duration of action of 4–6 hours
following a single dose, but meclizine and several second-generation agents
are longer-acting, with duration of action of 12–24 hours. The newer agents
are considerably less lipid-soluble than the first-generation drugs and are
substrates of the P-glycoprotein transporter in the blood-brain barrier; as a
result they enter the central nervous system with difficulty or not at all.
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Pharmacodynamics
Both neutral H1 antagonists and inverse H1 agonists reduce or block the actions of
histamine by reversible competitive binding to the H1 receptor. Several have been
clearly shown to be inverse agonists, and it is possible that all act by this
mechanism. They have negligible potency at the H2 receptor and little at the H3
receptor. H1 antagonists have several actions some of these actions are of
therapeutic value and some are undesirable.
1. Sedation—A common effect of first-generation H1 antagonists is sedation,
but the intensity of this effect varies among chemical subgroups. The effect
is sufficiently prominent with some agents to make them useful as “sleep
aids”and unsuitable for daytime use.
2. Antinausea and antiemetic actions—Several first-generation H1 antagonists
have significant activity in preventing motion sickness. They are less
effective against an episode of motion sickness already present.
3. Antiparkinsonism effects—Some of the H1 antagonists, especially
diphenhydramine, have significant acute suppressant effects on the
extrapyramidal symptoms associated with certain antipsychotic drugs. This
drug is given parenterally for acute dystonic reactions to antipsychotics.
4. Antimuscarinic actions—Many first-generation agents, especially those of
the ethanolamine, have significant atropine-like effects on peripheral
muscarinic receptors. This action may be responsible for some of the
(uncertain) benefits reported for nonallergic rhinorrhea but may also cause
urinary retention and blurred vision.
5. Adrenoceptor-blocking actions—Alpha-receptor-blocking effects can be
demonstrated for many H1 antagonists, especially those in the phenothiazine
subgroup, eg, promethazine. This action may cause orthostatic hypotension
in susceptible individuals. Beta-receptor blockade is not significant.
6. Serotonin-blocking actions—Strong blocking effects at serotonin receptors
have been demonstrated for some firstgeneration H1 antagonists, notably
cyproheptadine
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7. Local anesthesia—Several first-generation H1 antagonists are potent local
anesthetics. They block sodium channels in excitable membranes in the
same fashion as procaine and lidocaine. Diphenhydramine and promethazine
are actually more potent than procaine as local anesthetics. They are
occasionally used to produce local anesthesia in patients allergic to
conventional local anesthetic drugs.
8. Other actions—Certain H1 antagonists, eg, cetirizine, inhibit mast cell
release of histamine and some other mediators of inflammation. This action
is not due to H1-receptor blockade and may reflect an H4-receptor effect
Clinical Uses
First-generation H1-receptor blockers are still commonly used over-the-counter
drugs. The prevalence of allergic conditions and the relative safety of the drugs
contribute to this heavy use.
A. Allergic Reactions
 The H1 antihistaminic agents are often the first drugs used to prevent or treat
the symptoms of allergic reactions.
 In allergic rhinitis (hay fever), the H1 antagonists are second-line drugs after
glucocorticoids administered by nasal spray.
 In urticaria, in which histamine is the primary mediator, the H1 antagonists
are the drugs of choice and are often quite effective if given before exposure.
 In bronchial asthma, which involves several mediators, the H1 antagonists
are largely ineffective.
 Angioedema may be precipitated by histamine release but appears to be
maintained by peptide kinins that are not affected by antihistaminic agents.
 For atopic dermatitis, antihistaminic drugs such as diphenhydramine are
used mostly for their sedative side effect, which reduces awareness of
itching.
 the clinical effectiveness of one group may diminish with continued use, and
switching to another group may restore drug effectiveness for as yet
unexplained reasons.
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 The second-generation H1 antagonists are used mainly for the treatment of
allergic rhinitis and chronic urticaria.
B. Motion Sickness and Vestibular Disturbances
 Scopolamine and certain first-generation H1 antagonists are the most
effective agents available for the prevention of motion sickness.
C. Nausea and Vomiting of Pregnancy
Toxicity
 The wide spectrum of nonantihistaminic effects of the H1 antihistamines is
described above. Several of these effects (sedation, antimuscarinic action)
have been used for therapeutic purposes, especially in over-the-counter
remedies. Nevertheless, these two effects constitute the most common
undesirable actions when these drugs are used to block histamine receptors.
 Less common toxic effects of systemic use include excitation and
convulsions in children, postural hypotension, and allergic responses.
 overdosage of the older agents resemble those of atropine overdosage and
are treated in the same way
 Overdosage of astemizole or terfenadine may induce cardiac arrhythmias;
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