Histamine

Introduction
Autacoids is a general term that refers to a number of compounds such as: histamine,
serotonin, endogenous peptides, prostaglandins, and leukotrienes
o The formal definition of autacoids is "self-remedy, referring to the action of local
hormones
Chemistry and Pharmacokinetics
o The formation of histamine occurs by the removal of a carboxyl group
(decarboxylation) from amino acid L-histidine
o One of the important issues associated with formation of a biologically active
compound is the mechanism that accounts for the compounds inactivation.
Histamine is active biologically, but the first step for its inactivation
involves the addition of a methyl group (CH3) followed by a chemical
oxidation.
o Most of the time very little histamine is excreted unchanged because of these
metabolic steps. One exception would be the case of neoplastic disease (cancer).
For instance, significant histamine is excreted unchanged in the presence of these
diseases: (a) systemic mastocytosis, (b) gastric carcinoid syndrome or (c) urticaria
pigmentosa.
Tissue Distribution:
o The primary site for histamine localization is the mast cell granules (or basophils)
Mast cells are important in that they release histamine in response to
potential tissue injury
Other sites include the central nervous system where histamine may
function as a neurotransmitter and the fundus of the stomach
(enterochromaffin-like cells) which are major acid secretagogues (They
promotes accretion by activation of acid-producing mucosal parietal cells.)
Histamine: Storage and Release
o Immunologic Release: The most important mechanism for histamine release is in
response to an immunological stimulus. In
Mast cells, if sensitized by surface IgE antibodies, degranulate when
exposed specific antigen. Degranulation means liberation of the contents
of the mast cell granules, including histamine. Degranulation is involved
in the immediate (type I) allergic reaction.

 Release regulation is present in most mast cells.

Histamine Modulation is associated with the inflammatory responses.

Following local injury, histamine first produces a local vasodilation

(reddening of the area) followed by an the release of acute inflammation
mediators. Inflammatory cells are involved in this process and include
neutrophils, eosinophils, basophils, monocytes & lymphocytes. In
Mechanical/Chemical Release: A second type of release occurs following

chemical or mechanical injury to mast cells. In these injuries caused

degranulation as noted above including again histamine release. Common drugs
such as morphine or tubocurarine can displace histamine from granule storage
sites.
Pharmacodynamics-- Mechanism of Action -- Histamine mediates its effects by
interacting with receptors. In
o Receptor Types include H1, H2,and H3 types. We will focus our attention on the
first two types (H1,H2)
Rece
ptor Localiz
Subt ation
ype

Receptor
coupling

Antago
nists
(partial
ly
selectiv
e)

H1

Receptor
Endothe
activation causes
lium,
and increased IP3,
brain,
DAG
smooth
(diacylglycerol)
muscle
production

H2

Ranitidi
Mast cel
ne
ls,
Receptor
(Zantac
gastric
activation causes
),
mucosa,
an increase in cimetid
cardiac
cAMP production
ine
muscle,
(Tagam
brain
et)

N/A

H3

Presyna
ptic:
brain,
mesente
ric
G protein coupled
plexus
(other
neurons
)

N/A

Receptor subtypes --H1, H2, and H3:

o Intracellular G protein interactions
H1:endothelial and smooth muscle cell localization
o H1 receptor activation causes can increase in phosphoinositol hydrolysis and an
increase in intracellular calcium.
H2 gastric mucosa, cardiac muscle cells, immune cell localization:
o H2 receptor activation causes an increase in cyclic AMP.

H3: primarily presynaptic

o Activation causes a decrease in transmitter release {transmitters:
histamine,acetylcholine, norepinephrine, serotonin)

Organ System Effects: Histamine

Cardiovascular:
o Systolic and diastolic blood pressure: Vasodilation of arterioles and precapillary
sphincters account for histamine's vasodilating effects. Vasodilation may be due in
part to nitric oxide liberation.
o Following from the reduced blood pressure, the heart rate increases by autonomic
reflex mechanisms and by direct action.
o Both H1 and H2 receptors involved in cardiovascular responses.
o Histamine-associated edema:H1 receptor effects (postcapillary vessels)
Increase in vessel permeability due to separation of endothelial cells,
allowing transudation of fluid and molecules as large as small proteins.
Responsible for urticaria (hives)
Endothelial cell separation: secondary to histamine-induced
calcium influx causing intracellular actin/myosin-mediated
contraction

o Direct cardiac effects:

Increased contractility (positive inotropism)
Increased pacemaker rate (positive chronotropism)
Gastrointestinal tract: Histamine promotes intestinal smooth muscle contraction which is
an H1 receptor mediated effect
Bronchiolar smooth muscle activation by histamine causes bronchoconstriction
(H1 receptor mediated )
o It is not surprising that inhaled histamine is a diagnostic, provocative test for
bronchial hyperreactivity (asthma or cystic fibrosis)
Nerve Endings: Sensory nerve endings are stimulated by histamine, especially those
endings which mediate pain and itching.
o These effects are H1 receptor mediated effect and represent part of the local
reaction to insect stings (urticarial responses)
Secretory tissue:
o Histamine cause the stimulation of release by secretory tissues. For example, a
significant increase in gastric acid secretion is caused by histamine. Other
examples of increased release include gastric pepsin.
o Mechanism of Action: Considering the gastric parietal cells, histamine interacts
with H2 receptors and initiates a second messenger response which proceeds by
(1) Increasing adenylyl cyclase activity which
(2) Results in an increase in the second messenger, cyclic AMP
which

(3) Causes an increase in intracellular calcium levels.

The increase in calcium triggers release.
This releasing characteristic of calcium
applies broadly in physiology.

Histamine:Clinical Pharmacology-- Uses

o Pulmonary Function: histamine aerosol may be used to test for bronchial

hyperreactivity.
Toxicities include:
o Flushing, hypotension, tachycardia, headache, bronchoconstriction,
gastrointestinal disturbances
Should not be given to asthmatics (except with extreme caution in
pulmonary function testing)

Should not be given to patients with active ulcer disease or

gastrointestinal hemorrhage.

Histamine Antagonists Introduction:

o Physiologic antagonists: example -- epinephrine, agents that produce opposing
effects, acting and different receptors
o Release inhibitors: reduced mast cell degranulation: example: cromolyn and
nedocromil
o Receptor antagonists: selective blockade of histamine receptors (H1, H2, H3 types)

H1 receptor antagonists:
o General properties:
H1 antagonists include both first-generation and second-generation
compounds
Both categories of agents are orally active and are metabolized by
the liver using the cytochrome P450 drug-metabolizing system
The average duration of pharmacological action is about 4-6 hours
Meclizine (Antivert) and several second-generation drugs
far longer acting, with effects lasting 12-24 hours.
First-generation agents tend to be relatively more sedating and more likely
than second-generation drugs to block autonomic receptors -- for example
antimuscarinic effects (blockade of cholinergic, muscarinic-type receptors)
Second-generation agents are relatively less sedating compared to the
earlier first-generation agents and exhibit less CNS penetration, which
accounts for reduced sedation.
Some of the second-generation agents are metabolized by a
cytochrome P450 type that is inhibited by other drugs, such as the
antifungal agent ketoconazole (Nizoral).
Therefore, plasma concentrations of certain second generation
H1 antagonists may increase, even the toxic levels, if the patients
also taking drugs such as ketoconazole (Nizoral) or erythromycin
estolate (Ilosone).
Histamine Pharmacodynamics:
o Histamine H1 Receptor Blockade:
H1 receptor blockers exhibit competitive antagonism for H1 receptor sites
whereas little effects at H2 receptor sites and negligible effects of H3 sites
are observed.

 H1 receptor blockers prevent bronchiolar or gastrointestinal smooth

muscle constriction
H1 receptor blockers do not completely prevent cardiovascular effects
(some of these effects are mediated by H2 receptors)
H1 receptor blockers cannot affect increases in gastric acid secretion or
mast cell histamine release because these effects are H2 receptor sitemediated.

Receptor Type:
Sites of Action
Endothelium,
H1 brain, smooth
muscle
Mast cells,
gastric
H2 mucosa,
cardiac
muscle, brain

Histamine Pharmacodynamics continued: Some important histamine promoted effects

occur not true histamine's interaction with histamine receptors but by histamine
interaction with other receptors. Many of these interactions are responsible for "side
effects" associated with antihistamines medications. One prominent example is the side
effect of sedation. The side effect is the basis for antihistamine use as a sleep aid.
o Non-Histamine Receptor-Mediated Effects
First-generation H1 receptor blockers cause effects mediated by many
other receptor systems. These other effects in the mediated by muscarinic
cholinergic receptors, alpha adrenergic receptors, serotonergic receptors
and local anesthetic receptor sites.
Sedation: Sedation is a common side effect of first-generation
H1 antagonists and provided the rationale for these agents to be used has
sleep-aids, i.e. hypnotics. These agents may produce a paradoxical
excitement and children and toxic reactions can include stimulation,
agitation, or even coma. The newer H1 antagonists, by contrast, cause
minimal or no sedation.
Anti-emetic/Antinausea: Some first-generation H1 antagonists prevent
motion sickness. In this application these agent should be used as

prophylaxis. Therefore they should be taken well in advance of the

activity which might be expected to induce motion-sickness.
Anti-Parkinsonism: Certain first-generation H1 antagonists, because of
their antimuscarinic properties, turn out to be effective in suppressing
Parkinsonian symptoms which are side-effects of some antipsychotic
medications. The antipsychotic drugs involved here tend to be "firstgeneration" agents which have numerous neurological side effects. The
side effects are much less prevalent with newer antipsychotic drugs, such
as olanzapine (Zyprexa) or risperidone (Risperdal).
Anticholinergic effects: Some first-generation H1 antagonists have strong
antimuscarinic actions (atropine-like effects). Prominent anticholinergic
effects include blurred vision (loss of accommodation) and urinary
retention. Therefore patients who may have benign prostatic hypertrophy
may exhibit significant worsening of their clinical state due to
antimuscarinic effects. Probably benign prostatic hypertrophy would be
one example of the syndrome for which there would be a relative
contraindications for these drugs.
Alpha adrenergic blocking effects: Some first-generation H1 antagonists
block alpha adrenergic receptors. Alpha-adrenergic receptor blockade can
cause orthostatic (postural) hypotension.
Serotonergic blockade: Some first-generation H1 antagonists block
serotonin receptors
Local Anesthetic effects:
Many first-generation H1 antagonists are local anesthetics,
exhibiting sodium channel blockade [similar in general to that
caused by procaine (Novocain) and lidocaine (Xylocaine)].
For example, diphenhydramine (Benadryl) and promethazine
(Pherergan) are more potent than procaine (Novocain) as a local
anesthetic

Clinical Uses: H1 Histamine Receptor Blockers

Allergic Reactions:
o The pharmacological objective in the use of these medications is to treat or
prevent symptoms of allergic reaction.
o H1 histamine receptor blockers are drugs of choice to treat allergic rhinitis and
urticaria. In both cases, histamine is the primary mediator of the symptoms

o By contrast, in asthma their multiple mediators and H1 histamine receptor

blockers are ineffective.
o Angioedema (hives) may be initiated by histamine but are maintained by
bradykinins. In this clinical setting H1 histamine receptor blockers are also
ineffective.
o For atopic dermatitis, diphenhydramine which is a H1 histamine receptor blocker
proves effective in control of itching and for sedation.
o For allergic conditions, an example being hay fever, the H1 histamine receptor
blockers are effective for symptomatic relief. The goal is to minimize sedating
effects while retaining beneficial symptomatic relief.
o The Second-generation H1 histamine receptor blockers, for example terfenadine
(Seldane) or astemizole (Hismanal) are beneficial because they exhibit minimal
sedation while being effective in management of allergic rhinitis and chronic
urticaria. At present, these medications tend to be more expensive than firstgeneration histamine receptor H1 antagonists.

Allergic Rhinitis

H1 antihistamines are effective for treating

nasopharyngeal itching, sneezing, watery rhinorrhea,
and ocular itching, tearing, erythema.
o Side effects associated with older

H1 antihistamines include sedation, visual

disturbance, urinary retention, and arrhythmias
Newer H1 antihistamines:
( terfenadine (Seldane) astemizole (Hismanal))
o These agents exhibit less sedation associated
with their reduced ability to cross the blood
brain barrier.
o However, there are very important drug-drug
interactions associated with this category.
For example, macrolide antibiotics such
as erythromycin, clarithromycin
(Biaxin), ketoconazole-class broadspectrum antifungal drugs, inhibit
terfenadine (Seldane) or astemizole

(Hismanal) metabolism.
Toxic levels of terfenadine (Seldane) or

astemizole (Hismanal) may induce

potentially fatal cardiac arrhythmias.
These new H1 antihistamines are

contraindicated for concurrent use with

macrolide antibiotics and ketoconazoleclass and fungal drugs or in the
presence of impaired hepatic function
or inpatients predisposed to
arrhythmias.
Topical -adrenergic agonists:
o Phenylephrine (Neo-Synephrine) or
oxymetazoline (Afrin) reduce nasal
congestion/obstruction.
Efficacy duration: limited due to

rebound rhinitis and systemic effects

which may include insomnia,
irritability, and hypertension -- the latter
which is seen more commonly with oral
alpha adrenergic agonists.
Oral -adrenergic agonists may be useful in

diminishing antihistamine-mediated sedation while

improving antihistamine efficacy in relieving
congestion. However, there is a concern that these
agents due to their potentially hypertensive effects,
may precipitate adverse cardiovascular effects, such as
stroke. Recently, there has been an effort to remove
such "pressor" agents from common over-the-counter
cold medications.
Cromolyn sodium: This agent is a liquid provided as a
nasal metered-does spray. Cromolyn sodium (Intal) is
not associated with side effects and typically is used
prophylactically to reduce episodic allergen nasal mast
cell activation. This agent may be used as part of a

anti-asthma drug regimen.

Intranasal glucocorticoids:
o Intranasal glucocorticoids are the most potent
drugs available for management of established
rhinitis (seasonal or perennial) and including
vasomotor rhinitis
Topical-to-systemic activity greater for:
flunisolide (AeroBid) or budesonide
(Rhinocort), compared to
beclomethasone (Banceril) or
triamcinolone (Aristocort).
o Despite the different route of administration,
intranasal-administered glucocorticoids exhibit
the same efficacy but with reduced systemic
side effects compared to same agent
administered orally.
o Side effects include local irritation, which is
the most frequent side effect to Candida overgrowth which is an unusual side effect
o Topical high potency glucocorticoids exhibit

superior efficacy compared antihistamines

during pollen season.
Immunotherapy (hyposensitization): This approach is
based on repeated, subcutaneous injections of
gradually increasing allergen (specific for the
symptom complex) over a period of 3-5 years.
o Contraindications include significant
cardiovascular disease and unstable angina
o Cautious use applies to patients receiving beta
adrenergic blockers (due to difficulty in
managing possible anaphylactoid responses to
treatment)
o Clinical Management Sequence:
Identification of allergens confirmed by
allergens-specific IgE skin testing

and/or serum assay.

Avoidance of offending allergen
Mild symptoms: prophylaxis with

topical cromolyn sodium or single

(bedtime) dose of chlorpheniramine
(Chlor-Trimeton) or astemizole
(Hismanal) or terfenadine (Seldane)
(decision based on side effects and
presence of other concurrent
medications or disease.
Prominent symptoms: Topical

beclomethasone (Banceril) or if needed

budesonide (Rhinocort) or flunisolide
(AeroBid)
Management failure: immunotherapy

Clinical Uses: H1 Histamine Receptor Blockers continued

Motion Sickness:
o Scopolamine and certain first-generation H1 blockers are among the most
effective drugs for motion sickness prevention
o Diphenhydramine and promethazine are the H1 blockers with the greatest
effectiveness
o Cyclizine (Marezine) and meclizine are also effective agents and are less sedating
than those above.

Nausea and Vomiting (Pregnancy)

o H1 blockers are not recommended for use in management of nausea and vomiting
associate with pregnancy because:
Difficulty in assessment of possible birth defects associated with certain

H1 (benedictin) antagonists and known teratogenic effects of others (e.g.,

doxylamine) in animal models.
H1 blockers: Toxicity
o Uncommon toxic effects following systemic demonstration:
excessive excitation and convulsions in children
orthostatic (postural) hypotension

 Allergic responses
o Drug allergy -- relatively common, following topical use of H1 antagonists
o First-generation overdosage: similar to atropine overdosage
o Second-generation overdosage: may induce cardiac arrhythmias
Drug-Drug Interactions
Second-generation H1 blockers:
o Myocardial toxicity:
Toxicity follows combination of terfenadine or astemizole combined with
ketoconazole (Nizoral), itraconazole (Sporanox), or macrolide antibiotics
(e.g.,erythromycin) because Q-T (ECG) prolongation
Ventricular arrhythmias which may be potentially fatal.
Terfenadine (Seldane)/astemizole (Hismanal) are contraindicated in
patients taking ketoconazole (Nizoral), itraconazole (Sporanox), macrolide
antibiotics, and patients with diminished liver function.
patients taking ketoconazole (Nizoral), itraconazole (Sporanox),

macrolide antibiotics, and patients with diminished

Fexofenadine (Allegra), a metabolite of terfenadine (Seldane), is safer.

H2 Receptor Antagonists
Introduction-- overview
o H2 receptor antagonists inhibit histamine-induced stomach acid secretion
o Interest in these drugs: based on the high incidence of peptic ulcer disease (and
related gastrointestinal disease)
o H2 receptor antagonists: frequently prescribed, available as over-the-counter
preparations in some dosage forms.
Pharmacology of H2 receptor blockers:
H2 receptor
blocker

Mechanism
of
Elimination

Cimetidine
Mainly renal
(Tagamet)
Ranitidine
(Zantac)

Mainly renal

Famotidine
Mainly renal
(Pepcid)
Nizatidine
(Axid)

Mainly renal

Pharmacodynamics: H2 Receptor Antagonists

Mechanism of action: H2 Receptor Antagonists involves selective competitive
antagonism at H2 receptor sites.
Effects on organ systems
o Acid secretion and gastric motility
The most important action is a reduction in gastric acid secretion due to
H2 receptor blockade.
Blockade of gastric acid secretion in the presence of H2 receptor blockade
following histamine, gastrin, cholinomimetics (acetylcholine-like drugs
such as bethanechol (Urecholine)) and vagal stimulation.
Reduced gastric acid volume
Decreased pepsin concentration

o Other effects: unrelated to H2 receptor blockade

Cimetadine (to lesser degree ranitidine; not famotidine or
nizatidine): inhibits cytochrome P450 microsomal drug metabolizing
system
Cimetadine and ranitidine inhibit renal clearance of basic drugs that use
renal secretory transport systems
Cimetadine, by binding to androgen receptors, produce antiandrogen
effects

Clinical Uses: H2 Receptor Antagonists

Peptic Ulcer Duodenal Disease:

o H2 receptor antagonists (low toxicity) by reducing gastric acidity has significantly
advanced treatment of peptic ulcer disease
Other agents that reduce gastric acid include:

1. Antimuscarinic drugs (at high dosages required, side effects are

significant)
2. Antacids which require frequent dosing and may be associated
therefore with poor patient compliance

3. Omeprazole (Prilosec) and lansoprazole (Prevacid) (proton pump

blockers and) are very effective in reducing gastric acid by directly

inhibiting an enzyme-pump which produce hydrogen ions
(protons) in the stomach thus decreasing pH
Sucralfate (Carafate) (a coating agent) promotes healing
Antibiotics are prominent in current therapy because of the importance
of H. pylori in gastric ulcer disease.

Gastric Ulcer:
o H2 receptor antagonists reduce symptoms and promote healing for benign gastric

ulcers
Gastroesophageal Reflux Disorder (erosive esophagitis)
o H2 receptor antagonists, at higher dosages than for management of peptic or

gastric ulcer disease,are used as one component of treatment. Proton pump

blockers (e.g. omeprazole) are usually also administered.
Hypersecretory Disease:
o Zollinger-Ellison syndrome is associated with acid hypersecretion which is
caused by gastrin-secreting tumor. This disorder is often fatal; however,
H2 receptor antagonists often control symptoms.
o Systemic mastocytosis and multiple endocrine adenomas are hypersecretory

conditions in which H2 receptor antagonists often control symptoms.

Toxicity:H2 receptor antagonists:
o Overview: these agents are generally well tolerated. The most common side
effects include diarrhea, dizziness, somnolence, headache and rash.
Cimetidine (Tagamet) has the most adverse effects whereas, nizatidine
(Axid) has the fewest adverse effects.
o CNS effects are uncommon. However, in the elderly confusional of states,
delirium, and slurred speech may occur. These effects are often associate with
cimetidine (Tagamet) and are unusual with ranitidine (Zantac).
o Endocrine effects are also relatively uncommon. However cimetidine (Tagamet)
does exhibit antiantherogenic effects because the drug blinds to androgen
receptors and therefore can cause gynecomastia (men) and galactorrhea (women).
Endocrine effects not associated with famotidine, ranitidine, nizatidine

o Other uncommon side effects include blood dyscrasias [cimetidine (Tagamet):

granulocytopenia, thrombocytopenia, neutropenia, aplastic anemia which is

extremely rare], hepatotoxicity with reversible cholestatic effects, reversible

hepatitis, liver enzyme test abnormalities.
o Use in pregnancy:
Harmful effects on the fetus have not been observed when H2 blockers are
prescribed to pregnant women even though H2 blockers are secreted into
breast milk and may affect nursing infants.

The general rule, however is that since these drugs across

the placenta, they should only be prescribed when
absolutely required.
Since these drugs to cross the placenta, the drugs should only be
prescribed when absolutely required.
Drug-drug Interactions:
o Cimetidine (Tagamet) is the prominent agent in this category for drug-drug
interactions.
This observation occurs because cimetidine (Tagamet) is particularly
effective in inhibiting the cytochrome P450 drug metabolizing system
therefore influencing the metabolism of other drugs.
Additionally, cimetidine (Tagamet) reduces liver blood flow and the
combination of effects on blood flow and metabolism tend to decrease the
clearance (removal from the body) of certain drugs.

Cimetadine inhibits clearance of these

agents (partial listing):
Phenyto Propran Metop
Warfar
in
olol
rolol
in
(Dilantin (Inderal (Lopre
)
)
ssor)

Labetal
ol
(Tranda
te,
Normo
dyne)

Quinid Caffeine Lidocai Theop Alpraz

ine
ne hylline olam
glucona
(Xyloca
(Xanax
te
ine)
)
(Quina
glute,
Quinala

n)
Triazol Chlordia Carbam
Tricycli
am zepoxide azepine Ethan
c
(Halcio (Librium (Tegret ol antidep
n)
)
ol)
ressants
Diaze Fluraze
Metron Calcium
Sulfon pam
pam
idazole channel
ylureas (Valiu (Dalma
(Flagyl) blockers
m)
ne)

1. Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids
(Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical
Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.

2. Friedman, L. S. and Peterson, W.L. Peptic Ulcer and Related Disorders In Harrison's
Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E.,
Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health
Professions Division), 1998, pp. 1597-1616.