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
o  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)

Receptor
Localization Receptor coupling Antagonists
Subtype
diphenhydramine,
Endothelium, receptor activation causes
chlorpheniramine,
H1 brain, smooth and increased IP3, DAG
hydroxyzine, and
muscle (diacylglycerol)  production  
others
mass and cells, ranitidine
receptor activation causes
gastric mucosa, (Zantac),
H2 an  increase in cAMP
cardiac muscle, cimetidine
production 
brain (Tagamet)
presynaptic:
brain, mesenteric
H3 G protein coupled N/A
plexus (other
neurons)

 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)

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 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 bronchodilation (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.

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 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
site-mediated.

Receptor Type: Sites of Action

H1 endothelium, brain, smooth muscle
mast cells, gastric mucosa, cardiac
H2
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 "first-
generation" 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

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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 first-generation histamine receptor H1 antagonists.  

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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 broad-spectrum
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 ketoconazole-class and
fungal drugs or in the presence of impaired hepatic function or
inpatients predisposed to arrhythmias.
 Topical alpha-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 alpha-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 over-growth 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 (Bendictin) antagonists and known teratogenic effects of others (e.g.,
doxylamine) in animal models. Prospective studies with Bendectin did not
show increased incidence of birth defects but as result of negative
publicity, lawsuits, Bendectin was withdrawn from the U.S. market by the
manufacturer. (1983). The drug remains available in Canada and Europe
(and perhaps other markets).
  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

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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 (Tagamet) Mainly renal
 Ranitidine (Zantac) Mainly renal
 Famotidine (Pepcid) Mainly renal
 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):

 labetalol
 phenytoin  propranolol  metoprolol
 warfarin (Trandate,
(Dilantin) (Inderal) (Lopressor)
Normodyne)
 Quinidine
gluconate  lidocaine  alprazolam
caffeine theophylline
(Quinaglute, (Xylocaine) (Xanax)
Quinalan)
 triazolam chlordiazepoxide carbamazepine tricyclic
ethanol
(Halcion) (Librium) (Tegretol) antidepressants
 metronidazole calcium channel  diazepam  flurazepam
 sulfonylureas
(Flagyl) blockers (Valium) (Dalmane)

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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.