South African Family Practice 2015; 57(1):43-49

S Afr Fam Pract

Open Access article distributed under the terms of the ISSN 1608-4356 EISSN 1727-9835
Creative Commons License [CC BY-NC-ND 4.0] © 2014 The Author(s)
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Review (CPD)

An overview of anti-allergic drug therapy and the histamine-1 antihistamines

Natalie Schellacka*, Gustave Schellackb and Mia Janse van Rensburgc

aSenior Lecturer, Department of Pharmacy, Faculty of Health Sciences, University of Limpopo (Medunsa Campus)
bClinical Trial Manager in the Pharmaceutical Industry, Specialising in Clinical Research and Applied Pharmacology
cDepartment of Pharmacy, Faculty of Health Sciences, University of Limpopo (Medunsa Campus)

*Corresponding author: Natalie Schellack, e-mail: nschellack@gmail.com

Abstract
Allergic disease decreases the daily quality of life of many people, and can increase the number of working days lost owing to
sick leave. Associated symptoms with allergic disease depend on the origin of the disease, and can either be allergic, non-allergic
and purulent, or can cause rhinitis as a result of a common cold. Treatment depends on the origin of the rhinitis. However, an
antihistamine is indicated in most instances. Combination treatment includes sympathomimetic drugs (either local or systemic)
and corticosteroid medication (when indicated, and in most instances, used locally). The article provides an overview of the nature
and the management of allergic disease and the histamine 1 antihistamines.

Keywords: anti-allergic drug therapy, H1 antihistamines, histamine receptors, allergic rhinoconjunctivitis, allergy health

Introduction degranulation occurs. This degranulation may be triggered in

the following ways:1-3
Acute allergic reactions and anaphylaxis are mediated by
histamine release from degranulated mast cells. Histamine, • Physical trauma of the tissue cells in question
in combination with other vasoactive substances, such as • An interaction between immunoglobulin E (IgE) antibodies
bradykinin, serotonin, prostaglandins and leukotrienes, causes and suitable IgE antigens, i.e. the formation of antigen-
glottis oedema; bronchospasm; increased capillary permeability antibody complexes that cause allergic reactions (localised
and vasodilatation with a subsequent drop in arterial blood histamine release) or anaphylaxis (systemic histamine release)
pressure; skin signs, such as blushing, pruritus and urticaria; as • Exposure to snake and wasp venom
well as gastrointestinal symptoms, such as cramping, nausea,
• Large molecules, such as those found in the serum of animals,
vomiting and diarrhoea.1-3
e.g. equine serum, or the rather large molecules of dyes and
Histamine is an interesting and important signal transmitter alkaloid bases, such as morphine, and the depolarising skeletal
substance since it acts both as a neurotransmitter within the muscle relaxants, such as tubocurarine and atracurium.
central nervous system (CNS) and as an important autacoid within
Of the four currently identified histaminergic receptor subtypes,
peripheral tissue, a characteristic that it shares with serotonin.
i.e. the H1-H4 receptors, the H1 receptor is especially well known
Histamine is synthesised from the amino acid, histidine.1-3
for its active role in mediating acute allergic reactions. Some of
Peripherally, histamine is stored in a bound and inactive form the effects of H1-receptor stimulation include allergic rhinitis and
within the storage vesicles or granules of mast cells in tissue conjunctivitis, urticaria, pruritus (histamine stimulates sensory
and the basophils in the bloodstream. Mast cells have a highly neurons to produce itching) and angioneurotic oedema.1-3
predictable distribution pattern inside the human body since
Stimulation of these receptors is also responsible for the
they serve to protect open-ended organ systems. These organ
vasodilatation and the increased vascular (capillary) permeability
systems, being “open” to the external environment, contain an
that accompanies allergic reactions and inflammation. Erythema
abundance of these cells. They are the open-ended tracts of the
and oedema, including potentially fatal glottis oedema, may
respiratory and gastrointestinal systems.1-3
ensue. Blood pressure may be decreased to such an extent that
The obvious exposure of the skin to the external environment anaphylactic shock sets in. Bronchial smooth muscle contraction
also explains the abundance of mast cells found on it, especially causes bronchoconstriction, with wheezing and possible
in areas that readily blush. Histamine is also secreted in the bronchospasm. The contraction of gastrointestinal smooth
fundus of the stomach, where its function is to interact with muscle results in colic. Exocrine gland secretions are increased
histamine-2 (H2) receptors, and thereby stimulate the secretion through H1-receptor stimulation.1-3
of gastric acid by the stomach’s parietal cells.1-3
Histamine acts as an excitatory neurotransmitter within the
Histamine is a particularly important mediator of the CNS, via H1-receptor activation. Therefore, antagonists at these
inflammatory process. This process, as a pathophysiological central H1 receptors cause somnolence and sedation. In addition,
entity, is activated within peripheral tissue areas when mast cell the emetic or vomiting centre in the medulla oblongata also

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44 S Afr Fam Pract 2015;57(1):43-49

contains H1 receptors, in which case receptor antagonism results cytokines, tumour necrosis factor (TNF)-alpha (TNF-α) and
in an antiemetic effect.1-3 interleukin (IL)-4. The release of these molecules causes oedema
and fluid secretion, resulting in congestion and other nasal
Allergic rhinoconjunctivitis
symptoms. The role of leukotrienes as mediators in allergic
An allergy may be viewed as a hypersensitivity disorder of the rhinitis is well supported in the literature. Cysteinyl leukotrienes
immune system. Jointly, allergies constitute the fifth leading are able to facilitate the maturation of eosinophil precursors and
group of chronic diseases worldwide. The broader name, allergic act as eosinophil chemoattractants, promoters of eosinophil
rhinoconjunctivitis (the involvement of the eyes and nose), is not adhesion and inhibitors of eosinophil apoptosis. The leukotrienes
that well known, and is commonly referred to as allergic rhinitis. and thromboxane A2 (TXA2) are arachidonic acid derivatives, and
Allergic rhinitis presents with nasal symptoms of congestion and it has been shown in animal models that TXA2 agonists increase
rhinorrhoea, and is more commonly associated with complaints nasal airway resistance and vascular permeability. An acute-
of ocular symptoms.4-7Allergic conjunctivitis is an inflammatory phase allergic reaction is also characterised by the production
response of the conjunctivae to allergens, such as pollen (grass), of prostaglandin D2 (PGD2), a major proinflammatory prostanoid,
environmental antigens (dust) and animal dander.4,5,7-9 which results in vasodilation and bronchoconstriction, as well
as a number of inflammatory biomarkers, such as N-alpha-
Allergic rhinoconjunctivitis may be an acute or chronic illness,
tosyl L-arginine methyl ester (TAME)-esterase and eosinophil
and is typically classified as being either seasonal or perennial,
cationic protein (ECP). PGD2 is also believed to be associated with
based on the type of allergen and the occurrence of symptoms
hypertrophic inflammation and acts as a recruiter of eosinophils.
during the course of the year. Seasonal rhinoconjunctivitis
usually occurs during the spring and autumn, when levels of The late-phase or chronic inflammatory response involves
outdoor allergens (pollen) are elevated, whereas perennial cellular infiltration, which sustains tissue swelling and
rhinoconjunctivitis is present throughout the year, is more oedema, and further exacerbates congestion. The ensuing
chronic in nature and is caused by indoor allergens, e.g. pets, cytokine release results in the nasal mucosa being infiltrated
dust mites and cockroaches. with inflammatory cells. These inflammatory cells, including
eosinophils, neutrophils, basophils, mast cells and lymphocytes,
However, more recently this classification was revised by the
sustain and intensify the nasal mucosal inflammatory reaction.
Allergic Rhinitis and its Impact on Asthma workshop. The new
The predominant cell type, the eosinophil, characterises the
classification does not consider the type of allergen, but rather
chronic inflammatory process that is present during the late-
involves the duration of symptoms and their subsequent
phase allergic response. These eosinophils release a broad
impact on a person’s quality of life. Furthermore, the revision
range of proinflammatory mediators, including the cysteinyl
now differentiates between either intermittent (not more than
leukotrienes, ECP, eosinophil peroxidase and major basic protein.
four weeks in duration) or persistent (more than four weeks in
These cells are also known to serve as a major source of IL-3, IL-
duration) allergic conjunctivitis or rhinitis.4,10
5, granulocyte-macrophage colony-stimulating factor and IL-13.
The most common antigens for allergic rhinitis are inhalant The number of circulating eosinophils is increased in patients
allergens, of which dust mites, animal dander and pollen cause with allergic disorders, and infiltration at the site of aggravation
the most concern. When a patient is sensitised, an antigen has been generally attributed to the influx of mature cells. In
comes into contact with the nasal mucosa. This leads to cross- some studies, eosinophil infiltration has been shown to have a
linking of IgE-mediated receptors on the mast cells. This, in turn, significantly negative correlation with nasal airflow in patients
leads to degranulation of the mast cells, with a resultant release with allergic rhinitis. In addition to the eosinophils, other
of histamine and proteases from the preformed granules. In proinflammatory cells are also known to accumulate within the
addition, an array of early-phase proinflammatory molecules are nasal epithelium during the late-stage response. These include
synthesised and released, especially prostaglandins, leukotrienes, basophils, mast cells and T cells. The key inflammatory mediator

Table I: A summary of the different types of rhinitis and their associated management strategies

Rhinitis associated with a Purulent rhinitis Allergic rhinitis Non-allergic rhinitis

common cold (vasomotor rhinitis)
• Steam inhalations • When associated with • Avoidance of the allergen • Avoid precipitating factors
• Systemic decongestants sinusitis, antibiotics may be wherever possible • Short-term topical
• Local decongestants needed • Systemic antihistamines, decongestants may be used
• Nasal decongestants where needed when necessary
• Nasal irrigations with saline • Topical corticosteroids: As
• Check for a foreign body in prophylaxis, they should
the nose in children be started two weeks prior
to the allergy season and
continued until the season
is over
• Systemic corticosteroids
• Local decongestants
• Hyposensitisation
with allergen-specific
immunotherapy

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An overview of anti-allergic drug therapy and the histamine-1 antihistamines 45

difference between allergic rhinitis and non-allergic rhinitis may

be explained by the presence of precipitating factors. Allergic
rhinitis may be induced by IgE-mediated inflammation of the
Early
nasal mucous membranes. The patient may present with nasal
breastfeeding
(sneezing, nasal obstruction or congestion, and rhinorrhoea or
postnasal drip and congestion) and non-nasal symptoms (an
Avoid the Regular physical
excercise
itchy palate or ears, and conjunctivitis). Non-allergic rhinitis may
unnecessary use
of antibiotics present with symptoms relating to a physiological response to
heat, smoke, cold and dust.2,18,19 Table I provides a summary of
Allergy the different types of rhinitis and their associated management
prevention
strategies.
strategies
Probiotic Medicine management of allergic diseases
Do not smoke bacteria may be
or smoke anti-inflammatory
Nonpharmacological strategies, as well as pharmacological
around children
strategies, can be used in the management of allergic diseases.
If nonpharmacological strategies do not alleviate the condition,
A healthy diet then the following pharmacological agents may be used, either
topically or systemically, for the prevention and management
of allergic disease.4 Table II consists of over-the-counter
pharmacological preparations that are available to manage
Figure 1: Prevention strategies in the management of allergy disease allergic diseases.18,20
Local decongestants
of the late-phase response is TNF-α, and TNF-α levels increase
dramatically roughly an hour after an allergen challenge. This These agents contain sympathomimetic drugs, like xylometa-
cytokine has been confirmed to activate T cells, endothelial zoline, oxymetazoline and phenylephrine.2,18,21 They produce
cells, fibroblasts and macrophages. TNF-α is also responsible vasoconstriction via α1-adrenergic receptor stimulation. This,
for an increase in the expression of cell adhesion molecules. in turn, reduces mucosal oedema and local vasodilation.
Patients with allergic rhinitis also have elevated proinflammatory Nevertheless, these effects only last for a limited period.
interleukins (IL-1β, IL-6 and IL-8). All of these events, including After prolonged use, rebound rhinitis and conjunctivitis
IgE synthesis and eosinophil or basophil priming, contribute to or conjunctivitis medicamentosa may set in, usually after
the venous engorgement, inflammation, nasal and ocular hyper- roughly five days of continuous use. Oxymetazoline and
reactivity and symptoms of allergic rhinoconjunctivitis.4,5,10-16 xylometazoline have a long-acting effect on the α1 receptor,
whereas phenylephrine has a shorter-acting effect, lasting up to
The symptoms that are associated with allergic rhinoconjunctivitis approximately four hours.4,18,19,21
due to an IgE-mediated inflammatory response include nasal Systemic decongestants
symptoms, such as congestion, nasal itching, sneezing and
rhinorrhoea; and ocular symptoms, such as itching, redness, Many of these preparations also contain antihistamines. The
watering or tearing and burning. These symptoms are frequently antihistamines have an antagonistic effect on histaminergic
reported by allergic rhinitis patients, and are more prominent in H1 receptors. This will be discussed in the subsequent section.
patients experiencing seasonal allergic rhinitis. Pseudoephedrine, phenylpropanolamine and phenylephrine are
available systemic decongestants in South Africa. These agents
The symptoms of allergic rhinitis can affect patients’ quality of life, produce vasoconstriction through α1-receptor stimulation,
including a reduction in sleep quality, the performance of daily reducing oedema, redness and itching. However, the combination
activities, cognitive function, work productivity and examination of a systemic decongestant and an older-type H1 antihistamine
performance. These symptoms also have an impact on patients’ may produce drowsiness and a lack of coordination. The use of
psychosocial well-being.7,10,13,15,16 phenylpropanolamine produced subarachnoid bleeding with
a haemorrhagic stroke in women who used it as an appetite
Practical actions to promote allergy health
suppressant. The total daily dosage of phenylpropanolamine
Certain behavioural activities have been shown to provide some should not exceed 100 mg.4,18,19,21
protection against, or may alleviate some of the symptoms Local corticosteroids
derived from, a current allergic reaction. Other practical
interventions include prevention strategies (Figure 1.)17 These Glucocorticosteroids modify protein synthesis directly
strategies may improve immune tolerance. However, the by regulating transcription, and indirectly by altering the
benefits of probiotics in either preventing or treating allergic activity or half-life of the transcription factors and mRNA. The
following intranasal corticosteroids are currently available:
disease remain inconclusive.17
beclomethasone, budesonide, fluticasone, mometasone,
The prevention strategies identified in Figure 1 may be triamcinolone and ciclesonide. Intranasal administration of the
combined with more specific management principles according newer agents, mometasone, fluticasone, and ciclesonide, results
to the type of rhinitis that the patient is experiencing.2,18 The in minimal systemic effects.22 The most common local side-
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46 S Afr Fam Pract 2015;57(1):43-49

Table II: Over-the-counter medications used for allergic rhinitis

Preparation Active ingredients Indications Price

Local decongestants
Iliadin® Oxymetazoline (0.100 mg/ml) Short-term symptomatic relief of nasal R31.90
congestion
Drixine® Oxymetazoline (0.5 mg/ml) Short-term symptomatic relief of nasal R32.26
congestion
Nazene Adult® Oxymetazoline (0.5 mg/ml) Short-term symptomatic relief of nasal R35.99
congestion
Otrivin® Xylometazoline (1 mg/ml) Short-term symptomatic relief of nasal R53.71
congestion
Sinutab nasal spray® Xylometazoline (1 mg/ml) Short-term symptomatic relief of nasal R35.00
congestion
Vibrocil-S® Phenylephrine and dimethindene (250 mg/100 g) Short-term symptomatic relief of nasal R37.19
congestion
Local corticosteroids
Avamys Fluticasone Furoate Maintenance therapy for allergic rhinitis R165.81
(120 metered sprays)
Beclate Aquanase® Beclomethasone dipropionate (50 µg/spray) Maintenance therapy for allergic rhinitis R55.70
Beconase ®
Beclomethasone dipropionate (50 µg/spray) Maintenance therapy for allergic rhinitis R107.66
Clenil AQ Nasal Spray ® Beclomethasone dipropionate (50 µg/spray) Maintenance therapy for allergic rhinitis R51.35
Flomist® Fluticasone propionate(50 µg/spray) Maintenance therapy for allergic rhinitis R73.92
Flonase ® Fluticasone propionate (50 µg/spray) Maintenance therapy for allergic rhinitis R68.40
Nexomist ®
Mometasone furoate (50 µg) Maintenance therapy for allergic rhinitis R170.74
Rinelon® Mometasone furoate (50 µ) Maintenance therapy for allergic therapy R74.81
(60 metered sprays)
R174.57
(140 metered sprays)
Topical antihistamines or antiallergic agents
Rhinolast® Azelastine (0.14 mg/spray) Short-term intermittent allergic rhinits R51.30
Sinumax allergy nasal Levocabastine (0.5 mg/ml) Short-term intermittent allergic rhinitis R69.51
spray®
Vividrin® Cromoglicic acid (2.6 mg/spray) Intermittent or persistant allergic rhinitis R34.58
Other nasal preparations
Mistabron® Mesna (50 mg/ml) Nasal obstruction due to thick secretions R101.97
Systemic nasal decongestants with antihistamines
Actifed® Pseudoephedrine HCl (30 mg) Systemic decongestion of nasal mucosa and R19.54
Triprolidine HCl (1.25 mg) sinuses associated with colds and flu
Betafed Be-Tabs® Pseudoephedrine HCl (30 mg) Systemic decongestion of nasal mucosa and R17.05
Triprolidine HCl (1.25 mg) sinuses associated with colds and flu
Demazin Syrup® Phenylephrine HCl (2.5 mg/5ml) Systemic decongestion of nasal mucosa and R39.52
Chlorpheniramine (1.25 mg/5 ml) sinuses associated with colds and flu
Demazin NS® Pseudoephedrine sulphate (120 mg) Systemic decongestion of nasal mucosa and R26.51
Loratidine (5 mg) sinuses associated with colds and flu
Systemic decongestant and/or analgesic and/or antihistamine combinations
Nurofen cold & flu® Ibuprofen (200 mg) Symptomatic relief of colds and flu 47.66
Pseudoephedrine HCl (30 mg)
Sinuclear® Paracetamol (325 mg) Symptomatic relief of colds and flu R33.61
Phenylpropanolamine HCl (18 mg)
Sinugesic® Paracetamol (500 mg) Symptomatic relief of colds and flu R22.54
Pseudoephedrine HCl (30 mg)
Sinumax® Paracetamol (500 mg) Symptomatic relief of colds and flu R45,31
Pseudoephedrine HCl (30 mg)
Sinustat® Paracetamol (325 mg) Symptomatic relief of colds and flu R21.16
Phenylpropanolamine HCl (18 mg)
Sudafed sinus pain® Paracetamol (500 mg) Symptomatic relief of colds and flu R14.23
Pseudoephedrine HCl (60 mg)

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An overview of anti-allergic drug therapy and the histamine-1 antihistamines 47

Table II: Over-the-counter medications used for allergic rhinitis

Antihistamines
Acuzyrt® Cetirizine dihydrochloride (10 mg) Symptomatic treatment of allergic conditions R50.16 (30 tablets)
Adco-Cetirizine ®
Cetirizine dihydrochloride (10 mg) Symptomatic treatment of allergic conditions R61.83 (30 tablets)
Allecet ®
Cetirizine dihydrochloride (10 mg) Symptomatic treatment of allergic conditions R52.03 (30 tablets)
Preparation Active ingredients Indications Price
Sinutab Sinus Allergy ®
Cetirizine dihydrochloride (10 mg) Symptomatic treatment of allergic conditions R18.25
Texa Allergy® Cetirizine dihydrochloride (10 mg) Symptomatic treatment of allergic conditions R55.07 (30 tablets)
Zyrtec ®
Cetirizine dihydrochloride (10 mg) Symptomatic treatment of allergic conditions R144.14
Allergex ®
Chlorpheniramine maleate (4 mg) Management of allergic disorders R34.29 (30 tablets)
Rhineton® Chlorpheniramine maleate (4 mg) Management of allergic disorders R137.42
Allergex Non Drowsy ®
Loratadine (10 mg) Symptomatic treatment of allergic conditions R39.65 (30 tablets)
AP Loratadine ®
Loratadine (10 mg) Symptomatic treatment of allergic conditions R46.90 (30 tablets)
Cipla-Loratadine® Loratadine (10 mg) Symptomatic treatment of allergic conditions R47.33 (30 tablets)
Clarinese ®
Loratadine (10 mg) Symptomatic treatment of allergic conditions R15.61 (10 tablets)
Luara® Loratadine (10 mg) Symptomatic treatment of allergic conditions R44.18 (30 tablets)
Lorfast ® Loratadine (10 mg) Symptomatic treatment of allergic conditions R38.48 (30 tablets)
Cetlev 5 ® Levocetirizine dihydrochloride (5 mg) Symptomatic treatment of allergic conditions R66.65 (30 tablets)
Xyzal® Levocetirizine dihydrochloride (5 mg) Symptomatic treatment of allergic conditions R192.16 (30 tablets)
Dazit ®
Desloratadine (5 mg) Symptomatic treatment of allergic conditions R114.26 (30 tablets)
Desaway ®
Desloratadine (5 mg) Symptomatic treatment of allergic conditions R123.50 (30 tablets)
Deselex® Desloratadine (5 mg) Symptomatic treatment of allergic conditions R197.19 (30 tablets)
Desodene ®
Desloratadine (5 mg) Symptomatic treatment of allergic conditions R113.95 (30 tablets)
Neoloridin® Desloratadine (5 mg) Symptomatic treatment of allergic conditions R113.95 (30 tablets)
Pollentyme ®
Desloratadine (5 mg) Symptomatic treatment of allergic conditions R113.95 (30 tablets)
Fastway ®
Fexofenadine HCl (120 mg) Allergic rhinitis R35.20 (10 tablets)
Fexaway® Fexofenadine HCl (120 mg) Allergic rhinitis R35.20 (10 tablets)
Fexo ® Fexofenadine HCl 1(20mg Allergic rhinitis R37.14 (10 tablets)
Telfast ®
Fexofenadine HCl (120 mg) Allergic rhinitis R74.44 (10 tablets)
Tellerge® Fexofenadine HCl (120 mg) Allergic rhinitis R34.74 (10 tablets)
Phenergan ®
Promethazine HCl (10 mg) Allergic conditions R57.77 (100 tablets)
Receptozine® Promethazine HCl (10 mg) Allergic conditions R109.51 (1000 tablets)
Tinset ® Oxatomide (30 mg) Allergic rhinitis R243.00 (30 tablets)
HCl: hydrochloride

effects experienced with the intranasal corticosteroids include mizolastine. The most compelling difference between the two
dryness, stinging, burning and epistaxis. Chronic use of topical generations of H1 antihistamines lies in the fact that the first-
corticosteroids may lead to atrophy of the nasal mucosa.13,18,22 generation drugs have the ability to cross the blood-brain
Although the use of corticosteroids constitutes the most effective barrier, while agents belonging to the second-generation have
treatment for the inflammation experienced in allergic rhinitis, a very limited ability to do so, or none at all. In addition to the
when these agents are used for seasonal allergic conjunctivitis,
aforementioned two generations of systemic (oral and/or
pulse dosing should rather be utilised for as short a treatment
parenteral) agents, topical (including intranasal and ophthalmic)
duration as possible.4
H1antihistamines are available as well.13,23 Examples of currently
The histamine-1 antihistamines available antihistamines are provided in Table III.
The H1-receptor antagonists or H1 antihistamines include the First-generation histamine-1 antihistamines
older-type, sedating, multipotent blockers, or the so-called
first-generation H1 antihistamines, including promethazine, Owing to the fact that these agents have the ability to cross the
chlorpheniramine, dexchlorpheniramine and cyclizine, and blood-brain barrier, in addition to being multipotent blocking
the newer, non-sedating, selective H1-receptor blockers, or agents (meaning that they effectively act as receptor blockers in
the so-called second-generation H1 antihistamines. Examples more than one receptor system), their chemical structures allow
of these non-sedating antihistamines include cetirizine them some degree of the nonselective, antagonistic effects
(and levocetirizine), loratadine, ebastine, fexofenadine and of an antimuscarinic (or anticholinergic), or an effect that is
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48 S Afr Fam Pract 2015;57(1):43-49

Table III: Examples of currently available histamine-1 antihistamines a few examples of the active enantiomers of racemic drugs), the
following examples are of particular interest:1-3,23
First-generation histamine-1 Second-generation
antihistamines* histamine-1 antihistamines** • Fexofenadine has the shortest half-life of the systemic agents.
Examples include: Examples include: Therefore, it should be taken twice daily. (The others only
• Chlorpheniramine • Cetirizine require once-daily dosing intervals). Also, it does not display
• Cyclizine (syn. meclizine) • Desloratadine
any H1-receptor occupancy inside the CNS at therapeutic
• Cyproheptadine (used as an • Ebastine
appetite stimulant because of • Fexofenadine dosages (Figure 2)
to its distinct antiserotonergic • Levocetirizine
• Cetirizine has the greatest likelihood of displaying some
activity) • Loratadine
• Hydroxyzine • Mizolastine degree of H1-receptor occupancy inside the CNS, which
• Mepyramine may result in some level of sedation, albeit in higher-than-
• Oxatomide recommended dosages
• Promethazine, a phenothiazine
• Trimeprazine (syn. alimemazine), • The first two examples of the so-called second-generation
a phenothiazine H1 antihistamines, namely terfenadine and astemizole, were
• Diphenhydramine
withdrawn from the market because of unacceptable levels of
• Doxylamine
• Triprolidine cardiac toxicity.
*: These are the so-called sedating antihistamines. They cross the blood-brain barrier and act as
multipotent receptor blockers. They cause drowsiness, somnolence and impairment of motor Note that the H1 antihistamines do not form the mainstay of
function. Drivers, pilots and operators of heavy machinery should avoid using these agents treatment in cases of severe angioedema or anaphylaxis, but
**: These agents do not cross the blood-brain barrier to any significant degree and do not may be used as effective adjunctive therapy to adrenaline and
produce any anticholinergic side-effects.They are non-sedating antihistamines
other emergency drugs and resuscitative interventions in such
instances.1-3
antihistaminergic, α1-adrenergic blocking, anti-serotonergic and
local anaesthetic in nature. Ophthalmic (eyedrop) preparations include levocabastine,
epinastine, olopatadine and ketotifen. (The latter also acts as a
Other examples include the tricyclic antidepressants and the
mast cell stabiliser). Levocabastine, in addition to azelastine, is
phenothiazines. Because of the multipotency of their receptor-
also available as a nasal spray for use in patients with allergic
blocking capabilities, the first-generation H1 antihistamines
rhinitis.
have a variety of indications and uses ranging from allergies and
rhinoconjunctivitis, to nausea and vomiting, motion sickness Conclusion
and insomnia. However, their anticholinergic side-effects limit
their usefulness in a variety of settings, including patients with Currently, the second-generation H1 antihistamines are widely
glaucoma, benign prostatic hyperplasia and in cardiac patients, considered to be the mainstay of treatment for allergic disease,
such as those suffering from ischaemic heart disease, myocardial especially since they have been found to be largely devoid of the
infarction and congestive heart failure. cumbersome side-effects and resultant contraindications of the
older-type, first-generation H1 antihistamines. The latter drugs
Of the wide variety of agents belonging to this group, the are no longer favoured in this setting, but are still being widely
following examples are particularly noteworthy:1,2,3,22 used for a number of other diverse indications. In addition to
• Sedation: Options include hydroxyzine, promethazine and systemic treatment, the topical application of second-generation
diphenhydramine. However, more suitable agents can be used H1 antihistamines, as well as that of the decongestants and
to manage insomnia corticosteroids, is also used successfully in the management of
• Antiemetic agents: Examples include cyclizine (syn. meclizine), allergic rhinoconjunctivitis. The H1 antihistamines are a diverse
diphenhydramine, hydroxyzine or promethazine. First- and very useful class of pharmacotherapeutic agents with high
generation H1 antihistamines may be very useful in the application value in the clinical practice setting.
management of postoperative nausea and vomiting, as well
as vertigo References
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of allergic reactions. Saunders; 2013.
3. Brunton L, Chabner B, Knollman B, editors. Goodman and Gilman’s the
It should be noted that these older-type drugs have never been pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill
optimally investigated and profiled from a clinical pharmacology Medical Publishing Division; 2011.
perspective.23 4. Bielory BP, O’Brien T, Bielory L. Management of seasonal allergic conjuctivitis:
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Second-generation histamine-1 antihistamines
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www.tandfonline.com/ojfp 48 The page number in the footer is not for bibliographic referencing
An overview of anti-allergic drug therapy and the histamine-1 antihistamines 49

+++ Sedation, somnolence and

impairment of motor coordination

Additive to alcohol and other CNS depressants;

i.e. a “antihistamine hangover”

Degree of CNS penetration and resultant

CNS side-effects
0

Hydroxyzine Chlorpheniramine Cetirizine Fexofenadine

First-generation H1 antihistamines Second-generation H1 antihistamines

CNS: central nervous system, H1: histamine 1, +++: represents maximal central nervous system side-effects, 0: represents an absence of central nervous system side-effects
Figure 2: An approximation of the degree of central nervous system penetration and the resultant central nervous system side-effects of the
first-generation histamine-1 antihistamines versus the second-generation histamine-1 antihistamines

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