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252 Chapter 10 Allergies: rhinitis and urticaria
OH
OH
Decongestants
ese drugs are sympathomimetics, acting by direct
stimulation of 1-adrenoceptors in the blood vessels of the
nasal mucosa and leading to vasoconstriction (Figure 10.2).
is results in reduced oedema and swelling of the nasal
mucosa and shrinkage of the sinuses, decreasing
congestion and reducing resistance to airow. In
addition, vasoconstriction reduces the blood ow to
glands in the nasal tissue, resulting in reduced nasal
secretions. Such drugs are used in allergic rhinitis when
congestion is a major symptom, and can be administered
both orally and intranasally. Examples of nasal
decongestants include ephedrine, phenylephrine,
oxymetazoline, and xylometazoline, which are
structurally similar analogues of noradrenaline, the
endogenous agonist for 1-adrenoceptors (Figure 10.4).
ese drugs are immediately eective in reducing the
symptoms of congestion. However, their withdrawal after
prolonged or too frequent use can induce the condition of
rhinitis medicamentosa (rebound congestion). is is
possibly caused by overstimulation of the 1adrenoceptors, leading to fatigue of the constrictor
muscles of the nasal blood vessels, and to hypoxia of the
mucosa cells because of sustained vasoconstriction. e
result is that the mucosa becomes engorged and
oedematous. Ephedrine is less likely to cause the
condition than the more potent sympathomimetics,
oxymetazoline and xylometazoline. To prevent rebound
congestion arising, the use of nasal decongestants should
be limited to 5 days. When the condition does arise,
decongestants should be stopped immediately, and if
H
N
CH
3
OH
CH
3
H
N
CH
3
3
Pseudoephedrine Phenylephrine
Ephedrine Noradrenaline
Figure 10.4 Structures of common decongestants
highlighting similarities to noradrenaline.
HO
HO
OH
(R)
OH
H
N
NH
necessary corticosteroids should be used to speed
recovery.
Oral decongestants, most commonly phenylephrine or
pseudoephedrine, are less eective but are not
associated with rhinitis medicamentosa. ey are useful
in combination with antihistamines to treat congestion in
persistent allergic rhinitis. Alternatively, they can be used
together with nasal corticosteroids in the period before
the steroid takes eect.
Pseudoephedrine has been replaced by phenylephrine in
many preparations as the former can be easily extracted
from tablets (even when compounded with other drugs)
and converted to methamphetamine, a popular illicit
drug with stimulatory properties (see Chapter 21).
While generally well tolerated, oral decongestants can
cause restlessness and CNS stimulation, leading to
diculty sleeping. ey should be used with caution in
patients with certain conditions, including
hyperthyroidism, diabetes, angle-closure glaucoma, and
hypertension. Where blood pressure is well controlled,
however, they do not cause signicant elevation.
All decongestants interact with antidepressant
monoamine oxidase (MAO) inhibitors such as
moclobemide (see Chapter 19). MAO inhibitors can
potentiate the eect of sympathomimetic decongestants
by decreasing their metabolism, and could lead to a
hypertensive crisis. For this reason they should not be
used within 14 days of MAO inhibitors.
Antimuscarinic drugs
e short-acting antimuscarinic ipratropium bromide
acts by blocking the eects of ACh at the M3 receptor in
the nasal mucosa. It is used only rarely as a nasal spray to
reduce excessive rhinorrhea (watery secretions) in
allergic rhinitis, but with little benet for other symptoms.
To be eective, it must be used three or four times daily. It
is well tolerated; the main side eects are local irritation
and dry mouth.
Leukotriene receptor antagonists
2
ese drugs work by antagonizing the eect of
leukotrienes produced by mast cells and eosinophils.
Leukotrienes are inammatory mediators produced
following oxidation of arachidonic acid by the enzyme
lipo-oxygenase (see Figure P3.3 in the Introduction to
Part 3). Receptors for leukotrienes are Gq-coupled GPCRs,
with activation leading to increased intracellular Ca2+
10.3 Urticaria 253
concentration which potentiates the inammatory
response. Leukotriene receptor antagonists are
recommended third line in allergic rhinitis, and while
they reduce congestion, they have minimal eect on the
symptoms of itching, sneezing, and rhinorrhea. ese
drugs are also used in the treatment of asthma, and may
be particularly useful for the symptomatic relief of
seasonal allergic rhinitis in asthmatic patients (see
Chapter 11). Examples include montelukast and
zafirlukast. eir main side eects are gastrointestinal
upset and headache, although these are rare.
Biological agents
Omalizumab is a genetically engineered monoclonal
antibody that binds to circulating immunoglobulin E (IgE)
and so prevents it from attaching to mast cells. It thereby
indirectly inhibits mast cell degranulation which limits
development of both the early- and late-response phases
of allergic rhinitis (see also details in Chapter 11, Box 11.1).
Omalizumab is administered by subcutaneous injection
once or twice a month at a dose informed by IgE levels. It
is the most expensive drug option available, used only for
severe cases which are unresponsive to other drugs.
Anaphylactic and injection site reactions are the main
adverse eects.
Immunotherapyordesensitization
Immunotherapy refers to the immunomodulator
techniques used to alter the immune system with the aim
of curing or managing some diseases, such as allergic
rhinitis. Desensitization is one such technique. is form
of treatment is only considered in severe and complicated
cases. It involves exposing the patient rst to extremely
small, but then gradually increasing, doses of the
identied allergen. is prompts adaptation of the
immune system, so that future exposure does not evoke
an allergic response.
Evidence has shown that this technique is most eective
when used in younger children. e most common side
eects are injection site reactions and anaphylactic
shock. is can be avoided with prophylactic
administration of antihistamines.
10.3 Urticaria
Urticaria, commonly called hives, is also referred to as
anaphylaxis of the skin. e eruptions seen arise as a
result of the inammatory process in the skin, which
causes small amounts of interstitial uid to leak from the
capillaries to the dermis (the structure of the skin is shown
in Chapter, Box 8.1). is leakage results in oedema of the
dermis, producing raised red weals (Figure 10.5).
In most cases, the weals appear almost instantly on
exposure to the causative substance or condition, and
cause intense itching. ey commonly disappear after a
few hours, although urticaria can persist (see below).
Urticaria can be divided into two main groups: allergic
and non-allergic (also called physical urticaria).
Subclassications of urticaria are detailed in Table 10.4.
Allergic urticaria, which can be either acute or chronic,
results from exposure of the susceptible individual to a
specic allergen. It shares the same underlying
pathophysiology as allergic rhinitis, with release of
inammatory mediators from mast cells following
interaction of allergen with IgE antibodies attached to
their surface (see Section 10.1.2). e most common
allergen is nickel, found in cheap jewellery.
Figure 10.5 Severe facial urticaria.
254 Chapter 10 Allergies: rhinitis and urticaria
Table 10.4 Subtypes of urticaria
Urticaria type Onset Duration Cause
Acute allergic Few minutes after contact Hours to weeks Food antigen (e.g. shellfish, nuts, eggs, fish)
Chronic allergic
Drug-induced
allergic
Non-allergic Few minutes to weeks after
1–4 weeks after ingestion Weeks NSAIDs
exposure
>6 weeks
Hours to weeks Water: aquagenic urticaria
Virus or bacteria
Nickel
Opiates
Sulphonamides
Sulphonylureas
Aspirin
Penicillin
Heat: cholinergic urticaria
Cold: chronic cold urticaria
Scratching: dermatographic urticaria
Sun: solar urticaria
Pressure
In non-allergic urticaria, histamine release from mast cells
is provoked directly without interaction between allergen
and IgE. is can be caused by certain drugs including
NSAIDs, by heat or cold, by neuropeptides released by
stress, or by porphyria, a disorder of the biosynthesis of
haem which leads to deposits in the skin (see Table 10.4).
10.4 Treatment and management of urticaria
e ideal management of urticaria is avoidance of
triggers. is may, however, be dicult, particularly as
often the actual cause is never identied, and individuals
are frequently aected by more than one allergen.
Treatment is also problematic because of the time
required for drugs to reach eective levels, often longer
than for symptoms to clear unaided. Where drugs are
used, they are usually antihistamines or corticosteroids.
10.4.1 Antihistamines
Most cases of acute urticaria can be treated with H1-type
antihistamines. e less-sedating drugs (e.g. cetirizine)
are usually preferred (see Section 10.2.1). However, if
night-time itching is a particular problem, the sedating
properties of rst-generation antihistamines may be of
benet. Antihistamines should be taken regularly as
prophylaxis, or as required during attacks to reduce
symptoms. For more severe or persistent urticaria, a
combination of H1- and H2-type antihistamines has been
shown to be eective in some cases.
10.4.2 Corticosteroids
corticosteroids in chronic urticaria is not recommended
because of the many associated side eects (see
Section 10.2.2).
10.4.3 Tricyclic antidepressants
Certain tricyclic antidepressants, for example doxepin,
exhibit potent H1 and H2 antihistamine eects and are
sometimes used, applied topically, in the management of
unresponsive urticaria. e sedative eects can be helpful
for nocturnal symptoms.
10.4.4 Other treatments
Clinical trials for the prevention of solar urticaria are
currently being undertaken with an analogue of an
-melanocyte-stimulating hormone called
afamelanotide. is condition develops in susceptible
individuals following exposure to certain wavelengths of
sunlight. Afamelanotide acts as an agonist at G-proteincoupled melanocortin receptors, which are present in
specialized skin cells called melanocytes responsible for
production of melanin. e drug is delivered as a
subcutaneous implant.
e oral corticosteroid prednisolone is sometimes used
short term for severe acute urticaria although its
eectiveness is questionable. e long-term use of
Leukotriene receptor antagonists (e.g. montelukast) may
be useful in the treatment of some patients with
unresponsive chronic urticaria.
10.3 Urticaria 255
Key references and suggested reading
Barnes PJ. Molecular mechanisms of corticosteroids in allergic
diseases. Allergy 2001; 56: 928–36.
Golightly LK, Greos LS. Second-generation antihistamines:
actions and ecacy in the management of allergic disorders.
Drugs 2005; 65: 341–84.
National Prescribing Centre. Common questions about hay
fever. MeReC Bulletin 2004; 14(5): 17–20.
Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J Invest
Allergol Clin Immunol 2006; 16: 148–55.
SUMMARY OF DRUGS USED FOR ALLERGIC RHINITIS AND URTICARIA
256 Chapter 10 Allergies: rhinitis and urticaria
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse drug
reactions
Nasal (local)
antihistamines
Ocular (local)
antihistamines
Oral (systemic)
antihistamines
Nasal corticosteroids Beclometasone
Azelastine
Levocabastine
Azelastine
Levocabastine
Ketotifen
Emedastine
Olopatadine
Rupatadine
Sedating: e.g.
Chlorphenamine
Cinnarizine
Clemastine
Promethazine
Less sedating:
e.g. Cetirizine
Loratadine
Fexofenadine
Levocetirizine
Ciclesonide
Fluticasone
Mometasone
Triamcinolone
Inhibit H1 receptors, reducing
inflammatory response mediated
by histamine
Alter gene transcription to reduce
inflammatory response
Allergic rhinitis Nasal irritation
Allergic rhinitis
Allergic conjunctivitis
Allergic rhinitis
Urticaria (prophylaxis and
treatment)
Allergic reactions
Anaphylactic shock
(clemastine, promethazine)
Nausea and vomiting (e.g.
cyclizine, cinnarizine)
Allergic rhinitis (prophylaxis
and treatment)
Sedating antihistamines tend to
have shorter duration of action
Several weeks to take effect
Used once or twice daily
Ocular discomfort including
stinging, burning, irritation
Sedation
Headache
Urinary retention
Dry mouth
Blurred vision
GI disturbance
May still cause drowsiness,
although rare
Dryness of nose
Irritation of nose and throat
Nosebleeds (epistaxis)
Nasal ulceration (most commonly
with fluticasone, mometasone)
Headache
Systemic
corticosteroids
Mast cell stabilizers Sodium cromoglicate Mast cell stabilizers with additional
Prednisolone See drug summary table in Chapter 9
Nedocromil Eyedrops
Used only rarely, for short periods for severe persistent urticaria or for disabling symptoms of allergic rhinitis
effects which may include:
1) blocking chloride channels
2) reducing sensory nerve activity
Allergic rhinitis (prophylaxis)
Allergic conjunctivitis
Asthma
Nasal and eyedrops Local irritation
Burning, stinging
Oral decongestants Phenylephrine
Nasal decongestants Ephedrine
Nasal antimuscarinics Ipratropium bromide Blocks action of ACh at M3
Leukotriene receptor
antagonists
Biological agents Omalizumab Binds circulating IgE and so
Topical tricyclic
antidepressants
Pseudoephedrine
Phenylephrine
Oxymetazoline
Xylometazoline
Montelukast
Zafirlukast
Doxepin See Chapter 19 Urticaria Cream applied topically Drowsiness
Stimulate 1-adrenoceptors
leading to vasoconstriction
Result in reduced tissue swelling
and decreased congestion
receptor in nasal mucosa to
reduce secretion of mucus
Block effects of pro-inflammatory
cysteinyl leukotrienes at receptors
prevents mast cell degranulation
Nasal congestion
symptoms in allergic rhinitis
Rhinorrhea See Chapter 11 for use in asthma
Allergic rhinitis (congestion
symptoms)
Asthma
Resistant severe allergic
rhinitis
Severe persistent allergic
asthma
Not as effective as nasal
decongestants, but not associated
with rhinitis medicamentosa
Instant effect Rhinitis medicamentosa (more
and COPD
Useful for allergic rhinitis in asthmatic
patients
Administered by subcutaneous
injection in specialist centre
IgE levels monitored before treatment
Expensive
10.4 Treatment and management of urticaria 257
Nausea
Vomiting
Hypertension
Tachycardia
Headache
Anxiety
Restlessness
common with oxymetazoline and
xylometazoline)
Local irritation
Nausea
Headache
Nosebleeds (epistaxis)
Nasal dryness and irritation
Abdominal pain
GI disturbance
Respiratory infections
Headache
Abdominal pain
Injection site reaction
Fever
Local burning, stinging, irritation,
rash
ACh, acetylcholine; COPD, chronic obstructive pulmonary disease.
WORKBOOK 7
Allergic rhinitis and urticaria
Dorothy: a simplified case history
Dorothy jumps up with a start when she hears her name called, asking her to go to Room 2. She
has been deeply engrossed in thought while waiting for her GP appointment. She cannot stop
sneezingorblowingherrunnynose.Shehasasevereheadacheandfeelsgenerallytiredand
miserable.
She has been thinking how isolated she has become from all her friends, and how lonely and
depressed she feels. Everything started to unravel soon after the family moved house. What
hadbeenmildsneezinginthespringmonthshadbecomeconstantsneezing,runnynose,itchy
and watery eyes, and headaches. Her symptoms disappeared in the winter, once they had
replaced all the carpets and curtains, but returned worse than ever at the start of spring, and
she now rarely ventures from the house.
For 18 months she has resisted going to see a doctor, worried that he would prescribe the
same drug she had been recommended by a chemist whilst on holiday in Cyprus. Although it
had worked wonders and her symptoms had magically disappeared, all she could do was sleep
all day. She had also been very alarmed by the extreme reaction she experienced after drinking
wine while taking the drug.
It is now the beginning of the school summer holidays and she has finally accepted that she
needs to do something.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR DOROTHY AT THE GP SURGERY
Age: 28 years
PC: Itchy and runny nose, sneezing, nasal congestion, itchy watery eyes, headaches, and tiredness
HPC: Mild itchy and runny nose in the spring months for about 4 years. Two years ago after moving into
a house whose previous owner had three cats, her symptoms worsened, and persisted all year. After the
carpets and curtains were replaced, symptoms vanished until spring when they resurfaced.
Symptoms of allergic rhinitis are:
• itchyandrunnynose,sneezing,nasalcongestion,itchyandwateryeyes,alteredsenseofsmell
• headaches,malaise,andtirednesssometimespresent
• nasaldischarge,whichisclear.
WORKBOOK 7 Allergic rhinitis and urticaria 259
These symptoms are similar to those of the acute rhinitis of a cold, and so details are collected
about their onset, character, frequency, severity, and duration. This information is obtained during a
detailed patient interview (see below).
PMH: Dermatitis as a child
FH: Both parents have asthma. Her 5-year-old son Sam has asthma.
Dorothy had dermatitis as a child. It was diagnosed as atopic, the most common type of dermatitis
which is linked to hay fever and asthma (the atopic triad).
Members of her family also have atopic conditions.
Atopy is the inherited predisposition to develop allergic diseases due to hypersensitivity to
substances (allergens). Atopic conditions are immunoglobulin E (IgE) mediated, and patients usually
have high levels of these antibodies.
Allergic rhinitis is very common globally, estimated to affect 10–25% of the population. Because the
symptoms are predominantly self-managed, these statistics probably underestimate the actual
prevalence.
DH: Currently nil. Previously: methyldopa for hypertension in pregnancy, chlorphenamine for hay fever
Her history of gestational hypertension is relevant, as she may later develop essential hypertension,
in which case she should avoid oral decongestants.
DS: Chlorphenamine—severe sedation and drowsiness
Her adverse drug reaction to the antihistamine chlorphenamine, and the interaction with alcohol,
has scared Dorothy so much that she has refused to consult the doctor. The sedative action of
sedating antihistamines is potentiated by other substances that depress the CNS, such as hypnotics
and alcohol.
O/E: Oral and dental changes, consistent with long-term breathing through the mouth.
When nasal congestion is present, breathing through the mouth is very common, and when carried
out over long periods can transform the mouth and face, and lead to significant jaw pain.
O/Q:
A firm diagnosis of rhinitis is not based on a laboratory test. It can only be reached by reviewing
information on medication history, family history, and the onset, duration, and severity of
symptoms, together with some tests and physical examination.
A general approach to a patient with suspected allergic rhinitis should begin with evaluation of the
answers to the following questions.
1) Which symptoms is he/she experiencing?
2) What colour are the nasal secretions?
Clear secretions are indicative of allergic rhinitis. Coloured secretions would suggest another form
of rhinitis.
3) When did these symptoms first appear?
This may correlate with exposure to allergens.
4) Are the symptoms associated with change in environment?
5) How often do symptoms appear, and for how long do they persist?
260 Chapter 10 Allergies: rhinitis and urticaria
This will distinguish between intermittent and persistent allergic rhinitis. Intermittent allergic
rhinitis (e.g. hay fever) persists over a season, while persistent allergic rhinitis may continue year
long owing to the continued presence of allergen (e.g. dust mites).
6) What precipitates symptoms?
The most common allergens for intermittent (seasonal) allergic rhinitis are pollen and mould on
trees and herbs. Persistent (perennial) allergic rhinitis is most commonly triggered by house dust
mites, feathers, animal dander (hair or dead skin), and sometimes foodstuffs (e.g. cow’s milk, eggs,
or nuts).
7) Which activities precipitate symptoms?
8) Do symptoms disturb the patient’s normal functioning?
Dorothy answers these questions at her appointment.
Diagnosis: Moderate allergic rhinitis
Table 10.2 details the criteria used for diagnosis.
Plan:
Commence loratadine
PART 1
1) What is allergic rhinitis?
2) What is the difference between allergic rhinitis and acute rhinitis?
3) Describe the structure of the nose and the function of its component parts.
4) Explain the pathogenesis of allergic rhinitis.
5) What is the role of the autonomic nervous system in the functioning of the nose?
6) Explain why older antihistamines cause sedation.
Dorothy is concerned that the new antihistamine will cause sedation, as chlorphenamine did.
The doctor tells her this is very unlikely, and that as long as she takes it regularly her symptoms
should soon improve. She is also worried about having to take it several times a day, as with
chlorphenamine, but is assured that she only need take it once daily.
7) What is the mechanism of action of antihistamines?
After 2 weeks all of Dorothy’s symptoms have improved except the congestion in her nose, and
she goes to the pharmacy. The pharmacist sells her decongestant drops to use for a maximum
of 5 days.
WORKBOOK 7 Allergic rhinitis and urticaria 261
8) Explain how decongestants work to relieve nasal congestion.
9) Why must Dorothy not use too much of the decongestant, and not for longer than 5 days?
Dorothy is ecstatic when the congestion improves dramatically. For the first time in months she
can breathe easily through her nose. She uses the decongestant drops for a month, despite the
pharmacist’s advice, and only stops when they run out. The congestion returns, worse than
before, so she returns to the doctor. He tells her that she is now suffering from rebound
congestion, or rhinitis medicamentosa, because she used the decongestant for too long.
He prescribes the oral decongestant phenylephrine for 1 week only. He also prescribes
fluticasone nasal spray to continue long-term. He explains that it will reduce the inflammation
from rebound congestion, and will also help with her nasal congestion.
10) Explain how steroids improve symptoms of allergic rhinitis.
When Dorothy goes to her pharmacy she suddenly remembers that she forgot to tell the doctor
she is pregnant. The pharmacist advises her to return to the doctor as her medication will need
to be altered. The doctor tells her she will have to stop taking loratadine, and prescribes
another first-generation antihistamine which is considered safer in pregnancy. Although she
suffered from drowsiness with chlorphenamine (also a first-generation antihistamine), not all
drugs of this type have this effect. The doctor also promises to alter her medication if this
happens again, and she finally agrees. He also discontinues the phenylephrine.
Sheimprovesonpromethazineanduticasonenasalspray.
A year later, Dorothy is back at surgery with her 5-year-old son Sam, who is suffering from the
same symptoms that Dorothy used to have. He also has asthma.
Following a detailed examination, Sam is put on cromoglicate nasal spray.
11) What is the mechanism of action of cromoglicate?
12) Explain how it should be used and why.
A month later Sam is no better, and Dorothy takes him back to the surgery. The doctor
prescribes montelukast, a leukotriene receptor antagonist.
13) Explain how leukotriene receptor antagonists act to reduce the symptoms of allergic rhinitis. Why is
montelukast ideal for Sam?
Sam improves significantly.
A year later Dorothy returns to the surgery as her nasal fluticasone spray has caused
nosebleeds and become too irritant, and her symptoms are no longer controlled.