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ANTIHISTAMIN

Systemic antihistamines are commonly prescribed to relieve the symptoms of


itch (pruritus) including urticaria, pruritic dermatoses such as eczema, chronic
pruritus, insect bites and stings allergic drug reactions and as an adjunct to adrenaline
(epinephrine) in the emergency treatment of anaphylaxis and histaminergic
angioedema.

Classification and mode of action


H1 antihistamines are classified as first generation, which are sedating include
chlorpheniramine, diphenhydramine, promethazine and hydroxyzine) and newer non-
sedating, and include loratadine, desloratadine, cetirizine, levocetirizine,
fexofenadine, acrivastine, bilastine, ebastine, mizolastine and rupatadine. Some of
sedating (first generation) antihistamines have additional antimuscarinic,
antiadrenergic, antiserotonergic antagonizing or local anaesthetic effects.
The time course of action is variable, although symptomatic relief usually
begins within 15–30 minutes, lasts for 1–2 hours and in some cases lasts for 12–24
hours or longer. It is usually maximal within 1–2 hours and continues for 3–6 hours
or longer. Cetirizine, levocetirizine, loratadine, desloratadine and mizolastine have a
slower onset and prolonged duration of action, peak blood levels from 45 minutes and
lasting for at least 24 hours. Therefore, they are effective when given once as a daily
dosage.
Most H1 antihistamines are extensively metabolized in the liver. Some H1
antihistamines and their metabolites are eliminated predominantly by renal
mechanisms (acrivastine, cetirizine and levocetirizine, an isomer of cetirizine).
Prolonged use of H1 antihistamines may lead to some reduction in effectiveness.

Indication and dermatological uses


 The licensed indications of most antihistamines include urticaria with or without
angioedema. Second-generation (non-sedative) antihistamines are the drugs of
choice for daytime symptoms. First-generation antihistamines may be useful to
relieve symptoms at night because of their sedating properties.
 Sedating antihistamines may be useful in the treatment of pruritus caused by other
dermatological conditions such as atopic eczema.
 H1 antihistamines are also used for type I hypersensitivity reactions including
anaphylaxis.
 Some antihistamines have antiemetic properties, such as diphenhydramine and
promethazine. These may be used in motion sickness.

Formulation/Presentation
The following are available in solution or syrup form: cetirizine, chlorpheniramine,
clemastine, cyproheptadine, diphenhydramine, desloratadine and promethazine. Some
can be given parenterally, but this frequently causes local irritation. Some topical
antihistamines are available but prolonged use should be avoided because of a
relatively high risk of contact sensitization.
Generic names and dosages and suggested regimens of antihistamines used in
dermatology in the UK.
Dossages and suggested regimen
Antihistamines are usually given orally. If standard dosing is not effective in chronic
urticaria, increasing the dosage up to fourfold is recommended. For patients who do
not respond to a fourfold increase in dosage second-line therapies should be added to
the antihistamine. Treatment options include montelukast 10 mg daily, omalizumab
300 mg by s/c injection every 4 weeks or immunosupressant drugs, e.g. ciclosporin.

Baseline investigation and consideration


No routine monitoring is required.

Contraindication and cautions


 Mizolastine is partly metabolized by CYP3A4. It should not be given to patients
in whom there may be impaired drug metabolism, such as those with liver
disease, the elderly or those taking drugs that inhibit CYP450. Patients should be
instructed not to drink grapefruit juice, which inhibits CYP450. Patients with
cardiac disease may be at increased risk of cardiac adverse effects.
 Antihistamines with substantial antimuscarinic (anticholinergic) activity (mainly
first-generation/sedating) should be used with caution or avoided in patients with
narrow-angle glaucoma or increased intraocular pressure, prostatic hypertrophy,
bladder neck obstruction, stenosing peptic ulcer, pyloroduodenal obstruction,
asthma and chronic obstructive airways disease, hyperthyroidism, cardiovascular
disease and hypertension.
 Severe renal impairment: reduced dosage or frequency of doing may be required.
 Seizure disorders: use non-sedating antihistamines

Important drug interactions


 Mizolastine should not be given with drugs that can inhibit CYP450, as these may
increase its plasma levels and predispose to cardiac toxicity.
 Central nervous system (CNS) depressants, such as barbiturates, anxiolytics,
opioid analgesics and alcohol, may have additive CNS depressive effects to those
of the sedating antihistamines.
 Monoamine oxidase inhibitors, used less frequently than in the past, are
contraindicated with chlorphenamine as they may prolong and intensify the
anticholinergic and sedative effects.

Adverse effects and their management


 Sedation occurs predominantly with first-generation antihistamines because they
are highly lipid-soluble and cross the blood–brain barrier readily, blocking central
as well as peripheral H1 receptors. Headache, dizziness, lassitude, sleep
disturbances, abnormal co-ordination and muscular weakness may also occur. In
some patients effects disappear spontaneously after 2–3 days.
 Paradoxical stimulation (excitement) also occurs predominantly with first
generation antihistamines. Restlessness, insomnia, tremors, euphoria,
nervousness, delirium and seizures may occur, particularly in children.
 Cardiovascular adverse effects are uncommon, and are usually limited to
overdose situations, adverse cardiac effects are due to anticholinergenic or
quinidine-like effects, and include tachycardia.
 Gastrointestinal adverse effects include epigastric pain, anorexia, nausea,
vomiting, diarrhoea and constipation. Increased appetite and weight gain may
occur with cyproheptadine and mizolastine.
 Hypersensitivity reactions: prolonged topical use of antihistamines should be
avoided because of the risk of developing allergic contact dermatitis.
 Anticholinergic effects occur predominantly with first-generation antihistamines,
and include dryness of the mouth, nose and throat, dysuria, urinary retention,
impotence, gastric reflux, constipation, vertigo, visual disturbance, blurred vision,
diplopia, tinnitus, acute labyrinthitis, insomnia, tremor, nervousness, irritability
and facial dyskensia.
 Haematological adverse effects are rare and include agranulocytosis, haemolytic
anaemia, leukopenia, thrombocytopenia and pancytopenia.

Use in special situations


Pregnancy/Lactation
The manufacturers of antihistamines advise avoidance of their use during
pregnancy. There is no evidence of teratogenicity, apart from for hydroxyzine (FDA
Category C), which has been associated with toxicity when given in high doses in
animal studies. Chlorphenamine (FDA Category B) may be used in the first two
trimesters. It should be avoided if possible in the third trimester because of a rare
association with neonatal seizures. Other adverse effects in neonates include
irritability and tremor.
Loratadine and cetirizine (Category B) are now recommended as the treatment
of choice when any perceived risks are outweighed by potential benefits.
Promethazine (FDA Category C) may interfere with several immunological urinary
pregnancy tests and also interferes with blood grouping in the ABO system. Most
antihistamines can be found in breast milk to varying degrees but are not known to be
harmful. However, manufacturers advise avoiding their use in mothers who are
breastfeeding. Antihistamines may also inhibit lactation
Essential patient information
Patients should be warned about the sedative effects of H1 antihistamines and that
additive CNS depression may occur if taken with other sedatives and alcohol. Major
side-effects of the older antihistamines include drowsiness, although paradoxical
stimulation may occur.

H2 ANTIHISTAMINES
There is controversy about the use of H2 antagonists in urticaria. H1 and H2 receptor
activation can cause vasodilation and increased vascular permeability, while H1
receptors mediate itch and flare. Theoretically therefore, H2 receptor antagonists may
reduce whealing. Their dermatological use is unlicensed and they should not be used
as monotherapy. Ranitidine can be given at doses of 150 mg twice daily and is
usually choenrather than cimetidine, as it does not inhibit CYP450.

Doxepin
Doxepin is a tricyclic antidepressant with potent H1 and H2 antihistamine effects, it
is a useful drug in the treatment of adult urticaria and pruritus night-time sedation is
required. initial dose of 25 mg/d at night is usually sufficient, and may be adjusted to
response. An alternative low-dose regimen is 10 mg two or three times a day. A
topical formulation of doxepin is licensed for use as an antipruritic.

Important drug interactions


Doxepin is metabolized by CYP450, and can prolong the QT interval, causing
arrhythmias and heart block.

Adverse effects & their management


 Adverse effects include sedation, convulsions, hepatic and haematological
reactions, antimuscarinic effects (such as dry mouth, blurred vision, constipation
and urinary retention), sweating, hypotension and syncope, hyponatraemia and
weight gain.
 sedative effects and associated risk of falls, caution in the elderly
 may cause allergic contact dermatosis
 Avoid in glaucoma, urinary retention, liver disease.
 Caution in epilepsy, thyroid disease.

Use in special situations


Pregnancy
Doxepin (FDA Category C; B for topical use) should not be used in pregnancy
because of limited available information.
Lactation
Doxepin should be avoided in lactation, may cause sedation and neonatal respiratory
depression.
Children Doxepin is not recommended in children under 12 years

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