Antihistamine

antihistamine
An antihistamine is a drug which serves to reduce or
eliminate effects mediated by histamine, an endogenous
chemical mediator released during allergic reactions,
through action at the histamine receptor. Only agents
where the main therapeutic effect is mediated by
negative modulation of histamine receptors are termed
antihistamines - other agents may have antihistaminergic
action but are not true antihistamines.
In common use, the term antihistamine refers only to H1receptor antagonists, also known as H1antihistamines. It has been discovered that these H1antihistamines are actually inverse agonists at the
histamine H1-receptor, rather than antagonists per se

Pharmacology

In allergic reactions an allergen (a type of antigen) interacts with and

cross-links surface IgE antibodies on mast cells and basophils.
Once the mast cell-antibody-antigen complex is formed, a complex
series of events occurs that eventually leads to cell degranulation
and the release of histamine (and other chemical mediators) from
the mast cell or basophil. Once released, histamine can react with
local or widespread tissues through histamine receptors.
Histamine, acting on H1-receptors, produces pruritus, vasodilatation
, hypotension, flushing, headache, tachycardia, bronchoconstriction,
increases vascular permeability, potentiates pain, and more.
(Simons, 2004)
While H1-antihistamines help against these effects, they only work if
taken before contact with the allergen. In severe allergies, such as
anaphylaxis or angioedema, these effects may be so severe as to
be life-threatening. Epinephrine, often in the form of an autoinjector (
Epi-pen), is required by people with such hypersensitivities.

Clinical use of antihistamines

Indications
H1-antihistamines are clinically used in the treatment of histaminemediated allergic conditions. Specifically, these indications may
include: (Rossi, 2004)
Allergic rhinitis
Allergic conjunctivitis
Allergic dermatological conditions (contact dermatitis)
Urticaria
Angioedema
Pruritus (atopic dermatitis, insect bites)
Anaphylactic or anaphylactoid reactions - adjunct only
Nausea and vomiting (first-generation H1-antihistamines)
Sedation (first-generation H1-antihistamines)

 Antihistamines can be administered topically (through

the skin, nose, or eyes) or systemically, based on the
nature of the allergic condition.
The authors of the American College of Chest
Physicians Updates on Cough Guidelines (2006)
recommend that for cough associated with the common
cold, first-generation antihistamine-decongestants are
more effective than newer, nonsedating antihistamines.
First generation antihistamines include Diphenhydramine
(Benadryl); Carbinoxamine (Clistin); Clemastine
(Tavist);Chlorpheniramine (Chlor-Trimeton)and
Brompheniramine (Dimetane).

Adverse drug reactions

Adverse drug reactions are most commonly associated with the firstgeneration H1-antihistamines. This is due to their relative lack of selectivity
for the H1-receptor.
The most common adverse effect is sedation; this "side effect" is utilized in
many OTC sleeping-aid preparations. Other common adverse effects in
first-generation H1-antihistamines include: dizziness, tinnitus, blurred vision,
euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting,
constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse
effects include: urinary retention, palpitations, hypotension, headache,
hallucination, and psychosis. (Rossi, 2004)
The newer second-generation H1-antihistamines are far more selective for
peripheral histamine H1-receptors and, correspondingly, have a far
improved tolerability profile compared to the first-generation agents. The
most common adverse effects noted for second-generation agents include:
drowsiness, fatigue, headache, nausea and dry mouth. (Rossi, 2004)

First-generation H1-receptor
antagonists

These are the oldest antihistaminergic drugs and are relatively inexpensive
and widely available. They are effective in the relief of allergic symptoms,
but are typically moderately to highly potent muscarinic
acetylcholine receptor-antagonists (anticholinergic) agents as well. These
agents also commonly have action at -adrenergic receptors and/or
5-HT receptors. This lack of receptor-selectivity is the basis of the poor
tolerability-profile of some of these agents, especially compared with the
second-generation H1-antihistamines. Patient response and occurrence of
adverse drug reactions vary greatly between classes and between agents
within classes.
The first H1-antihistamine discovered was piperoxan, by Jeff Forneau and
Daniel Bovet (1933) in their efforts to develop a guinea pig animal-model for
anaphylaxis at Ryerson University. Bovet went on to win the 1957
Nobel Prize in Physiology or Medicine for his contribution. Following their
discovery, the first-generation H1-antihistamines were developed in the
following decades. They can be classified on the basis of chemical
structure, and agents within these groups have similar properties.

First-generation H1-receptor
antagonists
Ethylenediamines
Ethylenediamines were the first group of clinically-effective H1antihistamines developed.
Mepyramine (pyrilamine), Antazoline
Ethanolamines
Diphenhydramine was the prototypical agent in this group. Significant
anticholinergic adverse effects, as well as sedation, are observed in
this group but the incidence of gastrointestnal adverse effects is
relatively low.
Diphenhydramine
Carbinoxamine
Doxylamine
Clemastine
Dimenhydrinate

Alkylamines
The isomerism is a significant factor in the activity of the agents in this
group. E-triprolidine, for example, is 1000-fold more potent than Ztriprolidine. This difference relates to the positioning and fit of the
molecules in the histamine H1-receptor binding site. (Nelson, 2002)
Alkylamines are considered to have relatively fewer sedative and
gastrointestinal adverse effects, but relatively greater incidence of
paradoxical CNS stimulation.

Pheniramine
Chlorphenamine (chlorpheniramine)
Dexchlorphenamine
Brompheniramine
Triprolidine

Piperazines
These compounds are structurally-related to the
ethylenediamines and the ethanolamines; and produce
significant anticholinergic adverse effects. Compounds
from this group are often used for motion sickness,
vertigo, nausea and vomiting. The second-generation
H1-antihistamine cetirizine also belongs to this chemical
group.
Cyclizine
Chlorcyclizine
Hydroxyzine
Meclizine

Tricyclics
These compounds differ from the phenothiazine antipsychotics in the
ring-substitution and chain characteristics. (Nelson, 2002) They are
also structurally-related to the tricyclic antidepressants, explaining
the antihistaminergic adverse effects of those two drug classes and
also the poor tolerability profile of tricyclic H1-antihistamines. The
second-generation H1-antihistamine loratadine was derived from
compounds in this group.
Promethazine
Alimemazine (trimeprazine)
Cyproheptadine
Azatadine
Ketotifen

Second-generation H1-receptor
antagonists
These are newer drugs that are much more
selective for peripheral H1 receptors in
preference to the central nervous system
histaminergic and cholinergic receptors. This
selectivity significantly reduces the occurrence of
adverse drug reactions compared with firstgeneration agents, while still providing effective
relief of allergic conditions.

Second-generation H1-receptor
antagonists
Systemic
Acrivastine
Astemizole
Cetirizine
Loratadine
Mizolastine
Terfenadine (withdrawn from most markets due
to risk of cardiac arrhythmias and replaced with
fexofenadine)

Topical
Azelastine
Levocabastine
Olopatadine

Third-generation H1-receptor
antagonists
These are the active enantiomer (levocetirizine) or
metabolite (desloratadine & fexofenadine)
derivatives of second-generation drugs intended
to have increased efficacy with fewer adverse
drug reactions. Indeed, fexofenadine is
associated with a decreased risk of cardiac
arrhythmia compared to terfenadine. However,
there is little evidence for any advantage of
levocetirizine or desloratadine, compared to
cetirizine or loratadine respectively.

Systemic
Levocetirizine
Desloratadine
Fexofenadine