An overview of

antihistamines
A histamine antagonist is an agent which serves to
inhibit the release of histamine.

The term antihistamine usually refers to the

classical H1 receptor blockers.

Reversible & competitive H1 receptor antagonists

block the binding of histamine to its receptors.

These compounds do not influence the formation

or release of histamine. [Cromolyn which inhibits the
release of histamine from mast cells and is useful in the
treatment of asthma.]
Many are available without prescription, both
alone and in combination formulations such as
cold pills and sleep aids.
Different
antihistamines
Three generations of antihistamines-

Each generation improved on the previous one.

Share general characteristics and properties.

The first generation drugs are still widely used

because they are effective and inexpensive.

However, the other agents, because they do not

penetrate the blood-brain barrier (???), show less
CNS toxicity than the older drugs.
First generation
antihistamines
Small, lipophilic molecules that could cross the
blood brain barrier.

Highly sedating.

Not specific to the H1 receptor (lack of selectivity for

the H1 receptor), most also have considerable
anticholinergic activity which can provide an
antiemetic effect (particularly against motion
sickness) by blocking the muscarinic actions of
acetylcholine.
 Used to treat May increase
motion sickness appetite and wt. gain

Marked potential for Reduction of allergic

producing hypotension reactions
Indication
s- Mainly used for IgE mediated hypersensitivity
reactions
Allergic rhinitis
Allergic conjunctivitis
Allergic dermatological conditions (contact
dermatitis)
Urticaria
Angioedema
Pruritus (atopic dermatitis, insect bites)
- Anaphylaxis - adjunct only (as other autacoids are
mainly responsible, not histamine)
- Nausea and vomiting
- Insomnia
Commonly used first generation antihistamines:
Chlorpheniramine
Cyclizine ⇒ Common anticholinergic side
Diphenhydramine effects:
Dimenhydrinate Blurred vision
Doxepin Dry mouth
Doxylamine Constipation
Hydroxyzine Tachycardia
Meclizine Urine retention
Promethazine Confusion and memory impairment
Second generation
antihistamines
Modifications of the first generation antihistamines
to eliminate side effects, resulted in the second
generation antihistamines.

More selective for peripheral H1 receptors.

Little or no anticholinergic or antiemetic effects.

Poorly penetrate the CNS, thus little or no

sedation.
Commonly used second generation
antihistamines:
Terfenadine (Terfenadine is a prodrug, generally
completely metabolized to the active form fexofenadine )
Loratadine
Cetirizine
Mizolastine
Astemizole
“Next” generation
antihistamines
Metabolite derivatives or active enantiomers of
existing drugs.

Safer, faster acting or more potent than second

generation drugs.

Examples:
Fexofenadine (Active form of terfenadine)
Desloratadine (Desloratadine is the major
metabolite of loratadine)
Levocetirizine (active isomer of cetirizine)
Why antihistamines are not effective in the
bronchial asthma and systemic anaphylaxis?

Bronchial asthma:
Main mediators: leukotriens and platelet
activating factor (PAF).
Anaphylaxis:
Main mediators: autacoids other than
histamine.
For these reasons antihistamines are not
effective against bronchial asthma and
anaphylaxis.
Main drug-
Actions
H1 antihistamines antagonize all actions of
histamine except for those mediated by H2
receptors. The action of all of the H1 receptor
blockers is qualitatively similar. However, most of
these blockers have additional effects unrelated to
their blocking of H1 receptors; these effects
probably reflect binding of the H1 antagonists to
cholinergic, adrenergic, or serotonin receptors.
Some of these actions are of therapeutic value and
some are undesirable.
Therapeutic
uses
Allergic conditions: H1 Blockers are useful in
treating allergies caused by antigens acting on
IgE-antibody sensitized mast cells.
For example, antihistamines are the drugs of
choice in controlling the symptoms of allergic
rhinitis and urticaria because histamine is the
principal mediator.
Motion sickness and nausea: Certain H1
receptor blockers, such as diphenhydramine,
dimenhydrinate, cyclizine, meclizine and
hydroxyzine are the effective agents for the
prevention of the symptoms of motion sickness.
The antihistamines prevent or diminish vomiting
and nausea mediated by both the chemoreceptor
and vestibular pathways.
Promethazine has perhaps the strongest
muscarinic-blocking activity among these agents
and is among the most effective of the H1
antagonists in combating motion sickness.
Somnifacients: Although they are not the
medication of choice, some of the first-generation
antihistamines, such as diphenhydramine and
doxylamine have strong sedative properties and
are used in the treatment of insomnia.

The use of first-generation H1 antihistamines is

contraindicated in the treatment of individuals
working in the job where wakefulness is critical.
Adverse effects
Sedation: The most frequently observed adverse
reaction is sedation. This effect is prominent in
first-generation antihistamine such as
chlorpheniramine, diphenhydramine, hydroxyzine
and promethazine. These drugs binds to H1
receptor and block the neurotransmitter effect of
histamine in the CNS.
Sedation is less common with the higher
generation drugs that do not readily enter the
CNS.
Dry mouth: Oral antihistamines also exert weak
anticholinergic effects, leading not only to a drying
of the nasal passage but also to a tendency to dry
the oral cavity.
Blurred vision can also occur with some drugs.
Drug interactions: Interaction of H1 receptor
blockers with other drugs can cause serious
consequences, such as the potentiation of the
effects of all other CNS depressants, including
alcohol.
Persons taking MAO inhibitors should not take
antihistamines, since the MAO inhibitors can
exacerbate the anticholinergic effects of the
antihistamines.
Actions not caused by histamine
receptor blockade
Sedation:
A common effect of first-generation H1 antagonists is
sedation.
At ordinary dosages, children occasionally (and
adults rarely) manifest excitation rather than
sedation.
At very high toxic dose levels, marked stimulation,
agitation, and even convulsions may precede coma.
Second-generation H1 antagonists have little or no
sedative or stimulant actions. These drugs (or their
active metabolites) also have far fewer autonomic
Antinausea and antiemetic actions
Several first-generation H1 antagonists have
significant activity in preventing motion sickness.
They are less effective against an episode of motion
sickness already present.
Certain H1 antagonists, notably doxylamine, were
used widely in the past in the treatment of nausea
and vomiting of pregnancy.
Anticholinoceptor actions
Many of the first-generation agents have significant
atropine-like effects on peripheral muscarinic
receptors.
This action may be responsible for some of the
(uncertain) benefits reported for nonallergic
rhinorrhea but may also cause urinary retention and
blurred vision.
Adrenoceptor-blocking actions
Alpha-receptor-blocking effects can be demonstrated
for many H1 antagonists, for example promethazine.
This action may cause orthostatic hypotension in
susceptible individuals. Beta-receptor blockade is not
observed.