Post on 13-Nov-2014
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.]
An overview of antihistamines
Many are available without prescription, both
alone and in combination formulations such as
cold pills and sleep aids.
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.
Different 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.
First generation antihistamines
Used to treat motion sickness
May increase appetite and wt. gain
Marked potential for producing hypotension
Reduction of allergic reactions
- Mainly used for IgE mediated hypersensitivity
reactions
- Anaphylaxis - adjunct only (as other autacoids are
mainly responsible, not histamine) - Nausea and vomiting- Insomnia
Allergic rhinitis Allergic conjunctivitis Allergic dermatological conditions (contact dermatitis) Urticaria Angioedema Pruritus (atopic dermatitis, insect bites)
Indications
Commonly used first generation antihistamines:Chlorpheniramine
Cyclizine
Diphenhydramine
Dimenhydrinate
Doxepin
Doxylamine
Hydroxyzine
Meclizine
Promethazine
Common anticholinergic side
effects:
Blurred vision
Dry mouth
Constipation
Tachycardia
Urine retention
Confusion and memory impairment
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.
Second generation antihistamines
Commonly used second generation antihistamines:
Terfenadine (Terfenadine is a prodrug, generally
completely metabolized to the active form fexofenadine )Loratadine Cetirizine Mizolastine Astemizole
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)
“Next” generation antihistamines
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-Bronchial asthma: bronchodilatorAnaphylaxis: epinephrine.
Why antihistamines are not effective in the bronchial asthma and systemic anaphylaxis?
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.
Actions
Some of these actions are of therapeutic value and
some are undesirable.
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.
Therapeutic uses
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.
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.
Adverse effects
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
effects than the first-generation antihistamines.
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.