11. 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.]

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.