Chapter 30: Antihistamines

Question 1

H1 ANTIHISTAMINES

Answer 1

Cetrizine ZYRTEC
Chlorpheniramine CHLOR-TRIMETON
Cyclizine MAREZINE
Desloratadine CLARINEX
Diphenhydramine BENADRYL
Dimenhydrinate DRAMAMINE
Doxylamine UNISOM SLEEPTABS
Fexofenadine ALLEGRA
Hydroxyzine VISTARIL, ATARAX
Levocetirizine XYZAL
Loratadine CLARITIN
Olopatadine PATANASE, PATANOL
Promethazine PHENERGAN
Brompheniramine LO-HIST, VAZOL
Clemastine TAVIST ALLERGY
Cyproheptadine
Meclizine BONINE, ANTIVERT
Alcaftadine LASTACAFT

Question 2

Therapeutic use of histamine 1 blocker

Answer 2

B. Therapeutic uses
1. Allergic and inflammatory conditions: H1
-receptor blockers
are useful in treating and preventing allergic reactions caused by
antigens acting on immunoglobulin E antibody. For example, oral
antihistamines are the drugs of choice in controlling the symptoms
of allergic rhinitis and urticaria because histamine is the principal
mediator released by mast cells. Ophthalmic antihistamines, such
as azelastine [a-ZEL-uh-steen], olopatadine [oh-loe-PAT-a-deen],
ketotifen [kee-toe-TYE-fen], and others (Figure 30.1), are useful
for the treatment of allergic conjunctivitis. However, the H1
-receptor
blockers are not indicated in treating bronchial asthma, because
histamine is only one of several mediators that are responsible
for causing bronchial reactions. [Note: Epinephrine has actions on
smooth muscle that are opposite to those of histamine. It acts via β2
receptors on smooth muscle, causing cAMP-mediated relaxation.
Therefore, epinephrine is the drug of choice in treating systemic
anaphylaxis and other conditions that involve massive release of
histamine.]
2. Motion sickness and nausea: Along with the antimuscarinic agent
scopolamine, certain H1
-receptor blockers, such as diphenhydramine
[dye-fen-HYE-dra-meen], dimenhydrinate [dye-men-HYE-dri-nate]
(a chemical combination of diphenhydramine and a chlorinated
theophylline derivative), cyclizine [SYE-kli-zeen], meclizine [MEK-li-
zeen], and promethazine [proe-METH-a-zeen] (Figure 30.4), are the
most effective agents for prevention of the symptoms of motion sick-
ness. They are usually not effective if symptoms are already present
and, thus, should be taken prior to expected travel. The antihista-
mines prevent or diminish nausea and vomiting mediated by both
the chemoreceptor and vestibular pathways. The antiemetic action
of these medications seems to be due to their blockade of central
H1
and M1
muscarinic receptors. Meclizine is also useful for the
treatment of vertigo associated with vestibular disorders.
3. Somnifacients: Although they are not the medications of choice,
many first-generation antihistamines, such as diphenhydramine
and doxylamine [dox-IL-a-meen], have strong sedative properties
and are used in the treatment of insomnia (Figure 30.4). These
agents are available over-the-counter (OTC), or without a prescrip-
tion. The use of first-generation H1
antihistamines is contraindicated
in the treatment of individuals working in jobs in which wakefulness
is critical. The second-generation antihistamines have no value as
somnifacients.

Question 3

Pharmacokinetics of H1 blockers

Answer 3

Pharmacokinetics
H1
-receptor blockers are well absorbed after oral administration, with
maximum serum levels occurring at 1 to 2 hours. The average plasma
half-life is 4 to 6 hours, except for that of meclizine and the second-
generation agents, which is 12 to 24 hours. First-generation H1
-
receptor blockers are distributed in all tissues, including the CNS. All
first-generation H1
antihistamines and some second-generation H1
antihistamines, such as desloratadine and loratadine, are metabo-
lized by the hepatic cytochrome P450 system. Levocetirizine is
the active enantiomer of cetirizine. Cetirizine and levocetirizine are
excreted largely unchanged in urine, and fexofenadine is excreted
largely unchanged in feces. After a single oral dose, the onset of
action occurs within 1 to 3 hours. The duration of action for many oral
antihistamines is 24 hours, allowing once-daily dosing. Azelastine,
olopatadine, ketotifen, alcaftadine [al-KAF-ta-deen], bepotastine
[bep-oh-TAS-teen], and emedastine [em-e-DAS-teen] are available in
ophthalmic formulations that allow for more targeted tissue delivery.
Azelastine and olopatadine have intranasal formulations, as well

Question 4

Adverse effects of H1 blockers

Answer 4

Adverse effects
First-generation H1
-receptor blockers have a low specificity, interact-
ing not only with histamine receptors but also with muscarinic cho-
linergic receptors, α-adrenergic receptors, and serotonin receptors
(Figure 30.6). The extent of interaction with these receptors and, as
a result, the nature of the side effects varies with the structure of the
drug. Some side effects may be undesirable, and others may be of
therapeutic value. Furthermore, the incidence and severity of adverse
reactions for a given drug varies between individual subjects.
1. Sedation: First-generation H1
antihistamines, such as chlorpheni-
ramine [klor-fen-IR-a-meen], diphenhydramine, hydroxyzine [hye-
DROX-ee-zeen], and promethazine, bind to H1
receptors and block
the neurotransmitter effect of histamine in the CNS. The most
frequently observed adverse reaction is sedation (Figure 30.7).
Diphenhydramine may cause paradoxical hyperactivity in young
children. Other central actions include fatigue, dizziness, lack
of coordination, and tremors. Sedation is less common with the
second-generation drugs, since they do not readily enter the CNS.
Second-generation H1
antihistamines are specific for peripheral
H1
receptors.
2. Other effects: First-generation antihistamines exert anticholiner-
gic effects, leading not only to dryness in the nasal passage but
also to a tendency to dry out the oral cavity. They also may cause
blurred vision and retention of urine. The most common adverse
reaction associated with second-generation antihistamines is
headache. Topical formulations of diphenhydramine can cause
hypersensitivity reactions such as contact dermatitis when applied
to the skin.
3. Drug interactions: Interaction of H1
-receptor blockers with other
drugs can cause serious consequences, such as potentiation of
effects of other CNS depressants, including alcohol. Patients tak-
ing monoamine oxidase inhibitors (MAOIs) should not take anti-
histamines because the MAOIs can exacerbate the anticholinergic
effects of the antihistamines. In addition, the first-generation anti-
histamines (diphenhydramine and others) with anticholinergic
(antimuscarinic) actions may decrease the effectiveness of cho-
linesterase inhibitors (donepezil, rivastigmine, and galantamine) in
the treatment of Alzheimer’s disease.
4. Overdoses: Although the margin of safety of H1
-receptor blockers
is relatively high, and chronic toxicity is rare, acute poisoning is rel-
atively common, especially in young children. The most common
and dangerous effects of acute poisoning are those on the CNS,
including hallucinations, excitement, ataxia, and convulsions. If
untreated, the patient may experience a deepening coma and col-
lapse of the cardiorespiratory system.

Question 5

H2 receptor blockers

Answer 5

Histamine H2
-receptor blockers have little, if any, affinity for H1
recep-
tors. Although antagonists of the histamine H2
receptor (H2
antagonists
or H2
-receptor blockers) block the actions of histamine at all H2
recep-
tors, their chief clinical use is as inhibitors of gastric acid secretion
in the treatment of ulcers and heartburn. The four H2
-receptor block-
ers cimetidine, ranitidine, famotidine, and nizatidine are discussed in
Chapter 31.