Antihistamines

Antonio Henrique Baccin Martins, M.Sc., Ph.D.

Pharmacology and Toxicology Department
baccin31@gmail.com
antonio.martins@upr.edu
787-2026288
Objectives
• Understand the mechanism of action of the different histamine
receptor blockers.
• Recognize the approved and off-label indications for the different
histamine receptor blockers.
• Summarize the side effects and contraindications of the members of
the antihistamine class.
• Recall the uses in dental practice.
Histamine (general)
Histamine is formed by decarboxylation of the amino acid L-histidine, a reaction
catalyzed in mammalian tissues by the enzyme histidine decarboxylase.

Histamine is either stored or rapidly inactivated.

The major metabolic pathways involve conversion to N-methylhistamine,

methylimidazoleacetic acid, and imidazoleacetic acid (IAA).

The synthesis of histamine occurs in mast cells and basophils of the immune system,
enterochromaffin-like (ECL) cells in the gastric mucosa, and certain neurons in the
central nervous system (CNS) that use histamine as a neurotransmitter.

Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or
basophils; the histamine content of many tissues is directly related to their mast cell
content.
Histamine synthesis and degradation
Histamine receptor subtypes
Pathophysiology of the IgE-mediated hypersensitivity reaction.
 Simplified two-state
model of H1 receptor.

A. H1 receptors coexist in two conformational states—

the inactive and active states—which are in
conformational equilibrium with one another.

B. Histamine acts as an agonist for the active

conformation of the H1 receptor and histamine binding
shifts the equilibrium toward the active conformation.

C. Antihistamines act as inverse agonists that bind and

stabilize the inactive conformation of the H1 receptor,
thereby shifting the equilibrium toward the inactive
receptor state.
Classification of First- and Second-Generation
H1-Antihistamines
• The finding that histamine is a major mediator of the allergic
hypersensitivity reaction led to the discovery of the first H1 -
antihistamines by Bovet and Staub in 1937.

• Currently, H1-antihistamines parse into two categories: first-

generation and second-generation H1-antihistamines
General structure of H1-antagonist drugs and examples of the major
subgroups. Subgroup names are based on the shaded moieties.

Diphenhydramine, hydroxyzine, chlorpheniramine, and

promethazine are among the most frequently used first-generation
H1-antihistamines.

H1-antihistamines are less selective for the H1 receptor and may

additionally bind cholinergic, α-adrenergic, and serotonergic
receptors at therapeutic doses
• The second-generation H1-antihistamines can be structurally
categorized into four main subclasses—alkylamines, piperazines,
phthalazinones, and piperidines.

• Widely used second-generation H1-antihistamines include loratadine,

cetirizine, fexofenadine.
Pharmacologic Effects and Clinical Uses

• Antihistamines are used in a broad spectrum of clinical conditions,

including allergy, itching, nausea, vomiting, motion sickness, and
insomnia.

• Allergy Disorders-H1-antihistamines are most useful in the treatment of

allergic disorders to relieve symptoms of rhinitis, conjunctivitis, urticaria,
and pruritus.

*H1-antihistamines strongly block the increased capillary permeability

necessary for the formation of edema and are therefore more effective
when used prophylactically than after an allergic reaction has begun.
• The most recently approved topical H1 antihistamine for allergy
disorders is bepotastine besilate ophthalmic solution, which
alleviates both ocular and non-ocular symptoms of allergic
conjunctivitis.

• Generalized Itching-Hydroxyzine and doxepin are potent antipruritic

agents, and their clinical effectiveness is likely related to their
pronounced CNS effects.

• Doxepin, a tricyclic antidepressant, is best used in patients with depression,

since even small doses can cause confusion and disorientation in
nondepressed patients.
 Nausea and Motion Sickness

• By inhibiting histaminergic signals from the vestibular nucleus to the

vomiting center in the medulla, H1-antihistamines such
as dimenhydrinate, diphenhydramine, meclizine,
and promethazine are useful as antiemetic agents.

• The vestibular nuclei are located in the medulla and pons of the hindbrain.
 Insomnia

• Due to their prominent CNS depressive effects, first-generation

H1-antihistamines such as diphenhydramine, doxylamine,
and pyrilamine are also used to treat insomnia.

• While effective in promoting sleep, the increased incidence of

adverse effects, including the tendency to cause next-day
sedation, limits their usefulness in clinical practice.
General side effects
• Anticholinergic adverse effects, which are more prominent with
first-generation than with second-generation H1-antihistamines:

• pupillary dilation,
• dry eyes,
• dry mouth, and REASON is important (muscarinic)
• urinary retention

Contraindications?
International Journal of Dental Sciences and
Research. 2014, 2(3), 50-54 doi:10.12691/ijdsr-2-
3-1

http://pubs.sciepub.com/ijdsr/2/3/1/index.html
Effects of histamine on human periodontal
ligament fibroblasts under simulated orthodontic
pressure
Assessment of cell number (a), cytotoxicity (b) and
viability (c) after compression with or without
histamine or inhibition with cetirizine.
Histamine-dependent expression of histamine
receptors and COX-2 by periodontal ligament
fibroblasts
NOTE

Mild allergic reaction is treated with

antihistaminic, BUT severe allergy reactions or
anaphylactic attack is managed with epinephrine.
H2 Receptor Antagonists
Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those
catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4
Twenty-four-hour median intragastric acidity pretreatment (red) and after 1 month of treatment with either
ranitidine, 150 mg twice daily (blue, H2 block), or omeprazole, 20 mg once daily (green, PPI). Note that H2-receptor
antagonists have a marked effect on nocturnal acid secretion but only a modest effect on meal-stimulated secretion.
Proton-pump inhibitors (PPIs) markedly suppress meal-stimulated and nocturnal acid secretion
General
• Antihistamines are among the most commonly and incorrectly used medicines
worldwide.
• First-generation antihistamines are associated with substantial and sometimes
fatal adverse effects.
• Newer antihistamines are safer, as affordable and as efficacious as first-
generation antihistamines.
• Antihistamines should not be used instead of epinephrine to treat anaphylaxis.
• Most antihistamines are safe during pregnancy and breastfeeding.
• There is no specific antidote used for the treatment of antihistamine overdose.
However, physostigmine may be an option if a patient is experiencing delirium or
other toxicity side effects due to the anticholinergic effects of the antihistamine.