Assignment

Topic : Antiallergic drugs- Antihistamines

Course Title: Pharmaceutical Chemistry

Course Code: CHEM-437

Submitted By:
Masooma Liaqat 21017107-004
Muntaha Saleem 21017107-006
Shaneeza Kanwal 21017107-012
Eman 21017107-044
Ammara Amin 21017107-050
Faiza 21017107-056
Semester: BS-VII (evening)

Section-D

Submitted To:
Dr. Mubeen Arif
Submission date: 22 February 2023

Department of Chemistry

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 Table of contents

Contents Page #
1. Introduction…………………………………………………………………….……….03
1.1. Allergy…………………………………………………………………………..03
1.2. Allergic reactions……………………………………………………..................03
2. Common types of allergies……………………………………………………………...03
2.1. Food allergy……………………………………………………………………..03
2.2. Inhalant allergy………………………………………………………………….03
2.3. Perennial allergy………………………………………………………………...04
2.4. Pollen allergy…………………………………………………………………....04
2.5. Drug allergy……………………………………………………………………..04
2.6. Latex allergy…………………………………………………………………….04
2.7. Insect allergy………………………………………………………………….....05
3. Allergic reaction………………………………………………………………………...05
3.1. Stages of allergic reaction……………………………………………………….05
4. Allergic treatment……………………………………………………………………….06
5. Histamines……………………………………………………………………………....08
6. Synthesis and metabolism……………………………………………………………....08
7. Storage and release……………………………………………………………………...09
8. Degradation……………………………………………………………………………..10
9. Histamine receptors……………………………………………………………………..11
10. Antihistamines…………………………………………………………………………..13
10.1. Types of antihistamines………………………………………………………....14
11. Generation of antihistamines…………………………………………………………...18
12. References……………………………………………………………………………....21

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1. Introduction:
1.1. Allergy:
Allergies, also known as allergic diseases, refer to a number of conditions caused by the hypersensitivity
of the immune system to typically harmless substances in the environment. Allergies are your body’s
reaction to a foreign protein. Usually, these proteins (allergens) are harmless. However, if you have an
allergy to a particular protein, your body’s defense system (immune system) overreacts to its presence in
your body.
1.2. Allergic action:
An allergic reaction is the way your body responds to an allergen. If you have allergies, the first time you
encounter a specific allergen, your body responds by creating immunoglobulin E (IgE). Your immune
system makes antibodies to form IgE.

2. Common types of Allergies:

2.1. Food Allergy:

Food allergies develop when your body releases a specific antibody to a particular food. An allergic reaction
occurs within minutes of eating the food, and symptoms can be severe. Symptoms may include:

• Itching all over your body (generalized pruritus).

• Itching in just one certain part of your body (localized pruritus).
• Nausea and vomiting.
• Hives.
• Swelling around your mouth, including your throat, tongue or face.
If you have an IgE-mediated food allergy, symptoms may also include anaphylaxis. It may present as any
one of the above symptoms or a combination of the above symptoms. It usually occurs within 30 minutes
of ingesting a food you’re allergic to. In adults and children, the most common food allergies are milk,
eggs, wheat, soy, peanuts, tree nuts, shellfish.
2.2. Inhalant Allergy:
Inhalant allergies are airborne substances that you inhale (breathe in). They include allergens that may
affect you throughout the year (perennial allergens) and seasonal allergens.
Inhalant allergy symptoms include:
• Runny nose • Sneezing

• Stuffy nose • Watery eyes

• Itchy nose • Itchy eyes

If you have asthma, inhalant allergies can also trigger or worsen your symptoms, including wheezing and
shortness of breath.

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2.3. Perennial Allergens:
Perennial allergens include:

• Pets: Pet allergens include certain proteins in animal fur, skin (dander), urine (pee) and saliva (spit).

• Dust mite: Dust mites are tiny, eight-legged relatives of spiders. They’re too small to see with your
eyes. They live in dust and the fibers of household objects, such as pillows, mattresses, carpets and
upholstery.

• Cockroaches: Cockroaches are reddish-brown insects that are 1.5 to 2 inches (in) long. The proteins in
their feces (poop), spit, eggs and dead body parts can cause allergic reactions.

• Molds: Molds are tiny fungi (plural of fungus). They have spores that float in the air, like pollen.
Common mold allergies include Aspergillus, Cladosporium and Alternaria.
2.4. Pollen/Seasonal Allergy:
Seasonal allergies include pollens. Pollen is microspores from trees, grass or weeds that appear as a fine
dust on surfaces or float in the air. Tree pollens generally appear in the spring, while weed pollens generally
appear in the fall.
2.5. Drug Allergy:
Certain medications can cause an allergic reaction. The medicines may be herbal, over the counter (OTC)
or prescription. Common medications that cause allergies include Antibiotics, Nonsteroidal anti-
inflammatory drugs (NSAIDs), Insulin, Chemotherapy drugs.
Symptoms include:
• Rash
• Hives

• Itching
• Shortness of breath
• Swelling
2.6. Latex Allergy:
Latex allergies develop after repeated contact with natural rubber latex. Common natural rubber latex
products include rubber gloves, balloons, condoms, bandages, rubber balls. The most common reaction to
latex is skin irritation (contact dermatitis). It manifests as a rash on the area of skin that touched the latex.
It may develop within minutes of exposure to latex.
Other symptoms may include:
• Hives
• Runny nose
• Itchy nose
• Difficulty breathing

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2.7. Insect Allergy:
Stinging insects can inject venom, which is a toxic substance. The venom in insect stings can cause an
allergic reaction. The most common stinging insects that cause allergic reactions include:
• Bees
• Fire ants
• Hornets
• Wasps
• Yellow jackets
Venom symptoms are consistent with anaphylaxis. They may include:
• Difficulty breathing
• Hives
• Swelling in your face, mouth or throat
• Wheezing
• Difficulty swallowing
• Rapid pulse
• Dizziness
• Drop in blood pressure.

3. Allergic Reactions:
A person is exposed to allergens by inhaling it swallowing it getting by skin after person exposed is a
sequence of events that create an allergic reaction.
3.1. Mechanism / process:
The body produces an antibody or protein IgE to bind with the allergen antibodies attaches to mast cells
found in airways intestine and elsewhere Allergens bind to IgE attached with mast cell and mast cells
release variety of chemicals into blood known as HISTAMINE. HISTAMINE causes symptoms of an
allergic reaction.
3.2. Difference b/w an Allergy and Reaction:
The substance that causes allergic reactions is ALLERGENS. When someone has allergies, their immune
system makes an antibody called IMMUNOGLOBIN E (IgE). These antibodies respond to allergens the
symptoms that result are an allergic reaction.

4. Allergy Treatment:
There are two types of allergy treatment:
1. Medication
2. Immunotherapy

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1.Medication:
Antihistamines are most common help to reduce stuffy and runny nose sneezing and itching.
Corticosteroids spray treat inflammation in nose.
2. Immunotherapy:
In this type of preventive treatment for allergic reaction involves giving gradual increase doses of allergens
slow increase of allergens allows immune system to become less sensitive to the allergen.
• Allergic reactions occurs:
Allergies occur when Immune system mistakenly triggers by an allergy to an allergen. Severe / worst / life
threatening allergy cause anaphylaxis.
• Deficiency causes Allergy:
Vitamin D deficiency is caused allergic reaction in a body.
• Some Blood cells causes allergies:
Some cells in a body causes allergy such as:
• White Blood Cells WBCs
• T-cells
• Mast cells
• Basophils
• Eosinophils
4.1. Stages of an Allergic reaction:
The Allergic responses have TWO PHASES:
a. Acute
b. Chronic
These are observed as Wheal and Flare occur rapidly after allergen exposure (< 1hour) caused by
degranulation of mast cells and release of HISTAMINE and other MEDICATOR.
a. Acute Allergic reaction:
In this type of the severe allergy anaphylaxis causes the immune system to release flood of chemicals that
can cause you to go in shock blood pressure drop suddenly airways become narrow and blocking breathing.
Symptoms:
The main symptoms are as follows:
a. Rapid weak pulse
b. Nausea
c. Vomiting
b. Chronic Allergic reaction:
In this type of allergy, the generally occur in 6-12 hours of initial allergy Cellular response Caused by T-
cells Eosinophils Cells release enzymes Toxic proteins, cytokines Leading more inflammation.

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• Ways to control Allergies without medication:
There are several ways to control allergy such as:
1. Take vitamin C 6. Keep out fresh breeze.
2. Cleanse your nose, eyes and other body area 7. Wash up infected area.
3. Manage stress 8. Wear mask
4. Eat healthy items 9. Explore herbal remedy.
5. Try probiotics 10. Detox body by
• Prevent Allergy by medication:
Some ways to prevent allergy by medication such as:
1. Take your medicine as prescribed
2. Wear a medical alert bracelet or necklace
3. Keep dietary supplements
4. If you are at risk for anaphylaxis keep your epinephrine auto injectors all time
5. Know what to do in allergic reaction
• Tablets best for Allergy:
There are some medicines for relief allergy such as:
➢ Claritin / loratadine: 24-hour Allergy relief
➢ Zyrtec / cetirizine: 24-hour Allergy relief
➢ Nasacort: 24-hour Allergy relief
➢ Nasacort: 24-hour Children Allergy relief (syrup)
➢ Pataday: once daily relief extra strength
➢ Fexofenadine
➢ Softin for sneezing relief cause by birds
• Allergy receivers with their advantages and disadvantages
1. Total serum IgE → Sample of blood is taken to measure IgE amounts.
▪ Advantages: More comfortable than skin test
▪ No risk of anaphylaxis
▪ Unaffected by medication use
▪ Disadvantage : Test results delayed
▪ Require large volume of blood for multiple test which may be harden for younger children
▪ High cost
▪ Fewer allergens tested.
2. Atopic patch test → Skin exposure to allergens over long period of time (24-72 hours). Used to
assess non IgE food allergy responses.
▪ Advantages : Assess late onset of symptoms

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 ▪ Can help to identify allergens for patients with eosinophilic.
▪ Eosinophilic or Atopic Dermatitis
▪ Disadvantages : Highly variable in testing method
▪ Preparations and results
3. Oral food challenge → Specific foods are introduced to patient and symptoms are assessed. Must
be a double-blind placebo-controlled food challenge.
▪ Advantage: The most accurate testing method for food allergies
▪ Criterion standard
▪ Disadvantage: Risk of anaphylactic reactions
▪ Significant amount of time and manpower needed.
▪ Cost
▪ Facility must have proper tools and equipment to perform this test.

5. Histamine:
Histamine is an important chemical that has a role in several different bodily processes. It stimulates gastric
acid secretion, plays a role in inflammation, dilates blood vessels, affects muscle contractions in the
intestines and lungs and affects your heart rate. It also helps transmit messages between nerve cells and
helps fluids move through blood vessel walls. Histamine is also released if your body encounters a threat
from an allergen. Histamine causes vessels to swell and dilate, leading to allergy symptoms.

6. Synthesis and metabolism:

Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by
the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.

Once formed, histamine is either stored or rapidly inactivated by its primary degradative
enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine
released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other
tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further
process the immediate metabolites of histamine for excretion or recycling.

Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those
found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine
production by bacteria in spoiled food, particularly fish.

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Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion
performed by fermenting bacteria or yeasts. Sake contains histamine in the 20–40 mg/L
range; wines contain it in the 2–10 mg/L range.

Fig.1: storage and release of histamine

7. Storage and release:

Fig.2 : Mast cells

Most histamine in the body is generated in granules in mast cells and in white blood cells (leukocytes)
called basophils. Mast cells are especially numerous at sites of potential injury – the nose, mouth, and feet,
internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including
the hypothalamus region of the brain, where it functions as a neurotransmitter. Another important site of
histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.

The most important pathophysiologic mechanism of mast cell and basophil histamine release
is immunologic. These cells, if sensitized IgE antibodies attached to their membranes, degranulate when
exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine,
and curare alkaloids, can displace histamine in granules and cause its
release. Antibiotics like polymyxin are also found to stimulate histamine release.

Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE
overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-
release of histamine.

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8. Degradation:
Histamine is released by mast cells as an immune response and is later degraded primarily by two
enzymes: diamine oxidase (DAO), coded by AOC1 genes, and histamine-N-methyltransferase (HNMT),
coded by the HNMT gene. The presence of single nucleotide polymorphisms (SNPs) at these genes are
associated with a wide variety of disorders caused by an overactive immune system, from ulcerative
colitis to autism spectrum disorder (ASD). Histamine degradation is crucial to the prevention of allergic
reactions to otherwise harmless substances.

DAO is typically expressed in epithelial cells at the tip of the villus of the small intestine mucosa. Reduced
DAO activity is associated with gastrointestinal disorders and widespread food intolerances. This is due to
an increase in histamine absorption through enterocytes, which increases histamine concentration in the
bloodstream. One study found that migraine patients with gluten sensitivity were positively correlated with
having lower DAO serum levels. Low DAO activity can have more severe consequences as mutations in
the ABP1 alleles of the AOC1 gene have been associated with ulcerative colitis. Heterozygous or
homozygous recessive genotypes at the rs2052129, rs2268999, rs10156191 and
rs1049742 alleles increased the risk for reduced DAO activity. People with genotypes for reduced DAO
activity can avoid foods high in histamine, such as alcohol, fermented foods, and aged foods, to attenuate
any allergic reactions. Additionally, they should be aware whether any probiotics they are taking contain
any histamine-producing strains and consult with their doctor to receive proper support.

HNMT is expressed in the central nervous system, where deficiencies have been shown to lead to
aggressive behavior and abnormal sleep-wake cycles in mice. Since brain histamine as a neurotransmitter
regulates several neurophysiological functions, emphasis has been placed on the development of drugs to
target histamine regulation. Yoshikawa et al. explores how the C314T, A939G, G179A, and T632C
polymorphisms all impact HNMT enzymatic activity and the pathogenesis of various neurological
disorders. These mutations can have either a positive or negative impact.

Some patients with ADHD have been shown to exhibit exacerbated symptoms in response to food additives
and preservatives, due in part to histamine release. In a double-blind placebo-controlled crossover trial,
children with ADHD who responded with aggravated symptoms after consuming a challenge beverage
were more likely to have HNMT polymorphisms at T939C and Thr105Ile. Histamine’s role in
neuroinflammation and cognition has made it a target of study for many neurological disorders, including
autism spectrum disorder (ASD).

De novo deletions in the HNMT gene have also been associated with ASD. Mast cells serve an important
immunological role by defending the body from antigens and maintaining homeostasis in the gut
microbiome. They act as an alarm to trigger inflammatory responses by the immune system.

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Their presence in the digestive system enables them to serve as an early barrier to pathogens entering the
body. People who suffer from widespread sensitivities and allergic reactions may

have mast cell activation syndrome (MCAS), in which excessive amounts of histamine are released
from mast cells, and cannot be properly degraded. The abnormal release of histamine can be caused by
either dysfunctional internal signals from defective mast cells or by the development of clonal mast cell
populations through mutations occurring in the tyrosine kinase Kit.
In such cases, the body may not be able to produce sufficient degradative enzymes to properly eliminate
the excess histamine. Since MCAS is symptomatically characterized as such a broad disorder, it is difficult
to diagnose and can be mislabeled as a variety of diseases, including irritable bowel
syndrome and fibromyalgia.

Histamine is often explored as a potential cause for diseases related to hyper-responsiveness of the immune
system. In patients with asthma, abnormal histamine receptor activation in the lungs is associated
with bronchospasm, airway obstruction, and production of excess mucus. Mutations in histamine
degradation are more common in patients with a combination of asthma and allergen hypersensitivity than
in those with just asthma. The HNMT-464 TT and HNMT-1639 TT are significantly more common among
children with allergic asthma, the latter of which is overrepresented in African American children.

Fig: synthesis and degradation of histamine

9. Histamine Receptors
Histamine actions are mediated by the binding of histamine to one of four receptor subtypes: H1, H2,
H3, and H4. All four subtypes are seven-transmembrane, G protein-coupled receptors, and all demonstrate
constitutive activity independent of agonist binding. The receptor isoforms differ in their expression levels,
second messenger pathways, and tissue distributions.
▪ H1 Receptor
▪ H2 Receptor
▪ H3 Receptor
▪ H4 Receptor

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These are discussed as follows. Also, there pharmacological effects are discussed in these factors. These
factors have special type of place or site of action where they attack and effect on it. That area of working
of that receptor. These receptors have their own effect which we discussed.
H1 Receptors

H1 receptors are expressed primarily on vascular endothelial cells and smooth muscle cells. These receptors
mediate inflammatory and allergic reactions. Tissue-specific responses to H1 receptor stimulation
include (1) edema, (2) erythema, (3) bronchoconstriction, and (4) sensitization of primary afferent nerve.
terminals. H1 receptors are also expressed on postsynaptic neurons in the tuberomammillary nucleus of the
hypothalamus, cerebral cortex, and limbic system. These neurons appear to be involved in the control of
circadian rhythms, wakefulness, and energy metabolism.

H2 Receptors
The major function of the H2 receptor is to mediate gastric acid secretion in the stomach. This receptor
subtype is expressed on parietal cells in the gastric mucosa, where histamine acts synergistically with
gastrin and acetylcholine to regulate acid secretion (see Chapter 47). H2 receptors are also expressed on
cardiac muscle cells, on some immune cells, and on certain postsynaptic neurons in the CNS. H2 receptors
on parietal cells activate a G protein-dependent cyclic AMP cascade, leading to enhanced proton pump-
mediated delivery of protons into the gastric fluid.

H3 Receptors
H3 receptors are predominantly located on presynaptic neurons in distinct regions of the CNS, including
the cerebral cortex, basal ganglia, and tuberomammillary nucleus of the hypothalamus. H3 receptors appear
to function as both auto receptors and heteroreceptors, thereby limiting the synthesis and release of
histamine as well as other neurotransmitters, including dopamine, acetylcholine, norepinephrine, GABA,
and serotonin. This complex interaction between histamine and various neurotransmitter systems
contributes to histamine’s widespread effects on CNS functions, including wakefulness, appetite, and
memory. The downstream effects of H3 receptor activation are mediated via a decrease in cAMP.

H4 Receptors
H4 receptors are primarily localized to cells of hematopoietic origin, primarily mast cells, eosinophils,
dendritic cells, and basophils. H4 receptors share 40% homology with H3 receptors and bind many
H3 receptor agonists, although with lower affinity.
Coupling of the H4 receptor to Gi/o leads to decreased cAMP and activation of phospholipase Cβ, and
downstream events result in increased intracellular Ca2+. H4 receptors are of particular interest because they
are thought to play an important role in inflammation. activation of H4 receptors mediates histamine-
induced leukotriene B4 production, adhesion molecule up-regulation, and chemotaxis of mast cells,
eosinophils, and dendritic cells.

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10. Antihistamine:
Antihistamines are a class of drugs commonly used to treat symptoms of allergies. These drugs help treat
conditions caused by too much histamine, a chemical created by your body’s immune system.
Antihistamines are most commonly used by people who have allergic reactions to pollen and other
allergens. They are also used to treat a variety of other conditions such as stomach problems, colds, anxiety
and more.
Antihistamine drug

• Cetirizine (Zyrtec, Zyrtec Allergy)

• Desloratadine (Clarinex)
• Fexofenadine (Allegra, Allegra Allergy)
• Levocetirizine (Xyzal, Xyzal Allergy)
• Loratadine (Alavert, Claritin)

Structure of antihistamine

There are many anti histamine are used and they have different structure from each other.

Cetirizine

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History of antihistamine:
The first H1 receptor antagonists were discovered in the 1930s and these drugs were marketed in the
1940s.Piperoxan was discovered in 1933 and was the first compound with antihistamine effects to be
identified.However, piperoxan and its analogues were too toxic to be used in humans. Phenbenzamine
(Antergan) was the first clinically useful antihistamine and was introduced for medical use in 1942.
Subsequently, many other antihistamines were developed and marketed. Diphenhydramine (Benadryl) was
synthesized in 1943, tripelennamine (Pyribenzamine) was patented in 1946, and promethazine (Phenergan)
was synthesized in 1947 and launched in 1949.By 1950, at least 20 different antihistamines had been
marketed.Chlorphenamine (Piriton), a less sedating antihistamine, was synthesized in 1951, and
hydroxyzine (Atarax, Vistaril), an antihistamine used specifically as a sedative and tranquilizer, was
developed in 1956.The first non-sedating antihistamine was terfenadine (Seldane) and was developed in
1973. Subsequently, other non-sedating antihistamines like loratadine (Claritin), cetirizine (Zyrtec), and
fexofenadine (Allegra) were developed and introduced.

The introduction of the first-generation antihistamines marked the beginning of medical treatment of nasal
allergies.Research into these drugs led to the discovery that they were H1 receptor antagonists and also to
the development of H2 receptor antagonists, where H1-antihistamines affected the nose and the H2-
antihistamines affected the stomach. This history has led to contemporary research into drugs which are H3
receptor antagonists and which affect the H4 receptor antagonists.Currently most people who use an H1
receptor antagonist to treat allergies use a second- or third-generation drug.

10.1. Types of antihistamine:

There are many types of antihistamine.

1. H1 antihistamine
2. H2 antihistamine
3. H3 antihistamine
4. H4 antihistamine

H1 antihistamine:

H1-antihistamines refer to compounds that inhibit the activity of the H1 receptor.Since the H1 receptor
exhibits constitutive activity, H1-antihistamines can be either neutral receptor antagonists or inverse
agonists.Normally, histamine binds to the H1 receptor and heightens the receptor’s activity; the receptor
antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by
comparison, the inverse agonists bind to the receptor and both block the binding of histamine, and reduce
its constitutive activity, an effect which is opposite to histamine’s.
Most antihistamines are inverse agonists at the H1 receptor, but it was previously thought that they were
antagonists.
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Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation
is a common side effect of H1-antihistamines that readily cross the blood–brain barrier; some of these drugs,
such as diphenhydramine and doxylamine, may therefore be used to treat insomnia. H1-antihistamines can
also reduce inflammation, since the expression of NF-κB, transcription factor the regulates inflammatory
processes, is promoted by both the receptor’s constitutive activity and agonist (i.e., histamine) binding at
the H1 receptor.

A combination of these effects, and in some cases metabolic ones as well, lead to most first-generation
antihistamines having analgesic-sparing (potentiating) effects on opioid analgesics and to some extent with
non-opioid ones as well.

The most common antihistamines utilized for this purpose include hydroxyzine, promethazine (enzyme
induction especially helps with codeine and similar prodrug opioids), phenyltoloxamine, orphenadrine, and
tripelennamine; some may also have intrinsic analgesic properties of their own, orphenadrine being an
example. Second-generation antihistamines cross the blood–brain barrier to a much lesser extent than the
first-generation antihistamines.

They minimize sedatory effects due to their focused effect on peripheral histamine receptors. However,
upon high doses second-generation antihistamines will begin to act on the central nervous system and thus
can induce drowsiness when ingested in higher quantity. Additionally, some second-generation
antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and
benzodiazepines.

H1 antagonist:

• Acrivastine
• Alimemazine (a phenothiazine used as antipruritic, antiemetic and sedative)
• Amitriptyline (tricyclic antidepressant)
• Amoxapine (tricyclic antidepressant)
• Aripiprazole (atypical antipsychotic, trade name: Abilify)
• Azelastine
• Bilastine
• Bromodiphenhydramine (Bromazine)
• Brompheniramine
• Buclizine
• Carbinoxamine

15
 Fig.3 Mechanism of H1 anti histamine

H2 antihistamine:

H2-antihistamines, like H1-antihistamines, exist as inverse agonists and neutral antagonists. They act on
H2 histamine receptors found mainly in the parietal cells of the gastric mucosa, which are part of the
endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H2 to stimulate acid
secretion; drugs that inhibit H2 signaling thus reduce the secretion of gastric acid.

H2-antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers
and gastroesophageal reflux disease. Some formulations are available over the counter. Most side effects
are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing
androgenic testosterone and DHT receptors at high doses.

Examples include:

• Cimetidine
• Famotidine
• Lafutidine
• Nizatidine
• Ranitidine
• Tiotidine

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H3 antihistamine:

An H3-antihistamine is a classification of drugs used to inhibit the action of histamine at the H3 receptor.
H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic
nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary
release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors
in the cerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3-antihistamines
have stimulant and cognition-modulating effects.

Examples of selective H3-antihistamines include:

• Clobenpropit
• Ciproxifan
• Conessine
• Thioperamide
H4 antihistamine:

H4-antihistamines inhibit the activity of the H4 receptor.

Examples:

• Thioperamide
Side effects of antihistamine:

Like all medicines, antihistamines can cause side effects.

Side effects of antihistamines that make you drowsy can include:

• Sleepiness (drowsiness) and reduced co-ordination, reaction speed and judgement – do not drive or
use machinery after taking these antihistamines
• Dry mouth
• Blurred vision
• Difficulty peeing

Side effects of non-drowsy antihistamines can include:

• Headache
• Dry mouth
• Feeling sick
• Drowsiness – although this is less common than with older types of antihistamines

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11. Generations of Antihistamines:
There is a range of antihistamines available which characterized into following generations:

First-generation antihistamines:
First generation antihistamines are the oldest H1-antihistaminergic drugs. They are widely available and
inexpensive. They are effective in the relief of allergic symptoms but are moderately to highly potent
muscarinic acetylcholine receptor antagonists as well. Patient response and occurrence of adverse drug
reactions vary between classes and between agents within classes. Adverse drug reactions are most
associated with the first-generation H1-antihistamines. This is due to their relative lack of selectivity for
the H1 receptor and their ability to cross the blood brain barrier.
First-generation oral antihistamines, including both of the diphenhydramine (Benadryl) and
chlorpheniramine (Chlor-Trimeton), easily cross the blood-brain barrier and affect H1 receptors in
the central nervous system (CNS). H1 receptors in the CNS help regulate the body’s sleep-wake cycle.
First-generation antihistamines have sedative properties. By binding to receptors in the CNS, first-
generation antihistamines can impair cognitive and motor functions and cause drowsiness.
Just like the name implies, the first-generation antihistamine was the first type approved by the Food and
Drug Administration (FDA).

They began to be approved in the United States in the 1930s and are still prescribed today. They work on
histamine receptor in the brain and spinal cord along with other types of receptors. Most notable about this
generation of antihistamines is that they cross the blood-brain barrier, which results in drowsiness.

Examples of first-generation antihistamines:

Other examples of first-generation antihistamines include:

• Brompheniramine • Chlorpheniramine
• Cyclizine • Doxepin
• Benadryl • Dramamine
• Hydroxyzine • Sominex
• Ccarbinoxamine • doxylamine
• hydroxyzine (Atarax, Vistaril) • promethazine (Phenergan)

Side effects of 1st generation antihistamines:

Other severe side effects associated with first-generation antihistamines include:

• poor sleep quality • dizziness

• blurred vision • acute liver damage
• anxiety • increased appetite leading to weight gain
• insomnia • nausea and vomiting

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 • constipation and diarrhea • dry mouth
• dizziness • low blood pressure

Although several types of first-generation antihistamines are available, some trusted Source healthcare
professionals may not recommend them if a newer version is available.

Second generation Antihistamines:

Second-generation H1-antihistamines are newer drugs that are much more selective for peripheral H1
receptors as opposed to the central nervous system H1 receptors and cholinergic receptors. This selectivity
significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing
effective relief of allergic conditions. The reason for their peripheral selectivity is that most of these
compounds are zwitterionic at pH around 7.4. They are very polar, meaning that they do not cross the
blood–brain barrier and act outside the central nervous system.
Examples of 2nd generation antihistamines:
Some commonly used second generation antihistamines are:
• Cetirizine • Allegra
• Claritin • Clarinex
• fexofenadine • Loratadine
Second-generation antihistamines were approved by the FDA and first came to market in the 1980s. The
second-generation antihistamines do not cross the blood-brain barrier to the extent that first-generation do
and therefore do not cause drowsiness at standard dosage levels. Second-generation antihistamines are
considered to be safer than first generation antihistamines because they do not cause drowsiness and interact
with fewer drugs. Some of the common side effects of second-generation antihistamines include:
• Headache • Cough
• Tiredness • Sore throat
• Abdominal pain or discomfort • Nausea or vomiting
Second- and third-generation antihistamines do not have sedative properties. According to an article in the
journal National Institute of Diabetes and Digestive and Kidney Diseases, second- and third-generation
antihistamines are less likely trusted source to cross the blood-brain barrier. This means they do not have
such significant effects on the CNS as first-generation types.
These antihistamines are safe for adults and children over 12 years old Trusted Source to use.

Third generation antihistamines:

Third generation H1 – antihistamines are second generation antihistamines formally labelled third
generation because the active enantiomer (Levocetirizine) or metabolite (Desloratadine) derivatives of
second-generation drugs intended to have increased efficacy with fewer adverse drug reactions.

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Examples :
• Norastemizole (Metabolite of astemizole) •Decarboethoxy loratadine (Metabolite of loratadine)
• Levocetirizine (Active enantiomer of cetirizine) • bilastine (Bilaxten)
• desloratadine (Clarinex) •loratadine (Claritin)
• fexofenadine (Allegra)

Second generation antihistamines over first generation antihistamines:

First generation antihistamines are highly lipid soluble, crossing the blood-brain barrier ease and antagonize
H1 receptors in both CNS and periphery. On the other hand, second generation antihistamines are larger
molecules and less lipophilic, and thus less likely to cross the blood-brain barrier.
First generation antihistamines block both histaminic and muscarinic receptors, Second- generation
antihistamines block histaminic receptors. That is why second-generation antihistamines are more selective
and do not produce more side effect just like 1st generation antihistamines occur. Both first- and second-
generation antihistamines are competitive antagonists to histamine at the H1-receptor site.
An additional pharmacological activity of first-generation, but not second-generation antihistamines is the
competitive antagonism of acetylcholine at neuronal and neuromuscular muscarinic receptors.
Third generation antihistamines over first generation antihistamines:
Third generation antihistamine is used for treatment of allergic rhinitis and chronic urticaria, although first
generation antihistamine is used before to treatment along with sedation, but this third-generation
antihistamine does not produce sedation.

Treatment of diseases other than allergies:

First-generation H-1 antihistamines also treat:
• Insomnia
• Motion sickness and anxiety
H-2 antihistamines treat:
• Heartburn.
• Gastroesophageal reflux disease (GERD)
• Duodenal and gastric ulcers
• Zollinger-Ellison syndrome
Other conditions antihistamines treat include:
• Anorexia
• Headaches
• Anaphylaxis
• Vertigo
• Parkinson’s disease (to decrease stiffness and tremors)

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12. References :
• Randall KL, Hawkins CA. Antihistamines and allergy. Aust Prescr. 2018 Apr;41(2):41-45. Doi:
10.18773/austprescr.2018.013. Pub 2018 Apr 3.
• Simons FE, Simons KJ. H1 antihistamines: status and future directions. World Allergy Organ
J 2008; 1:145-55.
• Castillo M, Scott NW, Mustafa MZ, Mustafa MS, Azura-Blanco A. Topical antihistamines and mast
cell stabilisers for treating seasonal and perennial allergic conjunctivitis. Cochrane Database Syst
Rev 2015;1:CD009566.
• Carson S, Lee N, Thakurs S. Drug class review: newer antihistamines: Final report update two
[Internet]. Portland (OR): Oregon Health & Science University; 2010.
• Randall KL, Hawkins CA. Antihistamines and allergy. Aust Prescr. 2018 Apr;41(2):41-45. Doi:
10.18773/austprescr.2018.013. Epub 2018 Apr 3. PMID: 29670310; PMCID: PMC5895478.
• del Cuvillo A, Mullol J, Bartra J, Dávila I, Jáuregui I, Montoro J, et al. Comparative pharmacology
of the H1 antihistamines. J Investig Allergol Clin Immunol 2006;16 Suppl 1:3-12.
• Castillo M, Scott NW, Mustafa MZ, Mustafa MS, Azuara-Blanco A. Topical antihistamines and
mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis. Cochrane Database
Syst Rev 2015;1:CD009566.
• Corren J, Baroody FM, Togias A. Allergic and nonallergic rhinitis. In: Burks AW, Holgate ST,
O'Hehir RE, et al, eds. Middleton's Allergy: Principles and Practice. 9th ed. Philadelphia, PA:
Elsevier; 2020: chap forty.
• hurmond RL, Desai PJ, Dunford PJ, Fung-Leung WP, Hofstra CL, Jiang W, et al. A potent and
selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp
Ther (2004) 309:404–13.
• Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, Malolepszy J, et al. Histamine regulates
T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature (2001)
413:420–5.
• Parsons ME, Ganellin CR. Histamine and its receptors. Br J Pharmacol (2006) 147(Suppl 1): S127–
35.
• Thomas L. Lemke; David A. Williams, eds. (24 January 2012). Foye's Principles of Medicinal
Chemistry. Lippincott Williams & Wilkins.

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