Allergy, Histamines & Antihistamines related to science

1. 1
Dr. Jyotsna S. Meshram
Professor and Head,
Department of Chemistry,
Rashtrasant Tukadoji Maharaj,
Nagpur University, Nagpur,
Maharashtra, India
ALLERGY, HISTaminesand antihistamines
29th May 2020

2. (CH2)n NX
Ar
Ar1 CH3
CH3
2
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healthy
A insect bite/mosquito bite causes the body to release
histamines in the area of bite, making the skin swollen,
red and itchy

3. 3
 Allergy
 Allergens
 Histamine- INTRODUCTION
 Conditions releasing histamines
 Formation of Histamine
 Antihistamine- Therapeutic uses
 H-1 Receptor Antagonistics
 Inhibitors of histamine release
 Histamine Intolerance
 classification
CONTENTS

4. 4

5. 5
Allergy
80-90% world population suffers from allergies
caused by the abnormal response to immune
system which can be developed at any age
If both parents have allergies, the son/daughter
has 70% chances of having it. However if
only one of the parent has then the chances
are 48% ( American Academy of Asthama,
Allergies and Immunology,Spring 2003)
Allergy
FOOD
SKIN
PETDUST
SKIN
DRUG

6. 6
Allergens
Allergens when encountered activates mast cells/
basophiles to release massive amounts of histamines
1. Skin allergens- Plant Poison, Animal scratches,
pollen, latex
2. Ingestant allergans- Food stuff by swallowing
3. Inhalant allergens- Pollens, dust, mold and mildew,
animal dander
4. Infectant allergens- Pathogenic micro-organisms
5. Infestant allergens- Parasatic micro-organisms in/on
body, hookworms, tapeworms
6. Injectant allergens- Penicillin injection
7. Aeroallergens
8. Insect stings- Bees, Wasps, Hornets
9. Spiders, mites, lice, ticks, snakes, scorpions,
centipede
10. Foods, Medicines, Cosmetics, Perfumes, Detergents,
Climate change

7. 7
Allergies can be of different
kinds, affecting different parts
of body-
 Skin allergy
 Drug allergy
 Latex allergy
 Mold allergy
 Dust allergy
 Insect sting allergy
 Pet allergy
 Food allergy- Milk, egg, wheat,
citrus fruits, peanuts, fish
Peanuts
Tomatoes
Strawberries
Wheat
Eggs
Food
allergies

8. 8
The allergies can be of different
kinds, contd.-
 Urticaria- Hives
 Allergic rhinitis- common cold
 Allergic conjunctivitis- pink
eye
 Angioedema- Swelling of skin
 Puritus- Atopic Dermatitis,
Insect bites
 Anaphylatic shock- severe
allergies, can be fatal

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• Histos - Tissue
• Histamine – Biogenic tissue amine that occurs
in all tissues. It is present abundantly in Animal
tissue (Venoms, Insect stings, ) and Plant
tissue also
• It is one of the key chemical, a organic natural
compound which acts as chemical messenger,
involved in local immune response responsible
for allergic reactions
• It stimulates gastric secretions, mucous
production, causes dilation of capillaries,
constriction of bronchial smooth muscles,
sinusitis and decreases blood pressure, skin
reactions
Histamine- Introduction

10. 10
• It acts as neurotransmitter, transmitting signals
from one neuron cell to other neuron cell
• It is a protein released by the body in response to
allergy
• When histamines are released in the blood
stream, they cause symptoms e.g itchy, puffed
eyes, skin, lips, sneezing, coughing, shortness of
breath, itching of hands, soles of feet, peeling of
the skin, redness of skin,running nose, hay fever,
hives
• Histamines cause inflammatory reactions, play a
major role in body’s system including immune,
digestive and neurological system
Histamine- Introduction- Contd.

11. 11
Conditions that releases
Histamines-
• Tissue Injury- Any physical or chemical agent
that makes the injuries to the tissues, skin or
mucosa, will immediately release histamines
from mast cells
• Allergic reactions caused by mites, pollen, dust
wherein the mucous membranes of the eyes and
nose are inflamed resulting in running nose,
watery eyes
• Drugs , Chemicals, other foreign compounds
• Certain foods, food colours
• Stress

12. 12
• Synthesized locally from aminoacid histidine
• Amino acid Histidine Histamine
• Decarboxylase catalyses the transformation of
histidine to histamine, a physiologically active
amine C5H9N3, imidazoline ring with ethylene
amino group
L-Histidine Histamine
Histidine
decarboxylase
Formation of Histamine

13. 13
 Histamines are concentrated in basophiles
and mast cells and produced by them
 Basophiles appear in specific kind of
inflammatory reactions causing allergic
symptoms. It contains anticoagulant Heparin
and also vasodilator histamine
 Mast Cells – They are stimulated to release
granules and powerful chemical mediators e.g.
histamines, heparin into the environment
causing the characteristic symptoms of
allergy
 Histamines are also present in high amounts
in skin, lungs, liver, gastric mucosa

14. 14
Antihistamine-
Introduction and Therapeutic uses-
• It is a pharmaceutical drug that reduces or
inhibits the effects of histamine
• It inhibits the enzymatic activity of 1- histidine
decarboxylase which catalyses the
transformation of histidine to histamine
• The term antihistamine is used to describe H-1
and H-2 receptor antagonists.
• The Ist antihistamine Piperoxan was developed in
1933 by Jeff Forneau and Daniel Bovent, for
which they received Nobel Prize in 1957
• Antihistamine e.g.- Benadryl (First generation)

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H-1 Receptor Antagonists
• They do not prevent histamine release or bind to the
histamine
• They are used clinically to treat various allergic
disorders like seasonal or perennial allergic rhintis ,
eczema, breathing disorders
• H-1 receptor antagonists are classified into-
• First Generation and Second generation
• First Generation- effective, penetrate central nervous
system, used for the treatment of allergic
conjunctivitis, morning sickness, skin rashes,
potential drugs for producing sedation e.g-
Promethazine, Cinnarizine, Cypropatidine,
metabolized by liver and excreted in urine
• Side effects- Sedation, dizziness, blurred vision,
insomnia, morning sickness, anxiety, dry cough

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H-1 Receptor Antagonists Contd.----
• Second Generation- Do not penetrate the blood
brain barrier, less toxic compared to second
generation, they are more selective for peripheral
H1 receptors involved in allergies as opposed to the
H1 receptors in CNS. eg. Loratadine, Terfenadine,
Certizine
• The second generation drugs have weak potential
for producing sedation and selected drugs are non
sedative
• The R& D activities done on second generation
drugs show that they are effective for management
of inflammation in allergic airway disease(Devalia
and Davies)
• Side effects- Fatigue, drowsiness, morning
sickness, dry mouth

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 The non-steroid anti-inflammatory drugs, indomethacin,
flufenamate and meclofenamate, inhibited the release of
histamine from rat peritoneal mast cells induced by
pharmacological or immunological challenge in vitro.
Anaesthetic drugs that release histamine directly
include atracurium, mivacurium, morphine and meperidine
 How to stop the release of histamines-
Some of the most common medical treatments include:
taking antihistamine medication.
taking DAO enzyme supplements.
switching prescription medications.
avoiding medicines associated with histamine intolerance,
such as most anti-inflammatory and pain drugs.
taking corticosteroids.
Inhibitors of Histamine Release

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People who are allergic to histamine rich
foods have a condition called “ Histamine
Intolerance”
It is fairly rare and only estimated to occur in
1% of the total population.
It occurs in the body when there is
overproduction of histamine in the body.
Incomplete breakdown of histamine in the
body.
Poor histamine balance leading to
histamine intolerance.
Histamine intolerance

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The reasons can be-
1. OTC, NSAIDS, use of antibiotics, antihypertensive drugs,
antimalarial drugs, painkillers, antipsychiotics,
antitubercular drugs, antineoplastic drugs etc.
2. Extreme temperature conditions, Environmental factors
3. Nutritional deficiencies
4. Medical conditions, Diet, Alcohol consumption
5. Vitamin B-6 deficiency. Vitamin C deficiency
6. Injury, trauma, Low oxygen level
7. Sleep disorders, Constipation
8. Swelling around eyes, lips, face
9. Acid reflux, Heat burn
10.Hormonal changes
Histamine intolerance cont.--

20. 20
The common symptoms for histamine
intolerance include-
Diarrhoea
Migraine
Stress, injury
Morning sickness
Flushing of face, chest
Irregular heart beat
Low blood pressure
Running, itchy nose
Red, itchy, watery eyes
Insomnia, anxiety
Dizziness, fatigue, stomach upset, itchy skin
shortness of breath, sneezing, trauma
Symptoms- Histamine intolerance

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Low Histamine Diet
The high histamine levels can gradually reduce over time if
the cause of allergic reaction be found out. There is no
histamine free diet, however one can follow a low
histamine diet.
For low histamine diet foods one should try to prepare
their own food, keep it to the natural form as far as
possible, maintaining of record of the dairy food or the
food that causes some abnormal reactions, avoiding junk
food and consumption of fresh food.
Food with high levels of Histamines-
Fermented dairy products- Cheese, yogurt, sour cream,
fermented meat- sausages, pickle, wine, beer,
soy sauce, spinach, eggplant
Note- Low histamine diet may lead to malnutrition

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Classification
1. Amino alkyl ethers
2. Ethylenediamine derivatives
3. Propylamine derivatives
4. Phenothiazine derivatives
5. Piperazine derivatives
6. Miscellaneous
7. Non sedative antihistamines

23. CLASSIFICATION :-
1. Amino alkyl ethers
OAr
Ar1
R
N
2. Ethylenediamine derivatives
N
Ar
Ar1
N
3. Propylamine derivatives
a. Saturated analogues
Ar
Ar1
CH2CH2 N
b. Unsaturated analogues
N Ar
Ar1
4. Phenothiazine derivatives
N
S
R
5. Piperazine derivatives
N N R1
R
23

24. Ar Ar1 R
Diphenhydramine H
Doxylamine CH3
Carbinoxamine H
Medrylamine
Clemastine
Cl
N
N
O
O
N
Cl
24
OAr
Ar1
R
N
1. Amino alkyl ethers

25. 2. Ethylenediamine derivatives
Ar Ar1
Pyrilamine
Tripelennamine
Methapyrilene
Thonzlamine
N
N
N
N
N
CH2
CH2CH3O
CH2CH3O
S
CH2
25
N
Ar
Ar1
N

26. 3. Propylamine derivatives
a. Saturated analogues
Ar
Ar1
CH2CH2 N
Ar Ar1
Pheniramine
Chlorpheniramine Cl
N
N
26

27. 3. Propylamine derivatives
b. Unsaturated analogues
N Ar
Ar1
Ar Ar1
Pyrrobutamine
Triprolidine
N
CH2Cl
CH2H3C
27

28. R
Promethazine
Trimeprazine
Methadilazine
H2C CH N
CH3
CH3
CH3
H2C CH
CH3
CH2 N
CH3
CH3
N CH3H2C
28
N
S
R
4. Phenothiazine derivatives

29. 5. Piperazine derivatives
N N R1
R
R R1
Cyclizine H CH3
Chlorcyclizine Cl CH3
Hydroxyzine Cl
Medlizine Cl
Bulizine Cl
Cinnarizine H
CH3
C(CH3)3H2C
CH2
CH2CH2OCH2CH2OH
29

30. (CH2)n NX
Ar
Ar1 CH3
CH3
30
Structure Activity Relationship :-
Substitution on aryl group, change of the heterocyclic ring, increased
branching of CH2 has a marked effect on the potency of drug
In general if the terminal nitrogen is tertiary amine, it shows maximum
therapeutic use
The terminal nitrogen can be a part of heterocyclic system e.g- cyclizine
Branching or extension of 2-aminoethyl side chain results in less activity
Ar- Phenyl ring
Ar1- Phenyl, benzyl, pyridyl

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Mechanism of Action
1. Histamine exerts its action by binding to the proteins in the body H-1
receptor.
2. H-1 antagonists act by inhibiting the effects of histamines at H-1
receptor site.
3. Antihistamines work by binding to H-1 receptor blocking the path of
histamine, thus preventing the allergic response.
4. However if histamine is already bound to the receptor, when
antihistamines are administered, the drugs cannot disrupt the
interaction and cannot push the histamine off the receptor,thus they
should be consumed when allergic symptoms are expected.
5. Some corticosteroids also act on immune system by reducing the
allergic reactions.

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REFERENCES-
1.Medicinal Chemistry- D. Sriram and P. Yogeeswari, Pearson, 2007, pp 145-167
2.Textbook of Medicinal Chemistry- Volume-II, V.Algarsamy, Elsevier, 2010,pp 3-45
3.https://www.healthline.com/health/low-histamine-diet
4.https://www.healthline.com/health/histamine-intolerance
5,https://www.healthline.com/health/histamine-intolerance
THANKS