The document discusses antihistamines and histamine. It begins by defining antihistamines as drugs that reduce the effects of histamine, which is released during allergic reactions. It then discusses the structure, functions, and synthesis of histamine. The document outlines the causes and types of allergies and describes the clinical uses and adverse effects of various classes of antihistamines, including first-generation and newer second-generation drugs. It discusses the actions of histamine at different receptor sites and concludes by summarizing the classification and structures of representative antihistamines.

1. AntihistAmines
Prepared by:
Ms. Aishwarya C. Porje
(Assistant professor)
Department of Pharmaceutical Chemistry
KCT's R. G. Sapkal College of Pharmacy, Anjaneri,
Nashik.

2. WhAt is An AntihistAmine & histAmine?
• Antihistamine is a drug that reduces or eliminates the effects
mediated by the chemical histamine.
• Histamine is released by your body during an allergic reaction and
acts on a specific histamine receptor.
• Histamine is distributed in Mast Cells in all peripheral tissues of
the body and basophils, which circulate in the blood.
• Histamine stored in inactive bound form and release as a result of
Antigen-antibody reaction.
• Histamines functions in body such as:
– Mediator of inflamation and local immune responses
– Regulating physiological function in the gut and
– Acting as a neurotransmitter
STRUCTURE OF HISTAMINE

3. • During inflammation it is produced by basophils and by mast cells,
found in nearby connective tissues, which increases the permeability of
the capillaries to white blood cells and some proteins, to allow them to
engage pathogens in the infected tissues.
• In the gut/stomach it is produced by parietal cells and then promotes
gastric acid secretion and thus aids in digestion. Here it acts like a local
hormone.
• As a neurotranmitter, it effects sleeping and waking, food intake, thermal
regulation, emotions and aggressive behavior, locomotion, memory, and
learning.
• True antihistamines are only the agents that produce a therapeutic
effect that is mediated by negative modulation of histamine receptors
(other agents may have anti-histaminergic action but are not true
antihistamines)

4. synthesis of histAmine
■ Formed from the amino acid Histadine in a decarboxylation
reaction with the enzyme histadine decarboxylase
■ Occurs primarily in mast cells and basophils

5. WhAt Are Allergies?
• Allergies are caused by a hypersensitivity reaction of the antibody
class IgE (which are located on mast cells in the tissues and basophils
in the blood)
• When an allergen is encountered, it binds to IgE, which excessively
activates the mast cells or basophils, leading them to release massive
amounts of histamines.
• These histamines lead to inflammatory responses ranging from runny
nose to anaphylactic shock
• If both parents have allergies, you have a 70% of having them, if only
one parent does, you have a 48% chance (American Academy of
Asthma, Allergies and Immunology, Spring 2003).

6. CliniCAl Uses of AntihistAmines
• Allergic rhinitis (common cold)
• Allergic conjunctivitis (pink eye)
• Allergic dermatological conditions
• Urticaria (a rash of round)
• Angioedema (swelling of the skin)
• Pruritus (insect bites, severe itching of the skin)
• Anaphylactic reactions (severe allergic reactions)
• Nausea and vomiting
• Sedation

7. Adverse effeCts
■ Associated with the first generation H1-antihistamines and due to their lack of
selectivity for the H1receptor and anti-cholinergic activity. Side effects are
due to CNS depression:
• Sedation
• Dizziness
• Tinnitus (ringing in the ear)
• Blurred vision
• Euphoria
• Uncoordination
• Anxiety
• Insomnia
• Tremor
• Nausea/vomitting
• Dry mouth/ Dry cough

8. histAmine reCeptors

9. ACtions of histAmine by reCeptors

10. first Anti-histAmine
• Discovered in 1933 by Jeff Forneau and Daniel
Bovent while developing a guinea pig animal
model of anaphylaxis
• They received the Nobel Prize in 1957

11. ClAssifiCAtion of AntihistAmines

12. • An H1 receptor antagonist is a classification of drugs used to
block the action of histamine at the H1 receptor
• Competitive inhibitors of histamine action at tissue level.
• Binding is reversible and displaced by higher levels of
histamine.
• Additional anticholinergic activity, some possess anti-
serotoninergic activity and many of them also inhibit
neuronal uptake of norepinephrine.
• Also have local anesthetic effect, but carry risk of irritation
and sensitization.

13. • 2 aromatic rings, connected to a central carbon, nitrogen, or
oxygen
• Spacer between central atom and the amine, usually 2-3
carbons in length. (Can be linear, ring, branched, saturated
or unsaturated)
• The amine is substituted with small alkyl groups
• Chirality at X and having the rings in different planes
increases potency of the drug

14. ClAsses of 1st generAtion
h1 reCeptor AntAgonist AntihistAmines
• Ethylene diamine -Meperamine
• Ethanolamines -Diphenhydramine
• Alkylamines -Chlorphenamine
• Piperazines -Chlorcyclizine
• Tricyclics -Promethazine
• Phenothiazines -Trimeprazine
• Mast cells Inhibitors- Cromolyn sodium

15. 1. Ethylene diamine
*Tripelenamine Meperamine (Pyrilamine)
Antazoline
IUPAC: N,N-dimethyl-N-(phenylmethyl)-
N-pyridin-2-ylethane-1,2-diamine N-(4-methoxybenzyl)- N-
N',N'dimethyl- pyridin-2-ylethane-
1,2-diamine
IUPAC:
IUPAC:N-(4,5-Dihydro-1H-imidazol-2-
ylmethyl) -N-(phenylmethyl)aniline
• These were the first group of clinically effective H1-antihistamines.

16. 2. Ethanolamines (Aminoalkylether)
IUPAC: 2-(diphenylmethoxy)-
N,N-dimethylethanamine
Diphenhydramine (Benadryl)
• Oldest and most effective
antihistamine on the market
• Because it induces sedation,
it’s used in nonprescription
sleep aids such as Tylenol PM
•Tylenol PM Available over the
counter to help with insomnia.
• This class has significant anticholinergic side effects and sedation,
however reduced the gastroinestnal side effects

17. • 2nd drug which used
in effectiveness of anti-
allergy activity.
• Active ingredient in
NyQuil tab
• Potent anti-cholinergic
effects
IUPAC: (RS)-N,N-dimethyl-2-(1-phenyl-
1- pyridin-2-yl-ethoxy)-ethanamine.
Doxylamine Succinate

18. IUPAC: (2R)-2-{2-[(1R)-1-(4-
chlorophenyl)
-1-phenylethoxy]ethyl}-1-
methylpyrrolidine
• Exhibits fewer side effects
than most antihistamines
• Widely used as an
antiprurtic (stops itching)
• Used for treatment or
prevention of motion
sickness or symptoms of
nausea and dizziness.
• Also causes strong sedation
• Readily crosses the BBB
IUPAC: 2-benzhydryloxy-N,N-
dimethylethanamine;8-chloro-1,3-
dimethyl-7H-purine-2,6-dione

19. 3. Alkylamines (Aminopropyl Compound)
• Isomerism is an important factor in this class of drugs, which is
due to the position and fit of the molecules in the H1-receptor
binding site.
• These drugs have fewer sedative and GI adverse effects, but a
greater incidence of CNS stimulation.
• These drugs lack the “spacer molecule” (which is usually a
nitrogen or oxygen) between the two aromatic rings and at
least one of the rings has nitrogen included in the aromatic
system.

20. IUPAC: 3-(4-chlorophenyl)-N,N-
dimethyl- 3-pyridin-2-yl-propan-
1-amine
IUPAC: 2-methyl-9-phenyl-
2,3,4,9- tetrahydro-1H-
indeno[2,1-c]pyridine
• Originally used to prevent allergic
conditions
• Have antidepressant properties and
inhibit the reabsorption of serotonin.
(serotonin is a chemical messenger
that carry signals between neurons)
• The first SSRI (Selective Serotonin
Reuptake Inhibitor) type of
antidepressent was made as a
derivative of chlorphenamine.
• Used most often to
treat hay fever or
urticaria (skin rash)

21. IUPAC: 2-[(E)-1-(4-methylphenyl)
-3- pyrrolidin-1-yl-prop-1-enyl]pyridine
• Used to alleviate the
symptoms associated with
allergies
• Can be combined with other
cold medicine to relieve
“flu-like” symptoms

22. 4. Cyclizines (Piperazines)
IUPAC:1-[(4-Chlorophenyl)(phenyl)
methyl]-4-methylpiperazine
• Structurally related to the
ethylenediamines and the ethanolamines
and thus produce significant anti-
cholinergic effects
• Used most often to treat motion sickness,
vertigo, nausea and vomiting
• This drug is used to treat
motion sickness
IUPAC: (RS)-1-[(4-chlorophenyl)
(phenyl)methyl]- 4-(3-
methylbenzyl)piperazine
• It is most commonly used to
inhibit nausea and vomiting as
well as vertigo, however it does
cause drowsiness.

23. IUPAC: (RS)-1-[(4-chlorophenyl)- phenyl-methyl]
-4- [(4-tert-butylphenyl) methyl] piperazine
• It is considered to be an antiemetic, similar to
meclizine.

24. 5. Tricyclics
• These drugs are structurally related to tricyclic
antidepressants.
• This drug has extremely strong
anticholinergic and sedative effects
• It was originally used as an antipsychotic,
however now it is most commonly used as
a sedative or antinausea drug (also severe
morning sickness) and requires a
prescription.

25. Cyproheptadine Azatadine
IUPAC: 4-(5H-dibenzo [a, d]cyclohepten-5- IUPAC: 11-(1-methylpiperidin-4-ylidene)-
ylidene) -1-methylpiperidine hydrochloride 6,11-dihydro- 5H-benzo[5,6]cyclohepta
[1,2-b]pyridine

26. Ketotifen
IUPAC: 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro
-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one

27. 6. Phenothiazine
IUPAC: N,N,2-trimethyl-3-phenothiazin-10-
yl-propan-1-amine
• This drug is used to treat itchiness and sn
rashes that results from allergies.
• Since it causes drowsiness, it is useful for
rashes that itch worse at night time.
• It is also used to sedate young children before
operations.

28. 7. Mast cell inhibitors
• These drugs prevent the release of histamine and other chemicals that cause
allergic symptoms from mast cells when an individual comes into contact with an
allergen like pollen grains (male macrogametophytes of seed plants).
• Cromolyn sodium (Nasalcrom), a mast cell inhibitor, is used to prevent allergic symptoms
like runny nose or itchy eyes.
• Cromolyn sodium must be started 1-2 weeks before pollen season and continued daily to
prevent seasonal allergy symptoms. The response is not as strong as that of corticosteroid
nasal sprays.
• Cromolyn sodium probably interferes with the antigen-stimulated calcium transport across
the mast cell membrane, thereby inhibiting mast cell release of histamine, leukotrienes, and
other substances that cause hypersensitivity reactions.
• Used in the Prophylaxis of asthma, allergic conjuctivitis and allergic rhinitis.
IUPAC: disodium;5-[3-(2-carboxylato-4-
oxochromen-5-yl)oxy-2hydroxypropoxy]
-4-oxochromene-2-carbox ylate

29. • Nedocromil sodium is a medication considered as mast cell stabilizer
which act to prevent wheezing, shortness of breath, and other breathing
problems caused by asthma.
• It is administered by an inhaler under the brand name Tilade (although
its effects in this form are far less than those in albuterol or other well-
known inhaler medications) and as an eye drop under the brand name
Alocril.
• Nedocromil sodium has been shown to be effective in alleviating
symptoms of allergic conjunctivitis.
IUPAC: disodium;9-ethyl-4,6-dioxo-
10-propylpyrano[3,2-g]quinoline-
2,8-dicarboxylate

30. • These are the newer drugs and they are much more selective for the
peripheral H1-receptors involved in allergies as opposed to the H1-
receptors in the CNS
• Therefore, these drugs provide the same relief with many fewer adverse
side effects.
• The structure of these drugs varies and there are no common structural
features associated with them.
• They are however bulkier and less lipophilic than the first generation
drugs, therefore they do not cross the BBB as readily.
• Recent studies have also showed that these drugs also have anti-
inflammatory activity and therefore, would be helpful in the
management of inflammation in allergic airways disease.

31. Acrivastine
IUPAC: (E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-
1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid
IUPAC: (±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxy]acetic acid
• This drug relieves itchy rashes.
• It is non-sedating because it does not cross
the BBB
• It is a second-generation antihistamine
used to treat allergic rhinitis, dermatitis,
and urticaria.
• Effects generally begin within an hour and
last for about a day.
• Cetirizine appears to have more CNS actions
(sedative) than loratadine.
• recommended that cetirizine not be used by
pilots.

32. Terfenadine
IUPAC: (RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxyl
(diphenyl)methyl]piperidin-1-yl}-butan-1-ol
IUPAC: 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)
ethyl]-4-piperidyl]benzoimidazol-2-amine
• This drug has a long duration of action
• It suppresses the formation of edema and
pruritus (itching)
• It doesn’t cross the BBB
• It has been taken off the market in most
countries because of adverse interactions
with erythromycin and grapefruit juice
due to effects on cardiac K+ channels.
• It was used to treat allergic conditions
• In the 1990’s it was removed from the
market due to the increased risk of
cardiac arrythmias

33. IUPAC: Ethyl4-(8-chloro-5,6-dihydro-11H- benzo
[5,6]Cyclohepta[1,2-b]pyridin-11-ylidene) -1-
piperidinecarboxylate
• It is the only drug of its class available over the
counter
• It has long lasting effects.
• Common side effects include sleepiness, dry
mouth, and headache.
• It is not recommended in children less than two
years old.
• The drug is available in many different forms,
including tablets, oral suspension, and syrup,
and in combination with pseudoephedrine.Also
available in quick-dissolving tablets, which are
marketed as being faster to get into one's
circulatory system.

34. IUPAC: (±)-4-[1 hydroxy-4-[4-(hydroxyl diphenylmethyl)-1-
piperidinyl]-butyl]-a, a-dimethyl benzene acetic acid hydrochloride
• These drugs are derived from second generation antihistamines
• They are either the active metabolite of the second generation
drug.
• they are designed to have increased efficacy and fewer side
effects.
• It was developed as an alternative to Terfenadine
• Fexofenadine was proven to be more effective and safe

35. Levocetrizine
IUPAC: 2-(2-{4-[(R)-(4-
chlorophenyl)(phenyl)
methyl]piperazin-1-
yl}ethoxy)acetic acid
• This drug is the active metabolite of cetrizine and it is more
effective and have fewer adverse side effects.
• Also it is not metabolized and is likely to be safer than other
drugs due to a lack of possible drug interactions.
• It does not cross the BBB and does not cause significant
drowsiness.
• It has been shown to reduce asthma attacks by 70% in
children.

36. • H2- antagonists (H2-Blockers) or histamine H2-receptor
antagonists were discovered many years later after H1
antagonists.
• The first drug released on the market was cimetidine
followed by ranitidine, famotidine and nizatidine.
• Histamine released from ECL cells then stimulates the acid-
making cells (parietal cells) in the lining of the stomach to
release acid.
• What H2 blockers do is stop the acid-making cells in the
stomach lining from responding to histamine. This reduces
the amount of acid produced by your stomach.
• By decreasing the amount of acid, H2 blockers can help to
reduce acid reflux-related symptoms such as heartburn. This
can also help to heal ulcers found in the stomach.

37. • Cimetidine is an extremely successful drug in the treatment of ulcers.
• It is a member of the class of guanidines that consists of guanidine
carrying a methyl substituent at position 1, a cyano group at position 2
and a 2-{[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl}ethyl group at
position 3.
• It is a H2-receptor antagonist that inhibits the production of acid in
stomach
• However, cimetidine has several disadvantages. It leads to many
drug–drug interactions.It exhibits anti-androgenic action and can cause
gynecomastia.
C
S
H
N
H
N
CH3
N
H3C
NH N N
IUPAC: 1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)
methylsulfanyl]ethyl]guanidine

38. NS
N
NH2
NH2
N
N
H
S
SO2NH2
H
Famotidine
• Famotidine, a thiazole derivative, is potent than
Ranitidine or Cimetidine.
• No cases of gynecomastia have been reported
• Famotidine is used to treat and prevent ulcers in the
stomach and intestines.
• It also treats conditions in which the stomach produces
too much acid, such as Zollinger-Ellison syndrome.
IUPAC: N'-(aminosulfonyl)-3-[({2-
[(diaminomethylidene)amino]
-1,3-thiazol-4-yl}methyl)sulfanyl]
propanimidamide

39. CH3
CH3
N
NO2
O
S
H
N
H
N
CH3
HC
Ranitidine
• It is a furan derivative, an isostere of the imidazole with n electrons on the
oxygen, with 50% bioavailability.
• It is potent than Cimetidine.
• The tertiary amine side chain allows the formation of salts.
• It works by reducing the amount of acid your stomach produces.
• Ranitidine was also used to treat gastroesophageal reflux disease (GERD)
and other conditions in which acid backs up from the stomach into the
esophagus, causing heartburn.
*Ranitidine

40. • An H3 receptor antagonist is a classification of drugs used to
block the action of histamine at the H3 receptor.
Thioperamide:
• The first imidazole-based antagonist that was developed was
thioperamide which was very potent and selective but was not
usable as a drug due to hepatotoxicity.
• It was originally designed to improve wakefulness.
• H3 antagonists leads to histamine release into the cerebrospinal
fluid which promotes wakefulness. Therefore, thioperamide have
been studied in the hope of treating narcolepsy.
IUPAC: N-cyclohexyl-4-(1H-imidazol-5-
yl)piperidine-1-carbothioamide