Generation of Antihistamine Drug.

Antihistamine

An antihistamine is a type of pharmaceutical drug that opposes the activity of histamine

receptors in the body. Antihistamines are sub classified according to the histamine receptor that
they act upon: the two largest classes of antihistamines are H1-antihistamines and H2antihistamines. Antihistamines that target the histamine H1-receptor are used to treat allergic
reactions in the nose (e.g., itching, runny nose, and sneezing) as well as for insomnia. They are
sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear.
Antihistamines that target the histamine H2-receptor are used to treat gastric acid conditions (e.g.,
peptic ulcers and acid reflux). H1-antihistamines work by binding to histamine H1 receptors in
mast cells, smooth muscle, and endothelium in the body as well as in the tuberomammillary
nucleus in the brain; H2-antihistamines bind to histamine H2 receptors in the upper
gastrointestinal tract, primarily in the stomach.

Fig: Histamine structure

Histamine receptors exhibit constitutive activity, so antihistamines can function as either a
neutral receptor antagonist or an inverse agonist at histamine receptor Only a few currently
marketed H1-antihistamines are known to function as inverse agonists
Histamine produced increases vascular permeability, causing fluid to escape from capillaries into
tissues, which leads to the classic symptoms of an allergic reaction a runny nose and watery
eyes. Histamine also promotes angiogenesis.
Antihistamines suppress the histamine-induced wheal response (swelling) and flare response
(vasodilation) by blocking the binding of histamine to its receptors or reducing histamine
receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium, and mast
cells.

Generation of Antihistamine Drug.

Itching, sneezing, and inflammatory responses are suppressed by antihistamines that act on H1receptors.[1][5] Recently, antihistamines such as desloratadine, have been shown to be effective as
adjuvants to standardized treatment of acne due to their anti-inflammatory properties and their
ability to suppress sebum production.

Figure: Antihistamine
X = N, R1 = R2 = small alkyl groups
X=C
X = CO
Chirality at X can increase both the potency and selectivity for H1-receptors
For maximum potency, the two aromatic rings should be orientated in different planes
Stereochemistry
While histamine is an achiral molecule, histamine receptors exert high stereo selectivity toward
chiral ligands. Molecular modeling and stericactivity relationship studies of the influence of
conformational isomerism suggest the importance of trans-gauche rotameric structures in the
receptor binding of histamine. Although both conformers exist in solution, studies with
conformational restricted histamine analogs suggest that the trans-rotamer of histamine
possesses affinity for both H1- and H2-receptors, and the gauche conformer is preferred for H3receptors, but not H1- or H2-receptors.

Generation of Antihistamine Drug.

Biosynthesis and Distribution
Histamine is synthesized in Golgi apparatus of its principal storage cells, mast cells, and
basophils.6 Histamine is formed from the naturally occurring amino acid L-hisitidne (S-histidine)
via the catalysis of either the pyridoxal phosphate dependent enzyme histidine decarboxylase
(HDC, EC 4.1.1.22) or L-aromatic amino acid decarboxylase (L-AAAD) Substrate specificity is
higher for HDC versus L-AAAD. HDC inhibitors (HDCIs) include -fluoromethylhistidine
(FMH), a mechanism-based inhibitor, and certain flavonoids.7 Although useful as pharmologic
probes, HDCIs have not proved to be useful clinically.
Mechanism of Action
It is now known that H1-antihistamines act as inverse agonists that combine with and stabilize
the inactive form of the H1-receptor, shifting the equilibrium toward the inactivestate. Thus, they
effectively antagonize the actions of histamine at H1-receptors. Historically, H1-antihistamines
have been evaluated in vitro in terms of their ability to inhibit histamine- induced spasms in an
isolated strip of guinea pigileum. Antihistamines may be evaluated in vivo in terms of their
ability to protect animals against the lethal effects of histamine administered intravenously or by
aerosol. To distinguish antagonism of histamine from other modes of action, the index pA is
applied in in vitro assays. The index pA2 is defined as the inverse of the logarithm of the molar
concentration of the antagonist that reduces the response of a double dose of the agonist to that
of a single one. The more potent H1-antihistamines exhibit a pA2 value significantly higher than
6. Although there are many pitfalls to be avoided in the interpretation of structureactivity
relationship (SAR) studies using pA2 values, the following example illustrates distinguishing
competitive antagonism. pA2 values for pyrilamine (mepyramine) antagonism range from 9.1 to
9.4 with human bronchi and guinea pig ileum.24,25 By contrast, the pA2 value in guinea pig
(H2-receptor) is 5.3. Thus, one may conclude that pyrilamine is a weak, noncompetitive inhibitor
of histamine at the H2-receptors and a competitive
inhibitor at H1-receptors. The structural features required for effective interaction of these
receptors are discussed next. Some H1-antihistamines can also block histamine release. The
concentrations, however, are considerably higher than those required to produce significant
histamine receptor blockade. The H1-antihistamines do not, however, block antibody production
or antigenantibody interactions.

Generation of Antihistamine Drug.

3 Types of Histamine Receptors
1. H1 receptors: mediate effects on smooth muscle leading to vasodilation, increased vascular
permeability, and contraction of nonvascular smooth muscle.
2. H2 receptors: mediate histamine stimulation of gastric acid secretion and may be involved in
cardiac stimulation.
3. H3 receptors: feedback inhibitors in CNS, gastrointestinal tract, lung, heart.
Types of Antihistamines
H 1-antihistamines
First Generation Drugs
These are the oldest H1-antihistaminergic drugs and are relatively inexpensive and widely
available. They are effective in the relief of allergic symptoms, but are typically moderately to
highly potent muscarinic acetylcholine receptor (anticholinergic) antagonists as well. These
agents also commonly have action at -adrenergic receptors and/or 5-HT receptors. This lack of
receptor selectivity is the basis of the poor tolerability profile of some of these agents, especially
when compared with the second-generation H1-antihistamines. Patient response and occurrence
of adverse drug reactions vary greatly between classes and between agents within classes.
1) ALKYLAMINES as H1 receptor Blockers
The aminoalkyl ether antihistamines are characterized bythe presence of a CHO connecting
moiety (X) and a two- orthree-carbon atom chain as the linking moiety between thekey diaryl
and tertiary amino groups. Most compoundsin this series are simple
N, N-dimethylethanolaminederivatives and are so classified in several texts. Clemastineand
diphenylpyraline differ from this basic structuralpattern.

Fig: General structure of the aminoalkyl ethers

Generation of Antihistamine Drug.

Brompheniramine
Chlorpheniramine
Dexchlorpheniramine
Triprolidine
2) ETHANOLAMINES as H1 receptor Blockers
Carbinoxamine
Clemastine
Dimenhydrinate
Diphenhydramine
Doxylamine
3)

ETHYLENEDIAMINES

as

H1

receptor

Blockers

The ethylenediamine antihistamines are characterized by the presence

of a nitrogen-connecting atom (X) and a two-carbon atom chain as the
linking moiety between the key diaryl and tertiary amino moieties. All
compounds in this series are simple diarylethylenediamines except
antazoline, in which the terminal amine and a portion of the carbon
chain are included as part of an imidazoline ring system. Because it
differs significantly in its pharmacological profile, antazoline is not
always classified as an ethylenediamine derivative.

Fig:General structure of the ethylenediamines

Tripelennamine
Pyrilamine
4) PHENOTHIAZINES as H1 receptor Blockers
Methdilazine

Generation of Antihistamine Drug.

Promethazine
Trimeprazine
5) PIPERAZINE as H1 receptor Blockers
The piperazines derivatives or cyclicethylenediaminesin this series, however, the connecting
moiety (X) is a CHN group, and the carbon chain, terminal amine functionality, and the nitrogen
atom of the connecting group are all part of a piperazine moiety. Both nitrogen atoms in these
compounds are aliphatic and thus display comparable basicities. The primary structural
differences within this series involve the nature of the para aromatic ring substituent (H or Cl)
and, more importantly, the nature of the terminal piperazine nitrogen substituent.

Fig: General structure of the piperazines

Cyclizine,hydroxyzine,meclizine
6) PIPERIDINES as H1 receptor Blockers
Azatidine
Cyproheptdine
Second Generation Drugs
Second generation H1-receptorantagonists called "non- sedating" because they cause less
sedation than their predecessors. These are the newer drugs and they are much more selective for
the peripheral H1-receptors involved in allergies as opposed to theH1-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

Generation of Antihistamine Drug.

cross the BBB (reason of non sedating name)as readily Recent studies have also showed that
these drugs also have anti-inflammatory activityand therefore, would be helpful in the
management of inflammation in allergic airways disease
Examples:Loratidine
Astemazole
Terfenadine
Cetirizine
Third Generation Drugs
Third generation H1-receptor antagonists These drugs are derived from second generation
antihistamines They are either the active enantiomer or metabolite of the second generation drug
designed to have increased efficacy and fewer side effects Levocetirizine (Zyzal).This drug is the
active enantiomer of cetirizine and is believed to be 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 (Tillement). It does not cross the BBB and does not cause significant
drowsiness it has been shown to reduce asthma attacks by 70% in children
Third generation H1-receptor antagonists Deslortadine (Clarinex) Fexofenadine (Allegra). It is
the active metabolite of Lortadine. Even though it is thought to be more effective, there is no
concrete evidence to prove this .It was developed as an alternative to Terfenadine .Fexofenadine
was proven to be more effective and safe
H2-antihistamines
H2-antihistaminesoccur 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

Generation of Antihistamine Drug.

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

Roxatidine

Tiotidine

H3-antihistamines
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 H1antihistamines which are sedating, H3-antihistamines have stimulant and cognition-modulating
effects.
Examples of selective H3-antihistamines include:

Clobenpropit

Ciproxifan

Generation of Antihistamine Drug.

Conessine

Thioperamide

H4-antihistamines
The major H4 antihistamine discovered is Thioperamide which is apotentHRH4 antagonist and
selectiveHRH3antagonist capable of crossing the bloodbrain barrier, It was used by JeanCharles Schwartz in his early experiments regarding the H3 receptor,Thioperamide was found to
be an antagonist of histamine autoreceptors, which negatively regulate the release of histamine,
and enhances the activity of histaminergic neurons by blocking autoreceptors, leading to greater
release of histamine. Other H4 antihistaminee.gis JNJ 7777120, VUF-6002 which are in
research stage.

Fig: Thioperamide
Drugs Used In Treatment
The older first-generation drugs are still widely used because they are effective and inexpensive.
However, most of these drugs penetrate the CNS and cause sedation. Furthermore, they tend to
interact with other receptors, producing a variety of unwanted adverse effects. By contrast, the
second-generation agents are specific for H1 receptors, and because they do not penetrate the

Generation of Antihistamine Drug.

blood-brain barrier, they show less CNS toxicity than the first-generation drugs. Among these
agents desloratadine, fexofenadine, and loratadine show the least sedation.
Drugs Used In Treatment Of Peptic Ulcer
Cimetidine,Ranitidine,Famotidine,Nizatidine
DRUGS USED TO TREAT MOTION SICKNESS
Diphenhydramine,dimenhydrinate,Cyclizine,Meclizine
DRUGS USED IN ALLERGIC DISORDERS
Loratidine,Fexofenadine
ANTIPARKINSONIAN DRUGS
Diphenhydramine, Orphenadrine
General Pharmacological and Therapeutic Considerations
The classical antihistamines have been used extensively for the symptomatic treatment
(sneezing, rhinorrhea, and itching of eyes, nose, and throat) of allergic rhinitis (hay fever,
pollinosis), chronic idiopathic urticaria, and several other histamine- related diseases.10 These
uses are clearly attributed to their ability to counter the action of histamine at peripheral
H1-receptors, which mediate the immune and inflammatory processes characteristic of these
pathologies. These drugs best relieve the symptoms of allergic diseases at the beginning
of the season when pollen counts are low. The antihistamines also reduce the number, size, and
duration of wheals and itching in chronic urticaria when used promptly. Most clinical evidence
suggests that there is no significant difference in therapeutic efficacy for first- and secondgeneration agents in the treatment of these conditions. The antihistamines have been widely used
to relieve the symptoms of asthma and upper respiratory infections including the common cold,
otitis media, and sinusitis. Most clinical evidence does not support such use unless asthma or
infection is accompanied by allergic inflammation. Also, the antihistamines should not be used
alone in analphylaxis, but may be used with epinephrine to relieve any H1-receptormediated
symptoms. As the aforementioned general pharmacological profiles suggests, many
antihistamines can interact with various neurotransmitter receptors and other biomacromolecular
targets. This is most evident among the first-generation agents, many of which function as
antagonists at muscarinic receptors and, to a lesser extent, adrenergic, serotonergic, and
dopamine receptors. The first-generation agents also tend to achieve and maintain higher levels
in the brain than the second- generation agents, resulting in CNS-based pharmacologic actions.10

Generation of Antihistamine Drug.

Although some of these nontarget-receptor interactions may have therapeutic value (as
discussed next), more frequently they are manifested as adverse reactions that limit drug use.
This is particularly true of the peripheral anticholinergic effects produced by these drugs and of
interactions with several neurotransmitter systems in the CNS that result in sedation, fatigue, and
dizziness. Several first-generation antihistamines, particularly the phenothiazines and aminoalkyl
ethers, have antiemetic actions and thus may be useful in the treatment of nausea and vomiting
and for vertigo and motion sickness.10,26,27 Several of the phenothiazines have limited use in
parkinsonism as a result of their ability to block central muscarinic receptors.10,26,27
Antihistamines, including promethazine, pyrilamine, tripelennamine, and diphenhydramine, also
display local anesthetic activity that may be therapeutically useful.32 Many of the firstgeneration antihistamines readily penetrate the blood-brain barrier (BBB) because of their
lipophilicity, and maintain significant CNS concentrations because they are not substrates for Pglycoprotein effluxs pump that are expressed on endothelial cells of the CNS vasculature. The
lack of affinity by P-glycoprotein efflux pumps appears to be directly related to the relatively low
molecular weight and small size of the first-generation antihistamines. 10,33 Blockade of central
H1-receptors results in sedation, an effect that has contributed to the historical use
of antihistamines as nonprescription sleep aids, as well as drugs for perioperative sedation.10
However, the sedative actions of antihistamines are undesired effects in the treatment
of allergy-based diseases. Furthermore, the blockade of central H1-receptors also results in
decreased cognitive and psychomotor performance, as well as increased appetite and weight
gain, all considered to be therapy-limiting adverse effects.
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 meclizine,
which has a half-life of 12 to 24 hours. H1-receptor blockers have high bioavailability and are
distributed in all tissues, including the CNS. All first-generation H1antihistamine and some
second-generation H1antihistamine, such as desloratadine and loratadine, are metabolized by the
hepatic cytochrome P450 system. Cetirizine is excreted largely unchanged in the urine, and
fexofenadine is excreted largely unchanged in the feces. After a single oral dose, the onset of
action occurs within 1 to 3 hours. The duration of action for many oral H1antihistamine is at

Generation of Antihistamine Drug.

least 24 hours, facilitating once-daily dosing. They are most effective when used prophylactically
before allergen exposure rather than as needed. Tolerance to the action of H1antihistaminehas
not been observed.

Uses
Although antihistamines can't cure these conditions, they often provide relief from symptoms.
For example, antihistamines may be used to treat:
hay fever
allergic rhinitis inflammation of the nose caused by an allergic reaction to substances
such as dust mites
allergic skin conditions, such as eczema or urticaria (hives)
allergic conjunctivitis inflammation of the eyes
allergic reactions caused by insect bites or stings
mild or moderate allergic reactions caused by food allergies more severe allergic
reactions (anaphylaxis) usually require emergency treatment with adrenaline
Antihistamines

also

have

number

of

other

uses,

ulcers, insomnia (problems falling asleep) and motion sickness.

Antihistamines are available as
tablet or capsules (oral antihistamines)
creams, lotions and gels (topical antihistamines)
a nasal spray

such

as

treating

stomach

Generation of Antihistamine Drug.

Many antihistamines are available over the counter at a pharmacy, although some require a
prescription.
Side-Effects
Common side effects of first-generation antihistamines include:

drowsiness
impaired thinking
dry mouth
dizziness
constipation
blurred vision
an inability to fully empty the bladder (urinary retention)

It's important not to underestimate the effects of antihistamine-related drowsiness. Some firstgeneration antihistamines can impair co-ordination, reaction times and judgment in the same way
that alcohol consumption can. Therefore you shouldn't drive or use power tools or heavy
machinery after taking a first-generation antihistamine.
Less common side effects of first-generation antihistamines include:

insomnia (difficulty sleeping)

nightmares
hallucinations (seeing or hearing things that aren't real)
itchy skin

Rare side effects of first-generation antihistamines include:

rapid heartbeat
chest tightness
Second- or third-generation antihistamines
Second- or third-generation antihistamines are less likely to cause drowsiness. If you find
yourself feeling drowsy, don't drive, drink alcohol, or use tools or machines.

Generation of Antihistamine Drug.

Other side effects of second- or third-generation antihistamines include:
headache
dry mouth
dry nose
feeling sick
These side effects don't usually last long and should pass quickly.
Rarer side effects include:
rapid heartbeat
chest tightness
However, second- and third-generation antihistamines have been found to have less risk of heart
problems than first-generation antihistamines.
\

Reference
Organic Medicinal and PharmaceuticalChemistry
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(2015), Available from: http://www.nhs.uk/conditions/Antihistamines/Pages/Introduction.aspx
Clinical

and

Experimental

Allergy

Review,

(2005),

Available

from:

http://

www.netdoctor.co.uk/medicines/100002712.html, 5, 7-11
Nettis, E; Colanardi, MC; Barra, L; Ferrannini, A; Vacca, A; Tursi, A (2006). "Levocetirizine in
the treatment of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled
study". The British journal of dermatology. 154 (3): 5338
Rio, J. (2006). New antihistamines: a critical view, Available from:
http://www.scielo.br/scielo.php?pid=S0021-75572006000700007&script=sci_arttext&tlng=en

Generation of Antihistamine Drug.