ANTIHISTAMINIC AGENTS
1.1.1. Introduction
Histamine, a biologically active substance potentiates the inflammatory and
immune responses of the body. It also regulates the physiological functions in the
gut, and behaves as neurotransmitter. Anti-histaminic agents (or histamine
antagonists) are the drugs that antagonise the action of histamine. On the basis
of the type of H receptor targeted, antihistamines are divided into:
1) H1-Antihistamines: They are used for treating allergic
reactions and disorders mediated by mast cells. H1-antihistamines are subdivided into two generations. The first generation H1-antihistamines have a
central effect so are used as sedatives. The second generation H1-
antihistamines have low central effects so are used as anti-allergenic drugs.
2) H2-Antihistamines: They can reduce the production of stomach acid by
reversibly blocking the H2-histamine receptors found in the parietal cells of
gastric mucosa; thus, they are used in gastric reflux diseases.
The pregnant women and children should avoid using most H1- and H2-
antihistamines. First-generation H1-antihistamines are contraindicated in patients
having angle-closure glaucoma and pyloric stenosis.
1.1.2. Histamine
Histamines are nitrogen containing organic compounds belonging to the group of
amines. Histamines are produced in almost all the cells (present in an animal)
during a local immune response. They regulate various physiological functions of
the gut. In addition, histamines have also be en known to play a role in
neurotransmission. Release of histamines is the initiating factor of any
inflammatory response.
Histamines are synthesised and released by basophils and mast cells (found in the
nearby connective tissues) on stimulation (as a part of an immune response
against foreign pathogens). They cause increased vascular (capillary)
permeability for WBCs and other proteins to facilitate adequate invasion of
foreign bodies within the tissues.
1.1.3. Histamine Receptors and their Distribution in the
Human Body
The biological effects produced by histamine are mediated through histaminergic
receptors (H1, H2 and H3 types). Histamine was identified and anti-histamines (H1
blockers) were synthesised in the beginning of this century. Since then i t was
known that these anti-histamines cannot block all the histamine actions.
H4 receptors are linked to the pathology of allergy and asthma; and regulate the
changes in cellular shape, chemotaxis, and up -regulation of adhesi on molecules
(CD11b/CD18 and ICAM, P -selectin). H 4-receptors present on haematopoietic
cells (neutrophils and eosinophils) have been recognised lately.
1.1.4. Classification of Antihistaminic Agents
Following are the three types of histamine receptor antagonists:
1) H1-Antagonists: These are classical antihistamines blocking the
physiological effects of histamine and used in allergic disorders.
2) H2-Antagonists: Cimetidine, Ranitidine, and Famotidine are H 2-antagonists
reducing gastric HCl secretion and used in peptic ulcer diseases.
3) H3-Antagonists: Thioperamide is an H 3-antagonist regulating histamine
release from histaminergic neurons of CNS by presynap tic auto -regulatory
mechanism. It is not recommended to be used therapeutically.
1.1.5. Mechanism of Action
Histamine binds with the histaminergic receptors (H 1, H 2, and H 3) after being
released by the mast cells. This binding stimulates a series of events that facilitate
the characteristic responses by second messenger systems. The histaminergic
receptors are G -protein coupled type. Thus, the H1-receptors are coupled to
phospholipase-C and on activation they form inositol phosphate (Ip 3) and
diacylglycerol (DAG) from the cell membrane phospholipids.
Ca2+ ions are rapidly released from endoplasmic reticulum under the influence of
Ip3.
Protein kinase C is activated by DAG. Thus, the turnover of Ca 2+ ions and
protein kinase C stimulates the Ca2+/calmodulin dependent protein kinase and
phospholipase A 2. The anti -histaminergic (H 1-antagonist) binds to the H 1-
receptors and decreases the production of phospholipase-C and their activation to
form IP3 and DAG. Therefore, it inhibits the characteristic response of histamine.
Histamine forms cAMP-dependent protein kinase (also known as cyclic AMP or
3-5-cyclic adenosine monophosphate) on H2-receptors for producing a response
in the GIT. The H 2-antagonist and the H 2-receptors bind reversibly and this
decreases cAMP formation. Subsequently, the proton pump is activated and the
formation of gastric acid in the GIT decreases.
H3-receptors are a lso G-protein coupled receptors .
They decrease the Ca2+ ions
influx. H 3-receptors act as feedback inhibitors for histamine a nd other
neurotransmitters as they reduce calcium influx in the cells in CNS, decrease
gastrin secretion in the GIT, and down-stimulates histamine by auto-regulatory
effects. These effects are antagonised by blocking the H3-receptors, whereas the
clinical extendibility is narrow for H3.
1.1.6. Uses
Following are the therapeutic uses of antihistaminic agents:
1) They have same efficacy when used in suitable doses.
2) The H2-blockers are used for reducing gastric acid secretion.
3) Sometimes other types of therapy are similarly effective, still the H2-blockers
are chosen due to suitability and good patient acceptability.
1.1.7. Structure-Activity Relationship
H1-Receptor Antagonists
1) Aryl Groups: Diaryl substitution is required for H 1 affinity, and is found in
first-generation and second -generation antihistamines. The co -planarity of
two aryl substitutions influences the optimal antihistaminic activity. Active
aryl substitutions are as follows:
i) Ar is phenyl and hetero aryl group (like 2-pyridyl).
ii) Ar1
is aryl or aryl methyl group.
2) Nature of X: Antihistamines with X = carbon (pheniramine series ) signifies
the stereo selective receptor binding to the receptors because of its chirality.
The active substitutions of X are as follows:
i) X = Oxygen (amino alkyl ether analogue)
ii) X = Nitrogen (ethylene-diamine derivative)
iii) X = Carbon (mono amino propyl analogue)
3) Alkyl Chain: Mostly antihistamines have ethylene chain, t he b ranching of
which forms a less active compound.
This general chain is present in all the antihistamines.
4) Terminal Nitrogen Atom: The nitrogen atom at the terminal should be a
tertiary amine for maximum activity. The terminal nitrogen can be the part of
heterocyclic ring, for example , antazoline and chlorcyclizine have a high
antihistaminic activity. The am ino moiety on interaction with H 1-receptor
shows protonation due to basicity with pka 8.5-10.
H2-Receptor Antagonists
H2-blockers are not like H 1-blockers that are typically lipophilic amines. Instead,
they are very polar in nature ( e.g., cimetidine). H 2-blockers also have longer
uncharged side chains non -related to the protonated dialkylaminoalkyl side
chains present in H 1-blockers. The imidazole ring in H 2-blocker structure is
important for the identification of the receptor.
1) Imidazole Ring Substitutions : The imidazole ring is found in two
tautomeric forms as shown below. The first form (I) is important for maximal
H2-antagonistic activity. Mostly, the activity is potentiated when R is a –CH3
group
2) Chain: Four carbon atoms chain is best for the activity of H2-blockers. The
antagonist activity is extremely reduced in case of a shorter chain. The chain
should have an electron withdrawing substituent. An isosteric thioether
(─S─) link at the place of methylene group (─CH2─) gives more active
compounds.
3) Terminal Nitrogen Group: To achieve maximal antagonist activity t he
terminal N -group should be a polar, non -basic substituent. A positively
charged group binds more firmly to the receptor and this exerts an agonist
activity (and not an antagonist activity).
1.1.8. Recent Developments
The effect of first generation sedating H 1-antihistamines i n humans has never
been investigated. But, most of the second -generation non -sedating H 1-
antihistamines are well investigated. The H1-antihistamines are widely used in
the treatment of allergic rhinitis, allergic conjunctivitis, and chronic urticaria. The
second generation H1-antihistamines produce comparatively less CNS and
cardiac toxicity if taken in standard doses and even in overdose.
Screening and structural modification of the pre -existing second generation H1
antihistamines have led to the identification of many new medications of the
same class. For example, cetirizine is a metabolite of hydroxyzine, levocetirizine
is the active R -enantiomer of cetirizine, desloratadine is a metabolite of
loratadine, and fexofenadine is a metabolite of terfenadine.
New H1-antihistamines continue to be developed and introduced for clinical use;
however, they should be inspected carefully as they may or may n ot exhibit
clinically important features as compared to the existing second generation H1-
antihistamines. Till date, no second generation H1-antihistamine is found to have
efficacy superior to the others, though some are safer.
The terms third generation, new generation, or next generation are used to
market certain new H 1-antihistamines. But, clinically advantageous H 1-
antihistamines should be designated by these terms. Some of these medications
also have the intrinsic ab ility to down -regulate histamine a t H 2-, H 3-, or H 4-
receptors or to down-regulate leukotrienes or cytokines.
Without the discussion of histamine -globulin injection , any discussion on
histamine is incomplete. There are no double-blind placebo-controlled, published
studies on this formulati on, however , it is generally prescribed in India. This
combination should be banned
1.2. H1-ANTAGONISTS
1.2.1. Introduction
Until the discovery of H 1-receptors, no other histamine receptors had been
identified. The H1-antagonists, termed as antihistamines cause a co mpetitive
inhibition of only H1-receptors (they do not block any other histamine receptors).
Adrenaline is a physio logical antagonist of histamine. It acts via adrenergic
receptors and reverses the bronchodila tion and vasoconstriction effects of
histamine. Cromolyn sodium and corticosteroids block h istamine release from
mast cells. The H1-receptor antagonists are employed in the treatment of allergic
disorders.
The action of histamines on H 1-receptors is blocked by antihistamines (H 1-
blockers) categorised into first and second generations. The first generation
antihistamines bind to the central and peripheral H 1-receptors, while the second
generation antihistamines bind to the peripheral H1-receptors.
Though the sedative effects of second generation antih istamines are lesser as
compared to the first generation antihistamines, still they are beneficial for the
treatment of allergies.
1.2.2. Study of Individual Drugs
The following H1-antagonists are discussed below:
1) Diphenhydramine hydrochloride,
2) Dimenhydrinate,
3) Doxylamine succinate,
4) Clemastine fumarate,
5) Diphenylpyraline hydrochloride,
6) Tripelennamine hydrochloride,
7) Chlorcyclizine hydrochloride,
8) Meclizine hydrochloride,
9) Buclizine hydrochloride,
10) Chlorpheniramine maleate,
11) Triprolidine hydrochloride,
12) Phenindamine tartrate,
13) Promethazine hydrochloride,
14) Trimeprazine tartrate,
15) Cyproheptadine hydrochloride,
16) Azatadine maleate,
17) Astemizole,
18) Loratadine,
19) Cetirizine,
20) Levocetirizine, and
21) Cromolyn sodium.
1.2.2.1. Diphenhydramine Hydrochloride
Diphenhydramine is a first generation antihistamine which is mainly used for
treating seasonal allergies. But it also exhibits antiemetic, anti -Parkinson,
antitussive, and hypnotic properties.
Synthesis
Firstly, diphenylmethane undergoes bromination in the presence of light to form
diphenylbromomethane. Then, diphenylbromomethane, -dimethyl-aminoethanol, and sodium carbonate are heated in the presence of toluene to obtain
diphenhydramine base. The purified diphenhydramine after distilling-off toluene
converts into its hydrochloride form with hydrogen chloride.
Mechanism of Action
Diphenhydramine works through the antagonism of H 1-receptors found on the
respiratory smooth muscles, vascular endothelial cells, GIT, cardiac tissue,
immune cells, uterus, and CNS neurons. On stimulating the H1-receptors in these
tissues, they increase vascular permeability, stimulate vasodilation that leads to
flushing, decrease the conduction time of atrioventricular (AV) node , stimulate
the sensory nerves of a irways that leads to coughing, contract the smooth
muscles of bronchi and GIT, and cause eosinophilic chemotaxis that enhances the
allergic immune response. Diphenhydramine functions as an inverse agonist at
H1-receptors, and then it converses the histamine effects on capillaries, and
decreases the symptoms of allergic reaction
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