ANTIHISTAMINE

H
1
antagonist
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate
effects mediated by histamine, an endogenous chemical mediator released during allergic
reactions. Agents where the main therapeutic effect is mediated by negative modulation of
histamine receptors are termed antihistamines - other agents may have antihistaminergic action
but are not true antihistamines.
In common use, the term "antihistamine" refers only to H1 antagonists, also known as H1-receptor
antagonists and H1-antihistamines. It has been discovered that these H1-antihistamines are
actually inverse agonists at the histamine H1-receptor, rather than antagonists per se.
1!
Pharmacology
In allergic reactions, an allergen "a type of antigen# interacts with and cross-links surface Ig$
antibodies on mast cells and basophils. %nce the mast cell-antibody-antigen comple& is formed, a
comple& series of events occurs that eventually leads to cell degranulation and the release of
histamine "and other chemical mediators# from the mast cell or basophil. %nce released,
histamine can react with local or widespread tissues through histamine receptors.
Histamine, acting on H1-receptors, produces pruritus, vasodilation, hypotension, flushing,
headache, tachycardia, bronchoconstriction, increase in vascular permeability, potentiation of
pain, and more.
'!
(hile H1-antihistamines help against these effects, they work only if taken before contact with
the allergen. In severe allergies, such as anaphyla&is or angioedema, these effects may be so
severe as to be life-threatening. Additional administration of epinephrine, often in the form of an
autoin)ector "$pi-pen#, is re*uired by people with such hypersensitivities.
Clinical use of H1-antihistamines
Indications
H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions.
+pecifically, these indications may include,
-!
Allergic rhinitis
Allergic con)unctivitis
Allergic dermatological conditions "contact dermatitis#
.rticaria
Angioedema
/iarrhea
0ruritus "atopic dermatitis, insect bites#
Anaphylactic or anaphylactoid reactions - ad)unct only
1ausea and vomiting "first-generation H1-antihistamines#
+edation "first-generation H1-antihistamines#
H1-antihistamines can be administered topically "through the skin, nose, or eyes# or systemically,
based on the nature of the allergic condition.
2he authors of the American 3ollege of 3hest 0hysicians .pdates on 3ough 4uidelines "'556#
recommend that, for cough associated with the common cold, first-generation antihistamine-
decongestants are more effective than newer, non-sedating antihistamines. 7irst-generation
antihistamines include diphenhydramine "8enadryl#9 carbino&amine "3listin#9 clemastine
"2avist#9 chlorpheniramine "3hlor-2rimeton# and brompheniramine "/imetane#. However, it is
important to note that a 1:;; study of "antihistaminic drugs for colds," carried out by the ..+.
Army <edical 3orps, reported that "there was no significant difference in the proportion of cures
reported by patients receiving oral antihistaminic drugs and those receiving oral placebos.
7urthermore, essentially the same proportion of patients reported no benefit from either type of
treatment."
=!
Adverse drug reactions
Adverse drug reactions are most commonly associated with the first-generation H1-
antihistamines. 2his is due to their relative lack of selectivity for the H1-receptor.
2he most common adverse effect is sedation9 this "side-effect" is utili>ed in many %23 sleeping-
aid preparations. %ther common adverse effects in first-generation H1-antihistamines include
di>>iness, tinnitus, blurred vision, euphoria, uncoordination, an&iety, insomnia, tremor, nausea
and vomiting, constipation, diarrhea, dry mouth, and dry cough. Infre*uent adverse effects
include urinary retention, palpitations, hypotension, headache, hallucination, and psychosis.
-!
2he newer second-generation H1-antihistamines are far more selective for peripheral histamine
H1-receptors and have a far improved tolerability profile compared to the first-generation agents.
2he most common adverse effects noted for second-generation agents include drowsiness,
fatigue, headache, nausea and dry mouth.
-!
irst-generation !non-selective" classical#
2hese are the oldest H1-antihistaminergic drugs and are relatively ine&pensive and widely
available. 2hey are effective in the relief of allergic symptoms, but are typically moderately to
highly-potent muscarinic acetylcholine receptor-antagonists "anticholinergic# agents as well.
2hese agents also commonly have action at ?-adrenergic receptors and@or ;-H2 receptors. 2his
lack of receptor-selectivity is the basis of the poor tolerability-profile of some of these agents,
especially compared with the second-generation H1-antihistamines. 0atient response and
occurrence of adverse drug reactions vary greatly between classes and between agents within
classes.
Classes
2he first H1-antihistamine discovered was pipero&an, by $rnest 7ourneau and /aniel 8ovet
"1:--# in their efforts to develop a guinea pig animal-model for anaphyla&is at Institut 0asteur
"0aris, 7rance#.
;!
8ovet went on to win the 1:;A 1obel 0ri>e in 0hysiology or <edicine for his
contribution. 7ollowing their discovery, the first-generation H1-antihistamines were developed in
the following decades. 2hey can be classified on the basis of chemical structure, and agents
within these groups have similar properties.
Class $escri%tion E&am%les
$thylenediamines
$thylenediamines were the first group of
clinically-effective H1-antihistamines
developed.
<epyramine
"pyrilamine#
Anta>oline
$thanolamines
/iphenhydramine was the prototypical agent
in this group. +ignificant anticholinergic
adverse effects, as well as sedation, are
observed in this group but the incidence of
gastrointestinal adverse effects is relatively
low.
-!

6!
/iphenhydramine
3arbino&amine
/o&ylamine
3lemastine
/imenhydrinate
Alkylamines
2he isomerism is a significant factor in the
activity of the agents in this group. E-
triprolidine, for e&ample, is 1555-fold more
potent than Z-triprolidine. 2his difference
relates to the positioning and fit of the
molecules in the histamine H1-receptor
binding site.
6!
Alkylamines are considered to
have relatively fewer sedative and
gastrointestinal adverse effects, but relatively
greater incidence of parado&ical 31+
stimulation.
-!
0heniramine
3hlorphenamine
"chlorpheniramine#
/e&chlorpheniramine
8rompheniramine
2riprolidine
0ipera>ines
2hese compounds are structurally-related to
the ethylenediamines and the ethanolamines,
and produce significant anticholinergic
adverse effects. 3ompounds from this group
are often used for motion sickness, vertigo,
nausea, and vomiting. 2he second-generation
H1-antihistamine cetiri>ine also belongs to this
chemical group.
6!
3ycli>ine
3hlorcycli>ine
Hydro&y>ine
<ecli>ine
2ricyclics and
2etracyclics
2hese compounds differ from the
phenothia>ine antipsychotics in the ring-
substitution and chain characteristics. "1elson,
'55'# 2hey are also structurally-related to the
tricyclic antidepressants "and tetracyclics#,
e&plaining the H1-antihistaminergic adverse
effects of those three drug classes and also the
poor tolerability profile of tricyclic H1-
antihistamines. 2he second-generation H1-
antihistamine loratadine was derived from
compounds in this group.
0rometha>ine
Alimema>ine
"trimepra>ine#
3yproheptadine
A>atadine
Betotifen
Common structural features
2wo aromatic rings, connected to a central carbon, nitrogen or 3%
+pacer between the central C and the amine, usually '-- carbons in length, linear, ring,
branched, saturated or unsaturated
Amine is substituted with small alkyl groups, e.g., 3H-
' ( N" )1 ( )* ( small al+yl grou%s
' ( C
' ( C,
3hirality at C can increase both the potency and selectivity for H1-receptors
7or ma&imum potency, the two aromatic rings should be orientated in different planes
o for e&ample, tricyclic ring system is slightly puckered and the two aromatic rings
lie in different geometrical planes, giving the drug a very high potency.
Second-generation and third-generation !selective" non-sedating#
Second-generation
+econd generation H1-antihistamines are newer drugs that are much more selective for peripheral
H1 receptors in preference to the central nervous system histaminergic and cholinergic receptors.
2his selectivity significantly reduces the occurrence of adverse drug reactions compared with
first-generation agents, while still providing effective relief of allergic conditions.
+ystemic,
Acrivastine
Astemi>ole
3etiri>ine
Doratadine
<i>olastine
2erfenadine
2opical,
A>elastine
Devocabastine
%lopatadine
Third-generation
2hird-generation H1-antihistamines are the active enantiomer "levocetiri>ine# or metabolite
"desloratadine E fe&ofenadine# derivatives of second-generation drugs intended to have increased
efficacy with fewer adverse drug reactions. Indeed, fe&ofenadine is associated with a decreased
risk of cardiac arrhythmia compared to terfenadine. However, there is little evidence for any
advantage of levocetiri>ine or desloratadine, compared to cetiri>ine or loratadine, respectively.
2here is some controversy associated with the use of this term.
A!
+ystemic,
Devocetiri>ine
F!

/esloratadine
:!

7e&ofenadine
15!

H
*
antagonist
8all-and-stick model of cimetidine, the prototypical H'-receptor antagonist.
2he H*-rece%tor antagonists "H'GA, often shortened to H* antagonist# are a class of drugs used
to block the action of histamine on parietal cells in the stomach, decreasing the production of acid
by these cells. H' antagonist are used in the treatment of dyspepsia, although they have largely
been surpassed in popularity by the more effective proton pump inhibitors. In the .nited +tates,
all four 7/A-approved members of the groupHcimetidine, ranitidine, famotidine, and ni>atidine
Hare available over the counter in relatively low doses.
2he prototypical H' antagonist was cimetidine, developed by +mith, Bline E 7rench "now
4la&o+mithBline# in the mid-to-late 1:65s and first marketed in 1:A69 sold under the trade name
2agamet, cimetidine would later become the first ever blockbuster drug. 2he use of *uantitative
structure-activity relationships "I+AG# led to the development of other agentsHstarting with
ranitidine, first sold as JantacHwhich has fewer adverse effects and drug interactions and is
more potent.
History and develo%ment
3imetidine was the prototypical histamine H'-receptor antagonist from which the later members
of the class were developed. 3imetidine was the culmination of a pro)ect at +mith, Bline E
7rench "+BE79 now 4la&o+mithBline# by Kames (. 8lack, 3. Gobin 4anellin, and others to
develop a histamine receptor antagonist that would suppress stomach acid secretion.
In 1:6= it was known that histamine stimulated the secretion of stomach acid, but also that
traditional antihistamines had no effect on acid production. 7rom these facts the +BE7 scientists
postulated the e&istence of two histamine receptors. 2hey designated the one acted on by the
traditional antihistamines H1, and the one acted on by histamine to stimulate the secretion of
stomach acid H'.
2he +BE7 team used a rational drug design process starting from the structure of histamine.
Hundreds of modified compounds were synthesised in an effort to develop a model of the then-
unknown H' receptor. 2he first breakthrough was N

-guanylhistamine, a partial H'-receptor

antagonist. 7rom this lead the receptor model was further refined and eventually led to the
development of burimamide, a specific competitive antagonist at the H' receptor 155-times more
potent than N

-guanylhistamine, proving the e&istence of the H' receptor.

8urimamide was still insufficiently potent for oral administration and further modification of the
structure, based on modifying the pBa of the compound, led to the development of metiamide.
<etiamide was an effective agent9 however, it was associated with unacceptable nephroto&icity
and agranulocytosis. It was proposed that the to&icity arose from the thiourea group, and similar
guanidine analogues were investigated until the discovery of cimetidine, which would become the
first clinically successful H' antagonist.
Ganitidine "common brand name Jantac# was developed by 4la&o "also now 4la&o+mithBline#
in an effort to match the success of +mith, Bline E 7rench with cimetidine. Ganitidine was also
the result of a rational drug design process utilising the by-then-fairly-refined model of the
histamine H' receptor and *uantitative structure-activity relationships "I+AG#.
4la&o refined the model further by replacing the imida>ole-ring of cimetidine with a furan-ring
with a nitrogen-containing substituent, and in doing so developed ranitidine. Ganitidine was
found to have a far-improved tolerability profile "i.e. fewer adverse drug reactions#, longer-lasting
action, and ten times the activity of cimetidine.
Ganitidine was introduced in 1:F1 and was the worldLs biggest-selling prescription drug by 1:FF.
2he H'-receptor antagonists have since largely been superseded by the even more effective proton
pump inhibitors, with omepra>ole becoming the biggest-selling drug for many years.
Pharmacology
2he H' antagonists are competitive antagonists of histamine at the parietal cell H' receptor. 2hey
suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid.
2hey accomplish this by two mechanisms, histamine released by $3D cells in the stomach is
blocked from binding on parietal cell H' receptors which stimulate acid secretion, and other
substances that promote acid secretion "such as gastrin and acetylcholine# have a reduced effect
on parietal cells when the H' receptors are blocked.
Dike the H1-antihistamines, the H' antagonists are inverse agonists rather than true receptor
antagonists.
Clinical use
H'-antagonists are clinically used in the treatment of acid-related 4astrointestinal conditions.
+pecifically, these indications may include,
1!
0eptic ulcer disease "0./#
4astroesophageal reflu& disease "4$G/@4%G/#
/yspepsia
0revention of stress ulcer "a specific indication of ranitidine#
0eople that suffer from heartburn infre*uently may take either antacids or H'-receptor antagonists
for treatment. 2he H'-antagonists offer several advantages over antacids, including longer
duration of action "6M15 hours vs 1M' hours for antacids#, greater efficacy, and ability to be used
prophylactically before meals to reduce the chance of heartburn occurring. 0roton pump
inhibitors, however, are the preferred treatment for erosive esophagitis since they have been
shown to promote healing better than H'-antagonists.
+ome studies suggest that H'-antagonists might be effective in treating herpes viruses, such as
shingles and herpes simple& 1!.
Adverse effects
2he H' antagonists are generally well-tolerated, e&cept for cimetidine where all of the following
adverse drug reactions "A/Gs# are common. Infre*uent A/Gs include hypotension. Gare A/Gs
include, headache, tiredness, di>>iness, confusion, diarrhea, constipation, and rash.
1!
Additionally,
cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are
reversible upon discontinuation.
In a longitudinal study of elderly African Americans published in '55A, long-term use of H'
blockers appeared to increase the risk of cognitive decline.
'!
$rug interactions
+keletal formula of famotidine. .nlike cimetidine, famotidine has no significant interactions with
other drugs.
(ith regard to pharmacokinetics, cimetidine in particular interferes with some of the bodyLs
mechanisms of drug metabolism and elimination through the liver cytochrome 0=;5 pathway.
+pecifically, cimetidine is an inhibitor of the 0=;5 en>ymes 3N01A', 3N0'3:, 3N0'31:,
3N0'/6, 3N0'$1, and 3N0-A=. 8y reducing the metabolism of drugs through these en>ymes,
cimetidine may increase their serum concentrations to to&ic levels. <any drugs are affected,
including warfarin, theophylline, phenytoin, lidocaine, *uinidine, propranolol, labetalol,
metoprolol, tricyclic antidepressants, some ben>odia>epines, dihydropyridine calcium channel
blockers, sulfonylureas, metronida>ole,
-!
and some recreational drugs such as ethanol and
</<A.
2he more recently developed H'-receptor antagonists are less likely to alter 3N0 metabolism.
Ganitidine is not as potent a 3N0 inhibitor as cimetidine, although it still shares several of the
latterLs interactions "such as with warfarin, theophylline, phenytoin, metoprolol, and mida>olam#.
=!
7amotidine has negligible effect on the 3N0 system, and appears to have no significant
interactions.
-!
H
-
antagonist
An H--rece%tor antagonist is a classification of drugs used to block the action of histamine on
the Histamine H- receptor. .nlike the H1 and H' receptors which have primarily peripheral
actions, but cause sedation if they are blocked in the brain, H- 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 e&citatory
neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the
cerebral corte&. 3onse*uently unlike the H1 antagonist antihistamines which are sedating, H-
antagonists have stimulant and nootropic effects, and are being researched as potential drugs for
the treatment of neurodegenerative conditions such as Al>heimerLs disease.
$&amples of selective H- antagonists include clobenpropit,
1!
A82-'-:,
'!
cipro&ifan,
-!
and A-
-=:,F'1.
=!
H
.
-rece%tor antagonists
$&amples,
2hioperamide
K1K AAAA1'5
O.7-655'
H=-antagonists appear to have an immunomodulatory role and are being investigated as
antiinflammatory and analgesic drugs.
H1
1st gen
!non-selective"
classical#
Al+ylamines
8epotastine P 8amipine P 8rompheniramine P
3hlorpheniramine P /eschlorpheniramine P
/e&brompheniramine P /e&chlorpheniramine P
/imetindene P 7luorpheniramine P
Iodopheniramine P Iproheptine P 0heniramine P
0yrrobutamine P 2alastine P 2henalidine P
2olpropamine P 2riprolidine
Ethanolamines
!Aminoal+yl ethers#
8roma>ine@8romodiphenhydramine P
3arbino&amine P 3hlordiphenhydramine P
3hlorpheno&amine P 3lemastine P
/iphenylpyraline P /iphenhydramine P
/o&ylamine P $mbramine P
7luordiphenhydramine P Iododiphenhydramine
P p-<ethyldiphenhydramine P <o&astine P
%rphenadrine P 0henyltolo&amine P +etastine
Ethylenediamines
3hloropyramine P 3hlorothen P Histapyrrodine P
<ethafurylene P <epyramine P <ethapyrilene P
0yrilamine P 2alastine P 2henyldiamine P
2hon>ylamine P 2ripelennamine
"0yriben>amine#
Phenothia/ine Tricyclics
Ahistan P $tymema>ine P
Hydro&yethylprometha>ine P Isoprometha>ine P
Isothipendyl P <e*uita>ine P <ethdila>ine P
%&omema>ine P 0rometha>ine P 2hia>inamium
,ther Tricyclics
A>atadine P 3loben>epam P 3yproheptadine P
/eptropine P Isothipendyl
Pi%era/ine
8ucli>ine P 3hlorcycli>ine P 3innari>ine P
3locini>ine P Hydro&y>ine P 1iapra>ine P
%&atomide P 8en>hydryl compounds "3ycli>ine,
<ecli>ine#
*nd gen
Al+ylamineAcrivastine
Tricyclic%lopatadine
Pi%era/ine3etiri>ine
0en/hydryl2erfenadine
,ther1
ungrou%ed
Anta>oline P Astemi>ole P A>atadine P A>elastine P 8amipine P
3lemi>ole P 3loben>tropine P /eptropine P /imebon P
$bastine P $medastine P $pinastine P Betotifen P
Devocabastine P Doratadine P <ebhydrolin P <i>olastine P
0henindamine P 0imethi&ene P 0yrrobutamine P Gupatadine P
2henalidine P 2rito*ualine
-rd genDevocetiri>ine P /esloratadine P 7e&ofenadine
H* 3imetidine P 7amotidine P Ganitidine P Go&atidine P Dafutidine P 1iperotidine P 1i>atidine
H-
A--=:,F'1 P A-='-,;A: P A82-'-: P 87-'6=: P 8urimamide P 3ipro&ifan P 3lobenpropit P
3onessine P 4+B-1F:,';= P Impentamine P Iodophenpropit P K1K ;'5AF;' P <B-5'=: P
113 -F-15=: P +3H-A:6FA P 2hioperamide P O.7-;6F1
H. K1K AAAA1'5 P 2hioperamide P O.7-655'
Ma2or drug grou%s
3astrointestinal tract1meta4olism !A# stomach acid "Antacids, H* antagonists, 0roton pump
inhibitors# P Antiemetics P Da&atives P
Antidiarrhoeals@Antipropulsives P Anti-obesity drugs P Anti-
diabetics P Oitamins P /ietary minerals
0lood and 4lood forming organs !0#
Antithrombotics "Antiplatelets, Anticoagulants,
2hrombolytics@fibrinolytics# P Antihemorrhagics "0latelets,
3oagulants, Antifibrinolytics#
Cardiovascular system !C#
cardiac therapy/antianginals "3ardiac glycosides,
Antiarrhythmics, 3ardiac stimulants#
Antihypertensives P /iuretics P Oasodilators P 8eta blockers P
3alcium channel blockers P renin-angiotensin system "A3$
inhibitors, Angiotensin II receptor antagonists, Genin
inhibitors#
Antihyperlipidemics "+tatins, 7ibrates, 8ile acid se*uestrants#
S+in !$#
$mollients P 3icatri>ants P Antipruritics P Antipsoriatics P
<edicated dressings
)e%roductive system !3#
Hormonal contraception P 7ertility agents P +$G<s P +e&
hormones
Endocrine system !H#
Hypothalamic-pituitary hormones P 3orticosteroids
"4lucocorticoids, <ineralocorticoids# P +e& hormones P
2hyroid hormones@Antithyroid agents
Infections and infestations !5" P#
Antibiotics P Antifungals P Antimycobacterials "2uberculosis
treatment, Deprostatic agents# P Antivirals P Oaccines P
Antiparasitics "Antiproto>oals, Anthelmintics# P
$ctoparasiticide
Malignant disease !671-67*#
Anticancer agents "Antimetabolites, Alkylating, +pindle
poisons, Antineoplastic, 2opoisomerase inhibitors#
Immune disease !67--67.#
Immunomodulators "Immunostimulants,
Immunosuppressants#
Muscles" 4ones" and 2oints !M#
Anabolic steroids P Anti-inflammatories "1+AI/s# P
Antirheumatics P 3orticosteroids P <uscle rela&ants P
8isphosphonates
0rain and nervous system !N#
Anesthetics "4eneral, Docal# P Analgesics P Antimigraines P
Anticonvulsants P <ood stabili>ers P Antiparkinson drugs
0sycholeptics "An&iolytics, Antipsychotics,
Hypnotics@+edatives# P 0sychoanaleptics "Antidepressants,
+timulants@0sychostimulants#
)es%iratory system !)# /econgestants P 8ronchodilators P 3ough medicines P H1
antagonists
Sensory organs !S# %phthalmologicals P %tologicals
,ther ATC !8#
Antidotes P 3ontrast media P Gadiopharmaceuticals P
/ressings
)ece%tor agonists" antagonists" and reu%ta+e inhi4itors
0A1M
9-HT !serotonin# rece%tor
+erotonin receptor agonist ";-H2=# : +erotonin antagonist
";-H2-# : +erotonin uptake inhibitor "++GI#
$o%amine rece%tor
/opamine agonist : /opamine antagonist : /opamine
reuptake inhibitor
Adrenergic rece%tor
Adrenergic agonist "Alpha, 8eta 1@'# : Adrenergic
antagonist "Alpha 1@', 8eta# : Adrenergic uptake inhibitor
Histamine rece%torHistamine agonist : Histamine antagonist "H1, H', H-#
AA
3A0A rece%tor4A8A agonist : 4A8A antagonist
3lutamate rece%tor
1</A receptor "1</A receptor antagonist# : A<0A receptor
"Ampakine# : $&citatory amino acid agonist : $&citatory amino
acid antagonist
ANS
Acetylcholine rece%tor
3holinergic "<uscarinic, 1icotinic# : Anticholinergic
"<uscarinic, 1icotinic@4anglionic blocker@1euromuscular-
blocking drugs# : Acetylcholinesterase inhibitor
Adrenergic rece%tor"+A1+ onlyHsee above for details#
PANS
0arasympathomimetic "3holinergic, Acetylcholinesterase
inhibitor# : 0arasympatholytic "Anticholinergic, 4anglionic
blocker#
SANS
+ympathomimetic "Adrenergic agonist, <onoamine o&idase
inhibitor# : +ympatholytic "Adrenergic antagonist, Alpha
blocker, 4anglionic blocker#
,ther )As $ndothelin : Angiotensin II : 1B1 : 3annabinoid : Oasopressin