Chemistry of histamine and antihistamine drugs (H-1 and H-2 antagonist)

CHEMISTRY OF HISTAMINE AND
ANTI-HISTAMINICDRUGS
(H-1AND H-2 RECEPTOR ANTAGONIST)
1
Dr. Akhil Nagar
RC Patel Institute of Pharmaceutical
Education and Research

CONTENTS
 Introduction to histamine
 General history of histamine
 Synthesis, release, metabolism of histamine
 Histamine receptors
 Pharmacological effects of histamine
 Histamine related drugs
1. Physiological antagonist
2. Histamine release inhibitors
3. Histamine receptors antagonist
 Recent advance in antihistaminic agents.
 References
2Department of Pharmaceutical Chemistry

Histamine:
 Histamine(1) is an endogenous substance β-imidazoylethylamine that
is present in essentially all mammalian tissues.
 It is the first autocoids to be synthesized.
 Henry Dale and Patrick Laidlaw identified and described the
properties of histamine in 1910-1911 (from: histos = tissue, with an
amine constituent).
 Histamine is an organic nitrogen compound involved in local
immune responses as well as regulating physiological function
in the gut and acting as a neurotransmitter.

1910 Histamine discovered
1933 First antihistamines (AHs) synthesized
(Peperoxan)
1942 Antihistamines introduced for clinical use
1943 First CNS effects of AHs reported
1955 Antiallergic effects of AHs described
1981 2nd generation AHs introduced
1986 Cardio toxic effects of AHs reported
1991 Human H2 receptor cloned
1998 H1 receptor polymorphism described
General History of Histamine

Synthesis of histamine:
 Histamine(1) is synthesized by decarboxylation of the amino acid L-
histidine(2) by the action of the enzyme histidine decarboxylase in the
various sites like mast cells, basophils, some neurons in CNS and
peripheral NS, enterochramaffin cells in GIT.
 Once formed, histamine is stored at the site of synthesis.

Release of histamine:
1. Tissue injury
 Any phsical and chemical that injure skin and mucosa tend to release
histamine from mast cells.
2. Allergic reaction
 Food: eggs, peanuts, milk products, grains, strawberries, etc
 Drugs: penicillins, sulfonamides, etc
 Venoms: fire ants, snake, bee, etc
 Foreign proteins: nonhuman insulin, serum proteins, etc
 Enzymes: chymopapain

Department of Pharmaceutical Chemistry 7
 There are two stages:
1) First exposure to an antigen (inhalation,ingestion) results in the
formation of antibodies (type IgE) specific for that antigen. These
antibodies are fixed on mast cells.
2)Subsequent exposure to the same antigen
(may occur after a variable period, days,months)
Results in binding of the antigen to its specific IgE on mast cells and
cross linking of IgE receptors. This results in release of histamine.

Continued
3. Non allergic like
 Morphine and other opioids, i.v.
 Aspirin and other NSAIDs in asthma.
 Vancomycin, i.v. (Red man syndrome), Polymixin B.
 Some X-ray contrast media.
 Succinylcholine, D-tubocurarine
 Anaphylotoxins: c3a, c5a
 Cold or solar urticaria.

Histamine Receptors
All are part of the super family of G-protein coupled receptors:
1. H1 - Gq coupled to Phospholipase C (PLC).
2. H2 - Gs coupled to Adenylyl Cyclase (AC).
3. H3 - Gi coupled to AC, also to K- channels and reduce Ca influx,
inhibit presynaptic neurotransmitter release.
4. H4 - available data consistent with coupling to Gi/o in mast cells,
as well as eosinophils, that can trigger calcium mobilization 
mast cell chemotaxis.

Receptors: Distribution and Function
Location Type of receptor Effect Treatment
H1 Throughout the body,
specifically in smooth muscles,
on vascular endothelial cells, in
the heart and the CNS
G-protein
coupled, linked
to intercellular
Gq, which
activates
phospholipase C.
Mediate an increase
in vascular
permeability at sites
of inflammation
induced by
histamine and
bronchoconstriction
, vasodilation,
separation of
endothelial cells,
pain and itching,
allergic rhinitis,
motion sickness.
Allergies, nausea,
sleep disorders
H2 In more specific locations in the
body mainly in gastric parietal
cells, a low level can be found in
vascular smooth muscle,
neutrophils, CNS, heart, uterus
G-protein
coupled, linked
to intercellular
Gs which
activates adenyl
cyclase
Increases the
release of gastric
acid.
Stomach ulcers

Location Type of receptor Effect Treatment
H3 Found mostly in the CNS, with a
high level in the thalamus,
caudate nucleus and cortex, also
a low level detected in small
intestine, testis and prostate.
G-protein
coupled, possibly
linked to
intercellular Gi
Feedback inhibition
of histamine
synthesis and
release. They also
control release of
DA, GABA, ACh,
5-HT & NE.
Obesity
H4 They were recently discovered
in 2000. They are widely
expressed in components of the
immune system such as the
spleen, thymus and leukocytes.
Gi/o-protein
coupled
Anti-inflammatory In addition to
benefiting allergic
conditions,
research in the h4
receptor may lead
to the treatment of
autoimmune
diseases.
(rheumatoid
arthritis and IBS)
and Mediate mast
cell chemotaxis.
Continued

Effect of histamine release
(Pathophysiologic release)
Source of release Receptor Site of receptor Effect
Mast cells
(hypersensitivity)
H1 Smooth muscles 1. Bronchoconstriction
2. Contraction of GIT
H1 Endothelium 1. Vasodilatation
2. Increased capillary
permeability leading
to edema
H1 Sensory nerve endings 1. Pain and itch
H2 Smooth muscles of
blood vessels (only in
large doses)
1. Vasodilatation
H4 Immune active cells
(bone marrow, WBC)
1. Chemotaxis

Continued
Source of release Receptor Site of receptor Effect
ECL - cells in the
stomach
H2 Oxyntic cells of the
stomach
1. HCL secretion
Brain
(histaminergic
neurons – cell
bodies of these
neurons are found
in the
hypothalamus and
axons extend to all
areas of the brain)
H1 and H2 Post synaptic neurons
at all areas of the rain
1. 1- Arousal
2. Decreased appetite
H3 Presynaptic
histaminergic neurons
in the brain
1. Inhibit histamine
release producing
sleep
2. Modulate the release
of other
neurotransmitters

Termination of HistamineAction:
1. Cellular uptake
Uptake is a temperature and partially sodium dependent process
and uptake of histamine by many cells, like mast cells.
2. Metabolism:
The enzyme histamine N-methyltransferase (HMT), is widely
distributed among mammalian tissues and catalyses the transfer of
a methyl group from S-adenosyl-L-methionine(SAM) to the ring
tele-nitrogen of histamine, producing N-methylhistamine and S-
adenosyl-L-homocysteine. Histamine is also subject to oxidative
deamination by diamine oxidase(DAO) yielding imidazole acetic
acid, a physiologically inactive product excreted in the urine.
Similarly N-methylhistamine is converted by both DAO and
monoamine oxidase(MAO) to N-methyl imidazole acetic acid.
3. Very little amount is excreted

Histamine(2), N-methylhistamine(3), N-methylimidazole acetic acid(4),
Imidazole acetic acid(5), Imidazole acetic acid riboside(6)
HMT- histamine N-methyltransferase, DAO-diamine oxidase, PRT-
phosphoribosyl transferase
Metabolism of Histamine

Symptoms associated with
histamine release from mast cells
 Mild cutaneous release:
Erythema, urticaria, and/or itching.
 Moderate release:
Skin reactions, tachycardia, moderate hypotension, mild respiratory distress.
 Severe release (anaphylactic):
Severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm,
respiratory arrest.


Pharmacological Effects of Histamine
 Ranges from mild allergic symptoms to anaphylactic shock.
 Involves both the H1 and H2 receptors
 dilatation of small blood vessels  flushing (H1).
 decreased TPR and BP (H1 initial response, H2 sustained reaction)
 increased capillary permeability, edema (H1).
Triple Response ofWillis
 Subdermal histamine injection causes:
1. Red spot (few mm) in seconds: direct vasodilation effect , H1
receptor mediated.
2. Flare (1cm beyond site): axonal reflexes, indirect vasodilation,
and itching, H1 receptor mediated.
3. Wheal (1-2 min) same area as original spot, edema due to
increased capillary permeability, H1 receptor mediated.

SelectedActions of Histamine in Humans
Vascular
 H1 – in vascular endothelium NO and PG release 
vasodilation. In coronary vessels  vasoconstriction. Increased
permeability of post capillary venules
 H2 – in vascular smooth muscle cells  vasodilation mediated by
cAMP
Heart
 H1 - decreased AV conduction
 H2 - increased chronotropy,
decreased inotropy
 H1, H2 - increased automaticity

Continued
Gastrointestinal System
 H2 - acid, fluid and pepsin secretion
 H1 - increased intestinal motility and secretions
Cutaneous Nerve Endings
 H1 - pain and itching

Histamine related drugs:
1. Physiologic antagonists:
 Epinephrine has smooth muscle actions opposite to histamine but by
acting on different types of receptors. It is used in conditions of
massive release of histamine.
2. Histamine release inhibitors:
 Reduce immunologic release of histamine from mast cells.
a) Mast cell stabilizers: Cromolyn and Nedocromil

Nidocromil(7)
 Nedocromil sodium is a medication used to prevent wheezing,
shortness of breath, and other breathing problems caused by asthma.
 Liquid preparations are available for use for allergic eye reactions.
 Nedocromil acts as a mast cell stabilizer, inhibits the degranulation of
mastcells, prevents release of histamine and tryptase, so preventing
the synthesis of prostaglandins and leukotrienes.

Cromolyn(8)
 It is used for prophylactic management of bronchial asthma and
prevention of exercise induced bronchospasm.
 It’s solution is used for the prevention and treatment of allergic
rhinitis.
 Oral concentrate is used to treat mastocytosis (diarrhea, flushing,
headaches, vomiting, urticaria, abdominal pain, nausea, and itching).

Lodoxamide(9) Pemirolast(10)
 It is available in 0.1% solution.
 It is used in the treatment of
ocular disorders including
vernal keratoconjuctivitis,
vernal conjuctivitis, vernal
keratitis.
 Adverse reactions including
burning, stinging, or discomfort
on instillation.
 It is also available in 0.1% sterile
ophthalmic solution for topical
administration to the eye.
 This drug product is for ocular
administration only and not for
injection or oral use.
 It should be used with caution
during pregnancy or while nursing,
since its safety has not been
studied under these circumstances.

3. Histamine receptor antagonists
Histamine H1- Antagonists
 H1 antagonists may be defined as drugs that
competitively inhibit the action of
histamine tissues containing H1 receptors.

Different Generation ofAntihistamines
1st Generation:
Pyrilamine, Antazoline, Tripelennamine, Diphenhydramine,
Clemastine, Chlorpheniramine, Triprolidine, Promethazine,
Mequitazine, Hydroxyzine, Cyclizine, Azatadine,
2nd Generation:
Terfenadine, Astemizole, Cetirizine, Acrivastine, Ebastine,
Levocabastine, Loratadine, Mizolastine
New or 3rd Generation:
Levocetirizine, Carebastine, Desloratadine, Fexofenadine

First Generation:
 Sedating
 Lipophilic compounds that readily cross the blood-brain barrier
 Rapidly absorbed from the GIT
 Widely distributed
 Cross blood-brain barrier
 Extensively metabolized by the Cytochrome P450 and metabolites are
active and are excreted by the kidney
 Duration of action 4-6 hours.

General features:
 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.

Aminoalkyl ethers (Ethanolamines):
 Oldest and most effective antihistamine on the market.
 Available over the counter.
 Because it induces sedation, it’s used in nonprescription sleep aids
such as Tylenol PM.
 Also inhibits the reuptake of serotonin, which led to the search for
viable antidepressants with similar structures.
 Oral dose: 25-50mg/daily
Diphenhydramine(11):

Doxylamine(12) Carbinoxamine(13)
 Second in effectiveness of anti-
allergy activity only to Benadryl.
 Active ingredient in NyQuil.
 Potent anti-cholinergic effects.
 Oral dose: 12.5-25mg/4-6 hours
 Is used to treat Hay fever and is
especially popular to children due its
its mild taste.
 After 21 reported deaths in children
under 2, its now only marketed to
children above 3 (FDA, June 2006)
 Oral dose: 4-8 mg t.i.d. or q.i.d.

Clemastine(14) Dimenhydrinate(15)
 Exhibits fewer side effects
than most antihistamines.
 Widely used as an
antipruritic (stops itching).
 Oral dose: 4-8mg t.i.d.
q.i.d.
 Anti-emetic (anti nausea).
 Also causes strong sedation.
 Readily crosses the BBB.
 Oral dose: 50-100mg/4 hours.

Alkylamines:
 Isomerism is an important factor in this class of drugs, which is due to
the positioning 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.
 These agents most active H1 antagonists.
 They exhibits anticholinergic activity.
 The primary metabolites for these series includes N-dealkylation and
oxidation of the terminal amino moiety followed by glycine
conjugation has also been found.

Chlorpheniramine(16) Brompheniramine(17)
 Originally used to prevent
allergic conditions
 Shown to have antidepressant
properties and inhibit the
reuptake of serotonin
 Oral dose: 4mg/4-6 hours.
 Available over the counter
 Used to treat the common cold by
relieving runny nose, itchy,
watery eyes and sneezing
 Oral dose: 4mg t.i.d. or q.i.d.

Triprolidine(18) Pheniramine(19)
 Used to alleviate the symptoms
associated with allergies.
 Can be combined with other cold
medicine to relieve “flu-like”
symptoms.
 In this nitrogen is present in
pyrolidine ring.
 E-isomer is 1000 times more
active than Z-isomer.
 Used most often to treat hay
fever or urticaria (hives).
 Antihistamine component of
Visine-A.
 Oral dose: 20-40mg t.i.d.

Piperazines
 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
 These compounds are moderately potent anhihistaminics with a low
incidence of drowsiness.
 They have slow onset and long duration of action.
 Some of these compounds shows teratogenic effects e.g.,
norchlorcyclizine
 The primary pathway for the metabolism involves N-oxidation and N-
demethylation, and both of these metabolites devoid of antihistaminic
activity.

Chlorcyclizine(20) Hydroxyzine(21)
 This drug is used to treat motion
sickness, urticaria, hay fever,
and certain other allergic
conditions.
 Disubstitution or substitution of
halogen in the 2 or 3 positon of
the benzhydryl rings results in a
much lesss potent compounds.
 In addition to treating itches and
irritations, its an antiemetic, a
weak analgesic and an anxiolytic
(treat anxiety)
 It is highly lipophilic so have
CNS depressent effects.
 Oral dose: 25-50mg/4-6 hours.

Cyclizine(22)
 Used to treat the symptoms associated with motion sickness, vertigo
and post-operation following administration of general anaesthesia
and opiods
 Mechanism of inhibiting motion sickness is not well understood, but it
may act on the labyrinthine apparatus and the chemoreceptor trigger
zone (area of the brain which receives input and induces vomiting)
 Oral dose: 50mg/ 4-6 hours

Meclizine(23) Cetirizine(24)
 It is most commonly used to
inhibit nausea and vomiting as
well as vertigo, however it does
cause drowsiness
 Oral dose: 25-50mg
 It is primary acid metabolite of
hydroxyzine resulting from
complete oxidation of the
primary alcohol moiety. This
compound is zwitterionic and
relatively polar and thus does not
penetrate the BBB readily.
 It has no cardiac side effects.
 Oral dose: 5-10mg q.d.

Tricyclics
 These drugs are structurally related to tricyclic antidepressants, which
explains why they have cholinergic side effects
 Tricyclics compounds mainly contains phenothiazine and
dibenzocycloheptane and dibenzocycloheptane derivates.
 Here unbranched propyl chain is required as linkage between tricyle
and amino group for antihistaminic activity.
 Concurrent use of the alcoholic beverages and other CNS depressents
with the phenothiazines should be avoided.
 The combination of lengthening of the side chain and substitution of
lipophilic groups in the 2 position of the aromatic ring results in
compounds with decreased antihistaminic activity, and increased
psychotherapeutic properties.

Promethazine (Phenegran)(25)
 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
 Oral dose:12.5mg/4-6 hours or 25mg q.d.
 Drug Interactions: Masks ototoxicity of aminoglycoside antibiotics. It
may enhance the sedative effects of CNS depressants like alcohol,
hypnotics, barbiturates and opioids.
Potentially Fatal: Ventricular arrhythmias when used with drugs that
prolong QT interval.

Cyproheptadine(26)
 It is a 5-HT2 receptor antagonist and also blocks calcium channels.
 Used to treat hay fever and also to stimulate appetite in people with
anorexia
 Dose: PO Allergic conditions As HCl: 4 mg 3 times/day. Usual: 12-
16 mg/day in 3-4 divided doses, up to 32 mg/day if needed.
Prevention and treatment of migraine and other vascular
headaches As HCl: 4 mg, may repeat 30 mins later. Not to exceed 8
mg in a 4-6-hour period. Maintenance: 4 mg 4-6 hour.

Ketotifen (Zaditor)(27)
 This drug is available in two forms: an ophthalmic form used to treat
allergic conjunctivitis or itchy red eyes and an oral form used to
prevent asthma attacks.
 It has several adverse side effects including drowsiness, weight gain,
dry mouth, irritability and increased nose bleeds
 It may impair tasks requiring mental alertness e.g. driving or operating
machinery, history of epilepsy, pregnancy, lactation,Children <3 yr.
 Dose : Asthma prophylaxis; allergic condition 1 mg twice daily, up
to 2 mg twice daily if needed. Opthalmic allegies 0.025% soln: Instill
1 drop twice daily.

Alimemazine (Vallergan)(28)
 This drug is used to treat itchiness and hives 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.
 It Can mask signs of ototoxicity caused by aminoglycosides.
Potentially Fatal: Increased toxic effects of ergot alkaloids and
methotrexate.
 Dose: 10 mg 2-3 times/day

Azatadine(29)
 This drug is used to treat symptoms of allergies and the common cold
such as sneezing, runny nose, itchy watery eyes, itching, hives and
rashes.
 Special Precautions: Angle-closure glaucoma, increased intraocular
pressure,peptic ulcer, pyloroduodenal, epilepsy; renal and hepatic
impairment. It may impair ability to drive or operate machinery;
pregnancy.
 Dose:1 mg twice daily, may increase to 2 mg twice daily if needed.

Methdilazine(30)
 First generation antihistamine with anticholinergic properties.
 Contraindications Neonates; narrow-angle glaucoma; GI tract/urinary
outflow obstruction, paralytic ileus.
 Special Precautions: Elderly; caution in driving; peptic ulcer;
epilepsy; severe CV disease, benign prostatic hyperplasia; pregnancy
and lactation; asthma, bronchitis; hepatic or renal impairment;
Parkinson's disease. Drug Interactions Potentiates CNS depressant
action of various drugs. Antimuscarinic effects potentiated by MAOIs,
atropine and TCAs. May reduce effect of levodopa.
 Dose :8-16 mg twice daily

Ethylenediamines
 In all of the compounds the aliphatic or terminal amino group is a
significantly more basic than the nitrogen atom bonded to the diaryl
moiety so reduction in electron density on nitrogen decreases basicity.
Thus the non bonded electrons on the diaryl nitrogen delocalised by
the aliphatic amino group in the ethylenediamines is sufficiently basic
for the formation of pharmaceutically useful salts.
 Anti cholinergic effects are lower than other antihistamincs.
 They are metabolised by N-glucuronidation, N-oxidation, pyridyl
oxidation.
 The piperazine and phenothiazine type antihistamines also contain
ethylenediamine moiety.

Tripelennamine(31) Pyrilamine(32)
 It has high frequency of CNS
depressant and GI side effects.
 Dose :25-50 mg 4-6 hrly. Max:
600 mg/day.
 Adverse Drug Reactions:
Sedation; CNS depression;
antimuscarinic effects; GI
disturbances. Potentially Fatal:
Blood dyscrasis.
 Because of local anesthetic action, the
drug should not chewed, but taken
with food.
 Adverse reaction: Psychomotor
impairment; headache; paraesthesias,
extrapyramidal symptoms, tremor,
sleep and GI disturbances,
hypersensitivity reactions and blood
dyscrasis; hypotension; hair loss;
tinnitus.

Methapyrilene(33) Antazoline(34)
 Trans conformation is preferred
 It was found to be potential
carcinogen
 It is available in hydrochloride
salt
 Does: 4-5mg t.i.d.
 It has twice local aneshtehtic potency
of procaine and exibits anticholinergic
actions.
 Belongs to the class of topical
antiallergic preparations, excluding
corticosteroids. Used as nasal
decongestants.
 Dose: 0.5% solution for opthalmic
use.

Mequitazine(35)
 It is used to treat allergies and rhinitis
 Contraindication: Severe liver disease premature infants of full term
neonates.
 Special precautions: Pregnancy, lactation, severe cardio vascular
disorders, asthma
 Adverse drug reactions : CNS depression including slight drowsiness
to deep sleep.
 Contraindications: Severe liver disease; premature infants or full-term
neonates
 Dose: 5mg twice daily

Pharmacological Properties
Effects related to reversible competitive antagonism of H1
receptors (present in both first and second generations)
1- On smooth Muscles:
 They inhibit effects of histamine on smooth muscles, especially the
constriction of the bronchi.
2- On blood vessels:
 They inhibit the vasodilator effects that are mediated by activation of
H1 receptors on endothelial cells (synthesis/release of NO and other
mediators). Residual vasodilation is due to H2 receptors on smooth
muscle and can be suppressed by administration of an H2 antagonist.
3- On capillary permeability:
 They inhibit the increased capillary permeability and formation of
edema brought about by histamine.

Effects not related to blockade of H1 receptors
(present in some of the first generation drugs)
1. Anticholinergic Effects:
 Many of the first-generation H1 antagonists inhibit responses to
acetylcholine that are mediated by muscarinic receptors (have
atropine-like actions) e.g., promethazine. The second-generation
H1 antagonists have no effect on muscarinic receptors.
 Anticholinergic effects include dry mouth, blurred vision,
constipation and urinary retention.
 Perhaps because of their anticholinergic effects, some of the H1
antagonists have suppressant effects on drug-induced parkinsonism
symptoms.

Continued
2. On the central nervous system:
 Therapeutic doses of most of the first generation histamine H1
receptor antagonists produce CNS depression manifest as sedation.
 Excitation rather than sedation may occur in children and rarely in
adults
 Overdoses produce central excitation resulting in convulsions,
particularly in children. Individual variability as regards the CNS
exist.
 Some of the first generation drugs can prevent motion sickness
 The second-generation ("nonsedating") H1 antagonists do not affect
the CNS because they do not cross the blood-brain barrier when given
in therapeutic doses.

Drug interactions
 Co administering first generation H1 antihistamines together with
Cytochrome P450 inducers such as the benzodiazepines will decrease
their activity.
 Co administering first generation H1 antihistamines with drugs that
competitively inhibit P450 such as the macrolides, antifungals or
calcium antagonists will increase their activity.
 Additive with classical antimuscarinics.
 Masks ototoxicity produced by aminoglycosides. Increases gastric
degradation of levodopa and decreases its absorption by reduction of
gastric emptying.
 Potentially Fatal: Potentiates CNS depression with alcohol,
barbiturates, analgesics, sedatives and neuroleptics. Additive
antimuscarinic action with MAOIs, atropine and TCAs.

Second generation antihistamines
 Non-sedating.
 Poorly penetrate the blood-brain barrier.
 Rapidly absorbed from the GIT.
 Widely distributed.
 Do not cross the blood-brain barrier (less lipid soluble).
 Elimination: Cetirizine (urine) and Fexofenadine (bile).
 Recent studies have also shown that these drugs also have anti-
inflammatory activity.
 The structure of these drugs varies and there are no common
structural features associated with them.

Acrivastine(36) Loratadine(37)
 This drug relieves itchy rashes
and hives.
 It is non-sedating because it does
not cross the BBB.
 Dose: 8 mg 3 times/day.
 It is the only drug of its class
available over the counter.
 It has long lasting effects and does
not cause drowsiness because it
does not cross the BBB.

Astemizole(38)
 This drug has a long duration of action.
 It suppresses the formation of edema and pruritis.
 It has been taken off the market in most countries because of
adverse interactions with erythromycin and grapefruit juice.
 Dose: 10mg per day.
 Drug Interactions Imidazole, triazole
antifungals, and the macrolide
antibacterials inhibit the hepatic
metabolism of astemizole.Avoid
concomitant administration of other
potentially arrhythmogenic drugs.
Co-administration with diuretics may
cause electrolyte imbalance.
Concurrent use with terfenadine is
not recommended.

Terfenadine(39) Azelastine(40)
 It was formerly used to treat
allergic conditions
 In the 1990’s it was removed
from the market due to the
increased risk of cardiac
arrythmias. Risk is increased if
grapeful juice or agents that
inhibit Cytochrome P450 in liver.
 Dose: 12 yr and >50 kg: 60-
120 mg/day in the morning or 60
mg twice daily. Max: 120
mg/day.
 It is a mast cell stablilizer also.
 Overdosage: Accidental oral
ingestion of large doses may lead
to tremor, convulsions, decreased
muscle tone and salivation.
 Dose: Conjunctivitis As 0.05%
soln: Instill 1-2 drops twice daily.
Nasal Rhinitis 140 mcg into each
nostril twice daily.

Levocabastine(41) Olopatadine(42)
 It is used as eye drops to treat
allergic conjunctivitis.
 Dose : Allergic conjunctivitis As
0.05% susp: Instill 1 drop 2-4
times/day. Nasal Allergic rhinitis As
0.05% nasal spray: 1 spray into each
nostril 2-4 times/day.
 It is used as eye drops to treat allergic
conjunctivitis.
 Dose :Ophth As 0.1% soln: Instill 1-
2 drops twice daily 6-8 hrly.
Alternatively, as 0.2% soln: Instill 1
drop once daily.
(42)

Mizolastine(43) Mebhydrolin(44)
 It is fast acting and does not
prevent the actual release of
histamine from mast cells, just
prevent the binding to receptors.
 Side effects include dry mouth
and throat.
 It is used for symptomatic relief
of allergic symptoms
 Dose: PO 100-300 mg/day.
 Administration: Administration
Should be taken with food.
(Take during or shortly after
meals.)

Pharmacokinetics:
 Loratadine (L), Fexofenadine (F) well absorbed and are excreted
mainly unmetabolized form.
 Loratadine are primarily excreted in the urine.
 Fexofenadine is primarily excreted in the feces.
 They induce Cytochome P450 liver enzymes.

Adverse effects:
 In general, these agents have a much lower incidence of adverse
effects than the first generation agents.
 Terfenadine (seldane) and astemizole (hismanal) were removed from
the market due to effects on cardiac K+ channels - prolong QT
interval (potentially fatal arrhythmia)
 Cetirizine appears to have more CNS actions (sedative) than
Fexofenadine or Loratadine. recommended that cetirizine not be
used by pilots.
 Erythromycin and Ketoconazole inhibit the metabolism of
Fexofenadine and Loratadine in healthy subjects, this caused no
adverse effects.

Third generation antihistamines
 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.

PK, lower drug-drug
interactions
Receptor affinity and
selectivity, efficacy
Safety, lower
cardiotoxicity
Different Development Objectives
 General trend: improve tolerability and safety (less to no
sedation; reduce the cholinergic effects)
Targeted Molecules
for improvement
Type of Improvement
Loratadine
Hydroxyzine
Terfenadine
Astemizole
Objective
Class
Piperidine
Piperazine
Piperidine
Piperidine
Isomer Purification
Levocetirizine
Active metabolite
Desloratadine
Cetirizine
Fexofenadine
No possible improvement
not even designed as an antihistamine; discovered
during research of calcium channel-blocking agents

Levocetirizine(45)
 This drug is the active R(-)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.
 Dose: PO 10 mg once daily.

Deslortadine(46) Fexofenadine(47)
 It is the active metabolite of
Lortadine.
 Adverse Drug Reactions
Headache, fatigue, somnolence,
dizziness; nausea, dyspepsia;
xerostomia, dysmenorrhoea;
pharyngitis.
 Dose: PO 5 mg once daily
 It was developed as an alternative
to Terfenadine.
 Fexofenadine was proven to be
more effective and safe.
 Bioavailability may be increased by
verapamil. Efficacy may be reduced
by rifampin.
 Dose:PO Seasonal allergic rhinitis
120 mg/day once daily. Chronic
idiopathic urticaria 180 mg/day
once daily.

Clinical Uses ofAntihistamines H1 antagonist
 Allergic rhinitis (common cold).
 Allergic conjunctivitis (pink eye).
 Allergic dermatological conditions.
 Urticaria (hives).
 Angioedema (swelling of the skin).
 Pruritis (atopic dermatitis, insect bites).
 Anaphylactic reactions (severe allergies).
 Nausea and vomiting (first generation H1-antihistamines).
 Sedation (first generation H1-antihistamines).

Histamine H2 Antagonist:
 Histamine receptor on parietal cells Autonomic system: food
stimulates gastrin release, gastrin stimulates ECL cells,
stimulates histamine release, histamine stimulates parietal
cells secretion of HCl.
 Drugs which pharmacological action primarily involves
antagonism of the action of histamine at its H2 receptors find
therapeutic application in the treatment of acid-peptic
disorders ranging from heartburn to peptic ulcer disease,
Zollinger-ellison syndrome, gastroesophageal reflux disease,
acute stress ulcers, and erosions.

Development in H2 antagoinst
 Must bind but not activate H2 receptor site
 Addition of a functional group to bind with another binding region
and prevent the conformational change
 Addition of aromatic ring was unsuccessful.
 Addition of non-polar, hydrophobic substituents, none antagonists,
 Histamine produces agonist activity on both H1 and H2 receptors
but methylation at 4 position of the imidazole heterocyle (48) of
the histamine produces selective agonist at atrial histamine
receptors (H2)

4-Methylhistamine(48)
 Not an antagonist, but highly H2 selective Conformational isomers
show preferential binding.
4-methylhistamine
Conformation I
4-methylhistamine
Conformation II

Na –Guanylhistamine(49)
 First partial agonist
First signs of antagonistic activity.
Still allows partial conformational change.

Carbon chain lengthened
 Two-carbon chain, speculation of a carboxylate binding
region
 Three-carbon chain, speculation of different binding region
(50)
(51)

Cimetidine(54)
 Toxicity associated with the thiourea structural feature is eliminated
by replacing the thiourea sulfur with a cyano-imino function
 It reduces the hepatic metabolism by the Cytochrome P450
 It has weak androgenic effect.
 Gynecomastia may occur if treated for one month or more.
 Dose: PO Duodenal ulcer; Benign gastric ulcer Initial: 800 mg/day
at bedtime. Duodenal ulcers: ≥4 wk. Gastric ulcer: ≥6 wk.
Maintenance: 400 mg 1-2 times/day. Stress ulceration of upper GI
tract 200-400 mg 4-6 hrly. Zollinger-Ellison syndrome 300-400 mg
4 times/day.

Famotidine(55)
 Increased prolactin levels or impotent have been reported.
 No observable inhibition of cytochrome P-450.
 It is also useful in Zollinger-ellison syndrome.
 Absorption is lower (40 to 45% bioavilable).
 Dose: PO Benign gastric and duodenal ulceration 40 mg/day at
bedtime for 4-8 week. GERD 20 mg twice daily for 6-12 week. May
continue to prevent recurrence. Zollinger-Ellison syndrome Initial:
20 mg/6 hour, up to 800 mg/day if needed. Dyspepsia 10 mg twice
daily. Benign gastric and duodenal ulceration 20 mg/12 hour.

Ranitidine(56)
 Some antacid may reduce absorption so not taken within 1 hour of
administration of the drug.
 With Clarithromycin it is useful in duodenal blocker associated with
H. Pylori infection.
 It is excreted as S-oxide, and desmethyl ranitidine.
 Dose :daily for 6 week. Short-term symptomatic dyspepsia 75 mg,
up to 4 doses/day if needed. Max: 2 week of continuous use at each
time. Prophylaxis during NSAID treatment 150 mg twice
daily.Stress ulceration of upper GI tract Priming dose: 50 mg via
inj, then 125-250 mcg/kg/hr via infusion, then transfer to PO 150 mg
twice daily once oral feeding is resumed. IV/IM Acid aspiration
during general anesthecia 50 mg 45-60 mins before the induction of
anesthesia.

Continued
 Administration : It may be taken with or without food.
 Contraindications: Porphyria.
 Special Precautions :Exclude malignancy before treating gastric
ulcer. Renal and hepatic impairment. Infants, pregnancy and lactation.
 Adverse Drug Reactions: Headache, dizziness. Rarely hepatitis,
thrombocytopaenia, leucopaenia, hypersensitivity, confusion,
gynaecomastia, impotence, somnolence, vertigo, hallucinations.
 Potentially Fatal: Anaphylaxis, hypersensitivity reactions.
 Drug Interactions: Antacids may interfere with absorption. It may
decrease the GI absorption of Ketoconazole. Smoking may decrease
the plasma levels of ranitidine. It may cause an increase in the
bioavailability of furosemide.

76
Histamine receptors –
H1- Allergic responses. Watery eyes, congestion, etc. from allergies.
Anaphylaxis – bronchial larynx constriction.
Skin allergic response – reddening, rashes, welts.
Edema from injury.
H2 – Gastric secretion. Important for ulcer treatment and acid reflux
H3 – CNS receptors. There are also H1 receptors in the CNS.
Antihistamines are also used for motion sickness. In general their
antimuscarinic effects are similar to that of scopolamine, although weaker.

77
HN N
NH2
H
HN N
NH2
H
CH3
HN N
NH2
H3C
HN N
NH2
H
H
H3C
(R)-methyl histamine
H3 Agonist
4-methylhistamine
H2 Agonist
2-methyl histamine
H1 Agonist
Histamine
Histamine Agonists

78
Ethylenediamines
X
Ar1
Ar2
(CH2)n N
CH3
CH3
N
N
CH3
CH3
N
N
HN
SAR Prototype
Phenbenzamine
Antazoline
Antihistamines – H1 Blockers

79
H
O
N
CH3
CH3
R1
N
CH3
CH3
O
SAR Prototype
R1 is a small group like H, CH3,OCH3
Diphenhydramine
(Benadryl)
Aminoalkylethers
O
NCH3
Cl
Cl
N
N
CH3
Cl
O
N
CH3
CH3
Diphenylpyraline
Meclizine
Good H1 antagonist, but also
good antimuscarinic
Clemastine
(Tavist)
Piperazine/N-heterocycle Series
Antihistamine SAR

80
AlkylAmines
Long Duration, less sedation than ethylenediamines, ethanolamines. The “next best
thing” until the “2nd generation” were developed.
N
N
CH3
CH3
R
N
N
CH3
N
H3C
Cl
Pyrrobutamine (Pyronil)R = H Pheniramine
R = Cl Chlorpheniramine (Chlortrimeton)
R = Br Brompheniramine (Dimetane)
Triprolidine (Actidil)
N
CH3
CH3
N
Dimethindene (Forhistal)
N CH3
Phenindamine (Nolahist)

81
A Cl at the 2-position weakens H1 activity relative to antimuscarinic activity and D2
antagonist activity
N
NCH3
N
S
CH2CH2N(CH3)2
N
S
CH2CHN(CH3)2
CH3
Mebhydrolin
Fenthazine
Promethazine
(Pheregan)
N
S
CH2CH2CH2N(CH3)2
Cl
Chlorpromazine
N
N
N
N
OCH3
H
F Astemizole
(Hismanal)
RigidAnalogs(I)

82
Cl
O OCH2CH3
N
N
CH3
N
S
Cl
N
N
H
Primethixene Loratadine (Claritin) Desloratadine (Clarinex)
RigidAnalogs (II)

83
Hismanal was FDA approved in 1988 as an antihistamine for allergy and hay fever symptom relief.
The FDA first warned consumers and healthcare providers of new safety information regarding
Hismanal February 9, 1998 due to the risk of death, cardiovascular adverse events, anaphylaxis, and
serious drug interactions.
In addition, Hismanal labeling was changed to stress avoiding the use of Hismanal in combination
with certain other medications and for liver disorder patients to completely avoid its' use.
After a series of labeling changes and warnings Hismanal was recalled on June 21, 1999.
N
N
N
N
OCH3
H
F Astemizole
(Hismanal)
Astemizole

84
Terfenadine was discontinued when it became apparent that there was a high
frequency of heart arrythmia associated with the drug. Fexofenadine is a
metabolite and is the activated form responsible for antihistamine activity. In
patients with compromised liver metabolism, or when the presence of other
drugs limited the metabolism of terfenadine, persistent levels resulted in the
observed arrythmias. Therefore, the fexofenadine replaced terfenadine (1997).
Ventricular Arrythmias are not good!
N
OH
O
Cl
F
Haloperidol (Haldol)
Prototype butyrophenone antipsychotic
10xChlorpromazine
Antihistamines“related”tobutyrophenones

85
N
OH
OH
N
OH
COOH
OH
[OX]
Terfenadine
(Seldane)
Fexofenadine
(Allegra)
N N
H
O
Cl OH
O
Cetirizine
(Zyrtec)
Butyrophenone-like structures

86
O
N
CH3
CH3
N
N
CH3
Cl
N
Cl
NH
N
N
OCl
OH
O
Diphenhydramine
Meclizine
Desloratadine
Cetirizine
Linking the first generation with Non-sedative
Antihistamines.
Big Picture - Bottom Line
Structural Summary

87
Gastric receptors are pharmacologically distinct. The classic H1
antagonists don’t interact with H2 receptors. Antihistamines are
an important treatment for gastric disorders; antacids, ulcer
treatment, acid-reflux disease.
H2 Histamine antagonists.

88
HH
S
CH3
NNH
NHN
H3C
HH
S
CH3
NN
S
NHN
CN
H3C
HH
N
CH3
NN
S
NHN
CH2N(CH3)2
HH
CHNO2
CH3
NN
S
O
C(NH2)2
N
NSO2NH2
NH2
S
NS
Burimamide
(Non-selective)
Metiamide
(H2 Selective)
Cimetidine
(Tagamet)
Ranitidine
(Xantac)
Famotidine
(Pepcid)
H2 Histamine antagonists. - Structures

References
 Zhang, M-Q.; Leurs, R.; Timmerman, H. Histamine H1-receptor
antagonists.In Burger’s Medicinal Chemistry and Drug Discovery; 5th
Ed.; Wily-Interscince: New York, Vol. 5, 495-559; 1995.
 Nelson, W. L. Antihistamines and related antiallergic and antiulcer agents.
In Foye's Principles of Medicinal Chemistry. Williams D. A, Lemke T. L .
5th Ed.; Lippincott Williams & Wilkins: Philadelphia, 2002.
 Jaime N. D.,William A.R.: WILSON & GISVOLD’S Textbook of organic
Medicinal and Pharmaceutical Chemistry : Antineoplastic agents; Ch.
12:10th edition:Lippincott Williams & Wilkins:343-401;1998.
 Zhang , M.; Thurmond, R. L.; Dunford, P. J. The histamine H4 receptor: A
novel modulator of inflammatory and immune disorders, Pharmacology
& therapeutics; vol-113, 594-606, 2007.
 Macor E.J., Annual Reports in Medicinal Chemistry;first edition;Elsevier
publication;42 ;chp 5; Recent advance in the histamine H3 and
antihistaminc drugs : 76-78; 2007.

References
 Macor E.J., Annual Reports in Medicinal Chemistry;first
edition;Elsevier publication:33; chp 30; 340-356; 1998.
 Laurence L. B.:Goodman & Gilman's the pharmacological basis of
therapeutics;chp 51, histaminic agents and antagonist, 11th edition:
Medical publishing division;629-640, 2006.
 Mohan Harsh., Textbook of Pathology: chp 6; 141-143, 2005.
 Hancock, A. A. et al. Antiobesity effects of A-331440, a novel non-
imidazole histamine H3 receptor antagonist. European Journal of
Pharmacology, vol-487, 183-197, 2004.
 J.P. de Esch Iwan. et al., The histamine H4 receptor s a new
therapeutic target for inflammaion, Trends in Pharmaceutical
Sciences, vol-26, 462-469, 2005.

References
 http://clinicaltrials.gov
 http://www.fda.gov
 http://www.sciencedirect.com
 http://www.cimsasia.com

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