[2-(4-imidazolyl)ethylamine]
Imidazole ring
Ethyl amine
side chain

Found in smooth muscle of intestine, bronchi, blood vessels
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Effects blocked by classical H1-antagonists

Also found in brain but unevenly distributed
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Discovered in 1972 by Black et al
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Gastric parietal cells, guinea pig atria, uterus
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Control release of gastric acid from gastric parietal
cells
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Discovered in CNS in 1983
When histamine was shown to inhibit it’s own
synthesis and release
Probably via presynaptic autoreceptors
Histamine was also shown to modulate the
release of other neurotransmitters eg ACh,
dopamine, NAd, serotonin via H3 receptors
Predominantly present in basal ganglia,
hippocampus and cortical areas

Discovered in 2000

widely expressed in components of the immune system
such as the spleen, thymus and leukocytes

May benefit allergic conditions

may lead to the treatment of autoimmune diseases. e.g.
rheumatoid arthritis and IBS
pH 1
exists as a mixture of
different ionic and uncharged
tautomeric species
pH 16

exists almost exclusively (96.6%) as the monocationic
conjugate species (Na as NH3+ ) at physiological pH (7.4)

Nt-H (tele- tautomer) predominates (~ 80%)
G protein-coupled receptors (GPCRs)
 Seven-transmembrane domain receptors (7TM)

Extracellular
Extracellular
Extracellular
Effect of Agonist
(histamine)
Inactive
Active
Intracellular
N Engl J Med (2004) 351;2203-2217.
Inactive
Active
Intracellular
Effect of inverse
agonist (antihistamine)
Inactive
Active
Intracellular
Mepyramine (R=OCH3) 1943
Tripelenamine, (R=H) 1946
Significant CNS and sedative effects
Mepyramine
Relaxatabs - sedation
Anthisan – topical
e.g. Diphenhydramine maleate
(Benadryl)
Anticholinergic side-effects
Sedation
Low GI irritation
Benadryl Original, Benadryl Night Time
Unisom SleepGels (50mg)
Dramamine – Dimenhydrinate (50 mg)
Mixture of two drugs – diphenydramine (27.2 mg)
and 8-chlorotheophylline (22.8 mg)
Doxylamine succinate
• Potent anti-cholinergic effects
Mersyndol - paracetamol 450 mg,
codeine phosphate 9.75 mg,
doxylamine succinate 5 mg.
Clemastine (Tavist, Tavegyl)
• anti-puritic (stops itching)
R1=Ph or 2-Pyridine
R2=H or Me
R=Cl or H
X=H Pheniramine (Visine Allergy Drops)
X=Br Brompheniramine (Dimetapp)
X=Cl Chlorpheniramine (Demazin)
Less sedation,
High incidence of CNS stimulation
Low GI irritation
Used mainly in cold & flu remedies
Dexchlorpheniramine (Polaramine)
Triprolidine (Actifed)
Antazoline
•Antistine-Privine eye drops
•Albalon eye drops
Ar1= Aryl, substituted phenyl, heteroaryl eg 2-pyridyl
Ar2= Aryl, or benzyl (ArCH2)
R=tertiary acyclic eg NMe2, or cyclic eg pyrrolidino basic group
Ar-N+ distance ~ 5-6 Å
X=N ethylenediamines
CH-O aminoalkyl ethers
CH or C=C alkyl amines
Promethazine (Phenergan)
Alimemazine/trimeprazine - Vallergan
Antipruritic - eczema or poison ivy
Sedative
Anti-emetic - motion sickness.
Available as a syrup
Often used to help babies and small children sleep
Cyproheptadine - Periactin
Allergy
Migraine prophylaxis
Appetite stimulant
Antihistamine, anticholinergic and
antiserotonergic activity
Azatadine - Zadine
Antipruritic - eczema or poison ivy
Sedative.
Promethazine
In potent tricyclic systems, rings A and C are not in the
same plane
i.e. the B ring of phenothiazine is a boat shape
trans conformation
of diphenhydramine - Active
Fluorene analogue
100 times less active
Terfenadine R=CH3
Fexofenadine R=COOH (Telfast )
 Terfenadine metabolised in body to Fexofenadine
 Terfenadine removed from market due to serious cardiac sideeffects
H
C
OH
N CH2
+
CH2
CH
ion-ion bond
OOC
Fexofenadine
CH2
C
H3 C
CH3
OH
Astemizole
 also causes cardiac side-effects
 slow onset and long duration of action
Loratadine R=COOCH2CH3
Desloratadine R=H
 Related to first generation tricyclic antihistamines
 No reported cardiac side-effects
 Metabolite (desloratadine) reported to be more potent
Cetirizine (Zyrtec)
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Long duration of action

No reported cardiotoxicity, but some drowsiness

Single enantiomer - less sedation??
 Levoceterizine (Zyzal)
Acrivastine (Hismanal)
+
Ebastine R=CH3
Carebastine R=COOH
Azelastine
Levocabastine
Olopatadine (Patanol)
 General structure not as clearly defined as for first generation
antihistamines
 Most non-sedating H1 antagonists still
have large aromatic groups
at one side
 Lipophillic
t-butyl group seems to be associated with cardiotoxicity
 Active forms have a carboxylic acid group and are zwitterionic at
physiological pH, therefore don’t cross BBB
 Metabolism to carboxylic acid removes cardiotoxicity