[2-(4-imidazolyl)ethylamine] Imidazole ring Ethyl amine side chain

 Found in smooth muscle of intestine, bronchi, blood vessels  Effects blocked by classical H 1 -antagonists  Also found in brain but unevenly distributed

 Discovered in 1972 by Black et al  Gastric parietal cells, guinea pig atria, uterus  Control release of gastric acid from gastric parietal cells

 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

A basic organic compound, N  pK a 1=5.80 N , pK a 2=9.40 N , pK a 3=14.0 exists as a mixture of different ionic and uncharged tautomeric species pH 1 pH 16

 exists almost exclusively (96.6%) as the monocationic conjugate species (N  as NH 3 + ) at physiological pH (7.4)  N  -H (tele- tautomer) predominates (~ 80%)

Extracellular Intracellular Inactive Active Effect of Agonist (histamine) Effect of inverse agonist (antihistamine) N Engl J Med (2004) 351;  G protein-coupled receptors (GPCRs)  Seven-transmembrane domain receptors (7TM)

Mepyramine (R=OCH 3 ) 1943 Tripelenamine, (R=H) 1946 Significant CNS and sedative effects Mepyramine Relaxatabs - sedation Anthisan – topical

Anticholinergic side-effects Sedation Low GI irritation e.g. Diphenhydramine maleate (Benadryl) 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)

R 1 =Ph or 2-Pyridine R 2 =H or Me R=Cl or H

Less sedation, High incidence of CNS stimulation Low GI irritation Used mainly in cold & flu remedies X=H Pheniramine (Visine Allergy Drops) X=Br Brompheniramine (Dimetapp) X=Cl Chlorpheniramine (Demazin) Dexchlorpheniramine (Polaramine)

Triprolidine (Actifed)

Antazoline Antistine-Privine eye drops Albalon eye drops

Ar 1 = Aryl, substituted phenyl, heteroaryl eg 2-pyridyl Ar 2 = Aryl, or benzyl (ArCH 2 ) R=tertiary acyclic eg NMe 2, 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 Available as a syrup Often used to help babies and small children sleep Antipruritic - eczema or poison ivy Sedative Anti-emetic - motion sickness.

Cyproheptadine - Periactin Antihistamine, anticholinergic and antiserotonergic activity Allergy Migraine prophylaxis Appetite stimulant

Azatadine - Zadine Antipruritic - eczema or poison ivy Sedative.

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 Promethazine

trans conformation of diphenhydramine - Active Fluorene analogue 100 times less active

Terfenadine R=CH 3 Fexofenadine R=COOH ( Telfast )  Terfenadine metabolised in body to Fexofenadine  Terfenadine removed from market due to serious cardiac side- effects

Astemizole  also causes cardiac side-effects  slow onset and long duration of action

Loratadine R=COOCH 2 CH 3 Desloratadine R=H  Related to first generation tricyclic antihistamines  No reported cardiac side-effects  Metabolite (desloratadine) reported to be more potent

Cetirizine (Zyrtec)  Long duration of action  No reported cardiotoxicity, but some drowsiness  Single enantiomer - less sedation??  Levoceterizine (Zyzal)

Acrivastine (Hismanal) Ebastine R=CH 3 Carebastine R=COOH +

Azelastine Levocabastine Olopatadine (Patanol)

 General structure not as clearly defined as for first generation antihistamines  Most non-sedating H 1 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