بسم الله الرحمن الرحيم

Antihistaminic drugs

Histamine Histamine is an autacoid i.e physiologically active, endogenous substance that is produced within the body by decarboxylation of the amino acid Histidine and then stored in mast cells and basophils. It is released in response to a wide variety of stimuli mediating a hypersensitivity reaction. Histamine action is terminated by cellular reuptake and enzymatic inactivation.

Biosynthesis of histamine Nomenclature

Histamine Receptors or physiological effects of histamine

1.H 1 –receptors : Has a role in hypersensitivity reactions [Pruritis, Increased vascular permeability (oedema, swelling), Increased prostaglandin generation] and also Mediate smooth muscle contraction. 2.H 2 –receptors : mediate the gastric acid secretion as they are located on the cell membrane of acid secretory cells of the gastric mucosa 3.H 3 – receptor : described in 1999, modulate histamine synthesis and release in the CNS. N.B. H 4 subtype is recently discovered in 2000 and was suggested to have a role in regulation of immune system.

Histamine exhibits a wide variety of both physiologic and pathologic functions and this include: 1- An important but limited role as a chemical mediator of hypersensitivity reactions. 2- A major role in the regulation of gastric acid secretion. 3- A role as a neurotransmitter in the CNS.

Histamine has no therapeutic application. The compound is mainly used as 1- a positive control in the allergy skin testing. 2- a diagnostic agent to test the secretory action of the stomach.

Histamine H 1 - Receptor Antagonists

H 1 - antagonists are the drugs that competitively inhibit the action of histamine on the tissues containing H 1 -Receptors.

The H 1 -antagonists are commonly subdivided into two broad groups:  The first generation or classical antihistamines (sedating)  The second generation or (non sedating) antihistamines.

Structure Activity Relationship (S A R) of the first generation antihistamines

1- connecting atom X X= C O X= C X= N

2- The carbon chain of typical H 1 –antagonists consists of two or three carbon atoms. 3- The terminal nitrogen atom is a simple dimethyl amino moiety. However, it may be a part of a heterocyclic structure as in (piperazine, pyrrolidine, piperidine, imidazole…….).

4- Ar and Ar` are aryl groups, including phenyl, substituted phenyl (specially with halogen in para position) and heteroaryl such as 2-pyridly. The two aryl moieties must be non coplanar to each other for optimal interaction with H 1 receptor. The two aromatic systems may be linked as in the tricyclic antihistamines.

1- They have high lipid solubility so, they can penetrate BBB blocking central H 1 receptors and some CNS receptors. Sedation, dizziness. 2- They contain the basic pharmacophore required for binding to muscarinic as well as adrenergic and serotonergic receptors overlaping actions different pharmacological actions. ***** Characters of first generation antihistamines

A- Amino alkyl Ethers (Ethanolamines).

1- Diphenhydramine HCl (Benadryl) It is used in the treatment of urticaria, seasonal rhinitis, and some dermatoses.*** It is used as a sleep aid product. *** 2-(Diphenylmethoxy)-N,N dimethylethylamine HCl

Synthesis Metabolism Question?

B- Propylamine derivatives 1- Saturated dr. (pheneramines) 2- Unsaturated dr. (Olefinic) open chain dr. Cyclic analogues

1- saturated dr. A- chlorpheniramine Maleate Insertion of a halogen into the para position of the phenyl ring increases potency and duration. D optical isomer with S absolute configuration is more active ( dexchlorpheneramine maleate) 2-[ p-chloro-α-[ 2-dimethylaminoethyl ] benzyl] pyridine maleate.

2- unsaturated dr. A- open chain dr. Triprolidine Hydrochloride  E (trans geometric isomer in which the methylpyrolidinyl group is trans to the 2- pyridyl group) is more active than the Z (cis) isomer. N.B. adding polar group……..as 2-propenoic acid ……second generation (acrivastine). (E)-2- [ 1-(4-methylphenyl)3-(1- Pyrrolidinyl) 1-propenyl] pyridine.

B- Cyclic analogue Dimethindene maleate (fenistil)  The potent antihistaminic activity resides mainly in the levorotatory isomer. 2- [ 1-[2-(2-dimethylamino) ethyl] indene-3-yl]ethyl]] pyridine maleate.

c- Ethylenediamines The earliest series of H 1 -antagonists Characterized by high CNS side effects and lower anticholinergic and antiemetic effects

E-Tricyclic ring system 1-Phenothiazine 2- phenothiazine analogues (Cycloheptane and cycloheptene dr.)

1- Promethazine HCl [ phenergan]  It is the parent member of this series.  It forms HCl salt with the more basic nitrogen ?  In addition to its antihistaminic action, it has antiemetic, anticholinergic and sedating effects  It forms HCl salt with the more basic nitrogen? (±)10-[2-(Dimethylamino)propyl ] phenothiazine.

Preparation of Promethazine HCl

Phenothiazine analogues 1-Pimethixene 1- It is an example for thioxanthene derivatives as potent H 1 antagonist. 2- It is an example for the bioisosteric replacement of the nitrogen of phenothiazine nucleus by an SP 2 carbon atom.

2- Cyproheptadine HCl (periactin) It is an example for the bioisosteric replacement of the nitrogen of phenothiazine nucleus by an SP 2 carbon atom and the sulphur atom is replaced by an isosteric vinyl group. This compound can be used as an appetite stimulant and it exhibits both H 1 -antagonist and antiserotonergic activity. 4-(5H-Dibenzo [a,d] cyclohepten-5-ylidene)-1- methylpiperidine

1- It is structurally analogous to cyproheptadine. 2- It is a dual acting antihistaminic which acts as potent H 1 -antagonist and and mast cell stabilizer (it inhibits the release of the mediators which are involved in the allergic reaction) 3- It is used in prophylaxis of asthma Ketotifen (Zaditine)