Histamine and Antihistaminic Agents

Histamine, known trivially as 4(5-)(2-aminoethyl)imidaxole. structurally is composed of an imida/.ole heterocycle and ethylamine side chain. The methylene groups of the amino-ethyl side chain are designated a and p. The. side chain is attached, via the /S-CHa group, to the 4 position of an imida/.-ole ring. The imida/.ole N at position 3 is de.signatcd the pros 17T) N. whereas the N at position I i,s termed the tele (r) N. The side chain N is distinguished as N . 

stamine is a basic organic compound (N . pK i = S.80 N . pKa2 = 9.40 N. pK. ., = 14.0) capable of existing as a mixture of different ionic and uncharged tautomeric species (Fig. 21-1). Histamine exists almost exclusively (%.6%) 

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Because the vestibular system is replete with muscarinic-type cholinergic and histaminic (Hx) receptors, anticholinergics and antihistamines are the most commonly used pharmacologic agents to prevent and treat motion sickness. 

Intranasal anticholinergic agents (e.g., ipratropium) reduce the severity and duration of rhinorrhea but have no effect on other nasal symptoms.11,12,21 Ipratropium reduces cholinergic hyperreactivity and cholinergically mediated histamine- and antigen-induced secretion. Intranasal ipratropium acts locally, with only minimal systemic absorption. Clinical trials demonstrated that ipratropium bromide 0.3% reduced rhinorrhea in adults and children with PAR.11,12 Intranasal ipratropium is an option for patients in whom rhinorrhea is refractory to topical intranasal corticosteroids and/or antihistamines.8,12 Intranasal ipratropium is available only by prescription, and the dose is two sprays nasally two to three times daily.15 Adverse effects are minimal, but dry nasal membranes have been reported.11,12... 

Dixon and Mountain reported that exposure of mice to ozone at 1 ppm for 5 h resulted in a depletion of lung histamine content to as low as 75% of the control value 5 days later. They also observed that pretreatment with promethazine, an antihistaminic agent, resulted in a decrease in the amount of pulmonary edema produced by a sublethal dose of ozone. However, promethazine, in addition to being a potent antihistaminic agent, is a phenothiazine derivative and thus might act to trap fiee radicals or stabilize membranes. 

IgE-medlated release of mast cell contents. Inset, Intact mast cell with histamine stored In granules. An IgE antibody molecule Is depicted adjacent to the mast cell. Two IgE molecules combine with a mast cell (sensitization). The attachment of an antigen (allergen) to the sensitized mast cell Initiates release of histamine (and other substances) from the mast cell. This degranulation can be prevented by such agents as isoproterenol, theophylline, epinephrine, and cromolyn sodium. H antihistamines do not interfere with degranulation but instead prevent actions of histamine at various pharmacological receptors. 

The newer antihistaminics agents e.g. Azelastme inhibits histamine release and also inflammatory reactions evoked by leukotrienes and plasma activating factor (PAF). It is used for seasonal and perennial allergic rhinitis in the form of nasal spray. Mizolastine, a non-sedating antihistaminic is used in allergic rhinitis and urticaria. Ebastine, another non-sedating antihistaminic is used in nasal and skin allergies. 

Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H receptor-blocking as well as 5-HT2-blocking actions. The actions of cyproheptadine are predictable from its histamine and 5-HT receptor affinities. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It also has significant antimuscarinic effects and causes sedation. 

Angioedema may be precipitated by histamine release but appears to be maintained by peptide kinins that are not affected by antihistaminic agents. For atopic dermatitis, antihistaminic drugs such as diphenhydramine are used mostly for their sedative side effects and for some control of the itching. 

Histaminei (Hj) receptors mediate such actions as bron-choconstriction and the contraction of smooth muscles in the gastrointestinal tract. Ebastine is a histamine,-receptor blocker. Terfenadine, astemizole, loratadine, and certirizine are second-generation antihistamine agents that are relatively nonsedating. Other H,-receptor antagonists currently undergoing clinical trials are azelastine, ebastine, and levo-cabastine (see also Figures 34 and 59). 

Acetylcholine is a neurohormone that enhances peristalsis, wakefulness, and memory and is essential for nerve transmission. A deficiency of brain cell receptors that bind acetylcholine—cholinergic receptors—contributes to the characteristic loss of memory in Alzheimer s disease. Cholinergic receptors are structurally similar to those that bind histamine. Therefore, antihistamines and cholinergic agents show overlapping activities. As a result, the antihistamine diphenhydramine has been used to treat insomnia and to combat motion sickness. 

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