Histamine Hi-blockers

Histamine HI Blockers From Relative Failures to Blockbusters Within Series of Analogues... 

This second-generation histamine HI receptor blocker was put on the world market in the 1980s for the relief of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria [14], Janssen Pharmaceuticals marketed this dmg under the brand name Hismanal. The major benefit of these antihistamines was their... 

Since histamine is the main mediator of the allergic inflammation during both early and late phases, it is necessary to apply modern selective HI blockers (for example, ebastine, loratidine or cetirizine) in a parallel way to SLIT. This eliminates minimal persistent inflammation. It becomes evident on the cellular level and can be assessed by the presence of cellular inflammation mediators, interleukins and epithelial expression of adhesion molecules, but without clinical symptoms of allergy [14, 15],... 

Fig. 13.1 The potassium hERG channel as anti-target within drug discovery, (a) Homology model of hERG channel with compound MK-499 bound [2]. (b) Histamine HI antagonist terfenadine, which was found to be a strong blocker of the hERG channel inducing...

The use of premedication with steroids and Hi and Hg histamine receptor blockers can significantly reduce the adverse reactions to high osmolality contrast media. There are suggestions to extend their use to modify even the reactions to low osmolality contrast media. Pretesting of contrast media reactors by injecting 1 mL of the nonionic contrast medium has also been reported (539). 

A number of other agents may be required for the treatment of anaphylactic reactions. Corticosteroids (hydrocortisone sodium succinate intravenously) are recommended to reduce the risk of late-phase reactions. Aminophylline may be used as adjunctive therapy for bronchospasm. Histamine (Hi) receptor blockers (such as diphenhydramine) may be administered to reduce some of the symptoms associated with anaphylaxis however, these agents are not effective as primary therapy. 

Hf and H Receptors. Histamine exerts its actions by binding to receptors on cell membranes. Two types of histamine receptors, the Hi and H2 receptors, are known specific agonists and antagonists exist for each of these receptors. Black et al. (55) differentiated H and H2 receptors with the compounds, 2-methylhistamine and 4 methylhistamine. 2-Methylhistamine is active on tissues with H receptors 4-methylhistamine is active on tissues with H2 receptors. Classical antihistaminic drugs were developed in the 1930 s these compounds block H but not H2 receptors. Among the clinically used H -blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of... 

The effects of histamine on body tissues and organs can be diminished in four ways inhibition of histamine synthesis, inhibition of histamine release from storage granules, blockade of histamine receptors, and physiological antagonism of histamine s effects. Of these approaches, only the inhibition of histamine synthesis has not been employed clinically. The focus of this chapter is on Hi histamine receptor antagonists it provides a brief overview of the H2 blockers and the inhibitors of histamine release. More details can be found in Chapters 39 and 40. 

Many of these drugs have effects that are not mediated by Hi-receptors (Table 38.2). The antimuscarinic activity of several first-generation Hj-blockers may account for their effectiveness in combating motion sickness and their limited ability to suppress parkinsonian symptoms. The phenothiazines have some capacity to block a-adrenoceptors, whereas cyproheptadine Periactin) is an antagonist at serotonin receptors. Diphenhydramine Benadryl), pyrilamine (Ryna), and promethazine Phen-ergan) are effective local anesthetics. Many second-generation antihistamines also have been found to inhibit the non-histamine-mediated release of various... 

Diphenhydramine Competitive antagonism at Hi receptors Reduces or prevents histamine effects on smooth muscle, immune cells also blocks muscarinic and adrenoceptors highly sedative IgE immediate allergies, especially hay fever, urticaria some use as a sedative, antiemetic, and antimotion sickness drug Oral and parenteral t duration 4-6 h Toxicity Sedation when used in hay fever, muscarinic blockade symptoms, orthostatic hypotension Interactions Additive sedation with other sedatives, including alcohol some inhibition of CYP2D6, may prolong action of some 13 blockers... 

The term antihistamine, without a modifying adjective, refers to the classic Hi receptor blockers. These compounds do not influence the formation or release of histamine, but rather they competitively block the receptor-mediated response of a target tissue. [Note This contrasts with the action of cromolyn (see p. 220), which inhibits the release of histamine from mast cells and is useful in the treatment of asthma.] The H receptor blockers can be divided into first- and second generation drugs.(Figure 40.5). The first generation drugs are still widely used because they are effective and inexpensive. 

Adverse effects Hi receptor blockers have a low specificity, that is, they interact not only with histamine receptors but also with muscarinic cholinergic receptors, a-adrenergic receptors, and serotonin receptors (see Figure 40.6). The extent of interaction with these receptors and, as a result, the nature of the side effects, vary with the structure of the drug. Some side effects may be undesirable, and others may have therapeutic value. Furthermore, the incidence and severity of adverse reactions varies between individual subjects. 

Diphenhydramine (Benadryl) Hi receptor blocker Blocks the actions of histamine on Hi receptor... 

Loratadine Hi receptor blocker Antagonizes histamine effects... 

Histamine is in mast cells, basophils, and platelets. Human skin mast cells express H H2, and H4 receptors, but not H3 receptors. Hi and H2 receptors are involved in wheal formation and erythema, whereas only Hi-receptor agonists cause pruritus. Complete blockade of Hi-receptors does not totally relieve itching, and combinations of Hi and H2 blockers may be superior to H, blockers alone. 

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