Histamine, Hi-antagonists

Antagonism of Skin wheal and flare to i.d. histamine Hi antagonist... 

Several histamine HI antagonists, e.g. hydroxyzine, promethazine, and mepyramine, display considerable sedative effects and they are sometimes used as sedative/hypnotics. Symptoms after withdrawal are usually less severe than those seen with the above mentioned hypnotics and sedatives. Especially in the elderly caution with these agents is warranted as. 

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 CBS reduction has been employed in numerous synthetic applications.16 The cetirizine hydrochloride 32 (Zyrtec) is an effective treatment as a second-generation histamine HI antagonist for a range of allergic diseases. Zyrtec is one of the leading antihistamine drugs, with sales of 1.3 billion in 2004 in the United States alone. Corey and Helal prepared a chiral benzylic alcohol intermediate 34 en route to their enantioselective synthesis of Zyrtec17 (Scheme 4.3m). The asymmetric reduction of the ketone 33 in toluene with catecholborane in... 

Kahfa M, Drolet B, Daleau P et al. (1999) Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine Hi antagonist diphenhydramine. J Pharmacol Exp Ther 288 858-865... 

Fig. 10 Selected histamine (Hi) antagonists and 2,3-disubstituted thiazolidin-4-ones embedded with some of their structural features...

Yanni JM, Stephens DJ, Parnell DW, et al. Prechnical efficacy of emedastine, a potent, selective histamine HI antagonist for topical ocular use. J Ocul Pharmacol 1994 10 665-675. 

Yokoyama H, linuma K, Yanai K, Watanabe T, Sakurai E, Onodera K. Proconvulsant effect of ketotifen, a histamine HI antagonist, confirmed by the use of d-chlorpheniramine with monitoring electroencephalography. Methods Find Exp Clin Pharmacol 1993 15(3) 183-8. 

Yasuhara A, Ochi A, Harada Y, Kobayashi Y. Infantile spasms associated with a histamine Hi antagonist. Neuropediatrics 1998 29(6) 320-1. 

Finally, in this context we should watch closely the clinical development of compounds of a type not covered in this introduction. These are basic compounds, structurally more similar to histamine Hi-antagonists, which inhibit mediator release but which are also potent physiological or competitive antagonists ketotifen, from Sandoz, and oxatomide from Janssen are two recent examples of this type of compound. 

Yanai, K., Ryu, J.H., Watanabe, T., Iwata, R., Ido, T., Sawai, Y., Ito, K., and Itoh, M. (1995) Histamine HI receptor occupancy in human brains after single oral doses of histamine HI antagonists measured by positron emission tomography. Br. J. Pharmacol., 116, 1649-1655. 

The theory behind the inclusion of histamine Hi antagonists in the premedication is obvious but the mode of action of corticosteroids is not completely understood so some beheve its inclusion cannot be explained and justified. Corticosteroids ultimately inhibit kaUikrem, a peptide that lowers blood pressure and liberates bradykinin. Corticosteroids also act in the arachidonic acid cascade to inhibit the production of prostaglandins and leukotrienes, so there does seem to be some rationale for their use. There are some indications that premedication prevents the recurrence of many minor reactions. Some, or even many, of these reactions may not be immune mediated, proceeding instead via a nonspecific and low-level histamine release. In the case of severe inunediate reactions, IgE antibody-mediated explosive histamine release from mast cells may overwhelm the potential effectiveness of premedication. 

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