Histamine-2 receptor antagonists

The classical histamine receptor antagonists are stmcturaHy very similar, all being substituted ethylamines (2). Table 1 presents a member of each stmctural subclass. Presumably, the ethylamine core is needed to accomplish nonfmitfiil binding to the high affinity conformation of the receptor. 

Several histamine receptor antagonists are effective in treating motion sickness, Meniere s disease, morning sickness, uraemia and postoperative vomiting. They are not effective against cytotoxics. Antagonists with... 

Stress ulcer prophylaxis is recommended in septic patients. Patients at greatest risk for stress ulcers are coagulopathic, mechanically ventilated, and hypotensive. Histamine-receptor antagonists are more efficacious than sucralfate, and proton pump inhibitors have not been compared to histamine-receptor antagonists. However, they do demonstrate equivalence in the ability to increase gastric pH.24... 

Hydroxy or hydroxymethyl groups attached to quinolizine substrates normally show the expected reactivity. For instance, compound 109 was linked to histamine receptor antagonists by esterification with succinic anhydride followed by amidification with the antihistaminic drug to give the fluorescently labeled stmcture 110 for in vivo studies of receptor binding (Scheme 13) <2003BML1717>. 

Histamine-receptor Antagonists Serotonin agonists Serotonin antagonists Ergot alkaloids... 

Antidromic stimulation of sensory nerves produces vasodilatation and increased blood flow in the skin [57, 58] that is blocked by histamine receptor antagonists [59] or by pretreatment with compound 48/80 [60],... 

Neurotensin (NT) is a tridecapeptide (Table 4.2) first isolated from brain and gut by Carraway and Leeman [75] and reported by them to induce a rapid and transient hypotension, a cutaneous vasodilatation, and a cyanosis of the extremities in the anaesthetized rat. This report, along with others [76-78] indicating that the NT-induced hypotension and increased vascular permeability could be blocked by histamine receptor antagonists such as mepy-ramine [77] or by pretreatment with compound 48/80 [76], suggested that endogenous histamine (perhaps released from tissue mast cells) was involved in producing some of the biological effects of NT [78]. 

Suessbrich, H., Waldegger, S., Lang, F. and Busch, A.E. (1996) Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Letters, 385, 77-80. 

Young et at. [49] Histamine -receptor antagonists (cimetidines, guanidinothiazoles, ranitidines, and other small organic compounds)... 

Ranitidine is a histamine receptor antagonist. It acts essentially on the H2 receptor and blocks acid production. Ranitidine is used in the treatment and prevention of ulcers, NSAID-induced ulcers, Zollinger-Ellison syndrome and gastro-oesophageal reflux disease. 

UDP-a-glucuronic acid 90 unbound drug concentration 50 unbound drug 24,125 GABA uptake inhibitors 6 histamine -receptor antagonists uptake of drugs in the brain 6 urea 42 urine 62, 67... 

The longstanding use in some countries of hydroxyzine, a centrally-acting Hi-histamine receptor antagonist, is supported by positive findings in controlled trials in GAD (Ferreri and Hantouche 1998 Lader and Scotto 1998). Hydroxyzine promotes sleep and its anxiolytic effects have an early onset. Although it causes sedation, tolerance to this effect often occurs and effects on psychomotor performance are smaller than with benzodiazepines (de Brabander and Deberdt 1990). It is well-tolerated and withdrawal effects have not been reported. Although the evidence for its efficacy is not large, hydroxyzine provides an option for some patients with GAD for whom standard treatments are unsuitable. 

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. 

The i.c.v. injection of apamin or charybdotoxin, specific blockers of the SK and BK type of Ca2+-activated K+ channels, respectively, prevented the antinociception mediated by tricyclic antidepressants and H1 histamine receptor antagonists whereas 0C2 adrenoceptor-mediated supraspinal analgesia did not depend on the activation of these K+ channels (Table 1). 

Brookhuis KA, De Vries G, De Waard D. Acute and subchronic effects of the Hl-histamine receptor antagonist ebastine in 10, 20 and 30 mg dose, and triprolidine 10 mg on car driving performance. Br J Clin Pharmacol 1993 36 67-70. 

Readers should be aware that terfenadine (Seldane ), the once widely-used, selective Hi histamine receptor antagonist, has been voluntarily withdrawn from the market by the manufacturer. The withdrawal was instituted because of the risk of life-threatening cardiac arrhythmias when terfenadine was taken concomitantly with drugs such as keto-conazole that inhibit the CYP3A4 isozyme of cytochrome P-450. The active metabolite of terfenadine is currently being marketed as fexofenadine [fecks o FEN a deen] (carboxylated terfenadine), which lacks the cardiac toxicity of terfenadine. 

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