Hj and H2 receptor

Ring J, Rothenberger KH, Clauss W Prevention of anaphylactoid reactions after radiographic contrast media infusion by combined histamine Hj- and H2-receptor antagonists results of a prospective controlled trial. Int Arch Allergy Appl Immunol 1985 78 9-14. 

Histamine induces intracellular Ca " flux, actin polymerization, and chemotaxis in immature DCs due to stimulation of HRl and HR3 subtypes. Maturation of DCs results in loss of these responses. In maturing DCs, however, histamine dose-dependently enhances intracellular cAMP levels and stimulates IL-10 secretion, while inhibiting production of IL-12 via HR2 [16]. Interestingly, although human monocyte-derived dendritic cells have both histamine Hj and H2 receptors and can induce CD86 expression by histamine, human epidermal Langerhans cells express neither H nor Hj receptors [72]. 

Thomson NC, Kerr JW Effect of inhaled Hj and H2 receptor antagonist in normal and asthmatic subjects. Thorax 1980 35 428-434. 

In case of the histamine receptor ligands, Hj and H2 receptor antagonists such as fexofenadine... 

Maconochie, J. G., Woodings, E. P., and Richards, D. A., 1979, Effects of Hj- and H2 receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects, Br. J. Clin. Pharmacol. 7 231-236. 

Premedication regimens of glucocorticoids and histamine Hj and H2 receptor antagonists have been used to try to prevent or reduce hypersensitivity reactions. Various phase 1 trials have been successfully completed using infusion schedules of 1-120 hours and doses of 135-390 mg/rn, with a lower incidence of hypersensitivity reactions [31, 49, 42, SO , 56, 65 0 7T]. However, the use of premedication does not completely prevent such reactions. There were incidences of 16%, 13%, and 7% with 3, 6, and 24-hour infusion schedules respectively, despite premedication PF], while only 1.5% of patients developed... 

Immunologic Ixabepilone is formulated in Cremophor EL and so is usually administered with premedication using histamine Hj and H2 receptor antagonists. There have been reports of hypersensitivity in about 5-8% of cases, but these are usually mild and not treatment-limiting [153", 154", 155", 156"]. 

Doxepin hydrochloride capsules (most commonly 25 and 50 mg) are used but oral solutions exist as well as concentrates at 10 mg/mL. It consists of a mixture of E- and Z-isomers (85 15). Strong interactions with histamine Hj and H2 receptors are the basis for its use in the topical treatment of severe pruritus. 

Ketotifen fumarate, in addition to its dual action, decreases chemotaxis and activation of eosinophils. Ketotifen binds to multiple histamine receptors, including Hi, Hj, and H3, with the strongest affinity to the Hi and H2 receptors. Ketotifen is available over the counter. 

There are two types of histamine receptors Hj and H2. H2 receptors cause an increase in gastric secretions and are not involved in this response. The differences are illustrated in the charts. (See Antihistamine (Hj blocker) chart and Antihistamine Use to Treat Allergic Rhinitis chart.)... 

It is now clarified that there are two different receptors, Hj and H2, for histamine [1]. Cimetidine was synthesized as a typical antagonist of the H2 receptor of histamine [2]. This compound possesses an imidazole skeleton like histamine, and it occupies the H2 receptor of histamine to prevent the attachment of histamine, and finally it prevents the secretion of gastric juice. As a result, this compound became widely used for the treatment of stomach ulcers. 

Combined Hj /H2 receptor stimulation by histamine is responsible for vasodilation-related symptoms, such as hypotension, flushing, and headache, as well as for tachycardia stimulated indirecdy through vasodilation and catecholamine secretion. 

We examined the effects of selective activation of histamine Hj receptors on coronary hemodynamics in two groups patients with atypical chest pain and normal coronary arteries, and patients with vasospastic angina [48]. Selective Hj receptor stimulation was achieved by infusing histamine intravenously (0.5 pg/kg/min) for 5 min after pretreatment with cimetidine to antagonize the H2 receptors. Heart rate was kept constant (100 beats/min) by coronary sinus pacing. 

FIGURE 14-6 Main signaling pathways for histamine receptors. Histamine can couple to a variety of G-protein-linked signal transduction pathways via its four different receptors. The Hj receptor activates the phosphatidylinositol turnover via Gq/11 proteins. The other receptors either positively (H2 receptor) or negatively (H3 and H4 receptor) regulate adenylyl cyclase activity via Gs and GUo protein activation respectively. Several additional signaling pathways have been described, which are not shown. Abbreviations PfP2, phosphatidylinositol 4,5-bisphosphate PIC, phospholipase C AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic AMP PKC, protein kinase C PICA, protein kinase A. 

Histamine also acts on extravascular smooth muscles to cause contraction or relaxation. Most often, contraction is due to activation of Hj receptors and relaxation to activation of H2 receptors (32). In man, histamine causes contraction of bronchial and intestinal smooth muscles. Histamine-induced contraction of guinea pig ileum is a standard bioassay for histamine. Its effects on smooth muscle of the eye and genitourinary tract are important in some species but not in human ( ). In scombroid poisoning cases. 

Two membrane-receptive binding sites called and receptors mediate the pharmacological effect of histamine. Hj receptors are located in smooth muscle of vessels, and bronchial and gastrointestinal tract, while H2 receptors are found in the walls of the stomach, myocardium, and certain vessels. 

Therefore, it is very likely that contraction of nonvascular smooth muscle is an effect of activation of Hj receptors, while secretion of digestive juice and increased heart rate are connected to activation of H2 receptors and dilation of vessels and increased permeability of capillaries is a result of combined activation of both types of receptors. 

Antihistamine drags are classified as antagonists of Hj and receptors, and quantitatively speaking Hj antagonists dominate. Moreover, the term antihistamine drag is associated more with Hj antagonists. H2 blockers exhibit a specific effect on histamine receptive sites located in walls of the stomach and they significantly increase secretion of hydrochloric acid. 

Traditional or Hj antihistamine drugs block many effects caused by histamine however, it turns out that they are not able to withstand events mediated by H2 receptors, in particular excess gastric juice secretion. In 1977 an H2-receptor antagonist, cimetidine, was proposed, which revolutionized stomach ulcer treatment. Later on, ranitidine was proposed, followed by drugs with minor structural and pharmacological differences such as famotidine and nizatidine. 

Hj-receptor antagonists reversibly and competitively inhibit histamine action on H2 receptors. They are pure antagonists since they do not affect Hj receptors, j3-adrenorecep-tors, or muscarinic receptors. 

A slow intravenous injection of histamine produces marked vasodilation of the arterioles, capillaries, and venules. This causes a fall in blood pressure whose magnitude depends on the concentration of histamine injected, the degree of baroreceptor reflex compensation, and the extent of histamine-induced release of adrenal catecholamines. Vasodilation of cutaneous blood vessels reddens the skin of the face, while a throbbing headache can result from vasodilation of brain arterioles. Vasodilation is mediated through both Hj- and Hj-receptors on vascular smooth muscle. Stimulation of Hj-receptors produces a rapid and short-lived response, whereas stimulation of H2-receptors produces a more sustained response that is slower in onset. Stimulation of Hj-receptors on sympathetic nerve terminals inhibits the release of norepinephrine and its associated vasoconstriction. 

B. Hj-receptors are found on the surface of mast cells and basophils. All four types of histamine receptors belong to the G protein-coupled receptor superfamily. Only H2-receptors are coupled to adenylyl cyclase through the G protein G. ... 

The superiority of omeprazole-like irreversible HVK -ATPase inhibitors over H2-receptor antagonists in acid-related disorders of the upper gastrointestinal tract is quite obvious. Their clinically relevant advantages are related to their different mode of action which is independent of the kind of acid stimulation and to their longer duration of action. Reversible H /K -ATPase inhibitors share the secretagogue independent mode of action with the irreversible inhibitors but show a duration of action which is comparable with that of Hj-receptor antagonists. Their clinical advantage over irreversible inhibitors has still to be proven. Other H /K -ATPase inhibitors such as Cl channel blockers are, at present, of experimental interest only. 

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