Histamine mechanisms

Atopic Dermatitis. The mechanism of itching associated with atopic dermatitis remains unknown, but histamine is almost certainly involved to some extent as histamine concentrations are increased in the skin and in the plasma of patients with this disorder (39,42). Second-generation H receptor antagonists, unlike first-generation H receptor antagonists, have not been uniformly found to be effective in relieving itching in atopic dermatitis, which may be related to the absence of a sedative effect (43). 

Clinically Efficacy. It is evident from the mechanism of action of antihistamines and the etiology of allergic diseases that antihistamines in no sense achieve a cure of the patient s allergy. After the adrninistration of a therapeutic dose, a temporal blockade of the effects of histamine is obtained. Whereas classical antihistamines needed at least twice daily adrninistration, for most of the more recently introduced agents adrninistration once daily is sufficient. 

The process of reabsorption depends on the HpophiHc—hydrophiHc balance of the molecule. Charged and ioni2ed molecules are reabsorbed slowly or not at all. Reabsorption of acidic and basic metaboHtes is pH-dependent, an important property in detoxification processes in dmg poisoning. Both passive and active carrier-mediated mechanisms contribute to tubular dmg reabsorption. The process of active tubular secretion handles a number of organic anions and cations, including uric acid, histamine, and choline. Dmg metaboHtes such as glucuronides and organic acids such as penicillin are handled by this process. 

When exposure is repeated, the allergen binds between two adjacent IgE molecules. This causes release of inflammatory mediators (histamine, leukotrienes, chemotactic factors). These act locally and cause smooth muscle contraction, increased vascular permeability, mucous gland secretion, and infiltration of inflammatory cells (neutrophils and eosinophils). However, histamine can also be released by non-IgE-mediated mechanisms (e.g., due to exposure to certain fungi). 463... 

The release of arachidonate and the synthesis or interconversion of eicosanoids can be initiated by a variety of stimuli, including histamine, hormones such as epinephrine and bradykinin, proteases such as thrombin, and even serum albumin. An important mechanism of arachidonate release and eicosanoid syn-... 

The release of NO from the endothelium is induced by various chemical substances, including acetylcholine polypeptides such as substance P, bradykinin, and arginine vasopressin histamine ATP/ADP a2-adrenoceptor agonists thrombin and Ca2+ iono-phores. NO formed in response to mechanical stimuli like shear stress or transmural pressure plays an important role in maintaining basal blood flow. Endothelial NO causes vasodilatation, decreased... 

Figure 3.1 A schematic representation of the control mechanism that stimulates gastric acid secretion, and the intervention points used to treat ulcers. The parietal cells and gastric cells form part of the epithelial cell lining of the stomach. Histamine release is usually triggered as part ofthe enteric nervous system response to distension of the stomach when food is eaten.

TBT and TFT are membrane-active molecules, and their mechanism of action appears to be strongly dependent on organotin(IV) lipophilicity. They function as ionophores and produce hemolysis, release Ca(II) from sarcoplasmic reticulum, alter phosphatodylseiine-induced histamine release, alter mitochondrial membrane permeability and perturb membrane enzymes. Organotin(IV) compounds have been shown to affect cell signaling they activate protein kinase and increase free arachidonic acid through the activation of phospholipase... 

There are also other immimological mechanisms, especially via IgG or IgM antibodies with immune complex formation, which can lead to similar clinical conditions [20, 34, 42] as has been shown in dextran anaphylaxis (table 1). Triggering of mast cells and basophils leads to release of various vasoactive mediators, among which histamine was the first recognized in 1908 (fig. 3,4) [6]. 

Few prospective studies of induced anaphylaxis have been performed in human subjects to imderstand the molecular basis of systemic anaphylaxis, because of the potentially rapid, Ufe-threatening outcome. Accordingly, various models of anaphylaxis have been estabUshed in laboratory animals, particularly mice, and extensively studied to clarify the underlying mechanisms. Such studies revealed that the classical pathway utilizing mast cells, IgE and histamine cannot explain all cases of anaphylaxis. 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Silver RB, Mackins CJ, Smith NCE, Koritchneva IL, Lefkowitz K, Lovenberg TW> Levi R Coupling of histamine H3 receptors to neuronal Na+/H+ exchange a novel protective mechanism in myocardial ischemia, Proc Natl Acad Sci USA 2001 98 2855. Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. Proc Natl Acad Sci USA 2002 99 501. 

Mast cells express high-affinity IgE Fc receptors (FceRI) on their surface, contain cytoplasmic granules which are major sources of histamine and other inflammatory mediators, and are activated to release and generate these mediators by IgE-dependent and non-IgE-dependent mechanisms [1]. Disturbances either in the release of mast cell mediators or in mast cell proliferation are associated with clonal mast cell disorders including monoclonal mast cell activation syndrome (MMAS) and mastocytosis respectively, which are in turn associated with some cases of anaphylaxis [2], Molecular mechanisms have been identified which may link increased releasability of mast cell mediators and conditions leading to increased mast cell numbers [3]. Patients with mastocytosis have an increased risk to develop anaphylaxis [4, 5] and those with anaphylaxis may suffer from unrecognized mastocytosis or may display incomplete features of the disease [6-8]. 

With regard to epinephrines potential adverse cardiac effects, it is important to remember that in anaphylaxis, the heart is a target organ. Mast cells located between myocardial fibers, in perivascular tissue, and in the arterial intima are activated through IgE and other mechanisms to release chemical mediators of inflammation, including histamine, leukotriene C4, and prostaglandin D2. Coronary artery spasm, myocardial injury, and cardiac dysrhythmias have been documented in some patients before epinephrine has been injected for treatment of anaphylaxis, as well as in patients with anaphylaxis who have not been treated with epinephrine [11, 12]. 

The cause of pruritus is unknown, although several mechanisms have been proposed. Vitamin A is known to accumulate in the skin and serum of patients with CKD, but a definite correlation with pruritus has not been established. Histamine may also play a role in the development of pruritus, which may be linked to mast cell proliferation in patients receiving hemodialysis. Hyperparathyroidism has also been suggested as a contributor to pruritus, despite the fact that serum PTH levels do not correlate with itching. Accumulation of divalent ions, specifically magnesium and aluminum, may also play a role in pruritus in patients with CKD. Other theories that have been proposed include inadequate dialysis, dry skin, peripheral neuropathy, and opiate accumulation.43... 

Treatment of ocular allergy is aimed at slowing or stopping these processes. Antihistamines block the histamine receptors and some prevent histamine production and/or inhibit mediator release from the mast cells.15 Mast cell stabilizers inhibit the degranulation of mast cells, preventing mediator release. Some topical agents have multiple mechanisms of action, combining antihistaminic, mast cell stabilization, and antiinflammatory properties (Tables 60-3 and 60-4).16... 

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... 

---