Histamine receptor blockade

Besides weight gain, probably the most common side effect from antipsychotics in young people is sedation. Histamine receptor blockade appears to mediate this side effect. Excessive sleepiness can interfere with a youth s academic performance, cause sluggishness, and cause a child to appear drugged to their peers and family. 

The allergic reactions that have been described in association with polygehne are thought to be caused by direct histamine release as a result of allergenic stimulation of mast cells. These cases raise the questions of whether polygehne is appropriate for bronchoreactive patients and whether such patients should be protected by histamine receptor blockade. 

Monoamine oxidase inhibition Serotonin reuptake inhibition Norepinephrine reuptake inhibition Dopamine reuptake inhibition a2-Adrenergic receptor blockade Serotonin-2A receptor blockade Serotonin-2C receptor blockade Serotonin-3 receptor blockade op-Adrenergic receptor blockade Histamine-1 receptor blockade Muscarinic cholinergic receptor blockade... 

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. 

Typical Versus Atypical Antipsychotics. We discussed at length in Chapter 5 just what makes a typical antipsychotic typical and what makes an atypical antipsychotic atypical. We ll spare you a rehash of that lengthy discussion however, it is important to note that all typical antipsychotics are not created equal. Although they all work by blocking the dopamine D2 receptor, their potency at this receptor varies up to 100-fold. In addition, antipsychotic side effects are not due solely to dopamine receptor blockade. In many cases, the most troublesome side effects result from blocking other receptor types including histamine, acetylcholine, and the norepinephrine alpha-1 receptor system. 

Diphenhydramine is the antihistamine that is most widely used by psychiatrists, and it is most often used more for its acetylcholine-blocking effects than its histamine blockade. This is not to say that histamine-blocking effects are not problematic. In fact, a wide variety of psychiatric medications block histamine receptors. The... 

Blockade of histamine receptors. Allergic reactions are predominantly mediated by H receptors. Hi antihistamines (p. 114) are mostly used orally. Their therapeutic effect is often disappointing. Indications allergic rhinitis (hay fever). 

Mirtazapine has a novel mechanism of action that in theory should promote anxiolytic effects, although evidence from studies of anxiety disorders is awaited. It increases synaptic release of serotonin and noradrenaline via blockade of presynaptic inhibitory a2-adrenoceptors, as well as blocking post-synaptic 5-HT2 and 5-HT3 serotonin receptors and Hi histamine receptors. Mirtazapine has good efficacy for anxiety symptoms associated with depression (Fawcett and Barkin 1998), and in controlled studies was superior to... 

The TCA drugs have lost their place as first-line therapy for depression because of their bothersome side effects (Table 33.2) at therapeutic doses and lethal effects in toxic doses. In addition to their presynaptic effects on the neuronal uptake of norepinephrine and serotonin, they block several postsynaptic receptors. They are potent cholinergic muscarinic receptor antagonists, resulting in symptoms such as dry mouth, constipation, tachycardia, blurred vision and urinary retention. Blockade of histamine receptors (Hi) often results in sedation and weight gain. Antagonism of aj-adrenoceptors in the vasculature can cause orthostatic hypotension. 

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. 

Three types of histamine (H) receptors have been isolated. At present, it appears that receptor blockade... 

SSRIs were developed in an attempt to formulate reuptake-blocking drugs that lacked the troublesome side effects of TCAs. Of the five pharmacological properties of TCAs—blockade of muscarinic receptors, blockade of histamine Hj receptors, blockade of aj-adrenergic receptors, norepinephrine reuptake blockade, and serotonin reuptake inhibition—only the last remains intact in SSRIs. This selectivity has... 

Blockade of histamine receptors, which can produce sedation and possibly weight gain... 

There is a diversity of histamine receptors. The H2, H3 and H4 receptors are of interest in gastrointestinal pharmacology. Histamine H2 receptors are G protein-coupled receptors which act by increasing intracellular cAMP to stimulate gastric acid production, and blockade reduces acid secretion. 

Histamine H2-receptor antagonists are the mainstay of prevention of Mendelson s syndrome at present. Probably the best protection is afforded by a combination of H2-receptor blockade by ranitidine and a single oral dose of sodium citrate or bicarbonate. Because of its longer duration of action, and relative lack of enzyme inhibition, ranitidine is preferred to cimetidine for this purpose, although there is a latent period of 1-2 hours before it takes effect. Famotidine and nizatidine are probably equally effective in blocking acid secretion. 

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

Certain Hi antagonists, eg, cetirizine, inhibit mast cell release of histamine and some other mediators of inflammation. This action is not due to H -receptor blockade and may reflect an H4-receptor effect (see below). The mechanism is not fully understood but could play a role in the beneficial effects of these drugs in the treatment of allergies such as rhinitis. A few H4 antagonists (eg, terfenadine, acrivastine) have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain. The significance of this effect is not known. 

The first phenothiazine antipsychotic drugs, with chlorpromazine as the prototype, proved to have a wide variety of central nervous system, autonomic, and endocrine effects. Although efficacy of these drugs is primarily driven by D2-receptor blockade, their adverse actions were traced to blocking effects at a wide range of receptors including a adrenoceptors and muscarinic, Hi histaminic, and 5-HT2 receptors. 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

Fig. 1. Schematic diagram showing the different mechanisms of action proposed for the antiulcer action of flavonoids. 1. Blockade of add secretion by decreasing histamine production or inhibiting the proton pump. 2. Bactericidal effect on H. pylori. 3. Antioxidative activity by scavenging free radicals and preventing ROM formation. 4. Potentiation of the mucosal protective factors. PAF platelet activating factor ROM reactive oxygen metabolites H2 histamine receptor 2 M muscarinic receptor G gastrin receptor.

Blockade of HI histamine receptors causes sedation and weight gain (Fig. 

FIGURE 11—7. This figure represents an icon of a conventional antipsychotic drug. Such drugs generally have at least four actions blockade of dopamine 2 receptors (D2) blockade of muscarinic-cholinergic receptors (Ml) blockade of alpha 1 adrenergic receptors (alpha 1) and blockade of histamine receptors (antihistaminic actions [HI ). 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

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