Antihistamines are known to cause tiredness. The essential hormones of the body are insulin (glucose), parathyroid hormone (calcium) and aldosterone (Na-K ATPase, sodium). I am thinking how this tiredness symptom can come. There are so many different antihistamines so I am confused about the mechanism how they cause tiredness.
Histamine acts on parietal cells of stomach via H2 receptors to stimulate hydrogen ion secretion - cephalic phase. Excess of antihistamines can lead to decreased acidity of stomach so change in conversion of pepsinogen into pepsin. So less pepsin breaking down peptides and proteins. Body has to do something else to break those components - and this consumes much energy and makes you tired.
Small mucus food mass stays in the intestines. Delayed absorption. Nutrients needed so liver has to work and make essential things - amino acids and something else. Some waste management also may happen - because of tiredness.
Changes in blood sugar level. Delayed most probably after food intake. Very fast and fast insulin secretion mechanism starting during wrong times - all of the sudden. So less insulin secretion cumulatively:
- very fast mechanism - change of permeability of membranes (Na-K ATPase and sodium channels) reacting during times when not suitable - long after food intake
- fast mechanism (phosphorylation of different things) happening more, since sympaticus apparently is not so inhibiting here
- slow and very slow mechanisms however preferable (increased permeability of amino acids and mitoses)
So I think the tiredness of antihistamines is because of the increased amount of active fast mechanisms of insulin secretion, while less very fast mechanisms. To carry the raw food mass in the intestines also require much energy.
What is the physiological mechanism behind the tiredness of excess antihistamines?
Thanks to studies on animal behavior and on histamine dection in the Central Nervous System, researchers found out the "histaminergic system". It's thought that histamine-containing neurons regulate sleep-wake cyrcle, immunity, memory, body temperature, drinking, feeding rhythms. By the way, knockout rats who lack of histamine system don't show big defects in any function.
H1-Receptors for Histamine are distributed in the CNS and in the rest of the body. H1-antagonists (such as Promethazine, Chlorcyclizine, Loratadine… ) have different effects on CNS, depending on dose. At conventional doses central depression appears and patients are sedated. They can even experience an antihistamine "hangover" in the morning, even if they take these drugs at bedtime. By the way, antihistamine overdose typically shows with convulsions.
The "non-sedating" H1-antagonists, or "second generation" have a lot less effects on CNS. They have polar chemical structure: they can not cross the blood-brain barrier. By the way, a lot of typical and atypical anti-psychotic drugs have H1-antagonism effects on the brain (with H2 and H4 antagonism): their main goal is sedation to stop the patient from hurting himself (or others) during manic episodes.
So I think the last two sentences explain that sedation is almost a totally CNS-mediated side effect of antihistamine drugs.
H1-antagonists don't suppress gastic secretion, do not inhibit salivary, lacrimal or other exocrine secretions. Older H1-antagonists have an anti-colinergic effect on muscarinic receptors: they may reduce ACh-mediated secretions, typically in mouth and in the respiratory tree.
H2-antagonists are used to treat acid-peptic desease (as PPIs, proton pump inhibitors). CNS-related side effects are not commons, and include: confusion, delirium, hallucinations, slurred speech and headaches. These effects are mostly related with IV infusion of the H2-antagonist.
I just made a very small research on PubMed. I found this: http://www.ncbi.nlm.nih.gov/pubmed/3529778 as you can see it is a study (on only 9 patients, in 1986), about insuline-glucose-Cpeptide and ranitidine (H2-antagonist) relations. Their conclusion is "Ranitidine significantly increased the area under concentration/time curves for glucose and insulin but not that of C-peptide. Our data indicate that ranitidine does not affect pancreatic insulin release nor peripheral glucose utilization and are consistent with the hypothesis that ranitidine influences the hepatic clearance of glucose and insulin both of which undergo high first-pass liver extraction."
I think that tiredness is a typical CNS-mediated side effects of H1-antagonists (anti-allergic) but is not a side effect of H2-antagonists (anti-acid). Maybe H2-antagonists affects insulin action via hepatic effects.
*I'm italian (sorry for any english mistake) and I am a last-year medicine college student. I wrote trying to summarize some chapters (8, 32 and 45) of: - "Goodman & Gilman's The Pharmacological Basis of Therapeutics" - L. Brunton, B. Chabner, B. Knollman - 12th edition; McGrawth Hill 2011
Could Histamine Intolerance be the Underlying Cause of Your Chronic Fatigue Syndrome?
In today’s hectic, hyper-scheduled world, most of us are busier than ever — so it’s no wonder so many of us are tired.
But what happens when tired becomes exhausted? And what happens when that exhaustion starts interfering with every aspect of your life and nothing you do seems to improve your symptoms?
This is the reality for millions of people suffering from chronic fatigue syndrome. And if you’re currently struggling with the effects of this disorder, you know that finding answers can sometimes feel like an uphill battle.
And while m o dern medicine still has more questions than answers when it comes to this disorder, research has uncovered some promising findings that can help some patients address the underlying causes of their chronic fatigue syndrome.
Definitions and Concepts
Insulin is a peptide hormone secreted by the β cells of the pancreatic islets of Langerhans and maintains normal blood glucose levels by facilitating cellular glucose uptake, regulating carbohydrate, lipid and protein metabolism and promoting cell division and growth through its mitogenic effects.
Insulin resistance is defined where a normal or elevated insulin level produces an attenuated biological response 2 classically this refers to impaired sensitivity to insulin mediated glucose disposal. 3
Compensatory hyperinsulinaemia occurs when pancreatic β cell secretion increases to maintain normal blood glucose levels in the setting of peripheral insulin resistance in muscle and adipose tissue.
Insulin resistance syndrome refers to the cluster of abnormalities and related physical outcomes that occur more commonly in insulin resistant individuals. Given tissue differences in insulin dependence and sensitivity, manifestations of the insulin resistance syndrome are likely to reflect the composite effects of excess insulin and variable resistance to its actions. 3
Metabolic syndrome represents the clinical diagnostic entity identifying those individuals at high risk with respect to the (cardiovascular) morbidity associated with insulin resistance. 3
There are three mechanisms by which endocrine glands are stimulated to synthesize and release hormones: humoral stimuli, hormonal stimuli, and neural stimuli.
The term “humoral” is derived from the term “humor,” which refers to bodily fluids such as blood. A humoral stimuli refers to the control of hormone release in response to changes in extracellular fluids such as blood or the ion concentration in the blood. For example, a rise in blood glucose levels triggers the pancreatic release of insulin. Insulin causes blood glucose levels to drop, which signals the pancreas to stop producing insulin in a negative feedback loop.
Hormonal stimuli refers to the release of a hormone in response to another hormone. A number of endocrine glands release hormones when stimulated by hormones released by other endocrine glands. For example, the hypothalamus produces hormones that stimulate the anterior portion of the pituitary gland. The anterior pituitary in turn releases hormones that regulate hormone production by other endocrine glands. The anterior pituitary releases the thyroid-stimulating hormone, which then stimulates the thyroid gland to produce the hormones T3 and T4. As blood concentrations of T3 and T4 rise, they inhibit both the pituitary and the hypothalamus in a negative feedback loop.
In some cases, the nervous system directly stimulates endocrine glands to release hormones, which is referred to as neural stimuli. Recall that in a short-term stress response, the hormones epinephrine and norepinephrine are important for providing the bursts of energy required for the body to respond. Here, neuronal signaling from the sympathetic nervous system directly stimulates the adrenal medulla to release the hormones epinephrine and norepinephrine in response to stress.
Hyperthyroidism is a condition in which the thyroid gland is overactive. Hypothyroidism is a condition in which the thyroid gland is underactive. Which of the conditions are the following two patients most likely to have?
What are antihistamines used for?
Antihistamines are very good at relieving symptoms of an allergic reaction, such as:
- inflammation (redness)
- red and watery eyes
- a runny nose
This makes antihistamines very effective in the treatment of:
First generation antihistamines (see explanation below) also act in the brain and spinal cord, and on other receptors. This makes some of them also useful for:
- inducing sleep
- preventing or treating motion sickness
- reducing anxiety
- in people with Parkinson&rsquos disease unable to tolerate more potent agents.
Pathophysiology of Type 2 Diabetes Mellitus
Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.
Keywords: adipocyte cardiovascular disease insulin resistance liver muscle pathophysiology type 2 diabetes mellitus β-cell.
Conflict of interest statement
The authors declare no conflict of interest.
Signaling pathways involved in insulin…
Signaling pathways involved in insulin secretion in β-cells in physiological conditions ( A…
Type 2 Diabetes Mellitus (T2DM)…
Type 2 Diabetes Mellitus (T2DM) risk factors and the pathological changes leading to…
Mitochondrial dysfunction and contribution to…
Mitochondrial dysfunction and contribution to T2DM development. Oxidative stress, defective mitochondrial biogenesis and…
Insulin stimulation effects on healthy…
Insulin stimulation effects on healthy and hypertrophic adipose tissue. In healthy adipose tissue…
Signaling pathways involved in insulin…
Signaling pathways involved in insulin signaling in hepatocytes. Binding of insulin to INSR…
Factors implicated in cardiovascular risk…
Factors implicated in cardiovascular risk outcomes from T2DM and the interactions between them.…
Diabetic dyslipidemia: mechanisms leading to…
Diabetic dyslipidemia: mechanisms leading to T2DM dyslipidemia and lipoprotein clearance in physiological an…
Studies On Histamine's Effects
I wanted to make a single thread for myself to post histamine related studies. As Peat himself is not a fan of histamine, lumping it together with things like cortisol and serotonin, I want to stick to one thread for all studies instead of posting them each as their own seperate thread in order to respect the main stance of this community on histamine. So I will post a few now, and I can always come back here and post some more in time.
I will provide studies and post some excerpts from them. The studies in their entirety should be available for everyone to read and look into themselves (some may only have abstracts which I will try to avoid for the most part). More practical information will be bolded.
I want to emphasize that in someone that has very elevated histamine, raising histamine is obviously a not a good idea. So the kind of people that this applies to is those that are naturally very slender/underweight (meaning they stay thin without paying attention at all to food intake), have many histamine reactions and allergies and other histamine related disorders, etc.
Someone who is very thin to the point of being underweight should not do something that may further reduce bodyweight. Just to emphasize, terrible digestion and food intolerance is not due to high histamine but can be related to low histamine (though raising histamine alone may or may not fix the issue).
So we all need to be aware of ourselves and who we are and not go around lowering things that we already have too low and raising things that we already have too high. This applies to histamine, but also to everything else whatever it may be.
If you struggle with very poor cognition/very low motivation (dopamine is clearly involved in motivation as well) and/or are overweight and have trouble maintaining a normal weight because appetite is very high, consider low brain histamine. Increasing brain histamine will help reduce appetite and increase appetite control and improve cognition/motivation, libido and sexual function overall.
If you have questions, feel free to ask them in this thread. I didnt want to put this in the debate section, since this is not about debate. This is about providing information to those that may be struggling in large part due to chronically low histamine levels and also for those that are curious about histamine since its so easy to learn about the negatives of histamine but so I wanted to provide info for those wanting to learn about the positives of histamine.
TMN - Tuberomammillary nucleus: source of histamine pathways in the brain
Histamine methyltransferase (HMNT) - methylates histamine using SAM, deactivating it
HDC - Histidine Decarboxylase, synthesizes histamine from histidine
"Brain histamine promotes wakefulness and orchestrates disparate behaviors and homeostatic functions. Recent evidence suggests that aberrant histamine signaling in the brain may also be a key factor in addictive behaviors and degenerative disease such as Parkinson's diseases and multiple sclerosis."
"In fact, histamine signaling controls feeding behavior in a complex fashion and it has been considered for long, a satiety system, as brain histamine decreases the drive to consume food. In their paper, Ishizuka and Yamatodani (2012) demonstrated the fine regulation of histamine release during feeding and in taste perception. Furthermore, they showed that histamine neurons respond to both mechanical and chemical sensory input from the oral cavity, as may be expected for a danger detection system."
"Here, we review evidence indicating that brain histamine plays a central role in motivation and emphasize its differential involvement in the appetitive and consummatory phases of motivated behaviors. We discuss the inputs that control histaminergic neurons of the tuberomamillary nucleus (TMN) of the hypothalamus, which determine the distinct role of these neurons in appetitive behavior, sleep/wake cycles, and food anticipatory responses."
"The relationship between the motivation for food, arousal, and TMN activity was first studied using a model of restricted feeding. Rats placed on a feeding schedule that is restricted to a few daytime hours wake up in anticipation of mealtime. This anticipatory behavior has an important adaptive value because in nature, food may be available during the same few daily hours (Stephan, 2001), and the anticipatory physiological and behavioral activation prepares the animals to take advantage of this predictable phenomena."
"Novelty has reinforcing properties that motivate the exploration of new environments or novel objects. Evidence indicates that this exploration depends on an intact prefrontal cortex (Daffner et al., 2000) and histamine system. It has been shown that mice lacking the enzyme histidine decarboxylase (HDC) show decreased spatial novelty-induced arousal (Parmentier et al., 2002) and reduced exploratory activity in an open field but normal habituation to the same open field (Dere et al., 2004)"
"The nucleus accumbens (NAcc) is one site where histamine increases exploratory behavior through the activation of H1 and H2Rs (Orofino et al., 1999)."
"Orexin (hypocretin) neurons from the LHA, which are involved in appetitive behavior, in part because of their role in incentive saliency (Harris et al., 2005), form a well studied excitatory (Bayer et al., 2001 Eriksson et al., 2001) input to histaminergic neurons [while histamine has little effect on orexin neurons (Li et al., 2002)]. Orexin neurons may be considered a modulatory input to the TMN"
"Orexinergic neurons, perhaps under cortical influence (Monda et al., 2004), operate through type B receptors and histamine to increase brown adipose tissue sympathetic nerve activity (Yasuda et al., 2005) and thermogenesis."
"Regarding the histaminergic system, a reduction in H1R ligand binding in the frontal lobe of depressed patients (Kano et al., 2004) and schizophrenic patients (Iwabuchi et al., 2005) and the frontal and temporal regions of Alzheimer's disease patients (Higuchi et al., 2000) has been observed. "
"Parkinson's disease patients have increased levels of histamine but do not have increased levels of its metabolite, telemethylhistamine, in the putamen, substantia nigra compacta, and both divisions of the globus pallidus (Rinne et al., 2002) they also have increased histamine fibers in both divisions of the substantia nigra (Anichtchik et al., 2000). However, no increase in HDC mRNA expression was found in the TMN (Shan et al., 2012b) of Parkinson's disease patients, suggesting that there is no change in histamine production."
"Reduced H3R mRNA expression and increased histamine methyltransferase mRNA levels in the susbtantia nigra were also found in Parkinson's disease patients (Shan et al., 2012a)."
"Pharmacological evidence also indicates a causal relationship between histamine dysfunction and apathy. Methylphenidate strongly increases extracellular levels of dopamine, noradrenaline (Berridge et al., 2006), and histamine in the rat prefrontal cortex (Horner et al., 2007) and improves apathy scores in patients with Alzheimer's disease (Padala et al., 2010), stroke (Spiegel et al., 2009), and dementia (Dolder et al., 2010). It is possible that the increase in the histamine levels by methylphenidate is secondary to the increased extracellular concentration of dopamine, as is the case for systemic methamphetamine administration (Morisset et al., 2002), because D2 brain receptor activation enhances the TMN neuronal firing frequency, histamine release, and wakefulness in freely moving rats (Yanovsky et al., 2011)."
"A well studied example is the reliable and phasic decrease in food intake that follows a cyclic increase in estrogen in rodents and primates, including humans (Geary et al., 2001). While several hypothalamic nuclei, including the TMN, express estrogen receptors, the anorectic effect of estradiol appears to depend on its direct action on TMN neurons, in addition to the effects of corticotropin-releasing hormone on TMN neurons (Gotoh et al., 2005). Estradiol also acts on the paraventricular hypothalamic nucleus (an important anorexigenic region), which releases corticotropin-releasing hormone (Gotoh et al., 2009). Histaminergic neurons may act on ventromedial hypothalamic nucleus (VMH) neurons via H1R to decrease food intake (King, 2006)."
"Blockade of H1R within the VMH, but not in other hypothalamic nuclei such as the paraventricular hypothalamic nucleus or the LHA, increases both meal size and duration and suppresses the activity of glucose-responsive neurons (Fukagawa et al., 1989)."
"Rats with a strong preference for alcohol have elevated levels of brain histamine and its metabolites, as well as a higher density of histaminergic nerve fibers than rats with a lower preference for alcohol (Lintunen et al., 2001)."
"Local administration of histamine into the NAcc increases or decreases the firing rate of the accumbens neurons (Shoblock and O'Donnell, 2000) and increases local extracellular dopamine via H1 activation of cholinergic interneurons (Prast et al., 1999), which act on presynaptic nicotinic receptors to increase dopamine release (Wonnacott et al., 2000 Galosi et al., 2001)."
"Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Active solely during waking, they maintain wakefulness and attention. Three of the four known histamine receptors and binding to glutamate NMDA receptors serve multiple functions in the brain, particularly control of excitability and plasticity. H1 and H2 receptor-mediated actions are mostly excitatory H3 receptors act as inhibitory auto- and heteroreceptors. Mutual interactions with other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, learning, and memory in health and disease."
" The name histamine for imidazolethylamine indicates an amine occurring in tissues. The presence and biological activities of histamine were detected by Sir Henry Dale and co-workers almost a century ago: contraction of smooth muscles in the gut and vasodilatation (130). The stimulation of acid secretion in the stomach (582) was also recognized early. Feldberg (172) demonstrated histamine release from mast cells in the lungs during anaphylactic shock causing constriction of the bronchi. The presence of histamine in the brain, predominantly in the gray matter, was first shown by Kwiatkowski (1941 (378), and White (1959) (814) demonstrated its formation and catabolism in the brain. The sedative “side effects” of antihistamines (68) triggered early work and suggestions for histamine as a “waking substance” (488)."
"Histamine (CID 774) is synthesized from the amino acid histidine through oxidative decarboxylation by histidine-decarboxylase (HDC EC 184.108.40.206), a pyridoxal 5′-phosphate (PLP)-dependent enzyme (177) found in many species and highly conserved throughout the animal kingdom from mollusc, insect, rodent, to human"
Glutamatergic fibers from the cortex and the hypothalamus are present and glutamate excites TMN neurons, which carry both AMPA and NMDA receptors (840), and the neuronal glutamate transporter EAAC1 was detected by immunohistochemistry near histamine neurons (170). "
"A number of NMDA antagonists increase the synthesis and turnover of histamine, indicating the possibility of an (indirect) inhibitory action through NMDA receptors on TMN neurons which express the NR1, NR2A, and NR2B NMDA receptor subtypes"
GABAergic inputs come from several mostly hypothalamic locations, functionally prominent with respect to sleep-waking regulation is the innervation from the ventrolateral preoptic (VLPO) area which fires high during sleep and thus suppresses the firing of histamine neurons (159, 636, 678, 703). "
The TMN receives input from the noradrenergic cell groups including the locus coeruleus. Norepinephrine does not affect histaminergic neurons directly but effectively controls GABAergic input through α2-adrenoreceptors mediating an inhibition of IPSCs: evoked GABAergic IPSPs are reduced by norepinephrine and clonidine but not isoproterenol while exogeneously applied GABA responses remain unaffected (707). Dopamine also excites histamine neurons through D2 receptor activation (671)."
" ATP evokes fast nondesensitizing inward currents in TMN neurons. Single-cell RT-PCR and pharmacological analysis revealed P2X2 receptors as the major receptor type that occurs in all TMN neurons (796) five further types are expressed rarely. Zn2+ acts as a bidirectional modulator of P2X2 receptors (797). Zn2+ potentiation of ATP responses is caused by slowing ATP dissociation from the receptor, while inhibition at higher concentrations of Zn2+ is related to suppression of gating. ATP, ADP, UTP, and 2MeSATP excite TMN neurons through metabotropic receptors P2Y1 and P2Y4 are prevailing (670). "
"Both hypocretins (1 and 2, also known as orexin A and B) excite histamine neurons through the Hcrt2 receptor and activation of NCX (163, 165, 166, 664) (Fig. 9). This action is secondary to a rise in intracellular Ca2+ that probably comes from both extra- and intracellular sources. Hypocretin neurons also express dynorphin, which can contribute to the excitation of histaminergic neurons by suppressing inhibitory GABAergic inputs (164). "
"Neuropeptide Y (NPY)-containing fibers are found close to histaminergic neurons (734), and NPY indirectly affects histamine release (286). The appetite-stimulating stomach-derived ghrelin inhibits a potassium channel (Kir3) in cultured TMN neurons (39). Thyrotropin releasing hormone (TRH) reduces food intake (215) and sleeping time in rats and combats excessive sleepiness in canine models of narcolepsy (612). The majority of the TMN neurons are excited by TRH (673)."
"Prostaglandin E2 activates the TMN via the EP4 receptor to induce wakefulness in rats (273). Endocannabinoids increase histamine release selectively in the TMN through CB1R but independent from modulation of GABAergic transmission (100). Histaminergic neurons may also be involved in CO2-mediated arousal (306, 527)."
"Histamine through H1R excites neurons in most brain regions, including brain stem (45, 367, 407) (Fig. 12), hypothalamus, thalamus (462, 694, 855), amygdala, septum (213, 828), hippocampus (445, 659), olfactory bulb (299), and cortex"
"Classic antihistamines act at H1R (684) with well-known sedative properties (67, 407, 603). Many antidepressants or antipsychotics also bind to the H1R (336, 611)."
"Interestingly, the absence of histamine downregulates H2R expression but not H1Rs in a tissue-specific manner (175)."
"H2R couple to Gsα proteins to stimulate adenylyl cyclase and increase intracellular cAMP (40, 50, 197, 764), which activates protein kinase A (PKA) and the transcription factor CREB, all of which are key regulators of neuronal physiology and plasticity (35, 234, 462, 562, 563, 659). "
"A second messenger-mediated modulation of ionotropic receptors is common for several transmitters: facilitation of NMDA receptors through PKC and a reduction of the Mg2+ block have been described as a result of H1 receptor activation (561)."
Systemic l-thyroxine administration, along with rises in T3 and T4 levels, increases cortical 5-HT and histamine content,"
"Depletion of brain histamine decreases locomotion. Likewise, chronic loss of H3R function in H3R-KO mice is associated with reduced locomotion (762) and mice lacking histamine (HDC-KO), or the H1R (284) display altered ambulatory activity and reduced exploratory behavior, particularly in a novel environment (556)."
"H1 antihistamines impair cognitive performance in humans, and this action has been largely attributed to sedative effects (723) (see above) resulting from suppression of cholinergic subcortical (334, 335, 828) and cortical activity (60, 603, 828)."
"Histamine-deficient HDC-KO mice have elevated testicular and serum androgen levels but reduced testis weight, independent from GnRH expression, and their mating behavior and sexual arousal are strongly impaired (554). Likewise, administration of the H1 antihistamine astemizole affects testis weight and male reproductive behavior. Histamine may thus play a role in brain masculinization."
"Hypersomnia is currently treated mainly by drugs enhancing dopaminergic effects such as amphetamines and modafinil, which can also promote wakefulness by activating TMN histamine neurons (642)."
"Histamine- and histamine receptor-deficient animals show hyperphagia and disruption of feeding circadian rhythm and develop obesity, diabetes mellitus, hyperlipidemia, hyperinsulinemia, and disturbance of thermoregulation and cardiovascular functions (187, 311, 453, 739, 848), fundamental marks of metabolic syndromes. Behavioral and metabolic abnormalities produced by depletion of neuronal histamine from the hypothalamus mimic those of obese Zucker rats (628)."
"The neurotransmitter histamine is involved in the regulation of appetite and in the development of age-related obesity in mice. Furthermore, histamine is a mediator of the anorexigenic action of leptin. The aim of the present study was to investigate a possible role of histamine in the development of high-fat diet (HFD)-induced obesity."
"Both HDC-KO and WT mice fed an HFD for 8 weeks increased their body weight significantly more than STD-fed mice. A significant difference in body weight gain between HDC-KO mice fed an HFD or an STD was seen after 2 weeks, whereas a significant difference in body weight gain was first observed after 5 weeks in WT mice. "
"After 8 weeks epididymal adipose tissue size and plasma leptin concentration had increased significantly in HFD-fed WT and HDC-KO mice compared to their STD-fed controls."
"Therefore, we investigated the association between prescription H1 antihistamine use and obesity in adults using data from the 2005–2006 National Health and Nutrition Examination Survey (NHANES). Adults taking prescription H1 antihistamines were matched by age and gender with controls and compared on the basis of body measurements, plasma glucose and insulin concentrations, and lipid levels. Prescription H1 antihistamine users had a significantly higher weight, waist circumference, and insulin concentration than matched controls. The odds ratio (OR) for being overweight was increased in prescription H1 antihistamine users. H1 antihistamine use may contribute to the increased prevalence of obesity and the metabolic syndrome in adults given these medications are also commonly used as over the counter remedies."
"Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R), a leptin signaling pathway in the brain, regulate body weight and adiposity by affecting food intake and energy expenditure. Glucagon-like peptide-1 and/or corticotrophin-releasing hormone mediate leptin signaling to neuronal histamine. Leptin-induced suppression of food intake and upregulation of uncoupling protein-1 expression in brown adipose tissue were partially attenuated in histamine H(1)-R knockout (H(1)KO) mice. H(1)KO mice developed maturity-onset obesity. Hyperphagia and decreased energy expenditure assessed by the expression of uncoupling protein-1 mRNA were observed in older (48-wk-old) obese H(1)KO mice"
"Early disruption of H(1)-R-mediated functions in H(1)KO mice may lead to hyperphagia and decreased energy expenditure, which may contribute to the development of obesity in these animals."
"A recent Chinese supplementation study, in which obese middle-aged women diagnosed with metabolic syndrome received 12 weeks of supplemental histidine (2 g, twice daily) or matching placebo, achieved remarkable findings. Insulin sensitivity improved significantly in the histidine-supplemented subjects, and this may have been partially attributable to loss of body fat. Body mass index (BMI), waist circumference and body fat declined in the histidine-supplemented group relative to the placebo group the average fat loss in the histidine group was a robust 2.71 kg. Markers of systemic inflammation such as serum tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6, non-esterified fatty acids and oxidative stress also decreased in the histidine group"
"These intriguing findings were not altogether unexpected, as earlier rodent studies had shown that supplemental histidine tends to inhibit food intake, via an impact on the hypothalamus that is mediated by the neurotransmitter histamine. Acting via H1 receptors in the ventromedial and paraventricular hypothalamic nuclei, histamine suppresses feeding behaviour, promotes adipocyte lipolysis via sympathetic activation and raises metabolic rate. These effects are analogous to those of leptin on the brain, and indeed histamine has been shown to be a key mediator of leptin signalling in the hypothalamus. Leptin triggers histamine release in the hypothalamus, and histamine in turn prevents the downregulation of leptin receptors which mediates leptin resistance. Crucially, whether administered intraperitoneally or intraventricularly, histidine dose dependently increases hypothalamic levels of histamine as well as hypothalamic activity of histidine decarboxylase, the enzyme which converts histidine to histamine. Such administration also inhibits food consumption—an effect that is blocked in animals pretreated with an irreversible inhibitor of histidine decarboxylase"
"Transport of histidine into the brain may depend not only on plasma histidine level but also onneutral amino acids—including the branched-chain amino acids (BCAAs)—that can compete for access to the neutral amino acid transporter that mediates their transport through the blood–brain barrier. Hence, the rate of brain histidine uptake via this transporter should be proportionate to the plasma ratio of histidine to the sum of other neutral amino acids this sum is determined primarily by BCAA levels. This observation may be pertinent to cross-sectional studies concluding that plasma levels of BCAAs are elevated in those with type 2 diabetes, metabolic syndrome and/or obesity."
"Leptin resistance has recently been confirmed not only in animal obese models but in human obesity. Evidence is rapidly emerging that suggests that activation of histamine signaling in the hypothalamus may have substantial anti-obesity and antidiabetic actions, particularly in leptin-resistant states. To address this issue, effects of central, chronic treatment with histamine on food intake, adiposity, and energy expenditure were examined using leptin-resistant obese and diabetic mice. Infusion of histamine (0.05 pmol x g body wt(-1) x day(-1)) into the lateral cerebroventricle (i.c.v.) for 7 successive days reduced food intake and body weight significantly in both diet-induced obesity (DIO) and db/db mice. Histamine treatment reduced body fat weight, ob gene expression, and serum leptin concentration more in the model mice than in pair-fed controls. The suppressive effect on fat deposition was significant in visceral fat but not in subcutaneous fat. Serum concentrations of glucose and/or insulin were reduced, and tests for glucose and insulin tolerance showed improvement of insulin sensitivity in those mice treated with histamine compared with pair-fed controls. On the other hand, gene expression of uncoupling protein (UCP)-1 in brown adipose tissue and UCP-3 expression in white adipose tissue were upregulated more in mice with i.c.v. histamine infusion than in the pair-fed controls. "
Histamine synthesis in the brain is controlled by the availability of l-histidine and the activity of histidine decarboxylase
"Figure 14-4 depicts the dynamics of histamine in mammalian brain. Although histamine is present in plasma, it does not penetrate the blood—brain barrier. Thus, histamine concentrations in the brain must be maintained by synthesis. With a Km value of 0.1 mm for L-histidine under physiological conditions, HDC is not saturated by histidine concentrations in the brain, an observation which explains the effectiveness of large systemic doses of this amino acid in raising the concentrations of histamine in the brain. The essential amino acid l-histidine is transported into the brain by a saturable, energy-dependent mechanism (see Chap. 32)"
Normal corticosteroid levels are required for muscle maintenance, but altered glucocorticoid or mineralocorticoid levels can lead to muscle abnormalities. 58 Elevated aldosterone causes muscle weakness because of hypokalemia, while high glucocorticoid levels cause muscle wasting because of their catabolic effects on protein metabolism. Corticosteroid insufficiency results in decreased work capacity of striated muscle, weakness, and fatigue. This response reflects an inadequacy of the circulatory system rather than electrolyte and carbohydrate imbalances.
Chronic glucocorticoid administration results in induction of osteoporosis, a serious limiting factor in the clinical use of steroids. Glucocorticoid-induced bone loss is a multifaceted process. Glucocorticoids reduce bone remodeling by directly modulating osteoclast, osteoblast, and osteocyte function. They increase renal calcium excretion and decrease gastrointestinal calcium absorption, resulting in reduced serum calcium. Reduced serum calcium causes increased secretion of parathyroid hormone (PTH), and glucocorticoids increase PTH sensitivity. PTH action in turn stimulates osteoclast activity. 59 Other effects of high doses of glucocorticoids on the musculoskeletal system include aseptic or avascular necrosis of bone and spontaneous tendon rupture, presumably through an effect on collagen metabolism. 57, 60, 61
To understand H1-antihistamines, it is necessary to appreciate the state of science in the 1930s. In his review about his own work, Daniel Bovet wrote “Three naturally occurring amines, acetylcholine, epinephrine, and histamine, may be grouped together because they have a similar chemical structure, are all present in the body fluids, and exert characteristically strong pharmacologic activities. There are alkaloids which interfere with the effects of acetylcholine. Similarly, there are sympatholytic poisons which neutralize or reverse the effects of epinephrine. It seemed possible to me, therefore, that some substance might exist which exerts a specific antagonism toward histamine.” It was against this background that Bovet, who was looking for antagonists of acetylcholine, asked his student, Anne-Marie Staub, to test some of these compounds against histamine. This led to the discovery of the first H1-antihistamine in 1937. Although this compound was too toxic for use in humans, it opened the door for the introduction into the clinic of antergan in 1942, followed by diphenhydramine in 1945 and chlorpheniramine, brompheniramine, and promethazine later the same decade.
The histamine H1-receptor
The histamine H1-receptor is a member of the superfamily of G-protein-coupled receptors (GPCRs) [ Figure 1a ]. GPCRs may be viewed as llular switches” which exist as an equilibrium between the inactive or “off” state and the active or “on” state. In the case of the histamine H1-receptor, histamine cross links sites on transmembrane domains III and V to stabilize the receptor in its active conformation, thus causing the equilibrium to swing to the “on” position [ Figure 1b ]. H1-antihistamines, which are not structurally related to histamine, do not antagonize the binding of histamine but bind to different sites on the receptor to produce the opposite effect. For example, cetirizine cross links sites on transmembrane domains IV and VI to stabilize the receptor in the inactive state and swing the equilibrium to the “off” position [ Figure 1c ]. Thus, H1-antihistamines are not receptor antagonists, but are inverse agonists in that they produce the opposite effect on the receptor to histamine. Consequently, the preferred term to define these drugs is “H1-antihistamines” rather than “histamine antagonists.”
(a) Diagram of a histamine H1-receptor in a membrane showing seven transmembrane domains. Histamine stimulates the receptor following its penetration into the central core of the receptor. (b) A surface view of an activated receptor with histamine linking domains III and V. (c) A surface view of an inactive receptor with cetirizine linking domains IV and VI
The development of H1-antihistamines
Bearing in mind that first-generation H1-antihistamines derive from the same chemical stem from which cholinergic muscarinic antagonists, tranquilizers, antipsychotics, and antihypertensive agents were also developed, it is hardly surprising that they have poor receptor selectivity and often interact with receptors of other biologically active amines causing antimuscarinic, anti-α-adrenergic, and antiserotonin effects. But perhaps their greatest drawback is their ability to cross blood𠄻rain barrier and interfere with histaminergic transmission. Histamine is an important neuromediator in the human brain which contains approximately 64,000 histamine-producing neurons, emanating from the tuberomammillary nucleus. Stimulation of H1-receptors in all of the major parts of the cerebrum, cerebellum, posterior pituitary and spinal where they increase arousal in the circadian sleep/wake cycle, reinforce learning and memory, and have roles in fluid balance, suppression of feeding, control of body temperature, control of cardiovascular system, and mediation of stress-triggered release of adrenocorticotropic hormone (ACTH) and b-endorphin from the pituitary gland. It is not surprising then that antihistamines crossing the blood𠄻rain barrier interfere with all of these processes.
Physiologically, the release of histamine during the day causes arousal, whereas its decreased production at night results in a passive reduction in the arousal response. When taken during the day, first-generation H1-antihistamines, even in the manufacturers’ recommended doses, frequently cause daytime somnolence, sedation, drowsiness, fatigue, and impaired concentration and memory.[11,12] When taken at night, first-generation H1-antihistamines increase the latency to the onset of rapid eye movement (REM) sleep and reduce the duration of REM sleep. The residual effects of poor sleep, including impairment of attention, vigilance, working memory, and sensory motor performance, are still present in the next morning.[14,16] This is especially problematical with drugs with a long half-life [ Table 1 ]. The detrimental central nervous system (CNS) effects of first-generation H1-antihistamines on learning and examination performance in children and on impairment of the ability of adults to work, drive and fly aircraft have been reviewed in detail in a recent review.
Half-lives of first-generation H1-antihistamines
A major advance in antihistamine development occurred in the 1980s with the introduction of second-generation H1-antihistamines, which are minimally or nonsedating because of their limited penetration of the blood𠄻rain barrier. In addition, these drugs are highly selective for the histamine H1-receptor and have no anticholinergic effects. The latest EAACI/GA 2 LEN/EDF/WAO guidelines for the management of urticaria recommend that the first-line treatment for urticaria should be second generation, nonsedating H1-antihistamines. Further, it states “In patients with urticaria and no special indication, we recommend against the routine use of old sedating first-generation antihistamines (strong recommendation, high quality evidence).”
H1-antihistamines in urticaria
Most types of urticaria, including chronic spontaneous urticaria and the majority of inducible urticarias, are mediated primarily by mast cell-derived histamine which reaches very high concentrations due to the poor diffusibility of substances in the dermis.[21,22] They are characterized by short-lived wheals ranging from a few millimeters to several centimeters in diameter which are accompanied by severe itching which is usually worse in the evening or night-time. Standard licensed doses of H1-antihistamines are often ineffective in completely relieving symptoms in many patients for whom increasing the dosage up to four-fold is recommended.[19,24,25] Thus, it is clear that the attributes that dermatologists seek when choosing an H1-antihistamine are: Good efficacy, a rapid onset of action, a long duration of action, and freedom from unwanted effects. Although some of these attributes may be predicted from preclinical and pharmacokinetic studies, it is only in the clinical environment that they may be definitively established.
Two factors determine the efficacy of an H1-antihistamine: The affinity of the drug for H1-receptors (absolute potency) and the concentration of the drug at the sites of the H1-receptors. The affinity of an H1-antihistamine for H1-receptors is determined in vitro in preclinical studies. Comparing the three most recently developed drugs, desloratadine is the most potent antihistamine (Ki: 0.4 nM) followed by levocetirizine (Ki: 3 nM) and fexofenadine (Ki: 10 nM) (the lower the concentration, the higher the potency). The drug concentrations at its site of action could, theoretically, be calculated from its apparent volume of distribution (Vd) which are
5.6 l/kg for desloratadine, levocetirizine, and fexofenadine, respectively. However, Vd does not take into account other factors which influence local tissue concentrations in vivo, such as absorption, metabolism, and plasma binding. In the study of Gillard and colleagues, concentrations of unbound drug in the plasma rather than Vd were used to calculate receptor occupancy, a theoretical indicator of effectiveness in vivo [ Table 2 ]. The validity of these calculations of receptor occupancy is confirmed by the relative inhibition of wheal and flare responses by these drugs.[26,28]
Comparison of receptor occupancy for desloratadine, fexofenadine, and levocetirizine with inhibition of histamine-induced wheal and flare responses 4 and 24 h after drug administration
Speed of onset of action and duration of action
The speed of onset of action of a drug is often equated to the rate of its oral absorption and its duration of action by its plasma concentration. However, this is not strictly correct as seen from Figure 2 . In this study, in children,[31,32] plasma concentrations of drug are near maximum by 30 min and yet it takes a further 1½ h for the drug to diffuse into the extravascular space to produce a maximal clinical effect. In adults, the maximal inhibition of the flare response is
4 h for levocetirizine, fexofenadine, and desloratadine[28,30,33] but may be longer for drugs, such as loratadine and ebastine, which require metabolism to produce their active moiety.
Diagrammatic representation of the pharmacokinetics and pharmacodynamics of levocetirizine for a single oral dose of levocetirizine[31,32]
Figure 2 also shows that the duration of action of levocetirizine in inhibiting the histamine-induced flare response is also much longer than would be predicted from a knowledge of its plasma concentration.[31,32] This is presumably to “trapping” of the drug by its strong and long-lasting binding to histamine H1-receptors. Although less active in the wheal and flare test, desloratadine has a similarly long duration of action. However, the duration of action of fexofenadine, calculated as the time for the wheal to remain inhibited by at least 70%, is less prolonged being 8.5 h for 120 mg fexofenadine compared with 19 h for cetirizine. The primary reason for the shorter duration of action of fexofenadine is that it is actively secreted into the intestine and urine by P-glycoprotein.
The metabolism and elimination of H1-antihistamines have been extensively reviewed elsewhere[26,36] and will be only briefly summarized here. Cetirizine and levocetirizine are not metabolized and are excreted primarily unchanged in the urine. Desloratadine undergoes extensive metabolism in liver. Although this gives the potential for drug𠄽rug interactions, no significant interactions have been reported Fexofenadine, which is also minimally metabolized, is excreted primarily in the feces following its active secretion into the intestine under the influence of active drug transporting molecules. This gives the potential for interactions with agents, such as grapefruit juice and St Johns Wort, which inhibit these transporters. Although plasma concentrations of fexofenadine may be increased by these agents, no significant resulting adverse reactions have been reported.
A major reason for the reduced penetration of second-generation H1-antihistamines into the brain is because their translocation across the blood𠄻rain barrier is under the control of active transporter proteins, of which the ATP-dependent efflux pump, P-glycoprotein, is the best known.[37,38] It also became apparent that antihistamines differ in their substrate specificity for P-glycoprotein, fexofenadine being a particularly good substrate. In the brain, the H1-receptor occupancy of fexofenadine assessed using positron emission tomography (PET) scanning is negligible, π.1%, and, in psychomotor tests, fexofenadine is not significantly different from placebo. Furthermore, fexofenadine has been shown to be devoid of central nervous effects even at supraclinical doses, up to 360 mg.
Although fexofenadine is devoid of CNS effects, many other second-generation H1-antihistamines still penetrate the brain to a small extent where they have the potential to cause some degree of drowsiness or somnolence, particularly when used in higher doses. For example, PET scanning of the human brain has shown that a single oral doses of 10 mg and 20 mg cetirizine caused 12.5% and 25.2% occupancy of the H1-receptors in prefrontal and cingulate cortices, respectively. These results would explain the repeated clinical findings that the incidence of drowsiness or fatigue is greater with cetirizine than with placebo. Recent publications have suggested that, at manufacturers’ recommended doses, levocetirizine is less sedative than cetirizine and desloratadine causes negligible somnolence. [36,48] However, it should be pointed out that “mean results” do not reveal everything as some patients may show considerable somnolence, whereas others are unaffected.
The propensity of astemizole and terfenadine, to block the IKr current, to prolong the QT interval, and to potentially cause serious polymorphic ventricular arrhythmias such as torsades de pointes is well documented.[6,49] These two drugs are no longer approved by regulatory agencies in most countries. In addition, some first-generation H1-antihistamines, such as promethazine, brompheniramine, and diphenhydramine, may also be associated with a prolonged QTc and cardiac arrhythmias when taken in large doses or overdoses. No clinically significant cardiac effects have been reported for the second-generation H1-antihistamines: Loratadine, fexofenadine, mizolastine, ebastine, azelastine, cetirizine, desloratadine, and levocetirizine.
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