Spread the love


I. Introduction


Histamine was first discovered in the last century. It is the main medium for many biological reactions including allergic reactions. Some of these biological reactions are involved in the pathophysiological processes of common skin diseases. In theory, there are three ways to block the biological effects of histamine:

  • Reducing the synthesis of histamine.
  • Inhibiting the release of histamine.
  • Prevent the binding of histamine to the receptor.

Antihistamines work through a third pathway. There are currently two classes of antihistamines on the market: H1 antihistamines that inhibit H1 receptors and H2 antihistamines that inhibit H2 receptors.
Antihistamines are widely used in dermatology, especially H1 antihistamines, mainly for the treatment of pruritic skin diseases, even though histamine is not always involved in their pathophysiological processes.


II. Physiological pathology and pharmacological properties of histamine and its receptor


Histamine is a biogenic amine formed by decarboxylation of L-histidine. It is synthesized and stored in cytoplasmic secretory granules of human mast cells, basophils, gastric chromaffin cells and histaminergic neurons, and is released by IgE or non-IgE-mediated degranulation under various stimuli.
IgE-mediated degranulation is induced by the combination of two surface IgE molecules with high-affinity receptors (FCξRIαβγ) to form crosslinks, and can even be induced by specific allergens (type I hypersensitivity) or autoantibodies.
Non-IgE-mediated stimuli include cytokines, physical factors (such as contact with ramie), bifamily molecules including opioids such as cocaine and morphine, anaphylatoxins, neuropeptides (substance P), antibiotics (vancomycin or quinolones) ) and viral or bacterial antigens.
These stimuli bind to a specific receptor located on the surface of the target cell to cause histamine release. So far, four histamine receptors (H1, H2, H3 and H4) have been found. Most of the effects of histamine in allergic diseases are mediated by the H1 receptor. H1 and H2 vascular receptors are involved in the pathological process of hypotension, tachycardia, facial flushing, and headache. Stimulating H1 and H3 receptors can cause itchy skin and nasal congestion. A recent trial showed that H4 receptor antagonism can alleviate itching in mice through the potential effects of peripheral neurons. In addition to its role in early allergic reactions, histamine also stimulates the production of cytokines and the expression of cell adhesion molecules and class II antigens, thereby promoting late allergic reactions. Histamine also modulates the immune response through four types of receptors.

Histamine receptor

The four types of histamine receptors belong to the G-protein coupled receptor family and exhibit intrinsic activity (autonomous activity without histamine). They vary in cell expression, signal transduction effectors, and function.

H1 receptor

The H1 receptor is widely expressed in humans and mediates most of the effects of histamine. Activation of H1 receptor-coupled Gq/11 stimulates the phosphoinositide signaling pathway to produce IP3 (inositol triphosphate) and DAG (diacylglycerol), IP3 and DAG lead to activation of protein kinase C, causing intracellular Ca2+ concentration Raise. The H1 receptor also activates other signal transduction pathways, including phospholipase D and phospholipase A2, NOS and the transcription factor NF-kB. H1 receptor activation leads to vasodilation, increased vascular permeability, promotes smooth muscle contraction and mucus secretion, activation of sensory nerve endings leads to itching, slows the conduction time of the atrioventricular node, and causes coronary vasospasm. H1 receptor increases the expression of cell adhesion molecules such as intracellular adhesion molecule (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin by activation of macrophages and eosinophils. Improve the ability of antigen-presenting cells, co-activation of B cells, reduce humoral immunity and IgE production, induce cellular immunity (Th1), increase IFN-gamma autoimmunity, and polarize human dendritic cells into Th2 cell-promoting effects Effects such as dendritic cells support histamine involved in allergic inflammatory responses and immune regulation.

H2 receptor

Like the H1 receptor, the H2 receptor is widely expressed in humans and is mainly found on the surface of lymphocytes and basophils, coronary blood vessels and pulmonary blood vessels, myocardial tissue and gastric parietal cells. The H2 receptor is coupled to the Gs protein, which mediates an intracellular response. The main feature of this response is the increase in intracellular cAMP levels, which in turn activates adenylate cyclase, activates protein kinases, and regulates Ca2+ flux. Together with the H1 receptor, H2 receptor activation leads to increased vasodilation and vascular permeability. The H2 receptor also acts on the following organs, such as the cardiovascular system (positive muscle function), the gastrointestinal tract (increased secretion of gastric acid and pepsin), and the respiratory system (airway dilation and increased mucus secretion). Histamine can also inhibit the function of some lymphocytes through the action of H2 receptors, such as mitogen-induced lymphocyte proliferative response, antibody-secreting B-cell antibody synthesis, cell-mediated cytolysis and lymphokine production. Recruitment of CD4 helper T lymphocytes. Activation of the H2 receptor inhibits TNF-α production, stimulates IL-10 production, and promotes dendritic cell polarization to become a dendritic cell that promotes Th2 cells. Finally, activation of the H2 receptor inhibits chemotaxis of basophils and histamine release from mast cells and basophils, thereby reducing histamine release.

H3 receptor

The H3 receptor has been identified as a presynaptic receptor in the central and peripheral nervous systems that controls the release of histamine and other neurotransmitters. The H3 receptor is a Gi/0 protein-coupled receptor, and its activation inhibits adenylate cyclase leading to a decrease in cAMP and inhibition of Ca2+ influx. H3 receptors can also cause a decrease in the release of acetylcholine, neurokinin, and catecholamines, modulating the stimulatory effects of the H1 receptor. Finally, the H3 receptor regulates histaminergic neurotransmission: activation of the receptor results in a decrease in histaminergic neurotransmission leading to impairment of alert function, cognitive function, and cochlear-vestibular function. Like all other histamine receptors, H3 receptors have been shown to exhibit strong intrinsic activity.

H4 receptor

The H4 receptor is the last identified histamine receptor. They are highly expressed in bone marrow, peripheral hematopoietic cells, neutrophils, eosinophils, and T cells, and are expressed in the spleen, thymus, lung, small intestine, colon, heart, and brain. The H4 receptor, like the H3 receptor, acts in coupling with the Gi/0 protein. Activation of the H4 receptor inhibits forskolin-induced cAMP formation. Activation of the histamine H4 receptor promotes the accumulation of inflammatory cells (mainly eosinophils and mast cells) at sites of allergic inflammation. Studies have suggested that the H4 receptor and the H2 receptor are involved in controlling the release of IL-16 from human lymphocytes. Most of the effects of H4 receptor activation on target cells and tissues remain to be determined.


III. H1 antihistamine

Bovet and Staub discovered the H1 antihistamine in 1937, initially used to counteract the physiological effects of histamine and H1 receptor binding. For a long time, H1 antihistamines have been considered to be H1 receptor blockers or H1 receptor antagonists. Until recently, studies have shown that H1 antihistamines are inverse agonists of the H1 receptor. In fact, studies have now confirmed that under the basal state, the H1 receptor exhibits a reversible equilibrium state in which the activation and inhibition states coexist, and the H1 antihistamine changes the equilibrium state by binding to the H1 receptor. To inhibit the state, the inactivated configuration of the receptor is stabilized, thereby blocking not only the histamine-binding receptor but also the basic activity of the receptor.

The H1 antihistamine is composed of a nitrogenous base containing an aliphatic side chain, and has a core structure common to histamine, that is, an ethylamine group. This common ethylamine group allows the H1 antihistamine to bind to the H1 receptor. H1 antihistamines are divided into two categories, namely the first generation H1 antihistamine and the second generation H1 antihistamine. The two types of H1 antihistamines differ in their specificity and selectivity for histamine receptors and their ability to enter the central nervous system. However, there is no significant difference in the anti-H1 activity between the two classes of drugs.

First generation H1 antihistamine

First discovered are the first generation H1 antihistamines, which are classified into six classes depending on the chemical group: ethylenediamine, ethanolamine, alkylamine, phenothiazine, piperazine and piperidine. The first generation of H1 antihistamines inhibits the binding of histamine to the H1 receptor by reversible and concentration-dependent competition, so their binding to the receptor is reversible, due to the dissociation of the antihistamine from the receptor. Or reversed at high concentrations of histamine. Most of the first generation H1 antihistamine molecules also exhibit some other pharmacological responses due to the lack of specificity for histamine receptors and similarity to other organic amine structures. The first generation of H1 antihistamines also binds to serotonergic receptors, muscarinic receptors, and a-adrenergic receptors, which explains some common side effects of first-generation H1 antihistamines: Weight gain is associated with antiserotonergic receptors; atropine-like side effects such as urinary retention, elevated intraocular pressure, and dry eyes; anti-sickness effects are associated with anticholinergic effects. The first generation of H1 antihistamines, due to their ability to penetrate into the central nervous system, produced side effects in the central nervous system, manifested as: lethargy, potentially affecting activities of daily living including work and driving skills. All first-generation H1 antihistamines are metabolized by the liver (P450 cytochrome), and their active drugs or metabolites are eventually excreted in the feces or urine. The interaction between the first generation H1 antihistamines and other known drugs that are metabolized by P450 cytochrome may result in reduced efficacy or reduced side effects. Some first-generation H1 antihistamines have a short half-life and may require multiple doses per day. The receptor agonist effect may occur early in the treatment, causing a transient exacerbation of symptoms.

Second generation H1 antihistamine

The second generation of H1 antihistamines was successfully developed in the early 1980s. The main difference between the second-generation H1 antihistamine and the first-generation H1 antihistamine is its activity of binding-dissociation with the receptor and its osmotic effect on the central nervous system. Binding of the second-generation H1 antihistamine to the H1 receptor is considered “non-competitive” because the second-generation H1 antihistamine binds to a different position of histamine. Therefore, the binding of the second-generation H1 antihistamine to the receptor is more stable, the reversal process is slower, and it is not easily inhibited by the newly produced histamine influx. The second-generation H1 antihistamine has higher specificity and selectivity for the surrounding H1 receptor, and thus side effects are reduced, especially muscarinic side effects are reduced. The lipophilicity of the second-generation H1 antihistamine and the addition of the P-glycoprotein transfer factor that constitutes the substrate reduce the permeability of the drug to the blood-brain barrier, thereby reducing the side effects of the central nervous system, but the second generation The H1 antihistamine does not completely have no side effects on the central nervous system because the H1 receptor occupancy rate in the central nervous system is 0% to 30%.

The latest drug molecules are still mainly derived from previous molecules. For example, desloratadine and fexofenadine are metabolites of loratadine and terfenadine, the corresponding isomer of cetirizine. Some second-generation H1-antihistamines (azelastine, epothilate, loratadine, and imidazol) are primarily metabolized by cytochrome P450, while other drugs (Avastin, Fesso Fenadine, cetirizine, levocetirizine, desloratadine are not primarily metabolized by the cytochrome P450 system. Fexofenadine and levocetirizine can be excreted directly from the urine and feces without metabolism. Many drugs with longer half-lives can be administered once a day. Patients with impaired liver function (cetirizine, ebastine, loratadine) and renal failure (cetirizine, fexofenadine, loratadine and ivastatin) need to be adjusted Drug dosage.

Antiallergic and anti-inflammatory effects of antihistamines

Studies have shown that many H1 antihistamines have anti-allergic effects, including inhibition of mediator release (cetirizine, loratadine), and reduction of eosinophil chemotaxis (cetirizine, levocetirizine) Pyrazine, desloratadine and loratadine), inhibiting the expression of cell adhesion molecules (cetirizine, loratadine, desloratadine, fexofenadine), down-regulating H1 receptor activation Nuclear factor kB (cetirizine, azelastine). H1 antihistamines should be used with caution in young children, the elderly, pregnant women, and patients with kidney or liver damage. When the drug used requires cytochrome P450 in the liver to participate in metabolism, the use of macrolides, imidazoles, cytochrome P450 inducers, and alcohol intake should be avoided. Grapefruit juice also increases the drug concentration of loratadine and terfenadine. Several studies have shown that although there are cases of dysphonia caused by the use of first-generation brompheniramine and diphenhydramine, there is no evidence of increased teratogenic risk with H1 antihistamines. There have been no reports showing that the use of chlorpheniramine and dextropheniramine in animals and humans can cause malformations. Therefore, for pregnant women, these two drugs are preferred. There are some research data on second-generation H1 antihistamines, and most of these studies must be cautious when prescribing these drugs to women in the first trimester of pregnancy. In one study, infants born after taking loratadine or desloratadine developed hypospadias, but no subsequent cases were reported. There have been no reports of serious adverse events in lactating women after lactation using H1 antihistamines, but several studies have reported cases of irritability and lethargy after the first-generation H1 antihistamines. Reports have shown that after the mother received overdose of diphenhydramine (150 mg / j) and hydroxyzine, the drug withdrawal occurred in the newborn.


IV. Adverse reactions of H1 antihistamines

Effect on the central nervous system

It is well known that the first generation of H1 antihistamines can penetrate the blood-brain barrier and may impair human physical activity and intellectual ability. Clinical symptoms can include: drowsiness, dizziness, sedation, coordination, cognitive, memory, and decreased mental performance, occasionally causing muscle tone, dyskinesia, and excitement. This sedative effect can be beneficial because it can suppress the patient’s objective sensation of certain symptoms, mainly to suppress itching symptoms, so sometimes the first-generation H1 antihistamine is administered to the patient at night. However, several studies have shown that after taking a dose of the first-generation H1 antihistamine at night, the sedative effect lasts until the next day. The evidence for the central nervous system side effects of the first-generation H1 antihistamines that have been tolerated a few days after administration remains controversial. The second-generation H1 antihistamines are considered to be non-sedating drugs within the clinically recommended dose range, but when given high doses, some drugs may act as sedatives, such as loratadine, cetirizine, and Ibas Ting and Mizolastine. So far, fexofenadine has not been reported to cause side effects of the central nervous system even when administered at a super therapeutic dose. In H1 antihistamines, in addition to rupatadine, fexofenadine, desloratadine and levocetirizine, driving ability can be affected. It has been clearly established that diphenhydramine affects driving ability, just like drinking alcohol, even if there is no drowsy performance. The first generation of H1 antihistamines can cause a decline in the mobility of workers and casualties, which can be the cause of death in aircraft and traffic accidents. The first generation of H1 antihistamines (closten, chlorpheniramine, cyproheptadine, diphenhydramine) combined with alcohol or benzodiazepines can increase side effects on the central nervous system. There is no data to date indicating that this will occur in second-generation H1 antihistamines. Studies have shown that the first generation of H1 antihistamines affects children’s cognitive function, which affects their performance in school. This side effect has not been found in the second generation of drugs, and it has been reported that children with allergic rhinitis have improved their performance at school after taking loratadine. Children with atopic disease between 12 and 24 months have been shown to have no side effects on their mental development and cognitive function after taking 18 months of daily doses of cetirizine and levocetirizine.

Impact on the heart

Both first and second generation H1-antihistamines can cause side effects on the heart. Mainly because when the metabolism is abnormal, the plasma H1 antihistamine level will increase (due to abnormal liver metabolism caused by cytochrome P450 inhibitors such as ketoconazole, itraconazole and macrolide antibiotics, Liver damage due to cirrhosis or alcohol abuse). Impaired heart function, electrolyte imbalance, and other known drugs that extend the distance between the beginning of the Q wave and the end of the T wave (QT interval) in the ECG, such as tricyclic antidepressants and antipsychotics. May cause arrhythmia. It has been reported that arrhythmias caused by the second-generation H1 antihistamines, terfenadine and astemizole, include torsades, ventricular tachycardia, atrioventricular block, and even cardiac arrest. The drug later withdrew from the market. The side effects of antihistamines on the heart are not related to the antagonism of histamine, but are related to the delayed QT interval caused by delayed reversal of potassium ions in the myocardium. Other second-generation H1 antihistamines (loratadine, desloratadine, ebastine, and imazethide) can also inhibit potassium channel opening in vitro, but this effect is not tested in vivo. Cetirizine, levocetirizine, and fexofenadine had no effect on potassium channels. There are no reports of prolonged QT interval caused by loratadine, imazethide, cetirizine, azelastine, and fexofenadine, even if given at high doses. However, administration of high doses of espasin or imidazol, or simultaneous administration of ketoconazole, may result in prolonged QT interval. The combination of loratadine or fexofenadine with ketoconazole or macrolides does not prolong the QT interval. Second-generation H1 antihistamines, such as cetirizine, desloratadine, fexofenadine, and loratadine appear to be relatively free of cardiotoxicity.

Side effects of the digestive tract

Only the first generation of antihistamines (mepiride, androxazoline, tripyramine) have been reported to cause digestive side effects, including nausea, diarrhea, anorexia, and upper abdominal pain. There are no reports of second-generation antihistamines leading to gastrointestinal dysfunction.

Anticholinergic effect

The first generation of H1 antihistamines can cause anticholinergic effects, including dry mouth, eyes, nose, blurred vision, and urinary retention. Therefore, patients with glaucoma or enlarged prostate should ban first-generation H1 antihistamines.


Both the first and second generation H1 antihistamines have been reported to cause rashes. For example, eczema-like rash occurs after taking diphenhydramine, urticaria occurs after taking cetirizine and hydroxyzine, and fixed drug eruption occurs after taking hydroxyzine, loratadine, diphenhydramine, cetirizine.


V. Antihistamine medication for pruritus

H1 antihistamines are clinically common drugs in dermatology. Urticaria is still the primary indication for H1 antihistamines. H1 antihistamines are also widely used in the treatment of other pruritic skin diseases, even if these pruritic skin diseases are not histamine-mediated, sometimes for hypnosis. Apply these medicines. A large body of literature supports the use of H1 antihistamines for urticaria, and several studies have reported other indications for antihistamines.


H1 antihistamines are widely used in the treatment of acute and chronic urticaria due to the intense itching properties of urticaria and the current known role of histamine in its pathophysiology. Several studies have demonstrated that H1 antihistamines are effective in reducing pruritus and reducing the number, size and duration of wheals in the treatment of urticaria. While eliminating the cause, antihistamines have been shown to be effective in treating acute urticaria. Some second-generation H1 antihistamines (loratadine, cetirizine) have been reported to be superior to chlorpheniramine and to the first-generation H1 antihistamines (hydroxyzine, diphenhydramine). There is no difference. Two studies have shown that the inhibition of histamine-induced red wind group levocetirizine is superior to desloratadine, fexofenadine, loratadine and mizolastine, but the clinical relevance is not yet clear . H2 antihistamine alone has no effect, and combined with H1 antihistamine can promote early regression of skin lesions.

H1 antihistamines are a treatment option for chronic urticaria, and several studies have confirmed their effectiveness in reducing itching, edema, and wheal. Studies have shown that hydroxyzine, loratadine, imidazolone, cetirizine, ketotifen, ebastine, fexofenadine, desloratadine, levocetirizine and luphos The efficacy is better than placebo. The study found that the overall efficacy of the second-generation H1 antihistamine was equivalent to that of the first generation, but compared with diphenhydramine, loratadine and cetirizine compared with cetirizine, cetirizine Compared with sofinastine, the former is more effective and faster. It has been reported that the H1 antihistamines hydroxyzine and chlorpheniramine are combined with the H2 antihistamine cimetidine, which is slightly higher than the H1 antihistamine alone in reducing the itching and reducing the wheal. There is insufficient data to support such combinations that can be routinely used in clinical practice. The treatment of physical urticaria remains a major challenge, and few H1 antihistamines are effective. In the treatment of skin scratches, a small number of studies currently available have found that cetirizine and avastin are more effective than placebo, and hydroxyzine is more effective than chlorpheniramine. The combined use of H1 and H2 antihistamines, especially hydroxyzine combined with cimetidine, chlorpheniramine and cimetidine, is more effective than chlorpheniramine alone. The efficacy of cetirizine for delayed-onset urticaria, solar urticaria, and cholinergic urticaria was reported to be consistent with placebo. Hydroxyzine has been recommended for the treatment of water-borne urticaria and cholinergic urticaria, and ebastine is used to treat acquired cold urticaria. It has been reported that H1 antihistamine/anti-leukotriene combination is effective in the treatment of delayed stress urticaria and cold urticaria. H1 and H2 antihistamines are combined for the treatment of cold urticaria and localized heat. Urticaria is effective.

The assessment of the Health-Related Quality of Life Scale (HRQoL) has become a popular trend in assessing the efficacy of dermatological treatment. It is well known that chronic urticaria has a serious impact on the quality of life of patients due to its chronic and unpredictable nature. The Common Skin Disease Scale (DLQI, VQ-Derm) and the Chronic Urticaria Scale (CU-QoL) were developed for these populations. However, there are not many studies using these scales. There have been improved versions of H1 antihistamines (desloratadine, fexofenadine, levocetirizine and rupatadine). Report on the HRQoL scale.

Atopic dermatitis (AD)

There is evidence to support that the pathophysiological changes in the symptoms of atopic dermatitis are related to histamine, and H1 antihistamines are often used as an antipruritic agent in the treatment of atopic dermatitis. Although the efficacy of these drugs, cyproheptadine, hydroxyzine, cetirizine, loratadine, and fexofenadine, has been reported, there is currently no high-level evidence from a comprehensive study to support this clinical practice. There is some data to support the benefits of H1 antihistamines in children with long-term treatments. For example, a study with high-level evidence shows that children with atopic dermatitis treated with cetirizine for 18 months can be reduced. The effect of topical glucocorticoid doses, those who are allergic to grass pollen and dust mites, slow the development of asthma. The second-generation H1 antihistamine fexofenadine combined with topical glucocorticoids (60 mg x 2/j) was superior to placebo. One of the reasons for the above results may be due to changes in immune parameters (IgE number, lymphocyte proliferation index, and CD4: CD8 ratio reduction index).

Mast cell hyperplasia

H1 antihistamines are clinically widely used in the treatment of mastocytosis, although there is not much data for this type of study. The efficacy of azelastine, chlorpheniramine, cyproheptadine, ketotifen and hydroxyzine in the treatment of mastocytosis has been reported, but no placebo group was used as a control in these studies. There are no reports of second-generation antihistamines in this area.

Insect bite reaction

Loratadine, ebastine, and cetirizine were found to be more effective than placebo in preventing and delaying wheals and papules that occur in children and adults after being bitten by mosquitoes. However, cetirizine and ebastine were more effective in reducing edema and reducing itching compared with loratadine and placebo. Recent studies have found that levocetirizine is effective in reducing the size of the wheal and relieving itching in adult patients after being bitten by mosquitoes.

Drug eruption

The key to the treatment of drug eruptions is to detect the drugs that cause the sensitization as soon as possible and to stop the drugs. Since drug eruptions are usually accompanied by itching symptoms, H1 antihistamines are often used in the treatment of drug eruptions. In addition to urticaria-like drug eruptions, there are no studies to support the use of antihistamines in the treatment of drug eruptions.

Other pruritic skin diseases

Several studies and cases have reported the effectiveness of H1 antihistamines in the treatment of various pruritic skin diseases. The combination of cetirizine and cimetidine can effectively reduce the degree of itching in burn patients. It has been reported that oxalimide is effective in the treatment of senile pruritus, and topical oxapramine can effectively improve genital itching and idiopathic genital pruritus in female vulvar sclerosing moss. The use of dimethyl hydrazine maleate can effectively control the pruritus of children with varicella-zoster virus infection.


VI. Conclusion

H1 antihistamines are an effective treatment for urticaria and their efficacy has been widely demonstrated. They should not be used for all pruritic skin diseases, but are logically applicable to histamine-associated pruritic skin diseases. The second generation of drugs should be the first choice because of its advantages of fewer side effects and better pharmacokinetics. All second-generation drugs are comparable in efficacy, with mostly no sedative effects and cardiac side effects.

Leave a Reply

Your email address will not be published. Required fields are marked *