Are there long term side effects of antihistamine usage?

At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia. Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration. This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness. It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week). It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H receptor of the latter or may have to do with the use of optimal doses. Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion. This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65. Anticholinergic activity notably may interfere with the sleep-promoting effects of H receptor blockade.

Doxepin

Doxepin is a tricyclic antidepressant (TCA) used to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia). As a cream it is used for short term treatment of itchiness due to atopic dermatitis or lichen simplex chronicus.

At doses used to treat depression, doxepin appears to inhibit the reuptake of serotonin and norepinephrine and to have antihistamine, adrenergic and serotonin receptor antagonistic, and anticholinergic activities; at low doses used to treat insomnia it appears to be selective for the histamine H receptor.

It was introduced under the brand names Quitaxon and Aponal by Boehringer, which discovered it, and as Sinequan by Pfizer, and has subsequently been marketed under many other names worldwide.
Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia). As a cream it is used for short term treatment of itchiness to due atopic dermatitis or lichen simplex chronicus.

In 2016 the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence. The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar. A 2015 AHRQ review of treatments for insomnia had similar findings.

A 2010 review found that topical doxepin is useful to treat itchiness.

A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second-line treatment.

Known contraindications include:Its use in pregnant and lactating women is advised against, although the available preclinical evidence (based on animal studies) suggests it is unlikely to cause any deleterious effects on fetal development. The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the fetus and it is known to cross the placenta. Doxepin is secreted in breast milk and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.

Doxepin is licensed to be used in much smaller doses (viz., 3 mg and 6 mg) in some countries the side effects' profile of which may differ from this list.Like other TCAs, doxepin is highly toxic in cases of overdose. Mild symptoms include drowsiness, stupor, blurred vision, and excessive dryness of mouth. More serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia. Urinary retention, decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils, and hyperactive reflexes are other possible symptoms of doxepin overdose. Management of overdose is mostly supportive and symptomatic, and can include the administration of a gastric lavage so as to reduce absorption of the doxepin. Supportive measures to prevent respiratory aspiration is also advisable. Antiarrhythmic agents may be an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose. Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects. Haemodialysis is not recommended due to the high degree of protein binding with doxepin. ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.

Doxepin should not be used within 14 days of using a monoamine oxidase inhibitor (MAOI) such as phenelzine due to the potential for hypertensive crisis or serotonin syndrome to develop. Its use in those taking potent CYP2D6 inhibitors such as fluoxetine, paroxetine, sertraline, duloxetine, bupropion, and quinidine is recommended against owing to the potential for its accumulation in the absence of full CYP2D6 catalytic activity. Hepatic enzyme inducers such as carbamazepine, phenytoin, and barbiturates are advised against in patients receiving TCAs like doxepin owing to the potential for problematically rapid metabolism of doxepin to occur in these individuals. Sympathomimetic agents may have their effects potentiated by TCAs like doxepin. Doxepin also may potentiate the adverse effects of anticholinergic agents such as benztropine, atropine and hyoscine (scopolamine). Tolazamide, when used in conjunction with doxepin has been associated with a case of severe hypoglycaemia in a type II diabetic individual. Cimetidine may influence the absorption of doxepin. Alcohol may potentiate some of the CNS depressant effects of doxepin. Antihypertensive agents may have their effects mitigated by doxepin. Cotreatment with CNS depressants such as the benzodiazepines can cause additive CNS depression. Co-treatment with thyroid hormones may also increase the potential for adverse reactions.

Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities. It is specifically an antagonist of the histamine H and H receptors, the serotonin 5-HT and 5-HT receptors, the α-adrenergic receptor, and the muscarinic acetylcholine receptors (M–M). Similarly to other tricyclic antidepressants, doxepin is often prescribed as an effective alternative to SSRI medications. Doxepin is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose and its effectiveness as an analgesic (including in the treatment of neuropathic pain, as a migraine prophylactic, and as a local anesthetic). The potencies of doxepin in terms of its receptor antagonism specifically are as follows:Based on its values for monoamine reuptake inhibition, doxepin is relatively selective for inhibition of norepinephrine reuptake with much weaker effects on serotonin reuptake and negligible influence on dopamine reuptake.

The major metabolite of doxepin, nordoxepin (desmethyldoxepin), is pharmacologically active similarly, but relative to doxepin, is much more selective as a norepinephrine reuptake inhibitor. In general, the demethylated variants of tertiary amine TCAs like doxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.

Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day. Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg, although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia. At low doses, below 25 mg, doxepin is a pure antihistamine. At antidepressant doses of above 25 mg, doxepin has significant antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.

Doxepin is a mixture of ("E") and ("Z") stereoisomers with an approximate ratio of 85:15. When doxepin was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio. ("Z")-Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than ("E")-doxepin. The selectivity of doxepin for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of ("E")-doxepin in the mixture. Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit "E"-"Z" isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake.

Doxepin is a highly potent antihistamine, with this being its strongest activity. In fact, doxepin has been said to be the most or one of the most potent H receptor antagonists available, with one study finding an "in vitro" K of 0.17 nM. It is the most potent and selective H receptor antagonist of the TCAs (although the "tetracyclic" antidepressant (TeCA) mirtazapine is slightly more potent), and other sedating antihistamines, for instance the over-the-counter diphenhydramine (K = 16 nM) and doxylamine (K = 42 nM), show far lower affinities for this receptor in comparison. The affinity of doxepin for the H receptor is far greater than its affinity for other sites, and 10- to 100-fold higher doses are needed for antidepressant effects. In accordance, although it is often described as a "dirty drug" due to its highly promiscuous binding profile, doxepin acts as a highly selective antagonist of the H receptor at very low doses (less than 10 mg; typically 3 to 6 mg). At these doses, it notably has no clinically relevant anticholinergic effects such as dry mouth or cognitive/memory impairment, unlike most other sedating antihistamines, and similarly has no effect on other receptors such as adrenergic and serotonin receptors.

The H receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses. The incidence of side effects with doxepin and its safety at these doses was similar to that of placebo in clinical trials; the most frequent side effects were headache and somnolence/sedation, both with an incidence of less than 5%. Other side effects sometimes associated with antihistamines, including daytime sedation, increased appetite, and weight gain, all were not observed. Clinical evidence of H receptor antagonists and TCAs for the treatment insomnia shows mixed effectiveness and is limited in its quality due to weaknesses like small sample sizes and poor generalizability. However, doxepin is a unique and notable exception; it has been well-studied in the treatment of insomnia and shows consistent benefits with excellent tolerability and safety. Aside from diphenhydramine and doxylamine, which have historical approval as hypnotics, doxepin is the only H receptor antagonist that is specifically approved for the treatment of insomnia in the United States.

The effect sizes of very low-dose doxepin in the treatment of insomnia range from small to medium. These include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency. Conversely, very low-dose doxepin shows relatively weak effects on sleep initiation and does not significantly separate from placebo on this measure. This is in contrast to benzodiazepines and nonbenzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep onset latency. However, it is also in contrast to higher doses of doxepin (50 to 300 mg/day), which "have" been found to significantly reduce latency to sleep onset. A positive dose–response relationship on sleep measures was observed for doses of doxepin between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and older adults. However, the incidence of adverse effects appeared to increase with longer treatment duration. A dose of doxepin as low as 1 mg/day was found to significantly improve most of the assessed sleep measures, but unlike the 3 and 6 mg/day doses, was not able to improve wake time during sleep. This, along with greater effect sizes with the higher doses, was likely the basis for the approval of the 3 and 6 mg doses of doxepin for insomnia and not the 1 mg dose.

Antagonism of the H, 5-HT, 5-HT, and α-adrenergic receptors is thought to have sleep-promoting effects and to be responsible for the sedative effects of TCAs including those of doxepin. Although doxepin is selective for the H receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses. However, in contrast to very low doses of doxepin, rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses (25 to 50 mg/day) of the drug. In addition, one study found that although such doses of doxepin improved sleep measures initially, most of the benefits were lost with chronic treatment (by 4 weeks). Due to limited data however, more research on potential tolerance and withdrawal effects of moderate doses of doxepin is needed. At these doses of doxepin, dry mouth, an anticholinergic effect, was common (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also frequently observed, although these adverse effects were notably not significantly more frequent than with placebo in the study in question. In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects as well as apparent loss of hypnotic effectiveness with chronic treatment.

Doxepin at a dose of 25 mg/day for 3 weeks has been found to decrease cortisol levels by 16% in adults with chronic insomnia and to increase melatonin production by 26% in healthy volunteers. In individuals with neuroendocrine dysregulation in the form of nocturnal melatonin deficiency presumably due to chronic insomnia, very-low-dose doxepin was found to restore melatonin levels to near-normal values after 3 weeks of treatment. These findings suggest that normalization of the hypothalamic–pituitary–adrenal axis and the circadian sleep–wake cycle may be involved in the beneficial effects of doxepin on sleep and insomnia.

Doxepin has been identified as an inhibitor of CYP2D6 "in vivo" in a study of human patients being treated with 75 to 250 mg/day for depression. While it significantly altered metabolic ratios for sparteine and its metabolites, doxepin did not convert any of the patients to a different metabolizer phenotype (e.g., extensive to intermediate or poor). Nonetheless, inhibition of CYP2D6 by doxepin could be of clinical importance.

Doxepin is well-absorbed from the gastrointestinal tract but between 55 and 87% undergoes first-pass metabolism in the liver, resulting in a mean oral bioavailability of approximately 29%. Following a single very low dose of 6 mg, peak plasma levels of doxepin are 0.854 ng/mL (3.06 nmol/L) at 3 hours without food and 0.951 ng/mL (3.40 nmol/L) at 6 hours with food. Plasma concentrations of doxepin with antidepressant doses are far greater, ranging between 50 and 250 ng/mL (180 to 900 nmol/L). Area-under-curve levels of the drug are increased significantly when it is taken with food.

Doxepin is widely distributed throughout the body and is approximately 80% plasma protein-bound, specifically to albumin and α-acid glycoprotein.

Doxepin is extensively metabolized by the liver via oxidation and "N"-demethylation. Its metabolism is highly stereoselective. Based on "in vitro" research, the major enzymes involved in the metabolism of doxepin are the cytochrome P450 enzymes CYP2D6 and CYP2C19, with CYP1A2, CYP2C9, and CYP3A4 also involved to a lesser extent. The major active metabolite of doxepin, nordoxepin, is formed mainly by CYP2C19 (>50% contribution), while CYP1A2 and CYP2C9 are involved to a lesser extent, and CYP2D6 and CYP3A4 are not involved. Both doxepin and nordoxepin are hydroxylated mainly by CYP2D6, and both doxepin and nordoxepin are also transformed into glucuronide conjugates. The elimination half-life of doxepin is about 15–18 hours, whereas that of nordoxepin is around 28–31 hours. Up to 10% of Caucasian individuals show substantially reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal.

Nordoxepin is a mixture of ("E") and ("Z") stereoisomers similarly to doxepin. Whereas pharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of ("E")- and ("Z")-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the ("E")- and ("Z")-stereoisomers of nordoxepin, due to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1.

Doxepin is eliminated primarily in the urine and predominantly in the form of glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin.

Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.

Individuals can be categorized into different types of cytochrome P450 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most people are extensive metabolizers, and have "normal" metabolism of doxepin. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers break down doxepin much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.

A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 enzymes. In CYP2D6 extensive, intermediate, and poor metabolizers, the mean clearance rates of ("E")-doxepin were 406, 247, and 127 L/hour, respectively (~3-fold difference between extensive and poor). In addition, the bioavailability of ("E")-doxepin was about 2-fold lower in extensive relative to poor CYP2D6 metabolizers, indicating a significant role of CYP2D6 in the first-pass metabolism of ("E")-doxepin. The clearance of ("E")-doxepin in CYP2C9 slow metabolizers was also significantly reduced at 238 L/hour. CYP2C19 was involved in the metabolism of ("Z")-doxepin, with clearance rates of 191 L/hour in CYP2C19 extensive metabolizers and 73 L/hour in poor metabolizers (~2.5-fold difference). Area-under-the-curve (0–48 hour) levels of nordoxepin were dependent on the genotype of CYP2D6 with median values of 1.28, 1.35, and 5.28 nM•L/hour in CYP2D6 extensive, intermediate, and poor metabolizers, respectively (~4-fold difference between extensive and poor). Taken together, doxepin metabolism appears to be highly stereoselective, and CYP2D6 genotype has a major influence on the pharmacokinetics of ("E")-doxepin. Moreover, CYP2D6 poor metabolizers, as well as patients taking potent CYP2D6 inhibitors (which can potentially convert a CYP2D6 extensive metabolizer into a poor metabolizer), may be at an increased risk for adverse effects of doxepin due to their slower clearance of the drug.

Another study assessed doxepin and nordoxepin metabolism in CYP2D6 ultra-rapid, extensive, and poor metabolizers following a single 75 mg oral dose. They found up to more than 10-fold variation in total exposure to doxepin and nordoxepin between the different groups. The researchers suggested that in order to achieve equivalent exposure, based on an average dose of 100%, the dosage of doxepin might be adjusted to 250% in ultra-rapid metabolizers, 150% in extensive metabolizers, 50% in intermediate metabolizers, and 30% in poor metabolizers.

Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together with a side chain attached in its chemical structure. It is the only TCA with a dibenzoxepin ring system to have been marketed. Doxepin is a tertiary amine TCA, with its side chain-demethylated metabolite nordoxepin being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and trimipramine. Doxepin is a mixture of ("E") and ("Z") stereoisomers (the latter being known as "cidoxepin" or "cis"-doxepin) and is used commercially in a ratio of approximately 85:15. The chemical name of doxepin is ("E"/"Z")-3-(dibenzo["b","e"]oxepin-11(6"H")-ylidene)-"N","N"-dimethylpropan-1-amine and its free base form has a chemical formula of CHNO with a molecular weight of 279.376 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.

Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969. It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.

"Doxepin" is the generic name of the drug in English and German and its and, while "doxepin hydrochloride" is its,,, and. Its generic name in Spanish and Italian and its are "doxepina", in French and its are "doxépine", and in Latin is "doxepinum".

The "cis" or ("Z") stereoisomer of doxepin is known as "cidoxepin", and this is its while "cidoxepin hydrochloride" is its.

It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.

, doxepin is marketed under many brand names worldwide: Adnor, Anten, Antidoxe, Colian, Deptran, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinquan, and Zonalon. It is also marketed as a combination drug with levomenthol under the brand name Doxure.

The oral formulations of doxepin are -approved for the treatment of depression and sleep-maintenance insomnia and its topical formulations are FDA-approved the short-term management for some itchy skin conditions. Whereas in Australia and the United Kingdom, the only licensed indication(s) is/are in the treatment of major depression and pruritus in eczema, respectively.

As of 2017 there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.
Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives). As of 2017, it is in phase II clinical trials for this indication. The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.

Doxepin was under development by Winston Pharmaceuticals in an intranasal formulation for the treatment of headache. As of August 2015, it was in phase II clinical trials for this indication.

The vast majority of marketed H-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor. Clinically, H-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H-antihistamines that readily cross the blood–brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H-antihistamines can also reduce inflammation, since the expression of NF-κB, the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine) binding at the H receptor.

Antihistamine

Antihistamines are drugs which treat allergic rhinitis and other allergies. Antihistamines can give relief when a person has nasal congestion, sneezing, or hives because of pollen, dust mites, or animal allergy. Typically people take antihistamines as an inexpensive, generic, over-the-counter drug with few side effects. As an alternative to taking an antihistamine, people who suffer from allergies can instead avoid the substance which irritates them. However, this is not always possible as some substances, such as pollen, are carried in the air, thus making allergic reactions caused by them generally unavoidable. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Doctors recommend that people talk to them before any longer term use of antihistamines.

Although people typically use the word “antihistamine” to describe drugs for treating allergies, doctors and scientists use the term to describe a class of drug that opposes the activity of histamine receptors in the body. In this sense of the word, antihistamines are subclassified according to the histamine receptor that they act upon. The two largest classes of antihistamines are H-antihistamines and H-antihistamines. Antihistamines that target the histamine H-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) as well as for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antihistamines that target the histamine H-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). H-antihistamines work by binding to histamine H receptors in mast cells, smooth muscle, and endothelium in the body as well as in the tuberomammillary nucleus in the brain; H-antihistamines bind to histamine H receptors in the upper gastrointestinal tract, primarily in the stomach.

Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptors. Only a few currently marketed H-antihistamines are known to function as inverse agonists.

Histamine produces increased vascular permeability, causing fluid to escape from capillaries into tissues, which leads to the classic symptoms of an allergic reaction — a runny nose and watery eyes. Histamine also promotes angiogenesis.

Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells.

Itching, sneezing, and inflammatory responses are suppressed by antihistamines that act on H1-receptors. In 2014 antihistamines such as desloratadine were found to be effective as adjuvants to standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production.

H-antihistamines refer to compounds that inhibit the activity of the H receptor. Since the H receptor exhibits constitutive activity, H-antihistamines can be either neutral receptor antagonists or inverse agonists. Normally, histamine binds to the H receptor and heightens the receptor's activity; the receptor antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by comparison, the inverse agonists bind to the receptor and reduce its activity, an effect which is opposite to histamine's.

A combination of these effects, and in some cases metabolic ones as well, lead to most first-generation antihistamines having analgesic-sparing (potentiating) effects on opioid analgesics and to some extent with non-opioid ones as well. The most commonly used for the purpose include hydroxyzine, promethazine (enzyme induction especially helps with codeine and similar prodrug opioids), phenyltoloxamine, orphenadrine, and tripelennamine; some may also have intrinsic analgesic properties of their own, orphenadrine being an example.

Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors and therefore are less sedating. However, high doses can still induce drowsiness through acting on the central nervous system. Some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.

Examples of H antagonists include:

The H receptor inverse agonists include:

H-antihistamines, like H-antihistamines, occur as inverse agonists and neutral antagonists. They act on H histamine receptors found mainly in the parietal cells of the gastric mucosa, which are part of the endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H to stimulate acid secretion; drugs that inhibit H signaling thus reduce the secretion of gastric acid.

H-antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease. Some formulations are available over the counter. Most side effects are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing androgenic testosterone and DHT receptors at high doses.

Examples include:

These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently in human trials. H-antihistamines have a stimulant and nootropic effect, whereas H-antihistamines appear to have an immunomodulatory role.

An H-antihistamine is a classification of drugs used to inhibit the action of histamine at the H receptor. H receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H receptors in the cerebral cortex. Consequently, unlike the H-antihistamines which are sedating, H-antihistamines have stimulant and cognition-modulating effects.

Examples of selective H-antihistamines include:

H-antihistamines inhibit the activity of the H receptor.

Examples:

Inhibit the action of histidine decarboxylase:

Mast cell stabilizers are drugs which prevent mast cell degranulation.

Currently most people who use an antihistamine to treat allergies use a second generation drug.

The first generation of antihistamine drugs became available in the 1930s. This marked the beginning of medical treatment of nasal allergies. Research into these drugs led to the discovery that they were H1 antagonists and also to the development of H2 antagonists, where H1 antihistamines affected the nose and the H2 antihistamines affected the stomach. This history has led to contemporary research into drugs which are H3 receptor antagonist and which affect the Histamine H4 receptor.

Antihistamines can vary greatly in cost. Some patients consult with their doctor about drug prices to make a decision about which antihistamine to choose. Many antihistamines are older and available in generic form. Others are newer, still under patent, and generally expensive. The newer drugs are not necessarily safer or more effective. Because so many antihistamines are available, patients can have conversations with their health care provider to choose the right drug for them.

The United States government removed two second generation antihistamines, terfenadine and astemizole, from the market based on evidence that they could cause heart problems.

Not much published research exists which compares the efficacy and safety of the various antihistamines available. The research which does exist are mostly short term studies or studies which look at too few people to make general assumptions. Another gap in the research is in information reporting the health effects for individuals with long term allergies to take antihistamines for a long period of time. Newer antihistamines have been demonstrated to be effective in treating hives. However, there is not research comparing the relative efficacy of these drugs.

Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood. Older people are more likely to experience drowsiness from antihistamine use than younger people. Also, most of the research has been on white people and other ethnicities are not as represented in the research. The evidence does not report how antihistamines affect women differently than men. Different studies have reported on antihistamine use in children, with various studies finding evidence that certain antihistamines could be used by children 2 years of age, and other drugs being safer for younger or older children.

Astemizole (marketed under the brand name Hismanal, developmental code R43512) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel blockade).

Astemizole

Astemizole is a histamine H1-receptor antagonist. It has anticholinergic and antipruritic effects.

Astemizole is rapidly absorbed from the gastrointestinal tract and competitively binds to histamine H receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine).

Despite some earlier reports that astemizole does not cross the blood–brain barrier, several studies have shown high permeability and high binding to protein folds associated with Alzheimer's.

Astemizole may also act on histamine H receptors, thereby producing adverse effects.

Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase).

Astemizole has an oral LD of approximately 2052 mg/kg (in mice).


What is the national agency governing rail transportation in the Philippines?

The Philippine National Railways is a state-owned railway system in the Philippines, organized under the Department of Transportation (DOTr) as an attached agency. Established during the Spanish colonial period, the modern PNR was developed only in 1984. It formerly operated around 479 kilometres of track on the island of Luzon, where most Philippine rail infrastructure is located. Because of this, PNR has become synonymous with the Philippine rail system.

Rail transport in the Philippines

Rail transport in the Philippines is used mostly to transport passengers within Metro Manila and the nearby province of Laguna. Freight transport is nonexistent, although there are plans for a revival from Port Area, Manila to Laguna. Currently, the country has a railway footprint of only through LRT Line 1, LRT Line 2, MRT Line 3 and the Philippine National Railways (PNR) Metro Commuter Line. The government has plans to expand its current footprint to more than 320 kilometers by 2022.

The Philippine railway network consists of one commuter rail service provided by the PNR, and three mass rapid transit systems operated by the Light Rail Transit Authority and Metro Rail Transit Corporation. Within the last century, there were operating intercity rail lines extending from Manila both north and south, as well as on Panay and Cebu islands. The Philippine Railway Company, which operated both the Panay and Cebu lines, still exists but owns no rolling stock or rail, only property.

On-going railway projects include the 22.8-kilometer MRT Line 7, the 4-kilometer LRT Line 2 East Extension, and the 37.6 kilometer North-South Commuter Railway (North Line).

There has been rail transport in the Philippines for over 120 years. On June 25, 1875, King Alfonso XII of Spain promulgated a Royal Decree directing the Office of the Inspector of Public Works of the Philippines to submit a general plan for railroads on Luzon. The plan, which was submitted five months later by Don Eduardo Lopez Navarro, was entitled "Memoria Sobre el Plan General de Ferrocarriles en la Isla de Luzón", and was promptly approved. A concession for the construction of a railway line from Manila to Dagupan City was granted to Don Edmundo Sykes of the "Ferrocarril de Manila-Dagupan" on June 1, 1887. The construction and running of the railway was done by Manila Railway Company Ltd that was a British owned company. The first rail tracks were laid in 1891 and its first commercial run was in 1892.

At the Tutuban Central Terminal in a bustling district of old Manila was the terminal of the Philippine National Railways for two lines, to the north and to the south. From the center of Manila towards Baguio in the north, the line ended in San Fernando, La Union while the south line stopped in Legazpi in the Bicol region. To and from these points it carried people and their goods, their trade and livelihood.

Most of the improvements on the rail network were destroyed during Japanese invasion of the Philippines during the World War II. Of the more than a thousand route-kilometers before the war, only 452 were operational after it. For several years after the war, work was undertaken on what could be salvaged of the railroad system.

From the beginning of the American colonial period of the Philippines, the new American colonial Insular Government was committed to building new railways. The Philippine Railway Company, predecessor of the current Panay Railways, was incorporated in Connecticut on March 5, 1906. It was part of a "Manila syndicate", a collection of Philippine infrastructure companies including the Manila Electric Railway and Light Company, incorporated in New Jersey, the Manila Construction Company, and the Manila Suburban Railways Company. Later the Philippines Railways Construction Company was added. Cornelius Vanderbilt and William Salomon, among other leading American railwaymen sat on the board.

On May 28, 1906, the Philippine Commission granted to the Philippine Railway Corporation a concession to construct railways on the islands of Panay, Negros and Cebu.

Construction began on a railroad from Iloilo City to Roxas City in Capiz with crews working from both cities and meeting in the middle in 1907. Operations began immediately upon completion. In 1985 passenger operations ceased and in 1989 freight operations ceased.

The Philippine Railway Company, along with operating the Panay line, operated a line in Cebu from 1911 to 1942, when operations ceased because of the Japanese occupation of the Philippines during World War II. The line ran from Danao south through Cebu City to Argao. The line was built by the related Philippine Railways Construction Company.

Gloria Macapagal-Arroyo's Administration worked to rehabilitate rail transportation in the country, including the Philippine National Railways, through various investments and projects. Total reconstruction of rail bridges and tracks, including replacement of the current 35-kilogram (77-pound) track with newer 50-kilogram (110-pound) tracks and the refurbishing of stations, were part of the rehabilitation and expansion process. Much of those plans such as the Northrail Project were controversial and were never completed.

A portion of the PNR network, specifically the Metro Manila portion of the network called the Philippine National Railways Metro Commuter Line, is part of the Strong Republic Transit System (SRTS), and overall public transport system in the metropolis. It forms the backbone of all of Metro Manila's regional rail services, which extend to its suburbs and to provinces such as Laguna. However, other than reducing growing traffic congestion due to the rising number of motor vehicles in Metro Manila, PNR also aims to link key cities within the Philippines efficiently and to serve as an instrument in national socio-economic development.

However, the meeting of that goal has been beset with problems regarding degraded infrastructure and a lack of government funding, problems that are being rectified with current rehabilitation efforts. The rehabilitation of PNR, which has been touted by various administrations, seeks to not only tackle those problems, but also to spur Philippine economic growth through an efficient railway system. In 2007 the Philippine government initiated a rehabilitation project aiming to remove informal settlers from the PNR right-of-way, revitalize commuter services in Metro Manila, and restore the Manila-Bicol route as well as lost services in Northern Luzon. In July 2009, PNR unveiled a new corporate identity and inaugurated new rolling stock.

The Manila Light Rail Transit System is the main metropolitan rail system serving the Metro Manila area of the Philippines. There are two lines to the system: LRT-1, called the Yellow Line, and LRTA Line 2, called the Purple Line. Although the system is referred to as a "light rail" system, arguably because the network is mostly elevated, the system is more akin to a rapid transit (metro) system in European-North American terms. The Manila LRTA system is the first metro system in Southeast Asia, earlier than the Singapore MRT by three years. Quick and inexpensive to ride, the system serves 605,000 passengers each day. Every day around 430,000 passengers board the Yellow Line, and 175,000 ride the Purple Line.

Its along over 31 kilometers (19 mi) of mostly elevated track form two lines. LRT Line 1, also called the Yellow Line, opened in 1984 and travels a north–south route. All of the stations of the LRT-1 and LRT-2 are elevated, except for the Katipunan Station (which is underground). They follow one of two different layouts. Most Yellow Line stations are composed of only one level, accessible from the street below by stairway, containing the station's concourse and platform areas separated by fare gates.

Many passengers who ride the system also take various forms of road-based public transport, such as buses, to and from a station to reach their intended destination. Beep, a contactless smart card, is used to pay fares for the lines.

The system is not related to the Manila Metro Rail Transit System, or the Yellow Line, which forms a completely different but linked system.

The Manila Metro Rail Transit System has a single line, MRT-3 or the Blue Line. Although it has characteristics of light rail, such as the type of rolling stock used, it is more akin to a rapid transit system. It is not related to the Manila Light Rail Transit System, a separate but linked system.

One of its original purposes was to decongest Epifanio de los Santos Avenue (EDSA), one of Metro Manila's main thoroughfares and home to the MRT-3, and many commuters who ride the system also take road-based public transport, such as buses, to reach the intended destination from a station. The system has been only partially successful in decongesting EDSA, and congestion is further aggravated by the rising number of motor vehicles. The expansion of the system to cover the entire stretch of EDSA is expected to contribute to current attempts to decongest the thoroughfare and to cut travel times. The single line serves 13 stations on 16.95 kilometres (10.5 mi) of line. It is mostly elevated, with some sections at grade or underground. The line commences at North Avenue and ends at Taft Avenue ("Taft" on the map), serving the cities that EDSA passes through: Quezon City, Mandaluyong, Makati, and Pasay. By 2004 MRT-3 had the highest ridership of the three lines, with 400,000 passengers daily.

The automated guideway transit system in UP Diliman will be the first of its kind to be built in the Philippines. Plans for the system were revealed as early as December 2010. The groundbreaking ceremony was held on July 18, 2011. It is still currently under construction and it will be developed within the campus of the University of the Philippines Diliman in Quezon City. It will serve as test track for the first mass transit system to be built and developed in the country by local engineers.

The Bicutan Automated Guideway Transit System is an automated guideway transit (AGT) system under construction and development within the City of Taguig the Philippines. It will serve as test track for the second mass transit system to be built and developed in the country by local engineers.

In December 2013, the Metals, Industry, Research, and Development Center of the DOST and the Baguio City government entered into a memorandum of understanding for the conduct of a study on the possible use of mass transport system in the city, particularly tramline and monorail. The project feasibility study is now on its final stages and that appropriate validation and evaluation are being undertaken by technical personnel it is finalized and ready for submission to concerned local governments for approval and consideration. He also said that the DOTr will help in sourcing out funds for the eventual realization of the new transport project in the city.

A 28-kilometer monorail project has been endorsed by the City Government of Davao to the Department of Transportation (DOTr) and Philippine National Railways (PNR).

BYD, a Shenzhen-based company is conducting a two-month feasibility study to construct a monorail in Iloilo. They expect the first phase of the 20-kilometer (12-mile) system to start operations in 2019.

The East-West Rail (EWR) Project is a proposed 9.4-kilometer railway line from Diliman, Quezon City up to Lerma Street in the City of Manila. EWR is planned to have 11 stations. The proposal was submitted by the consortium of East West Rail Transit Corporation and AlloyMTD.

Along with the Mega Manila Subway project, the National Economic Development Authority also approved the construction of a new commuter line between Manila (Tutuban) and Los Baños, the Manila-Los Baños Railway, the construction of the Manila–Matnog railway, and reconstruction of the railway line into Batangas City, the latter being part of the PNR Long-haul Railway system. The Manila-Calamba Railway project will be built as a standard gauge, electrified railway with several sections built on at-grade, elevated, and depressed sections, and will serve at about 300,000 passengers at its initial year of operation. The Long-Haul Railway will involve reconstruction of the old line to Bicol and also reconstruction of the line to Batangas City, both as standard-gauge lines initially to operate on single-track configuration. The project is set on 2021.

Department of Transportation (DOTr) secretary Arthur Tugade approved the construction of a railway line connecting Manila with Clark Freeport. The initial plan for the line involves construction of five stations, and completion is expected by 2021, or 2020. The project revived a previous plan to reconstruct the railway line north of Manila, the Northrail project, which has been since the Arroyo administration, but was plagued by controversy and eventually stopped. In January 2018, JICA started the detailed engineering design for PNR North 2.

The Department of Transportation said it plans to revive the operation of a container cargo rail from Port Area in Manila to Laguna province. The tracks towards the berths of Manila International Container Terminal and Manila North Harbor to Laguna Gateway Inland Container Terminal in Calamba, Laguna will be revived to restart the container cargo service.

A proposed extension of LRT Line 1 that will add 8 stations over some 11.7 kilometers (7.3 mi) of new line, starting from its southern terminus at Baclaran Station in Pasay up to Bacoor in the province of Cavite.

There is a proposal for a 3.02-kilometer (1.88 mi) west extension for LRT Line 2. The construction of this said extension would add three stations, one in Tutuban near the Tutuban Centermall and the PNR Tutuban Station, one in Divisoria close to the district of San Nicolas, and its terminus would be near the North Port Passenger Terminal at Pier 4 in the Manila North Harbor. DOTr is aiming to finish the project by 2022. Construction is expected to begin in October 2018.

MMDA Chairperson Francis Tolentino said that a proposal to build a subway from the Bonifacio Global City in Taguig to an area near a shopping mall in Quezon City. Tolentino also said that the proposal has been complete with geological study showing that a subway is feasible, and that the project is supported by DPWH Secretary Rogelio Singson.

The subway system, costing about () was approved by the National Economic Development Authority in September 12, 2017.

On June 20, 2018, IRC Properties Inc. and its Chinese partners secured an ‘original proponent status’ from the city government of Makati for the proposed $3.7-billion Makati intra-city rail transport system. Under the proposal, the project would consist of eight to 10 stations in Makati. Its length would be 11 kilometers. It will be interconnecting with MRT 3, the proposed Metro Manila Subway and Pasig River ferry. The estimated total cost of the project is $3.7 billion.

As part of the Metro Cebu Integrated Intermodal Transport System, Cebu LRT will address the worsening traffic congestion in Metro Cebu. It will be partially operational by 2020, and will have a BRT feeder line. It will connect Carcar City and Danao City.

President Rodrigo Duterte expressed his support for the establishment of a railway system in the entire island of Mindanao which may be in operation after his term ends. The railway system to be built in Mindanao will have about 2,000 kilometers of trackage, and considered one of Rodrigo Duterte's primary infrastructure projects. The first phase, which is 105 km, will start construction in the third quarter of 2018 and is expected to be completed by 2022. The initial railway will connect the cities of Tagum, Davao City, and Digos in Davao Region, with planned extension to connect other major cities in Mindanao, such as General Santos, Cagayan de Oro, Zamboanga City, Cotabato City and Butuan.

MRT Line 7 is an under construction rapid transit line in the Philippines. When completed, the line will be serviced by 14 stations that runs from San Jose del Monte in the province of Bulacan up to the under construction Unified Grand Central Station in Quezon City. Construction started on April 2016, and its estimated completion date is 2020.

The current 13.8-kilometer long LRT Line 2 will be extended by another 4 kilometers eastward, starting from the eastern terminus of Santolan Station in Pasig up to Masinag, Antipolo in the province of Rizal. It will add two new stations. The estimated completion date is April 2019.

On December 22, 2017, DOTr Secretary Arthur Tugade signed a contract with JICA for the construction, supervision and bidding assistance of Phase 1 of the Philippine National Railways (PNR) Clark project linking Tutuban in Divisoria, Manila, to the City of Malolos in Bulacan province. Pre-construction commenced in January 2018.