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h histamine

Histamine is synthesized in tissues by decarboxylation of amino acid L-histidine, a process catalyzed by the pyridoxalphosphate-dependent enzyme L-histidinedecarboxylase. Histamine can enter the organism with food; it also can be generated by bacteria of the gastrointestinal tract. However, these sources do not create additional reserves of histamine since exogenous histamine is easily catabolized in the organism.

Histamine is dispersed and stored in mast cells in the majority of organs, in which it is preserved in secretory cytoplasmic granules in the form of a heparin-proteasic matrix making up over 10% of their mass. Histamine becomes physiologically active only after being released from granules. Histamine is also found in interstitial fluid such as digestive juices, blood, and urine. Only 2-3% of histamine leaves the body unaltered. It is primarily metabolized by two enzymes by deamination with deaminoxidase and methylating histamine with N-methyltransferase.

Upon being secreted from the tissue, histamine can cause a large number of physiological effects. Its role in various pathological processes associated with severe and chronic allergic reactions and hypersensitivity reactions has been uniquely proven. At the same time, functions of endogenous histamine (in development of nerve transmission, secretion of digestive juices, tissue growth and restoration) remain inconclusive.

Despite the fact that a number of various factors can cause the release of endogenous histamine, it is believed that the most important reason is an immunological response of the organism. Accepted knowledge states that during anaphylaxis and allergies, a specific reaction of immunoglobulin E with an antigen takes place on the surface of the mast cell and basophiles, which results in a cascade of biochemical events that lead to degranulation and a release of histamine.

Besides such antigen-antibody reactions, which play a critical role in the pathogenesis of many allergic, anaphylactic, and hypersensitivity reactions, histamine also can be released from tissue stores in response to physical stimuli, effects of the so-called histamine liberators, a number of chemical substances, various drugs, and toxins.

There is a large class of compounds that are capable of releasing histamine. They can be enzymes, toxins, morphine, d-tubocurarine, and polymers such as dextran. Moreover, tissue damage such as trauma, bites, and stress can also cause a release of histamine, and in all probability as a result, an endogenous polypeptide bradykinin is released. Action of all of these listed substances as well as a number of others can facilitate formation of ana-phylactic reactions in the organism.

Release of histamine is blocked by various enzyme inhibitors and other substances (nicotinamide).

The main physiological effect of histamine is exhibited in the cardiovascular system, nonvascular smooth musculature, and exocrine and adrenal glands.

Its most important pharmacological effects are dilation of veins and capillaries, increased permeability of capillaries, increased heart rate, contraction of nonvascular smooth musculature (constriction of bronchi, gastrointestinal tract peristalsis), stimulation of gastric juice secretion, and release of catecholamines from adrenal glands.

Two membrane-receptive binding sites called H1 and H2 receptors mediate the pharmacological effect of histamine. H1 receptors are located in smooth muscle of vessels, and bronchial and gastrointestinal tract, while H2 receptors are found in the walls of the stomach, myocardium, and certain vessels.

Therefore, it is very likely that contraction of nonvascular smooth muscle is an effect of activation of H1 receptors, while secretion of digestive juice and increased heart rate are connected to activation of H2 receptors; and dilation of vessels and increased permeability of capillaries is a result of combined activation of both types of receptors.

There are also specific differences in the location of receptors in various tissues and in various animals. If mice and rats are sufficiently stable to effects of histamine, then guinea pigs and humans will be very sensitive.

Antihistamine drugs are classified as antagonists of H1 and H2 receptors, and quantitatively speaking H1 antagonists dominate. Moreover, the term antihistamine drug is associated more with H1 antagonists. H2 blockers exhibit a specific effect on histamine receptive sites located in walls of the stomach and they significantly increase secretion of hydrochloric acid.

Allergic illnesses are a complex collection of disturbances with chronic and severe effects ranging from slight reddening, rashes, and runny nose to severe and even fatal ana-phylaxis. It has been shown that around 10% of the population may be prone to some form of allergy. Therapy directed toward removing the source of allergen is not always successful. In a number of cases, the allergen itself is never found. Therefore, symptomatic treatment using H1 antihistamines is carried out.

H1 antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include allergic rhinitis, allergic conjunctivitis, allergic dermatological conditions (contact dermatitis), pruritus (atopic dermatitis, insect bites), anaphylactic or anaphylactoid reactions—adjunct only nausea and vomiting, as well as sedation (first-generation H1 antihistamines).

Antihistamines can be administered topically (through the skin, nose, or eyes) or sys-temically, based on the nature of the allergic condition.

First-generation H1 antihistamines are the oldest antihistaminergic drugs and are relatively inexpensive and widely available. Representatives of first-generation H1 antihistamines are:

Ethanolamines—(diphenhydramine was the prototypical agent in this group). Ethylenediamines, which were the first group of clinically effective H1 antihistamines developed. (pyrilamine).

Alkylamines—pheniramine chlorphenamine, chlorpheniramine, dexchlorphenamine, brompheniramine.

Piperazines—compounds are structurally related to the ethylenediamines and to the ethanolamines: hydroxyzine, meclizine.

Tricyclics—compounds which differ from the phenothiazine antipsychotics in the ringsubstitution and chain characteristics—promethazine, trimeprazine, cyproheptadine, azatadine.

Second-generation H1-receptor antagonists are newer drugs that are much more selective for peripheral H1 receptors in preference to the central nervous system (CNS) histaminer-gic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief improved of allergic conditions The samples of second-generation H1-receptor antagonists are astemizole, fexofenadine, loratadine, mizolastine, terfenadine.

H2-receptor antagonists are drugs used to block the action of histamine on parietal cells in the stomach, decreasing acid production by these cells. These drugs are used in the treatment of dyspepsia; however, their use has waned since the advent of the more effective proton pump inhibitors.

H2 antagonists are clinically used in the treatment of acid-related gastrointestinal conditions. Specifically, these indications may include peptic ulcer disease, gastroesophageal reflux disease, and dyspepsia.

Cimetidine was the prototypical member of the H2 antagonists. Further developments, using quantitative structure-activity relationships led to the development of further agents with tolerability-profiles—cimetidine ranitidine, famotidine, nizatidine.

Currently, histamine itself does not have any therapeutic value and is not used in clinics, although there was an attempt to use it as a drug for treating achlorhydria (lack of hydrochloric acid in the stomach). It can be used in small doses for diagnostic purposes such as stimulating gastric glands for testing their ability to generate hydrochloric acid, and sometimes for pheochromocytoma diagnostics.

16.1 H., ANTIHISTAMINE DRUGS

Antihistamine drugs were discovered at the end of the 1930s. By 1950, highly effective histamine antagonists tripelennamine and diphenhydramine were synthesized, which triggered broad research in the area of synthesis of such drugs.

All of these compounds are reversible, competitive histamine H1 antagonists that do not exhibit substantial activity with respect to H2 receptors. H1-receptor antagonists bock effects of histamine in different degrees in various organs or systems, and can protect the organism from allergic and anaphylactic reactions. By themselves they do not have significant independent activity, and therefore they are only used therapeutically for blocking effects caused by histamine release. In other words, their effects are noticeable only with elevated histamine activity. Moreover, these antihistamine drugs only reduce the release or metabolism of histamine, but in no way affect its synthesis.

Despite the fact that there are minute differences in relative activity of these drugs, they have comparable pharmacodynamic properties and therapeutic use when viewed as a single group of drugs.

The most common H1 antihistamine drugs are structurally similar to histamine with a substituted ethylamine side chain; however, they have two aromatic rings and can be formally represented by the general formula:

where A^ and Ar2 are carbocyclic or heterocyclic aromatic rings, one or both of which can be separated from the X atom of carbon, and where X is oxygen, carbon, or nitrogen. R1 and R2 represent alkyl substituents, usually methyl groups.

Hj histamine receptor blockers can be grouped according to their chemical structures: ethanolamine derivatives (diphenhydramine, clemastine); ethylenediamine derivatives (tripe-lennamine, pyrilamine); alkylamines (chloropheniramine, dexchlorpheniramine, brompheniramine); piperazines (cyclizine, meclizine, hydroxizine); phenothiazines (promethazine, trimeprazine); piperidines (cyproheptadine, diphenylpyraline); and others that do not belong to a specific chemical classification (terfenadine, astemizole).

Their clinical efficacy and side effects differ significantly from group to group and from patient to patient. These drugs prevent action of both endogenic and exogenic histamine; however, they are considerably more effective in relation to the first.

They all act by competitively binding with H receptors. They are used for relieving symptoms of allergic diseases (allergic rhinitis and other allergic reactions), for treating anaphylactic reactions, for temporary relief of insomnia, as an adjuvant therapy for treating parkinsonism and extrapyramidal disorders caused by antipsychotics, relieving coughs due to colds, allergies, or other conditions, preventing and controlling nausea and vomiting, as an adjuvant drug for analgesia of post-operational pain, and for pre-operational sedation.

16.1.1 Aminoalkyl esters

Diphenhydramine: Diphenhydramine, N,N-dimethyl-(diphenylmethoxy)ethylamine (16.1.1), is synthesized by a simple reaction of benzhydrylbromide and 2-dimethylaminoethanol [1-3].

M CMS M 0H3

CH3 CH3

\J 1611

Diphenhydramine is one of the main representatives of antihistamine drugs that block H receptors. Besides antihistamine activity, diphenhydramine exhibits a local anesthetic effect, relaxes smooth muscle, and has sedative and soporific action.

Diphenhydramine is used for symptoms of allergies, for treating hives, hay fever, serum sickness, and other allergic illnesses, and also as a sedative and soporific drug as an independent as well as in combination with other drugs. Synonyms of this drug are dimedrol, benadryl, allergina, valdren, and many others.

Dimenhydrinate: Dimenhydrinate (16.1.2) is a complex compound of N, N-dimethyl (2-diphenylmethoxy)ethylamine—diphenhydramine with 8-chlorotheophylline. While blocking the H1 receptor, dimenhydrinate simultaneously acts on the vomiting center [4,5].

Dimenhydrinate is used for preventing and stopping sea or airsickness, and for nausea and vomiting. Synonyms of this drug are dramamine, dadalon, emedyl, travelin, and others.

Clemastine: Clemastine, 2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrroli-dine (16.1.4), is synthesized by reacting 1-(4-chlorophenyl)-1-phenylethanol (16.1.3) with 2-(2-chlorethyl)-2-methylpyrrolidine using sodium amide as a base. The starting 1-(4-chlorophenyl)-1-phenylethanol (16.1.3) is synthesized either by reacting 4-chloroben-zophenone with methylmagnesium chloride, or by reacting 4-chloroacetophenone with phenylmagnesium bromide [6-8].

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