HEALTH AND MEDICAL PRODUCTS:ALLERGYTR EATMENTS (ANTIHISTAMINES).

ALLERGYTR EATMENTS (ANTIHISTAMINES)

Allergy (also called hypersensitivity) involves an inappropriate or excessive immune response of the body to foreign substances called allergens. Allergens are simply antigens (antibody-generating substances) that trigger allergic reactions. Allergies are caused by an immune response to a normally nonharmful substance (e.g., pollen, dust, mold spores, animal dander) that comes in contact with agranular white blood cells (lymphocytes) specific for that substance, or antigen. An allergic reaction is an immune response that should not occur, as the substance that usually triggers the response is inherently not a danger to the body.

An antibody (also called an immunoglobulin [Ig]) is a soluble protein secreted by specialized blood cells (e.g., B-lymphocytes and plasma cells) in response to the body being exposed to an antigen. Although body fluid antibodies are formed in response to a vast number of different antigens, all antibodies are grouped into five classes: IgG, IgD, IgM, IgA, and IgE. Antibodies are capable of binding specifically with an antigen, and when an antibody molecule binds to its corresponding antigen, an antigen-antibody complex is formed. Allergic sensitivity to an allergen is mediated through IgE, such that when the body is first exposed to an antigen, cells called macrophages engulf the antigen (through a process called phagocytosis) and the antigen is subsequently presented on the macrophage combined with glycoproteins on the cell membrane surface. Cells called T-lymphocytes then interact with the antigen to initiate a T-cell-mediated response; additionally, B-lymphocytes produce IgE to complex with the antigen. The plasma membranes of mast cells and cells called basophils possess high-affinity IgE-binding sites. Basophils (granular white blood cells) and mast cells (normally found in loose connective tis- sue) contain secretory granules that store a variety of inflammatory mediator chemicals, including histamine. Once the IgE is fixed to mast cells and basophils after the primary exposure, a secondary exposure to the same allergen causes histamine to be released from the secretory granules. The allergen binds to the IgE molecules on the mast cell surface, causes cross-linking (also called cross-bridging) of the IgE molecules, which then leads to mast cell “degranulation,” whereby the histamine- containing granules are released into the surrounding tissues. Release of histamine subsequently causes the release of cytokines and numerous other chemical mediators of inflammation. Inflammation is the reaction of living tissue to injury, infection, or irritation. Inflamed tissues are char- acterized by pain, swelling, redness, and heat.

Histamine [2-(4-imidazolyl)-ethyl-amine], a vasoactive monoamine formed by the decarboxylation of histidine by the enzyme histidine car- boxylase, chemically mediates local immune responses. It is located in most body tissues but is highly concentrated in the lungs, skin, and gas- trointestinal tract. In the central nervous system (CNS), it may serve as a neurotransmitter. Histamine acts by binding to receptors on target cells, with different cell types expressing different currently characterized his- tamine receptor (H) types (e.g., H1, H2, H3, H4). Overall, histamine contributes to the inflammatory response, acts on the smooth muscle of blood vessels to cause vasodilation (increase in blood vessel diameter), causes an increase in the permeability of blood vessel walls, and affects nearby sensory nerves, resulting in itching (also called pruritus). De- pending on the route of allergen exposure (e.g., inhalation, skin or eye contact, ingestion, etc.), the effects of histamine cause the familiar symp- toms of allergy, including sneezing, inflammation of the nasal passage- ways, nasal itching, watery nasal discharge, and itchy, inflamed, tearing eyes. When released in the lungs, histamine causes smooth muscle con- traction of the airway bronchioles, which is an attempt of the body to prevent the offensive allergens from entering the lung tissue. Unfortunately, this type of response leads to the symptoms of wheezing and shortness of breath similar to that experienced by individuals with the life-threatening condition called asthma.

Allergies are frequently treated by drugs called antihistamines, because they antagonize/inhibit the activity of histamine. The use of antihista- mines allows individuals to live more safely and comfortably by counter- acting immunological mistakes and alleviating the annoying and potentially harmful symptoms associated with allergens. In 1937, D. Bovet and A. Staub discovered the first H1 receptor antagonist. This discovery marked the “first generation” of antihistamines characterized to treat allergic diseases, and modern over-the-counter oral antihistamines continue to be areasonable and effective treatment for the various symptoms associated with allergies. These drugs are efficiently absorbed into the bloodstream from the gastrointestinal tract, metabolized primarily within the liver, ex- creted through the urine, and usually possess a four- to six-hour duration of action. Antihistamines suppress the wheal (swelling) and flare (vasodilation) response after exposure to allergens by blocking the binding of histamine to its receptors on nerves, vascular smooth muscle, glandular cells, endothelium tissue, and mast cells. Classic first-generation antihistamines block the action of histamine at specific histamine receptors (e.g., H1 receptors). First-generation antihistamines are small lipophilic molecules, so they may cause adverse effects (e.g., sedation, impaired cognition, blurred vision, gastrointestinal symptoms, dryness of mouth, heart palpitations, urinary retention) because their structure closely resembles that of blockers of cholinergic (specifically muscarinic) and ex- adrenergic receptors of the autonomic nervous system and because of their ability to cross the blood-brain barrier to affect the CNS. These H1 receptor antagonists are reversible, competitive inhibitors of the pharma- cological actions of histamine on H1 receptors. Dozens of first-generation H1-blocking compounds are available in over-the-counter oral allergy treatments and may include chemical classes of drugs structurally related to histamine, such as ethanolamines, including diphenhydramine (2- diphenylmethoxy-N,N-dimethylethanamine; C17H21NO), doxylamine (N,N- dimethyl-2-[1-phenyl-1-(2-pyridinyl) ethoxy] ethanamine; C17H22N2O), and clemastine ([R-(R*, R*)]-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy] ethyl]-1-methylpyrrolidine; C21H26ClNO), and alkylamines (also known as propylamines), including brompheniramine (2-[p-bromo-ex-(2-di- methylaminoethyl) benzyl]pyridine; C16H19 BrN2) and chlorpheniramine (2-[p-chloro-ex-(2-dimethylaminoethyl)benzyl]pyridine; C16H19 ClN2).

Most antihistamines do not chemically inactivate or physiologically an- tagonize histamine, nor do they prevent histamine release. However, lor- atadine [4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)-1-piperidinecarboxylic acid ethyl ester; C22H23ClN2O2], a long-acting (often twenty-four hours) second-generation piperidine- derivative antihistamine with selective peripheral H1 receptor antagonist activity, is suspected of additionally decreasing histamine release from basophils. Second-generation (also called nonsedating) antihistamines are more lipophobic than first-generation antihistamines and are thought to lack CNS and cholinergic receptor-blocking effects when used at ther- apeutic doses.

Antihistamines are found in combination with other ingredients (e.g., decongestants, analgesics) in many over-the-counter cold, sinus, and al- lergy medications. In addition, liquid products often contain large amounts of alcohol as well.