Delineate effects of histamines on selected body tissues.
Describe the types of hypersensitivity or allergic reactions.
Identify the effects of histamine that are blocked by histamine1 (H1) receptor antagonist drugs.
Discuss first-generation H1 receptor antagonists in terms of prototype, indications and contraindications, major adverse effects, interactions, and administration.
Describe second-generation H1 receptor antagonists in terms of prototype, indications and contraindications, major adverse effects, interactions, and administration.
Understand how to use the nursing process in the care of patients receiving antihistamines.
Clinical Application Case Study
Gene Rudolph is a 72-year-old retired mail carrier. His medical history includes hypertension, benign prostatic hypertrophy, and coronary artery disease. He is visiting a medical clinic for a routine blood pressure check. He tells the nurse that he has been having symptoms of nasal congestion, sneezing, and watering of the eyes for the past several weeks and that the symptoms started after he began working in his garden.
KEY TERMS
Anaphylactic reactions: severe, whole-body reaction after sensitization to an allergen causing a severe allergic response
Anaphylactoid reactions: anaphylaxis-like reaction to a substance without development of IgE antibody that may occur on first exposure to the causative agent
Antihistamines: drugs that antagonize the action of histamine; commonly the H1 receptor antagonists
Histamine: first chemical mediator released in immune and inflammatory responses found mainly in mast cells surrounding blood vessels
Hypersensitivity: allergic reactions that are exaggerated responses by the immune system; produce tissue injury and may cause serious disease
Serum sickness: type III hypersensitive response is an IgG- or IgM-mediated reaction characterized by formation of antigen-antibody complexes that induce an acute inflammatory reaction in the tissues.
Introduction
The drugs that antagonize the action of histamine are commonly called antihistamines. There are three main types of receptors for histamine, histamine1 (H1), histamine2 (H2), and histamine3 (H3) receptors. This chapter focuses on those drugs that specifically prevent or reduce most of the physiologic effects that histamine normally induces at H1 receptor sites. (Prescribers use some H2 receptor antagonists, such as cimetidine, to treat peptic ulcers.) To understand the use of antihistamines, it is necessary to understand histamine and its effects on body tissues, the characteristics of allergic reactions, and the selected conditions for which antihistamines are used.
Overview of Histamine Release and the Allergic Response
Etiology and Pathophysiology
Histamine and Its Receptors
Histamine is the first chemical mediator to be released in immune and inflammatory responses. It is synthesized and stored in most body tissues, with high concentrations in tissues exposed to environmental substances (e.g., the skin and mucosal surfaces of the eye, nose, lungs, and gastrointestinal [GI] tract). It is also found in the central nervous system (CNS). In these tissues, histamine is located mainly in secretory granules of mast cells (tissue cells surrounding capillaries) and basophils (circulating blood cells).
Histamine is discharged from mast cells and basophils in response to certain stimuli (e.g., allergic reactions, cellular injury, extreme cold). After it is released, it diffuses rapidly into other tissues, where it interacts with H1 and H2 receptors on target organs. H1 receptors are located mainly on smooth muscle cells in blood vessels and the respiratory and GI tracts (see Fig. 30.2). When histamine binds with these receptors and stimulates them, effects include the following:
Figure 30.2 Action of antihistamine drugs. Histamine1 (H1) receptor antagonists bind to H1 receptors. This prevents histamine from binding to its receptors and acting on target tissues.
• Contraction of smooth muscle in the bronchi and bronchioles (producing bronchoconstriction and respiratory distress)
• Stimulation of vagus nerve endings to produce reflex bronchoconstriction and cough
• Increased permeability of veins and capillaries, which allows fluid to flow into subcutaneous tissues and form edema
• Increased secretion of mucous glands. Mucosal edema and increased nasal mucus produce the nasal congestion characteristic of allergic rhinitis and the common cold.
• Stimulation of sensory peripheral nerve endings to cause pain and pruritus. Pruritus is especially prominent with allergic skin disorders.
• Dilation of capillaries in the skin, to cause flushing
When H2 receptors are stimulated, the main effects are increased secretion of gastric acid and pepsin, increased rate and force of myocardial contraction, and decreased immunologic and proinflammatory reactions (e.g., decreased release of histamine from basophils, decreased movement of neutrophils and basophils into areas of injury, inhibited T-and B-lymphocyte function). Stimulation of both H1 and H2 receptors causes peripheral vasodilation (with hypotension, headache, and skin flushing) and increases bronchial, intestinal, and salivary secretion of mucus.
Limited information is available regarding H3 receptors; they are believed to play a role in regulation of the release of histamine and other neurotransmitters from neurons. Although several drugs affecting H3 receptors are currently undergoing human trials, none has a defined clinical use.
Hypersensitivity (Allergic) Reactions
In predisposed people, harmless environmental antigens that often do not cause a reaction sometimes may trigger an adaptive immune response, immunologic memory, and, on subsequent exposure to the environmental antigen, inflammation responses (see Chap. 14). Hypersensitivity, or allergic reactions, are exaggerated responses by the immune system that produce tissue injury and may cause serious disease. The mechanisms that eliminate pathogens in adaptive immune responses are essentially identical to those of natural immunity. Allergic reactions may result from specific antibodies, sensitized T lymphocytes, or both, formed during exposure to an antigen. Treatments and interventions are covered in other chapters.
Types of Responses to Cell-Mediated Invasion
Hypersensitivity reactions are grouped into four types according to the mechanisms by which they are produced. The substances that produce the effect for types I, II, and III hypersensitivity reactions are antibody molecules. The substances responsible for type IV reactions are antigen-specific T cells.
Type I (also called immediate hypersensitivity because it occurs within minutes of exposure to the antigen) is an immunoglobulin E (IgE)–induced response triggered by the interaction of antigen with antigen-specific IgE bound on mast cells, causing mast cell activation. Histamine and other mediators are released immediately, and cytokines, chemokines, and leukotrienes are synthesized after activation. Anaphylaxis is a type I response that may be mild (characterized mainly by urticaria, other dermatologic manifestations, or rhinitis) or severe and life threatening (characterized by respiratory distress and cardiovascular collapse). It is uncommon and does not occur on first exposure to an antigen; it occurs with a second or later exposure, after antibody formation was induced by an earlier exposure. Severe anaphylaxis (sometimes called anaphylactic shock; see Chap. 27) is characterized by cardiovascular collapse from profound vasodilation and pooling of blood in the splanchnic system so that the patient has severe hypotension and functional hypovolemia. Respiratory distress often occurs from laryngeal edema and bronchoconstriction. Urticaria often occurs because the skin has many mast cells that release histamine. Anaphylaxis is a systemic reaction that usually involves the respiratory, cardiovascular, and dermatologic systems. Severe anaphylaxis may be fatal if not treated promptly and effectively. Antihistamines are helpful in treating urticaria and pruritus but are not effective in treating bronchoconstriction and hypotension. Epinephrine, rather than an antihistamine, is the drug of choice for treating severe anaphylaxis.
Type II responses are mediated by IgG or IgM, generating direct damage to the cell surface. These cytotoxic reactions include blood transfusion reactions, hemolytic disease of newborns, autoimmune hemolytic anemia, and some drug reactions. Hemolytic anemia (caused by destruction of erythrocytes) and thrombocytopenia (caused by destruction of platelets), both type II hypersensitivity responses, are adverse effects of certain drugs (e.g., penicillin, methyldopa, heparin).
Type III is an IgG- or IgM-mediated reaction characterized by formation of antigen–antibody complexes that induce an acute inflammatory reaction in the tissues. Serum sickness, the prototype of these reactions, occurs when excess antigen combines with antibodies to form immune complexes. The complexes then diffuse into affected tissues, where they cause tissue damage by activating the complement system and initiating the immune response. If small amounts of immune complexes are deposited locally, the antigenic material can be phagocytized and digested by white blood cells and macrophages without tissue destruction. If large amounts are deposited locally or reach the bloodstream and become deposited in blood vessel walls, the lysosomal enzymes released during phagocytosis may cause permanent tissue destruction.
Type IV hypersensitivity (also called delayed hypersensitivity because of the lag time from exposure to antigen until the response is evident) is a cell-mediated response in which sensitized T lymphocytes react with an antigen to cause inflammation mediated by release of lymphokines, direct cytotoxicity, or both. The classic type IV hypersensitivity reaction is the tuberculin test, but similar reactions occur with contact dermatitis and some graft rejection.
Clinical Manifestations
Allergic Rhinitis
Allergic rhinitis is inflammation of nasal mucosa caused by a type I hypersensitivity reaction to inhaled allergens. It is a very common disorder characterized by nasal congestion, itching, sneezing, and watery drainage. Itching of the throat, eyes, and ears often occurs as well.
There are two types of allergic rhinitis. Seasonal disease (often called hay fever) produces acute symptoms in response to the protein components of airborne pollens from trees, grasses, and weeds, mainly in spring or fall. Perennial disease produces chronic symptoms in response to nonseasonal allergens such as dust mites, animal dander, and molds. Actually, mold spores can cause both seasonal and perennial allergies because they are present year round, with seasonal increases. Some people have both types, with chronic symptoms plus acute seasonal symptoms.
People with a personal or family history of other allergic disorders are likely to have allergic rhinitis. When mucous membranes in the nose are inflamed, symptoms can be worsened by nonallergenic irritants such as tobacco smoke, strong odors, air pollution, and climatic changes.
Allergic rhinitis is an immune response in which normal nasal breathing and filtering of air brings inhaled antigens into contact with mast cells and basophils in nasal mucosa, blood vessels, and submucosal tissues. With initial exposure, the inhaled antigens are processed by lymphocytes that produce IgE, an antigen-specific antibody that binds to mast cells. With later exposures, the IgE interacts with inhaled antigens and triggers the breakdown of the mast cell. This breakdown causes the release of histamine and other inflammatory mediators such as prostaglandins and leukotrienes (Fig. 30.1). These mediators, of which histamine may be the most important, dilate and engorge blood vessels to produce nasal congestion, stimulate secretion of mucus, and attract inflammatory cells (e.g., eosinophils, lymphocytes, monocytes, macrophages). In people with allergies, mast cells and basophils are increased in both number and reactivity. Thus, these cells may be capable of releasing large amounts of histamine and other mediators.
Figure 30.1 Type I hypersensitivity reaction: allergic rhinitis. A. The first exposure of mast cells in nasal mucosa to inhaled antigens (e.g., pollens from weeds, grasses, trees) leads to the formation of immunoglobulin E (IgE) antibody molecules. These molecules then bind to the surface membranes of mast cells. This process sensitizes mast cells to the effects of inhaled antigens (allergens). B. When sensitized mast cells are reexposed to inhaled pollens or other antigens, they release histamine and other chemical mediators, which then act on nasal mucosa to produce characteristic symptoms of allergic rhinitis.
Allergic rhinitis that is not effectively treated may lead to chronic fatigue, impaired ability to perform usual activities of daily living, difficulty sleeping, sinus infections, postnasal drip, cough, and headache. In addition, this condition is a strong risk factor for asthma. Studies have demonstrated that although antihistamines relieve symptoms of allergic rhinitis, antihistamine are not successful or recommended for treatment of the common cold.
Chapter 31 describes the many drugs used to manage the condition besides antihistamines.
Allergic Contact Dermatitis
Allergic contact dermatitis is a type IV hypersensitivity reaction resulting from direct contact with antigens to which a person has previously become sensitized (e.g., poison ivy or poison oak, cosmetics, hair dyes, metals, drugs applied topically to the skin). This reaction, which may be acute or chronic, usually occurs more than 24 hours after reexposure to an antigen and may last from days to weeks.
Affected areas of the skin are usually inflamed, warm, edematous, intensely pruritic, and tender to touch. Skin lesions are usually erythematous macules, papules, and vesicles (blisters) that may drain, develop crusts, and become infected. Lesion location may indicate the causative antigen.
Allergic Food Reactions
Typically, food allergies are an immune response to the ingestion of a protein. Some food allergens such as shellfish, fish, corn, seeds, bananas, egg, milk, soy, peanut, and tree nuts have a higher inherent risk of triggering anaphylaxis than others. However, many other foods have been identified as allergens, including certain fruits and vegetables. Commonly, children allergic to milk, eggs, wheat, or soy outgrow their allergy. Exclusive breast-feeding has been found to be protective against the development of food allergies in early life but to increase the risk of food allergies as a person ages. There is no known preventive strategy to prevent food allergies except to delay introducing allergy-prone foods to infants until the GI tract has had time to mature. The timing for this varies from food to food and from infant to infant. The most common food allergy among adults is shellfish, often first presenting later in life.
Allergic Drug Reactions
Virtually any drug may induce an immunologic response in susceptible people, and any body tissues may be affected. Allergic drug reactions are complex and diverse and may include any of the types of hypersensitivity described previously. A single drug may induce one or more of these states and multiple symptoms. There are no specific characteristics that identify drug-related reactions, although some reactions commonly attributed to drugs (e.g., skin rashes, drug fever, hematologic reactions, hepatic reactions) rarely occur with plant pollens and other naturally occurring antigens. Usually, however, the body responds to a drug as it does to other foreign materials (antigens). In addition, some reactions may be caused by coloring agents, preservatives, and other additives rather than the drug itself. It may be difficult to recognize in a person with atypical, resolving, or partially treated symptoms, as when skin signs such as urticaria are absent or masked by medications.
Allergic drug reactions should be considered when new signs and symptoms develop or when they differ from the usual manifestations of the illness being treated, especially if a reaction:
• Follows ingestion of a drug, especially one known to produce allergic reactions
• Is unpredictable and occurs in only a few patients when many patients receive the suspected drug
• Occurs approximately 7 to 10 days after initial exposure to the suspected drug (to allow antibody production)
• Follows a previous exposure to the same or similar drug (sensitizing exposure)
• Occurs minutes or hours after a second or subsequent exposure
Allergic Rhinitis
by UNIVERSITY OF MICHIGAN HEALTH SYSTEM
2007. Retrieved from http://www.guideline.gov/content.aspx?id=11684
Researchers completed a systematic review based on expert consensus to update the state of the science on the management of allergic rhinitis. The primary strategy to relieve the symptoms of allergic rhinitis is avoidance of the offending allergen. Should avoidance of allergens not achieve symptoms relief in patients with allergic rhinitis, indications for drug therapy suggest the following:
• Over-the-counter (OTC) second-generation anti-histamines, such as loratadine, should provide symptom relief in most situations.
• Prescription drugs may be effective. These include the following:
• Intranasal corticosteroids, such as fluticasone and flunisolide for adults, and mometasone for children (most potent drugs available to relieve symptoms except for ocular symptoms)
• Prescription second-generation antihistamine, such as fexofenadine
• Oral decongestants to decrease nasal swelling congestion
• If intranasal corticosteroids are not successful or the patient is not a candidate for corticosteroids:
Leukotriene inhibitors
Intranasal OTC cromolyn (also available over-the-counter)
Intranasal antihistamines, such as azelastine (also available over-the-counter)
• Ocular preparations for patients with allergic conjunctivitis can be considered if symptoms not adequately controlled with oral antihistamines.
IMPLICATIONS FOR NURSING PRACTICE: The use of evidence-based guidelines in the treatment of allergic rhinitis provides effective strategies for symptom relief. Appropriate drug therapy based on best practices maximizes symptom relief and reduces adverse effects, and it also decreases the cost of drug therapy. The nurse should educate patients regarding avoidance of the offending allergen and assess for effective symptom management.
• Occurs after small doses (reduces the likelihood that the reaction is due to dose-related drug toxicity)
• Occurs with other drugs that are chemically or immunologically similar to the suspected drug
• Produces signs and symptoms that differ from the usual pharmacologic actions of the suspected drug
• Produces signs and symptoms usually considered allergic in nature (e.g., anaphylaxis, urticaria, serum sickness)
• Produces similar signs and symptoms to previous allergic reactions to the same or a similar drug
• Increases eosinophils in blood or tissue
• Resolves within a few days of discontinuing the suspected drug
Virtually all drugs have been implicated in anaphylactic reactions. Penicillins and other antimicrobials, radiocontrast media, aspirin and other nonsteroidal anti-inflammatory drugs, and antineoplastics such as L-asparaginase and cisplatin are more common offenders. Less common causes include anesthetics (local and general), opioid analgesics, skeletal muscle relaxants used with general anesthetics, and vaccines. Approximately 10% of severe anaphylactic reactions are fatal. In many cases, it is unknown whether clinical manifestations are immunologic or nonimmunologic in origin.
Serum sickness is a delayed hypersensitivity reaction most often caused by drugs, such as antimicrobials. In addition, many drugs that produce anaphylaxis also produce serum sickness. With initial exposure to the antigen, symptoms usually develop within 7 to 10 days and include urticaria, lymphadenopathy, myalgia, arthralgia, and fever. The reaction usually resolves within a few days but may be severe or even fatal. With repeated exposure to the antigen, after prior sensitization of the host, accelerated serum sickness may develop within 2 to 4 days, with similar but often more severe signs and symptoms.
Systemic lupus erythematosus (SLE) is an autoimmune disorder that may be idiopathic from nondrug causes or induced by hydralazine, procainamide, isoniazid, and other drugs. Clinical manifestations vary greatly, depending on the location and severity of the inflammatory and immune processes, and may include skin lesions, fever, pneumonia, anemia, arthralgia, arthritis, nephritis, and others. Drug-induced lupus produces less renal and CNS involvement than idiopathic SLE.
Fever often occurs with allergic drug reactions. It may occur alone, with a skin rash and eosinophilia, or with other drug-induced allergic reactions such as serum sickness, SLE, vasculitis, and hepatitis. Dermatologic conditions (e.g., skin rash, urticaria, inflammation) commonly occur with allergic drug reactions and may be the first and most visible manifestations.
Pseudoallergic Drug Reactions
Pseudoallergic drug reactions resemble immune responses (because histamine and other chemical mediators are released), but they do not produce antibodies or sensitized T lymphocytes. Anaphylactoid reactions are like anaphylaxis in terms of immediate occurrence, symptoms (rash or hives, difficulty breathing, swelling of body parts), and life-threatening severity. The main difference is that they are not antigen–antibody reactions and therefore may occur on first exposure to the causative agent. The drugs bind directly to mast cells, activate the cells, and cause the release of histamine and other vasoactive chemical mediators. Contrast media for radiologic diagnostic tests are often implicated.
Drug Therapy
The H1 receptor antagonist group contains several classes of antihistamines: alkylamines (e.g., brompheniramine), ethanolamines (e.g., clemastine), piperidines (e.g., cyproheptadine), piperazines (e.g., hydroxyzine), ethylenediamines (tripelennamine), phenothiazines (e.g., promethazine), and a miscellaneous group. Choosing an antihistamine is based on the desired effect, duration of action, adverse effects, and other characteristics of available drugs. For most people, a second-generation H1 receptor antagonist is the first drug of choice. However, they are quite expensive. If costs are prohibitive for a patient, a first-generation drug may be used with minimal daytime sedation if taken at bedtime or in low initial doses, with gradual increases over a week or 2. Overall, safety should be the determining factor.
Table 30.1 lists the drugs given to block the effects of histamine. For ease of discussion in this chapter, the H1 receptor antagonists are divided into first-generation and second-generation drugs. The division is distinguished by the level of sedative and anticholinergic effects of the drugs. The following sections and the Drugs at a Glance tables describe selected H1 receptor and H2 receptor antagonists. (Chap. 31 discusses inhaled drugs used to decrease the histamine response.)
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