Goal

In order to provide effective pharmaceutical care, the pharmacist’s knowledge on therapeutic options and philosophies in the treatment of allergy must be constantly updated.

Objectives

Discuss current theories of allergy pathophysiology.
Describe the importance of treating allergies.
Discuss current treatment options for allergy.
Discuss relative advantages/disadvantages of available medications.
Recommend changes in individual therapeutic regimens for optimal outcome.
Discuss adverse effects and interactions for medications used to treat asthma.

Introduction

Hay fever, or allergic rhinitis is the single most common chronic illness in the human population,1 affecting 17% of the human population and 35 million people in the United States alone. But it is more than an annoyance, impairing the quality of life for millions with sneezing, itching, perpetual nasal discharge, postnasal drip,2 irritability, and fatigue.3 Rhinitis can result from any disruption of normal function described below and, like other allergic diseases, must be differentiated from similar syndromes with underlying causes other than allergy in order to provide the most efficacious treatment regimen, since about 50% of those who assume they suffer from allergies actually have nonallergic rhinitis.4 Nonallergic rhinitis can fall into a number of different categories reflecting different etiologies and necessitating different treatment strategies for optimal outcome.




Differentiations of Rhinitis

ALLERGIC or NONALLERGIC

Primary vasomotor instability can result from thyroid dysfunction, pregnancy (hormonal rhinitis), or medical therapy (as with beta-blockers) and proper identification of primary cause(s) is imperative. Treatment of a thyroid dysfunction, change of medication or adjustment of dosage, nasal corticosteroid therapy, or symptomatic treatment with something as benign as saline solution can be more effective than other therapies.

Vasomotor or irritant rhinitis is idiopathic and precipitated by pollutants, odors, temperature, and atmospheric changes. It usually occurs causes year-round congestion and headache in adults and is effectively treated with corticosteroids and decongestants.

Nonallergic rhinitis with eosinophilia syndrome (NARES) presents like allergic rhinitis with frequent sneezing and runny nose and commonly in response to environmental changes. It is remarkable in its lack of association with positive skin test results, absence of IgE, and lack of significant response to chromalyn sodium, antihistamines, and decongestants. Eosinophilia is the distinguishing characteristic, and treatment with topical corticosteroids is usually at least somewhat effective.

Rhinitis medicamentosa is common in patients who over-use topical decongestants, with severe rebound and disruption of the normal mucosal function. It is treated with abrupt cessation of the offending nasal sprays, and topical corticosteroids can be helpful.

Neutrophilic rhinitis or infectious rhinitis commonly follows or accompanies an upper respiratory infection (especially sinusitis, colds, or flu) to cause sinus pain, postnasal drip, and pussy exudate. Treatment may include antibiotic therapy, decongestants, and saline solution.

Atrophic rhinitis can be a primary condition or occur secondary to infection, trauma, or surgery. It is characterized by dryness of the nasal mucosa with severe congestion and no obvious obstruction; though foul odor may be noted. Treatment is aggressive lubrication and moisturization of affected mucosae as well as identification and treatment of any underlying causes

Rhinitis secondary to anatomical abnormalities can be caused by deformations of the nasal septum, either congenital or from trauma. It usually affects one nostril more than the other and may manifest as exacerbation of pre-existing rhinitis. Nasal polyps grow on the mucous membrane to cause occlusion, congestion, recurrent sinusitis, and loss of the sense of smell; and it is frequently associated with aspirin allergy and asthma. Decongestants and topical corticosteroids can provide some relief; and though surgery is sometimes more effective, regrowth can be a problem.


Depending on the pathogenesis of a particular type of non-allergic rhinitis, it may or may not respond to treatment with any of the various antihistaminic agents. Since the symptoms of sneezing, rhinorrhea, nasal congestion, itchy eyes and ears, and cough are common to both allergic and nonallergic rhinitis, treatment remains focused on reduction of symptoms to restore normal lifestyle.

Bacteria Known For Synthesis Of Histamine

Clostridium perfringens

Branhamella catarrhalis

Haemophilus parinfluenzae

Pseudomonas aeruginosa

Histamine Receptors

The effects of histamine on different tissues in different areas of the human body differ according to the type of receptor present on the surfaces of cells comprising the various tissues. The situation is analogous to that of serotonin and the very different effects it elicits via its own various receptors. Histamine receptors, like many other receptor types for other neurotransmitters, are G protein-coupled receptors. That is to say that receptor activation by appropriate ligands activates a G protein, which then modulates the activity of ion channels or regulatory enzymes.14

So far, three distinct types of histamine receptors have been identified, each having distinct functions. The H1 receptor seems largely responsible for allergic histaminergic symptoms, while the H2 receptor plays a major role in secretion of gastric acids; and the functions of H3 receptors have yet to be clearly identified, but are thought to play roles in energy metabolism, cerebral circulation, cardiovascular reflexes, pituitary hormone release, regulation of body temperature, and regulation of the release of histamine itself. Though the same H1 receptors exist both in the central nervous system and peripheral tissues, stimulation produces very different effects in those two general areas. In the central nervous system, stimulation serves primarily a neurotransmission function, while in peripheral tissues, pharmacological effects of stimulation include increased vascular permeability, pruritis, contraction of smooth muscle cells of the respiratory and gastrointestinal tracts, and release of inflammatory mediators (interleukins, cytokines, and chemotactic factors).

As a protein subject to extensive analysis, the structure of the H1 receptor has been carefully mapped. The 487 amino acid residues compose a three-dimensional structure that has been revealed by electron microscopy as having seven hydrophobic transmembrane domains arranged perpendicular to the lipid bilayer of the cell membrane. Six hydrophilic regions connect the seven hydrophobic domains to form three alternating extracellular and three alternating intracellular loops.(See Figure 1.)

The structure of the H1 and H2 receptors differs in that the H1 receptor has a large third loop typical of receptors whose signal transduction is mediated by membrane phosphoinositide hydrolysis. H2 receptors, though, have a small third loop indicative of cAMP turnover induction. Thus, when histamine activates an H1 receptor, phospholipase C is activated to hydrolyze membrane phosphoinositide, a process which generates two intracellular second messengers. Inositol 1,4,5-triphosphate (IP3) initiates release of intracellular calcium stores; while 1,2-diacylglycerol (DAG) activates protein kinase C. There is an associated influx of extracellular calcium, cAMP accumulates, and arachidonic acid (the essential precursor of prostaglandins and leukotrienes) is cleaved from phosphatidylcholine. The mechanism of receptor activation is that of an intracellular calcium channel.Pharmacological Effects Of H1 Receptor Activation In Allergic Rhinitis

Activation of peripheral H1 receptors produces a unique set of varied effects that directly contribute to the sympomatology of allergic rhinitis; and it can cause all such symptoms except for the late inflammatory phase. 15 Nasal congestion in allergic rhinitis is primarily the result of mucosal edema, which in turn may be the result of several contributing histaminic effects.

Vasodilation is induced by activated receptors on endothelial cells and mediated by release of prostacyclin, various prostaglandins (notably PGI2 and PGE2, and nitric oxide. Other inflammatory mediators also contribute to this effect (bradykinin, neuropeptides like substance P, and acetylcholine), a situation that helps explain why histamine antagonists only partially alleviate vasodilation induced by local inflammatory reactions. As mentioned earlier, single processes can seldom be considered as isolated systems among the complexity of an inflammatory allergic reaction.

Such activation itself is a complex cascade of varied actions produced by release of various vasoactive chemical mediators and neural reflexes apparently in both direct and indirect response to H1 activation. Thus the net result in skin, muscle, and splanchnic beds is reduction of arterial pressure and increase in flow.

Affecting endothelial cells of postcapillary venules in this manner causes contraction of the cells, which increases the spaces between contiguous cells to increase permeability of the vascular walls they comprise. Intraluminal fluid and macromolecules are thus allowed to leak into interstitial spaces to contribute to immediate edema and facilitate eventual migration of inflammatory cells to perpetuate the inflammatory response. This increase in vascular permeability is effectively reversed by agents that increase intracellular cAMP (terbutaline and other beta-adrenergic agonists, theophylline and other methylxanthines, and prostaglandin E1). Administration of H1 antagonists blocks this effect, while coadministration of both H1 and H2 antagonists is generally even more effective.

While histamine interacts with receptors of the CNS to autoregulate further production of histamine and inhibit its own synthesis, it also influences both release and activity of other neurotransmitters in other organs peripherally as well as in the peripheral nervous system. Such mechanisms are currently being investigated but as yet poorly understood; but their potential impact in allergic rhinitis cannot be overlooked. Parasympathetic interaction causing bronchoconstriction in asthma is well documented, while similar effects in nasal passages remains only conjecture. The vagal reflex effect on bronchospasm is more significant in low-dose histamine challenge than high-dose challenge and is effectively prevented by H1 blockade with no improvement by H2 blockade.

Pruritis, mucous hypersecretion, and sneezing associated with allergic rhinitis, though partially mediated by other interacting inflammatory factors like eicosanoids and kinins, are considered effects of local sensory nerve stimulation. Mucous secretion is a function of both vascular extravasation (80%) and muscarinic discharge.

Pharmacological Responses To Histamine Receptor Activation

Therapeutic OptionsFor the vast majority of allergic rhinitis patients, medical management is the preferred option due to its minimal invasiveness and side effects. In cases of structural abnormality or nasal polyps, surgery can be the most efficacious tack. Though extremely invasive, the resultant amelioration in symptoms and secondary complications can make a profound effect on the patient’s quality of life and dependence upon medical therapy.Immunotherapy too, though not effective for all patients and invasive in its own way with painful and inconvenient repeated injections, can make a dramatic difference in the atopic patient’s quality of life, reducing all symptoms of allergic rhinitis. Recent evidence has shown some efficacy with sublingual administration of allergens for desensitization therapy; and greater efficacy is seen when only one, rather than multiple allergens, are administered in desensitization efforts.Medical ManagementDecongestants

Both topical (via nasal spray) and oral decongestants reduce mucosal edema and nasal congestion by vasoconstrictive action in the nose; though it is important to realize that they have no effect on the underlying inflammatory pathology of allergic rhinitis. Topical agents can provide very rapid relief of congestion to facilitate drainage, drying of prolific watery secretions to some degree, and proper penetration of other nasally administered agents like glucocorticoids or mast-stabilizing agents. Their tendencies toward rebound congestion and rhinitis medicamentosa with continued use, though, are severe limitations; so they should be recommended judiciously. The rapid onset, long duration of action, and relative lack of systemic absorption and side effects of current favorites make them a logical choice over other options in many short-term situations.

Oral agents can provide substantial relief of congestion, especially when combined with an antihistamine; and such combinations can help assuage side effects of both decongestant (insomnia) and histamine antagonist (sedation). Though they do not generally contribute to rebound or rhinitis medicamentosa, they should be used with caution in patients with hypertension, coronary artery disease, diabetes, hypertension, angle closure glaucoma, congestive heart failure, hyperthyroidism, prostatic hypertrophy, urinary retention, or those taking monoamine oxidase inhibitors. Insomnia, irritability, headaches, nightmares, and palpitations can limit the use of decongestants; but their as-needed usage for acute symptomatic distress is considered an advantage.


Antihistamines – The Histamine H1 Receptor Antagonists

The proven efficacy of the first-generation histamine antagonists and reducing symptoms (sneezing, tearing, and itching of the eyes, nose, ears, and palate), their rapid onset of action, and ready over-the-counter availability have kept them a mainstay in the treatment of allergic rhinitis; but their tendency to cross the blood/brain barrier is a severe limitation in consideration of side effects. Sedation, xerostomia, and blurred vision can be particularly bothersome with the older agents; but depending on the individual, these effects may diminish with continued regular use.

The second-generation agents are less prone to crossing the blood/brain barrier, so their side effects are generally far less bothersome; though it is wise to warn patients that sedation remains a possible liability. The earlier agents (terfenadine and astemizole), though quite effective, have been plagued by accumulation and toxicity to cause arrhythmia with high doses or when hepatic elimination is impaired. Terfenadine is no longer available, but astemizole should be avoided in patients in cardiac patients with Q-T interval abnormality. Interactions of these earlier agents with other medications involving the cytochrome P450 enzyme system have also been common. Neither of these major problems seem to plague the new agents, though.

Though they provide little to no acute relief for congestion and generally have little effect on late-stage inflammation, histamine antagonists, especially the newer agents, are considered an essential part of any medical therapeutic regimen, producing minimal side effects. It is generally considered advantageous to take them regularly to prevent symptoms; and there is some evidence that several of these agents may do more toward reducing late-stage inflammation that at first thought.

Table of Histamine Antagonists

First-Generation Agents

Alkylamines
Brompheniramine maleate Dimetane
Chlorpheniramine maleate Clor-Trimeton
Dexbrompheniramine maleate Disomer
Dexchlorpheniramine maleate Polaramine

Ethanolamines
Dimenhydrinate Dramamine
Diphenhydramine Benadryl

Ethylenediamines
Pyrilamine maleate Dorantamin
Tripelennamine citrate Pyribenzamine

Phenothiazines
Promethazine HCl Phenergan

Piperazines
Cyclizine Marezine
Meclizine Antivert

Second-Generation Agents

“Non-sedating” agents

Acrivastine
Astemizole Hismanal
Azatadine Astelin
Azelastine
Cetrizine Zyrtec
Ebastine
Fexofenadine Allegra
Ketotifen
Levocabastine
Loratadine Claritin
Terfenadine Seldane

Anti-inflammatory StrategiesSince decongestants and histamine antagonists do little toward treating the late-phase inflammatory processes that tend to prolong and exacerbate allergic rhinitis, the use of agents that target these processes has become an important aspect of therapy. Preventing migration of inflammatory cells and development of chronic exacerbation have obvious benefits, but the systemic side effects of oral or injectable agents severely limit their use to extreme or complicated cases. The inhaled topical agents provide the advantage of minimal systemic absorption with a concomitant minimal tendency to cause systemic side effects.

Inhaled topical corticosteroids (beclomethasone, flunisolode, budesonide, triamcinolone, and fluticasone) reduce secretions and mucosal swelling by impeding the influx of basophils, mast cells, eosinophils, and neutrophils into nasal tissues, inhibiting both late and early inflammatory responses to inhaled allergens as well as early non-specific hyperreactivity of the nasal mucosa. These agents afford no acute symptomatic relief and can require up to two weeks to produce any clinical benefit. Thus, therapy should begin for the seasonally atopic patient at least a week or two before anticipated allergy seasons, and regular use is necessary to maintain suppression of the inflammatory condition and allergic symptoms. Treatment with one of these agents for true allergic rhinitis is considered imperative by most allergists in light of the phenomenon of nasal priming, where continued re-challenge with antigen requires increasingly smaller doses of allergen to produce symptoms. Regular use of this type of agent significantly reduces the impact of nasal priming.15

Common side effects are generally mild and seldom require cessation of therapy. Nasal irritation and stinging, epistaxis and hemorrhagic crusting of the nasal septum can be minimized by application of a small amount of petroleum jelly to the septum and by aiming the spray away from the septum. Irritation of the pharynx (sore throat) is not uncommon, and septal perforation has been reported on rare occasions.


Other Options

Nasalcrom™ (cromolyn sodium) inhibits activation and mediator release from mast cells, eosinophils, neutrophils, and macrophages, presumably by inhibiting irritant receptors, neural reflexes, plasma exudation, and/or calcium ion influx across inflammatory cell membranes. Though initially regarded as a “stabilizer” of mast cells, other agents have been shown more effective at stabilizing mast cells with little or no effect on asthma. Administered exclusively by inhalation, it is effective on the order of the antihistamines at reducing mucosal hyper-reactivity, inflammatory cell influx, and chemotactic activity. Cromolyn has minimal recognized side effects and can be used alone in prophylaxis or in conjunction with corticosteroids, but it has no value in treating the acute attack once begun. It generally requires regular use and can be effective against attacks triggered by cold air, sulfur dioxide, and specific allergens.

Atrovent™ Nasal Spray (ipratropium bromide) is an anticholinergic with little systemic absorption and minimal side-effect liability. Providing no significant relief from other symptoms of allergic rhinitis, its main benefit is in reducing nasal secretion to stop runny nose with 2 sprays to each nostril 2 to 3 times daily. Atrovent will help patients whose nasal discharge due to colds, allergy, spicy foods, or exposure to cold becomes significantly problematic.16,17




Conclusion

Though commonly viewed as merely annoying, allergic rhinitis takes significant toll on quality of life for millions of people and can become more severe and contribute to other problems if left untreated. It is important to differentiate it from other types of rhinitis to maximize effectiveness of therapy and to rule out other complicating factors; and anti-inflammatory treatment is imperative to avoid nasal priming. Histamine H1 antagonists and glucocorticoid therapy are basic necessities, depending on symptom severity; but decongestants, ipratropium bromide nasal spray, saline solution, and lubricants can afford relief of symptoms. Cromolyn sodium, when used on a regular basis can also ameliorate symptoms.

Exam

1. Nasal turbinates perform all of the following functions except:

A. Increase the surface area of the nasal mucosa

B. Filter particulate from the air on the way to the alveoli

C. Regulate blood flow to the ocular nerveD. Regulate turbulence of air passing over nasal mucosa




2. The mucus blanket covering the nasal mucosa:

A. Traps particulate from the air entering the respiratory system

B. Is perpetually replenished by goblet cells and islet cells in the mucosa

C. Mobilizes particulate into the sinuses

D. Is a complex mixture of twelve proteins derived from serum




3. Immunoglobulin E:

A. Protects against pathogenic eosinophilic invasion

B. Is too large to be phagocytized by macrophages

C. Acts as a chemotactic messenger in the sinuses

D. Is important in defense against parasitic worms




4. Increased levels of IgE in the nasal mucosa:

A. Are caused by increased histamine release

B. Are the result of invasion by parasitic worms

C. Are typically found in atopic individuals

D. Are produced by CD8+ cells in patients with eczema




5. The genetic tendency to be atopic and to produce IgE:

A. Involves a genetic predisposition to a particular cytokine environment

B. Depends on prenatal infection by parasitic worms

C. Requires exposure to low-molecular-weight antigensD. Is seen with TH2 domination




6. Environmental pollutants:

A. Protect against the harmful effects of second-hand smoke

B. Increase mucosal permeability to facilitate allergen entry

C. Increase production of IgE by thyroid overstimulation

D. Can be considered the cause of allergic breakthrough




7. Stage 1 of the typical allergic response includes all of the following except:

A. IgE specific for challenging antigen is produced by plasma cells.

B. Allergens are phagocytized and degraded by macrophages.

C. Basophils present antigen to T-lymphocytes.

D. IgE attaches to both basophils and mast cells


8. Histamine:A. Is the only mediator of symptoms in allergic rhinitis

B. Exerts its pharmacological effects by interacting with three kinds of receptors

C. Remains a target of IgE attack

D. Is metabolized by both goblet cells and islet cells




9. Histamine:

A. Functions as a neurotransmitter in the brain

B. Is responsible for the sedation seen with many medications

C. Causes both allergy and traumaD. Is released in response to both allergy and trauma




10. Histamine:

A. Is synthesized in the CNS and transported to peripheral tissues in subcellular granules of macrophages.

B. Is synthesized in platelets and transported to the CNS

C. Is synthesized locally and stored in sucbellular organelles of mast cellsD. Is synthesized locally and stored in subcellular granules of endothelial cells




11. Degranulation of mast cells to release histamine:

A. May be caused by cell lysis

B. Is carefully regulated by activation of the complement system

C. Is caused by physical displacement by histamine antagonistsD. Produces basic polypeptides via catalytic conversion by phospholipase A




12. Histamine:

A. Causes most cases of food poisoning

B. Is a major cause in many fish poisonings

C. Is produced by a number of pathogenic bacteria

D. Is essential in increasing vulnerability of bacteria to immunoglobulin attack




13. Histamine receptors:

A. Are responsible for the pharmacological effects of histamine on different organs

B. Are activated by G-protein cross-attachment to IgEC. Are IgE-coupled receptors

D. Modulate activity of potassium channels




14. Histamine H1 receptors:

A. Are found mainly in the gut and nasal mucosae

B. Are found mainly in peripheral tissues and CNS

C. Are found only in peripheral tissues

D. Are found only on mast cells




15. Activation of H1 receptors causes:

A. Mucosal edema

B. Vasoconstriction

C. Bradykinin toxicity

D. Scombrotoxism




16. Activation of H1 receptors causes reduction of arterial pressure and increase in blood flow in:

A. Skin, muscle, and splanchnic beds

B. Skin, nasal mucosa, and cranial arteries

C. Nasal mucosa, muscle, and splanchnic beds

D. Skin, nasal mucosa, and splanchnic beds




17. Vascular permeability:

A. Can be countered by activation of H3 receptors

B. Is enhanced by beta-blockers, theophylline, and erythromycin

C. Is enhanced by beta-blockers, terbutaline, and theophylline

D. Contributes to mucosal edema




18. Advantages of topical decongestants include all the following except:

A. Fast onset of action and short duration of action

B. Minimal systemic absorption

C. Minimal short-term side effects

D. Facilitate proper penetration of topical anti-inflammatory agents




19. The second-generation H1 antagonists:

A. Do not cause sedation

B. Provide little to no acute relief of congestion

C. Can cause paroxysmal atrial tachycardia when liver function is impaired

D. Are no longer available




20. Inhaled topical corticosteroids:

A. Do little toward treating the late-phase inflammatory processes in allergic rhinitis

B. Can cause paroxysmal atrial tachycardia when liver function is impaired

C. Are no longer available

D. Can be helpful in minimizing the effect of nasal priming




Answer KeyCADCABCBACACABAADABD


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