Regis University RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 PDF

Allergic Rhinitis RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References Stephanie James, PhD, MBA...

Allergic Rhinitis RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References Stephanie James, PhD, MBA Required [email protected] Integrated Pharmacotherapy 3 Allergic Rhinitis student notes (this document) 303-964-6168 Mathias, McAleer and Szollosi, Pharmacology of Immunotherapeutic Drugs, Springer Publishing, ISBN 978-3-030-19922- Leticia Shea, PharmD, BCACP 7) chapter 4 [email protected] 303-964-6182 Learning Objectives 1. Define rhinitis, allergic rhinitis, and allergic conjunctivitis. 2. Differentiate the definitions of perennial allergic rhinitis, seasonal allergic rhinitis, and episodic allergic rhinitis. 3. Differentiate the allergens causing perennial allergic rhinitis and seasonal allergic rhinitis. 4. Predict the allergens causing symptoms in a patient when given a patient who experiences worsening of symptoms in a given season. 5. List the risk factors for allergic rhinitis. 6. List the most common causes of drug-induced rhinitis. 7. Describe the structure and function of the nasal cavity. 8. Explain the structure and function of the mucous membrane. 9. Illustrate the function of nasal turbinates and their impact on airflow through the nasal cavity. 10. Describe the structure and function of conjunctiva. 11. Define hypersensitivity reaction. 12. Define the four types of hypersensitivity reactions, and provide an example for each. 13. Define allergen. 14. Define sensitization and describe the process of sensitization (specifically the roles of APCs, CD4 helper T cells, B cells, IL 4, and IL 13). 15. Explain the roles of mast cells, basophils, and eosinophils in allergic rhinitis. 16. Describe the two phases of allergic rhinitis and explain what immunological processes are involved in each (i.e. what immune cells are active, what mediators are being released, and what are the associated consequences). 17. Explain the biological mechanism for the following symptoms: rhinorrhea, nasal itching, sneezing, nasal congestion, and allergic conjunctivitis. 18. Define the role of TH2 cells in allergic rhinitis. 19. Describe the role of histamine in allergic rhinitis and explain its mechanism of action. 20. List the symptoms of allergic rhinitis and review the findings on physical exam for a patient with allergic rhinitis. 21. List the complications of allergic rhinitis. 22. Differentiate the available allergen tests. 23. Describe the nonpharmacotherapy patient counseling points for patients with allergic rhinitis. 24. Explain the rationale for intranasal drug delivery including advantages of intranasal drug delivery for management of allergic rhinitis. 25. List the patient counseling points for intranasal drug delivery. 26. When given a generic allergic rhinitis drug name, match the drug one of the following classes: first generation antihistamine, second generation antihistamine, intranasal antihistamine, intranasal corticosteroid, ophthalmic corticosteroid, mast cell stabilizer, sympathomimetic decongestant (vasoconstrictors), leukotriene receptor antagonists 27. Predict the pharmacologic response of blockade of H1 receptors in the central and peripheral nervous systems. 28. Describe the difference between first and second generation antihistamines with regard to drug distribution and autonomic receptor selectivity. 29. Predict the adverse effects of medications used to treat allergic rhinitis and differentiate between the adverse effect profiles of first generation oral antihistamines compared with second generation oral antihistamines. 30. When given the chemical structure of first generation antihistamines, differentiate between ethanolamine ether, alkyl amine and phenothiazine antihistamines. 31. Describe the chemical relationship between loratadine and desloratadine.  Learning Objectives 32. Rank the first generation antihistamines by relative sedative effects and apply this information to drug selection decisions. 33. Predict the effect of peripheral α-adrenergic receptor activation on tissues controlled by the autonomic nervous system. 34. Explain how α-1 adrenergic agonists are effective for relieving congestion. 35. Identify neurotransmitters that pseudoephedrine and phenylephrine mimic and explain why this is an effective drug design strategy. 36. Define rhinitis medicamentosa and conjunctivitis medicamentosa, explain the mechanism of these adverse effects, and describe patient counseling points that can help prevent these adverse effects. 37. Describe the general mechanism by which all corticosteroids work. 38. Describe the effect of corticosteroids on inflammatory and immunologic processes common to allergic rhinitis. 39. Describe and explain the difference in risk for HPA axis suppression between intranasal, ophthalmic and systemically-administered corticosteroids. 40. Explain why pseudoephedrine is more effective than phenylephrine when taken as an oral dosage form. 41. Explain the mechanisms exhibited with intranasal antihistamines and explain how these differ from oral antihistamines 42. Describe immunotherapy for the management of allergic rhinitis including adverse effects, good candidates for immunotherapy, and poor candidates for immunotherapy. 43. Differentiate subcutaneous immunotherapy and sublingual immunotherapy including their advantages and disadvantages. 44. Identify the metabolism profile of a drug that may have a pharmacokinetic interaction with antihistamines. 45. Identify the general type of drug that may have a pharmacodynamic interaction with antihistamines. 46. List the complementary medications that are considered possibly effective and possibly safe for allergic rhinitis and describe their proposed mechanism of action. 47. When given a patient case, select the most appropriate medication for the treatment of allergic rhinitis. 48. Identify the drugs of choice for the management of allergic rhinitis during pregnancy. Integrated Pharmacotherapy 3 2 Allergic Rhinitis INTRODUCTION TO ALLERGIC RHINITIS Definitions Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory Definitions disease of the nasal mucous membranes caused by inhaled allergens, which Rhinitis inflammation of the nasal mucous membrane provoke nasal symptoms including nasal congestion, rhinorrhea, sneezing, and with one or more of the following: nasal congestion, pruritis. rhinorrhea (runny nose), sneezing, and itching. There are several types of rhinitis including nonallergic rhinitis and Understanding allergic rhinitis requires familiarity with several definitions and occupational rhinitis, but this unit focuses on the care of classifications. The box at right provides definitions for terms important to patients with allergic rhinitis. allergic rhinitis. Allergic rhinitis an IgE-mediated inflammatory re- sponse of the nasal mucous membranes after exposure to inhaled allergens. Epidemiology Seasonal allergic rhinitis allergic rhinitis that occurs in Allergic rhinitis is a very common disease. Treatment of allergic rhinitis is response to specific allergens present at predictable times important to prevent the development of potential complications (see Clinical of the year Presentation section). Allergic rhinitis is the most common chronic disease in Perennial allergic rhinitis allergic rhinitis that occurs children and fifth most prevalent chronic illness in the United States overall. year round In childhood, allergic rhinitis is more frequent in boys, but in adults, allergic Episodic allergic rhinitis allergic rhinitis that occurs rhinitis is more frequent in women. by sporadic exposures to allergens that are not usually en- countered in the patient’s indoor or outdoor environment (e.g., visiting a home with pets when the patient has no pet exposure in their own home or work environment) Etiology Allergic conjunctivitis inflammation of the conjunctiva For a patient to have allergic rhinitis, they must be exposed to a protein that (the eye) that is medicated by IgE and is associated with elicits the allergic response (aka allergen). Patients have seasonal allergic rhinitis, itching, erythema (i.e., redness), and tearing perennial allergic rhinitis, or a combination of seasonal and perennial allergic rhinitis based on their allergic response to specific allergens. Allergens causing seasonal rhinitis and perennial allergic rhinitis are listed in Table 1 and Table 2. Flowering plants that depend on insect pollination usually do not cause allergic rhinitis because this type of pollen is too heavy to be carried by air. Risk factors for development of allergic rhinitis are listed in Table 3. Medications may also cause allergic rhinitis. The most common causes of drug-induced allergic rhinitis are listed in Table 4. Table 1. Table 2. Seasonal Allergic Rhinitis Allergens Perennial Allergic Rhinitis Allergens Tree pollens cause symptoms in the spring. Mold spores are present year round. Grass pollens cause symptoms in the late spring to early summer. House dust mite fecal proteins cause symptoms year round. Weed pollens cause symptoms in the late summer to early fall. Animal dander causes symptoms year round. Cockroaches cause symptoms year round. Table 3. Table 4. Risk Factors for Allergic Rhinitis Most Common Causes of Drug-Induced Rhinitis Family history of atopy ACE inhibitors Higher socioeconomic classes Aspirin and NSAIDs Higher serum IgE levels (> 100 IU/mL) before age six α-receptor antagonists Positive allergy skin prick test Clonidine Guanfacine Phosphodiesterase-5 selective inhibitors Integrated Pharmacotherapy 3 3 Allergic Rhinitis ANATOMY AND PHYSIOLOGY Allergic rhinitis is a hyperactive immune response resulting from contact between inhaled allergic molecules (allergens) and the nasal mucous membranes. This interaction elicits an immunological response causing sneezing, nasal itching, rhinorrhea, allergic conjunctivitis, and/or nasal congestion. The following sections present a brief overview of the anatomy of the nasal cavity and conjunctiva of the eye, followed by a discussion of the immune response to allergens in general as well as the specific immune response that characterizes allergic rhinitis. These course notes will build off your IP3 Introduction to Immunology TBL course notes. Figure 1. Anatomy of the Nasal Cavity Nasal Cavity The nose serves several important functions: 1) provides an airway for respiration, 2) moistens and warms entering air, 3) filters and cleans inspired air, 4) serves as a resonating chamber for speech, and 5) houses the olfactory (smell) receptors. The nasal cavity lies posterior to the external nose (see Figure 1) and comprises a large surface area lined by an epithelial mucous membrane. A mucous membrane consists of an epithelium (a sheet of cells) supported by an underlying layer of connective tissue, and is coated with a viscous fluid (mucus) secreted by either goblet cells strewn throughout the epithelium and/or underlying mucous glands. Also resident to the nasal cavity are serous glands which release a watery fluid containing the enzyme lysozyme which chemically destroys bacteria. Both serous fluid and mucus act to trap dust, bacteria, and other debris. In addition, the epithelial cells secrete natural antibiotics to destroy inhaled microbes. The cilia of the epithelial cells move the accumulated mucus and fluid posteriorly toward the throat where it is swallowed (and delivered to the acidic stomach compartment). The nasal mucosa is continuous with the pharynx, larynx, trachea, and lungs, is richly innervated with sensory nerve endings, and contains a complex network of capillaries that serves to warm incoming air as it passes through the nasal cavity. When the air is cold, this capillary plexus becomes engorged with blood. Figure 2. External Anatomy of the Eye Located in the nasal cavity are mucosa-covered projections called nasal conchae. These include the superior, middle, and inferior nasal conchae which extend the length of the nasal cavity and can increase the mucosal surface area when they become engorged with blood. As a consequence of increased blood flow, the conchae swell and reduce the air flow through the nose causing nasal congestion. Surrounding the nasal cavity are the paranasal sinuses, which are air-filled spaces located within the bones of the face. These spaces are continuous with the nasal cavity and produce mucus and fluids that drain into the nasal cavity. Eye The eye is often affected in patients with allergic rhinitis. The outer layer of the eye is a thin epithelium (see Figure 2) called conjunctiva. The conjunctiva is a thin, transparent mucous membrane that lines the eyelids and covers the visible part of the eye. It functions to lubricate the eye by secreting oils and mucus. Integrated Pharmacotherapy 3 4 Allergic Rhinitis Inflammation of the conjunctiva is referred to as conjunctivitis and can be caused by either an infection or an irritant, such as an allergen. A common infectious conjuctivitis caused by a bacterium is acute contagious conjuctivitis (or pinkeye). Of particular interest in this unit is that allergens can directly interact with this layer leading to symptoms of red, itchy and watery eyes (allergic conjunctivitis). PATHOPHYSIOLOGY Hypersensitivity Reactions In your IP3 Introduction to Immunology TBL course notes, it was clear that the immune system is necessary to defend against infections. However, an immune response in itself, if excessive or aberrant, can also cause tissue injury and disease. These injurious, or pathologic, immune responses are categorized as hypersensitivity reactions. There are four types of hypersensitivity reactions, outlined below, characterized by the immunologic mechanism responsible for the pathology: 1. Immediate Hypersensitivity (Type I; allergies): rapid, IgE antibody and mast cell-mediated vascular and smooth muscle reaction; often followed by inflammation; examples include hay fever, food allergies, bronchial asthma, and anaphylaxis 2. Antibody-Mediated Diseases (Type II): antibodies other than IgE against cells or extracellular matrix components may react with any tissue that expresses the specific antigen, but are usually specific for a particular tissue; antibodies are most often self- reactive (autoantibodies) and may cause tissue injury by inducing local inflammation; examples include autoimmune hemolytic anemia, Graves’ disease, and myasthenia gravis 3. Immune Complex-Mediated Diseases (Type III): immune complexes of circulating/soluble antigens and antibodies can deposit in blood vessels in various tissues and cause inflammation and tissue injury; examples include systemic lupus erythematosus and serum sickness 4. T cell-Mediated Diseases (Type IV): T cell-mediated autoimmune reactions directed against cellular antigens with restricted tissue distribution; examples include type 1 diabetes mellitus, rheumatoid arthritis, contact sensitivity (e.g., poison ivy reaction), and inflammatory bowel disease Figure 3. Immediate Hypersensitivity Reaction Allergic Rhinitis Allergic rhinitis is the result of a chronic immune reaction involving the nasal mucous membrane and conjunctiva, and is classified as a type I hypersensitivity, or immediate hypersensitivity. In this type of pathologic reaction, the immune system reacts to the 1) protein components of house dust mites or animal dander and 2) airborne pollen grains from trees, grasses, and weeds, producing the following symptoms: sneezing, nasal itching, nasal congestion, rhinorrhea, and allergic conjunctivitis. Sensitization (Production of IgE Antibody) Individuals prone to allergies produce IgE antibody following antigen-stimulation of CD4 helper T cells. Normal individuals do not activate CD4 T cells to most foreign antigens, and it is unknown why some individuals mount such an excessive response to rather innocuous molecules, or allergens. There is however a strong genetic basis with many contributory genes in the development of immediate hypersensitivity. The first time a person interacts with an allergen, APCs digest and process the allergen and display the protein fragment in association with a class II MHC protein (see Figure 3). Helper T cells bind to the antigen-class II MHC complex and activate the adaptive immune response. Allergen activation of CD4 T cells results in the secretion of two specific cytokines, interleukin (IL)-4 and IL-13. These cytokines stimulate B cells specific for the same foreign allergen to switch to IgE-producing plasma cells. The IgE antibodies bind to receptors in the plasma membrane of mast cells and basophils. This is called sensitization, because now these cells are sensitive to a subsequent encounter with the same allergen. IgE- bound mast cells and basophils are located in the nasal mucosa (and conjunctiva in the eye), easily accessible to allergens. Integrated Pharmacotherapy 3 5 Allergic Rhinitis Hypersensitivity/Allergic Reaction First/Early Phase Upon subsequent exposure to allergen, the allergen binds to and Figure 4. Resting (E) and Activated/Degranulated (F) cross-links the IgE molecules. This event causes mast cells and Mast Cell basophils, to a lesser extent, to rapidly release the contents of their secretory vesicles, a process called degranulation (see Figure 4), as well as to synthesize and secrete lipid mediators and cytokines. This first phase or early phase reaction occurs within seconds to minutes following exposure to an allergen. The most important products of mast cell activation include (see Figure 5): histamine--causes vasodilation, increased vascular permeability (edema), and the transient contraction of smooth muscle; proteases--causes damage to local tissues; Figure 5. Mast Cell Activation and Secretion of Mediators prostaglandins--arachidonic acid metabolite that causes vascular dilation; leukotrienes--arachidonic acid metabolite that stimulates prolonged smooth muscle contraction; and cytokines--induce local inflammation, and stimulate the recruitment of immune cells (eosinophils, neutrophils, and TH2 cells). Collectively, these molecules induce and propagate the immune reaction. Histamine is central to allergic rhinitis by binding to and activating histamine-1 (H1) receptors. Histamine causes most of the following symptoms associated with allergic rhinitis: rhinorrhea--results from reflexive stimulation of the parasympathetic nervous system leading to secretion of mucus from mucous glands, itching and sneezing--result from histamine stimulation of H1 receptors on sensory nerve endings, and nasal congestion, redness, heat--due to submucosal edema and engorgement of the nasal turbinates as a result of vasodilation and increased vascular permeability of the blood vessels in the nasal cavity. Allergic conjunctivitis occurs when the allergen interacts with the conjunctiva of the eyes. Conjunctivitis is associated with redness of the eyes due to vasodilation of the peripheral small blood vessels. Edema of the conjunctiva also occurs, as well as itching and increased lacrimation (production of tears). Second/Late Phase Reaction The cytokine-mediated recruitment of leukocytes to the site of inflammation causes the late phase reaction, which occurs four to eight hours following exposure to the allergen. This second phase reaction involves infiltration of additional mast cells and helper T cells which secrete molecules that exacerbate the reaction and prolong the inflammation. These secretions include proteases that cause tissue damage, and cytokines that stimulate and sustain mucus hypersecretion, IgE production and the infiltration of eosinophils and neutrophils. In patients with allergic rhinitis, an abnormally large number of helper T cells differentiate into TH2 cells, which if you recall from your IP 3 Introduction to Immunology course notes, stimulate mast cell- and eosinophil-mediated immunity, as well as the secretion of mucus. Eosinophils play a key role in allergic rhinitis, for they release chemical mediators that promote the migration of additional immune cells to the site, as well as chemicals that are destructive to epithelial tissues. These events lead to a hyperresponsive patient with an allergic response that is more easily triggered following exposure to low amounts of allergen. This effect may explain why patients continue to have allergic symptoms long after pollen levels have dropped. Integrated Pharmacotherapy 3 6 Allergic Rhinitis CLINICAL PRESENTATION Table 5. Table 5 lists the symptoms associated with allergic rhinitis, and Table 6 lists the Figure 6. Allergic Salute Symptoms of Allergic Rhinitis complications of allergic rhinitis. Clear rhinorrhea Sneezing The findings on physical exam include a Nasal congestion permanent transverse crease across the Pruritic ears, nose, or palate lower part of the nose. This results from Allergic conjunctivitis (itchy eyes and tearing) – more constant upward rubbing of the nose (aka frequent with seasonal allergic rhinitis the allergic salute, see Figure 6). Dark circles under the eyes (aka allergic shiners, Table 6. see Figure 7) may also be present. Allergic Complications of Allergic Rhinitis shiners result from venous pooling from Inability to sleep nasal congestion. Pale discoloration of Fatigue the nasal mucosa may also be present. Poor work or school efficiency Allergic rhinitis is often accompanied Post nasal drip with cough with symptoms of allergic conjunctivitis Loss of smell or taste (i.e., itching, erythema, and swelling of the High arched, V-shaped palate due to chronic edema and conjunctiva) (see Figure 8). venous stasis Permanent transverse crease across the lower part of the nose Dark circles under the eyes Asthma Recurrent and chronic sinusitis Epistaxis (i.e. nosebleed) Nasal polyps Sleep apnea Figure 7. Allergic Shiners Figure 8. Allergic Conjunctivitis Integrated Pharmacotherapy 3 7 Allergic Rhinitis DIAGNOSTIC TESTS IgE allergen tests are indicated in patients to provide evidence of an allergic basis for the patient’s symptoms, to confirm suspected causes of the patient’s symptoms, or to assess the sensitivity to a specific allergen for avoidance measures and/or allergen immunotherapy. There are three types of allergen tests: 1. Epicutaneous skin test (aka scratch or prick test) ӽ Performed by making a superficial wound in the outermost layer of the skin. Then a drop of antigen is placed in the wound and allowed to diffuse into the underlying skin. ӽ Fastest and least expensive screening tool available ӽ A positive test produces a wheal and flare reaction within 15 to 30 minutes ӽ Concurrent use of antihistamines, sympathomimetic agents, and/or H2-receptor antagonists may alter the test response. Discontinue first generation antihistamines 3 days before testing and discontinue second-generation antihistamines 10 days before testing. 2. Intradermal skin test ӽ Performed by injecting diluted allergen between the layers of the skin ӽ Useful in patients who have negative epicutaneous tests and suspected of having an allergic etiology for their symptoms ӽ A positive test produces a wheal and flare reaction within 15 to 30 minutes ӽ Concurrent use of antihistamines, sympathomimetic agents, and/or H2-receptor antagonists may alter the test response. Discontinue first generation antihistamines 3 days before testing and discontinue second-generation antihistamines 10 days before testing. 3. Radioallergosorbent test (RAST) ӽ In vitro assay that is more expensive and less sensitive than skin tests ӽ Useful when skin test extracts are not available, when negative controls produce a reaction, when antihistamine therapy cannot be discontinued, or in the presence of dermatographia (skin condition resulting in wheals from tracing the skin with a fingernail or a blunted instrument) CLASSIFICATION Allergic rhinitis can be classified by: 1) the temporal pattern and context of exposure to a triggering allergen; 2) frequency and duration of symptoms; and 3) severity of symptoms. The temporal pattern and context of exposure to a triggering allergen includes seasonal, perennial, or episodic (see Definitions section). Classification based on frequency and duration of symptoms is divided into intermittent (< 4 days/week or < 4 weeks/year) and persistent (> 4 days/week or > 4 weeks/year). Severity of symptoms is classified as mild when symptoms are present but not interfering with quality of life and more severe when symptoms are interfering with quality of life (e.g., asthma exacerbations, sleep disturbances, and impairment of daily activities such as leisure, sports, school, or work). GOALS OF THERAPY Minimize or prevent symptoms. Minimize side effects of medications. Prevent complications associated with poorly controlled allergic rhinitis (i.e., asthma) Maintain a normal lifestyle, including participating in outdoor activities, yard work, and playing with pets as desired. NONPHARMACOTHERAPY Nonpharmacotherapy consists of identifying triggers and avoiding triggers when practical (e.g., you may not want to tell someone to get rid of their cat, but they could do what they can to keep the cat out of the bedroom). Mold growth can be reduced by maintaining household humidity below 50% and removing obvious growth with bleach or disinfectant. Exposure to dust mites can be reduced by encasing mattresses and pillows with impermeable covers and washing bed linens in hot water at least every 2 weeks. Washable rugs Integrated Pharmacotherapy 3 8 Allergic Rhinitis are preferable over wall-to-wall carpeting. Acaricide (benzyl benzoate) treatment of carpets has been shown to denature the dust mite allergen. High-efficiency particulate air (HEPA) filters have minimal effect on the heavy allergens, but are effective in removing pollens, mold spores, dust mite allergen, and cat allergen. For seasonal allergic rhinitis, patients should keep windows closed and minimize time spent outdoors during pollen season. Avoid using fans that direct outside air into the house. Filter masks should be worn while gardening or mowing the lawn. Cold compresses and irrigation with saline solution or artificial tears may be used for mild allergic conjunctivitis. Nasal irrigation using a saline solution is also used for allergic rhinitis. Nasal irrigation clears out mucus, reduces congestion, and decreases histamine and leukotrienes. Acupuncture may be considered for patients who prefer nonpharmacotherapy over pharmacotherapy for allergic rhinitis. DOSAGE FORMS Intranasal Drug Delivery Many drugs for allergic rhinitis are delivered by direct administration to nasal tissue, which is advantageous for two reasons: 1. The site of the problem (i.e., allergic rhinitis) is in the nasal tissue. 2. Intranasal drug delivery minimizes systemic drug exposure. In other words, the drug does not distribute into and affect the rest of the body to nearly the same extent as oral drug delivery. This often translates into fewer adverse effects. Important counseling for intranasal drug delivery include: 1. Nasal passages should be cleared prior to administration (i.e., blow your nose prior to administration). 2. Avoid clearing nasal passage for about 10 minutes after administration (i.e., don’t blow your nose right after administration). 3. Direct the spray away from the nasal septum. 4. Do not use in patients with nasal septum ulcers, recent nasal surgery, or recent nasal trauma. 5. Local irritation may occur, particularly with initial dosing (e.g., stinging or burning in nasal passages). Cromolyn sodium Budesonide (INCS) (Mast cell stabilizer) Mometasone (INCS) Integrated Pharmacotherapy 3 9 Allergic Rhinitis Pharmacotherapy Options Antihistamines (H1 Receptor Antagonists) The term “antihistamines” technically includes both H1 and H2 receptor Antihistamines antagonists (recall that H2 receptor antagonists are useful for suppressing gastric Second Generation Oral Antihistamines acid in GERD). However when the term “antihistamine” is used by healthcare Acrivastine/Pseudoephedrine (Semprex-D®) (Rx) providers, it usually refers to H1 receptor antagonists. When patients use the term Cetirizine (Zyrtec®) (OTC) “antihistamine” they are nearly always referring to H1 receptor antagonists. These Levocetirizine (Xyzal®) (Rx) notes will use the term “antihistamine” and it is important to understand that use Fexofenadine (Allegra®) (OTC) Loratadine (Claritin®) (OTC) of this term is specifically referring to H1 receptor antagonists, not H2 receptor Desloratadine (Clarinex®) (Rx) antagonists. First Generation Oral Antihistamines (See PPT for complete list) Orally-administered antihistamines are classified by two generations. First and Chlorpheniramine (Chlor-Trimeton®) (OTC) second generation antihistamines. Diphenhydramine (Benadryl®) (Rx, OTC) Promethazine (Phenergan®) (Rx) Antihistamines block histamine from activating H1 receptors, and prevent most Intranasal Antihistamines of the effects of histamine on smooth muscle. In the peripheral nervous system Azelastine (Astelin®, Astepro®) (Rx) (PNS), this is useful for blocking the symptoms of allergic rhinitis due to excess Azelastine/Fluticasone (Dymista®) (Rx) histamine release as explained in the pathophysiology section above. In the CNS, Olopatidine (Patanase®) (Rx) blockade of H1 receptors is associated with drowsiness, sedation, and impairment Ophthalmic Antihistamines of daily activities (e.g., performance in school or ability to drive safely). A high Alcaftadine (Lastacaft®) (Rx) degree of variability exists from patient to patient in terms of the CNS response to Azelastine (Optivar®) (Rx) antihistamines. Bepotastine (Bepreve®) (Rx) Emedastine (Emadine®) (Rx) H1 receptor antagonists also block muscarinic acetylcholine receptors, producing Epinastine (Elestat®) (Rx) the classic “anticholinergic” effects (i.e., dry mouth and eyes, blurry vision, urinary Ketotifen (Zaditor®) (OTC) retention, constipation). Appendix A: Autonomic Receptor Tissue and Organ Olopatidine (Pataday®) (OTC) Effects at the end of this packet provides the autonomic receptor table to help you Notes review the effects of blocking muscarinic acetylcholine receptors. Anticholinergic Several ophthalmic and intranasal antihistamines also have mast cell stabilizing effects. effects from H1 receptor antagonists are often considered to be adverse effects. However, anticholinergic effects probably contribute to the drying effect that antihistamines have on patients (e.g., control of rhinorrhea). There are two major differences between first and second generation H1 receptor antagonists: 1) their ability to distribute across the blood-brain barrier into the CNS and 2) their affinity for binding to and blocking muscarinic acetylcholine receptors (see Figure 9 on page 11). H1 receptor antagonists that do not cross the blood-brain barrier wall are “peripherally selective” or simply “selective” H1 receptor antagonists, and most commonly referred to as second generation antihistamines. This means that they are relatively selective for blocking H1 receptors located in the PNS relative to the CNS. Some H1 receptor antagonists block muscarinic acetylcholine receptors extensively, and others do not. The greater the extent of blockade, the stronger the anticholinergic effects. First Generation Oral Antihistamines Several example chemical structures of first generation antihistamines are shown in Figure 10. First generation antihistamines are chemically diverse. Diphenhydramine is a representative ethanolamine ether antihistamine. Brompheniramine and chlorpheniramine are representative alkyl amine antihistamines. Promethazine belongs to a large group of drugs called phenothiazines, due to containing a phenothiazine ring. Most phenothiazine drugs are first-generation antipsychotics (an older class of antipsychotics) and are associated with many adverse effects. Promethazine shares some of this adverse effect potential, such as the risk for causing dystonic reactions (abnormal muscle contraction, particularly in the neck, arms and upper torso). First generation antihistamines block muscarinic acetylcholine receptors, ultimately resulting in anticholinergic adverse effects (see Figure 9). Some first generation antihistamines cause greater anticholinergic effects than others, but all have a greater risk for anticholinergic effects compared to second generation antihistamines. Integrated Pharmacotherapy 3 10 Allergic Rhinitis Figure 9. Selectivity of First and Second Generation H1 Receptor Antagonists Blood-Brain PNS Barrier CNS Blockade of M ACh receptors by first generation agents causes anticholinergic effects First Generation Antihistamines 1st Gen (also occurs in CNS) Muscarinic Extensive distribution into CNS Acetylcholine Receptors Extensive CNS-related adverse effects X Second Generation Antihistamines 2nd Gen Little distribution into CNS Second generation agents have little Less CNS-related adverse effects to no M ACh receptor blockade and do not cause significant anticholinergic effects First generation antihistamines cross the blood-brain barrier (see Figure 9) and may cause extensive CNS adverse effects related to Figure 10. First Generation Antihistamine Chemistry central histamine blockade and muscarinic acetylcholine receptor Example First Generation Agents blockade (e.g., drowsiness, sedation, and impairment of daily activities (e.g., performance in school or ability to drive safely). Their S ability to cross into the CNS is due to their greater lipophilicity as compared with second generation antihistamines. However, not all O CH2 CH2 N N first generation antihistamines cause sedation to the same degree. If N a first generation antihistamine is selected for a patient, the following relative sedative effects may be used to guide choice in therapy (listed from most sedating to least sedating): Diphenhydramine Promethazine (ethanolamine ether) (phenothiazine ring highlighted) promethazine = diphenhydramine = carbinoxamine > clemastine Br > brompheniramine = chlorpheniramine = cyproheptadine Cl Second Generation Oral Antihistamines Second generation antihistamines were developed after first CH2 CH2 N CH2 CH2 N generation antihistamines and are preferred for patients with allergic N N rhinitis due to their milder adverse effect profile. The second generation agents are less lipophilic and do not cross the blood-brain barrier into the CNS as extensively as first generation antihistamines (see Figure 9). As a result, they are associated with fewer CNS- Chlorpheniramine Brompheniramine (alkyl amine) (alkyl amine) related antihistamine adverse effects (drowsiness, sedation, and impairment of daily activities (e.g., performance in school or ability to drive safely). In addition, second generation agents have a low potential for blocking muscarinic acetylcholine receptors and are associated with very little, if any, anticholinergic effects. Similar to the first generation antihistamines, the second generation antihistamines are not all the same in terms of chemistry. Cetirizine and fexofenadine are chemically related, and levocetirizine is an enantiomerically-pure preparation of the active enantiomer of cetirizine (see Figure 11). Loratadine is chemically unique from most other second generation antihistamines, but has an active metabolite (desloratadine) that is also a marketed second generation antihistamine. Integrated Pharmacotherapy 3 11 Allergic Rhinitis Intranasal Antihistamines Azelastine is an intranasal antihistamine that avoids systemic exposure and therefore minimizes CNS antihistamine adverse effects. In addition to providing antihistamine activity, the intranasal antistamines also exhibit mast cell stabilizer activity. Astepro®, is available OTC, but olopatadine is remains prescription only for the intranasal formulation, however they were approved for RX-OTC switch for their opthalmic formulation (Brand name Pataday®, an extremely effective agent for allergic conjunctivitis). What about the structure provides mast cell stabilizing activity? Azelastine contains a phthalazinone ring system, which forms the central scaffold of the molecule. This heterocyclic structure likely plays a role in the compound’s ability to interact with mast cell membranes and receptors. Chlorobenzyl group: The presence of a 4-chlorobenzyl Figure 11. Second Generation Antihistamine Chemistry substituent at the 4-position of the phthalazinone ring Example Second Generation Agents OH enhances the molecule’s O lipophilicity. This may Cl O O facilitate its penetration into N OH N mast cell membranes and N OH interaction with intracellular HO targets. Ophthalmic Antihistamines Ophthalmic antihistamines Cetirizine Fexofenadine also exhibit this dual role (Levocetirizine is the levorotatory enantiomer of cetirizine) of antihistamine and mast cell stabilizing effect. Olopatadine, as discussed Cl Cl above is now an OTC N opthalmic antihistamine. It N CYP3A4 provides both antihistamine and mast cell stabilizing activity leaving it as a superior N N H agent in the management O of allergic conjunctivis. O Ophthalmic vasoconstrictors Loratadine Desloratadine (the opthlamic version of a decongestant) are also widely available, although like intranasal decongestants, drying and rebound can occur and are not as safe and effective as opthalmic antihistamines. Adverse Effects The most significant adverse effects of oral antihistamines are sedation (1st generation), anticholinergic effects,( also predominately first generation) (i.e., dry mouth and eyes, blurry vision, urinary retention, constipation, mucosal dryness), and impairment of daily activities (e.g., performance in school or ability to drive safely). The most significant adverse effects of intranasal antihistamines are bitter taste. The most significant adverse effect of ophthalmic antihistamines are ocular burning stinging upon administration. THERAPEUTIC CONSIDERATIONS FOR ANTIHISTAMINES Oral antihistamines are effective in treating rhinorrhea, nasal itching, sneezing, and allergic conjunctivitis. Oral antihistamines are less effective than intranasal corticosteroids. Oral antihistamines and less effective than intranasal antihistamines. However, they are options for those that do not like intranasal delivery or are only needed short term for predicted allergen exposures. Intranasal antihistamines are effective in treating nasal congestion, rhinorrhea, nasal itching, sneezing, and allergic conjunctivitis. Intranasal antihistamines are considered eqyally effective to intranasal corticosteroids, however more evidence of efficacy is available for intranasal corticosteroid. Intranasal antihistamines rapidly relieve symptoms and may be a useful alternative to oral antihistamines (especially for seasonal rhinitis). Ophthalmic antihistamines are effective in treating allergic conjunctivitis. Continuous use is most effective for seasonal and perennial allergic rhinitis, but antihistamines may be used PRN due to a rapid onset of action especially for episodic allergic rhinitis. For seasonal allergic rhinitis, patients should begin treatment 1 to 2 hours before allergen exposure. Combination of oral antihistamines with an intranasal corticosteroid is not recommended for patients with seasonal allergic rhinitis due to lack of additional therapeutic effect. Integrated Pharmacotherapy 3 12 Allergic Rhinitis  For perennial allergic rhinitis, oral or intranasal antihistamines may be used as an alternative to or in combination with an intranasal corticosteroid. Second generation antihistamines are preferred over first generation antihistamines due to less sedation, impairment of daily activities (e.g., performance in school or ability to drive safely), and anticholinergic effects. The American Geriatrics Society Beers Criteria recommends avoiding first generation antihistamines in older adults (age 65 and older) due to anticholinergic adverse effects. Additionally, cumulative use of first generation antihistamines with strong anticholinergic properties has been associated with higher risk of dementia. New evidence is suggestive of 1st generation antihistamines exhibiting an increase in seizure risk in young children, especially in those less than 2 years of age. If tolerance to the therapeutic effect of an antihistamines develops, changing to a different antihistamine or a different drug class may be effective. α1-Adrenergic Agonist Decongestants (Sympathomimetics, Vasoconstrictors) The term sympathomimetic refers to a drug that mimics the neurotransmitters released at the terminus of sympathetic nerves (norepinephrine and epinephrine). Some of these drugs are chemical mimics of epinephrine and norepinephrine, while others are close chemical analogs (see Figure 12). The sympathomimetic drugs useful for treatment of congestion associated with allergic rhinitis, as all are selective for activation of α1-adrenergic receptors (as opposed to β-adrenergic receptors). Most sympathomimetics (including phenylephrine) are extensively metabolized by first pass metabolism in the intestinal wall and the liver, to the point that they are not especially useful as oral drugs and must be delivered via the nasal route. Pseudoephedrine, however, avoids extensive first-pass metabolism due to the presence of a methyl group on its side chain (as compared with phenylephrine which is metabolized extensively by first-pass metabolism (see Figure 12). Therefore, pseudoephedrine is more effective as an oral medication compared to phenylephrine. Figure 12 shows the chemistry of epinephrine, norepinephrine and several intranasal decongestants. Phenylephrine and pseudoephedrine are close chemical mimics of norepinephrine and epinephrine, but have been chemically altered to be selective for α1-adrenergic receptors (as opposed to also binding to and activating β-adrenergic receptors as epinephrine and norepinephrine do). However, their potency for activating α1-adrenergic receptors is less than epinephrine because the potency of sympathomimetic drugs is reduced as aromatic substitution is reduced (pseudoephedrine Figure 12. α1-Adrenergic Agonist Decongestants (Sympathomimetics) < phenylephrine < epinephrine). Ephedrine is a sympathomimetic that has four active optical OH OH OH isomers, two of which are known as pseudoephedrine and two H N NH2 H N of which are known as ephedrine. Pseudoephedrine is the threo racemate of ephedrine and exists in two possible configurations: HO HO 1R:2R and 1S:2S. The erythro racemate (1R:2S and 1S:2R) is OH OH referred to as ephedrine, a controlled-substance due to CNS OH stimulation. Pseudoephedrine is a possible chemical precursor Epinephrine Norepinephrine Phenylephrine in the chemical synthesis of methamphetamines, or simply “meth” (the synthesis of meth will not be covered here), and OH OH has become a drug of abuse as a result. Many states have NHCH3 NHCH3 placed pseudoephedrine oral dosage forms behind the counter, + requiring either a prescription or a registry to restrict the amount dispensed. 1R:2R 1S:2S Others (e.g., naphazoline, oxymetazoline) are not direct chemical Pseudoephedrine mimics of norepinephrine and epinephrine, but are similar in terms of molecular and length of carbon chain between an aromatic ring and a substituted nitrogen (see Figure 12). H N These medications are called decongestants because they are HO N selective α1-adrenergic agonists that bind to vascular smooth N HN muscle leading to arterial vasoconstriction. (See Appendix A: Autonomic Receptor Tissue and Organ Effects to review the N NH effects of activation of α1-adrenergic receptors in tissues and organs). When α1-adrenergic agonists bind to vascular smooth Naphazoline Tetrahydrozoline Oxymetazoline muscle leading to arterial vasoconstriction this leads to reduced blood flow into the nasal mucosa and decreased swelling of the nasal turbinates. When nasal congestion is reduced airflow through the nasal cavity is increased. Decongestants delivered directly to Integrated Pharmacotherapy 3 13 Allergic Rhinitis nasal tissues by drops or sprays are called intranasal decongestants (or nasal Decongestants decongestants), while those delivered by oral administration are called systemic decongestants. Ophthalmic vasoconstrictors (aka ophthalmic decongestants) Systemic Decongestants Phenylephrine (multiple brand names, most OTC) are also useful for relieving ophthalmic congestion (i.e., vasodilation) that causes Pseudoephedrine (Sudafed®) (State-specific control) red eyes, tearing and itching. For this purpose, they are available as ophthalmic Intranasal Decongestants drops. Phenylephrine (Neo-Synephrine®) (OTC) Oxymetazoline (Afrin®) (OTC) Adverse Effects Tetrahydrozoline (Tyzine®) (OTC) Systemic decongestants have adverse effects related to activation of α1- Xylometazoline (Otrivin®) (OTC) adrenergic receptors in the PNS and enhancement of NE release in the Ophthalmic Decongestants CNS. These adverse effects include insomnia, irritability, decreased appetite, Naphazoline (Clear Eyes®, AK-Con®) (Rx, OTC) increased blood pressure, increased heart rate, and nervousness. Elevation Tetrahydrozoline (Visine®) (OTC) of blood pressure after taking an oral decongestant is rarely observed Notes in normotensive patients and occasionally in patients with controlled Decongestants are available under many brand names; in hypertension. However, based on variation among patients, hypertensive this table only selected popular brand names are listed. patients should be monitored. Decongestants are also commonly referred to as “vasocon- strictors”, due to their pharmacologic effects. The most important adverse effect of intranasal decongestants is rebound congestion (vasodilation), otherwise known as rhinitis medicamentosa. After three days of use, patients are at risk for rebound congestion when the nasal decongestant is discontinued. If the nasal decongestant is not discontinued, then an increasingly higher amount of drug will be required to prevent nasal congestion. This is due to receptor desensitization as covered in the IP 1 course notes Principles of Pharmacodynamics and SAR (if you do not recall the specific mechanisms of receptor desensitization, then review that portion of those notes prior to the RAT and exams). This adverse effect is especially important for pharmacists to discuss with patients, since most intranasal decongestants are available OTC. The risk of rhinitis medicamentosa can be reduced significantly by not using an intranasal decongestant for more than three days in a row, using the smallest amount necessary, and using this medication only when nasal congestion is present. If patients have rhinitis medicamentosa, treatment consists of discontinuing intranasal decongestants (slowly by withdrawing therapy for one nostril at a time) and treating with intranasal corticosteroids. Rhinitis medicamentosa symptoms usually resolve in 1 to 2 weeks. Nasal saline soothes the nasal mucosa and may also help. A short course of systemic corticosteroids may also be needed. Patient counseling should including informing the patient that their symptoms of rhinitis medicamentosa will get worse before they get better. Additional significant adverse effects of intranasal decongestants include burning/stinging, sneezing, and dryness of nasal mucosa. Ophthalmic vasoconstrictors also have an adverse effect very similar to rhinitis medicamentosa. Prolonged use (longer than ten days) of ophthalmic vasoconstrictors can lead to rebound hyperemia (conjunctivitis medicamentosa). The risk of conjunctivitis medicamentosa can be reduced significantly by not using an ophthalmic vasoconstrictor for more than ten days in a row, using the smallest amount necessary, and using this medication only when ocular redness is present or when allergic conjunctivitis is not relieved with other treatment options. Additional significant adverse effects of ophthalmic vasoconstrictors include increased intraocular pressure and ocular burning. Contact lenses should be removed when instilling these medications. Contact lenses can be reinserted 10 minutes after the drops have been placed in the affected eyes. In select patient populations decongestants have a potential to cause adverse effects due to their systemic activation of α1-adrenergic receptors (pediatric patients, geriatric patients, and patients with a history of cardiac arrhythmias, angina, cerebrovascular disease, uncontrolled hypertension, bladder neck obstruction, glaucoma, and/or hyperthyroidism). This is especially a risk with systemic decongestants, but theoretically may occur with intranasal decongestants because some of the dose may be absorbed from nasal tissue into the systemic circulation; however, systemic absorption of intranasal decongestants is rarely clinically significant. THERAPEUTIC CONSIDERATIONS FOR DECONGESTANTS Oral decongestants and intranasal decongestants are effective in treating nasal congestion. Ophthalmic vasoconstrictors are useful for relief of ocular redness, but they do not reduce the allergic response. Oral decongestants should only be used when symptoms of nasal congestion are present. Based on the information contained in this IP unit, which decongestant would you recommend – phenylephrine or pseudoephedrine? Intranasal decongestants may be used to assist in intranasal delivery of other medications when significant nasal mucosal edema is present. Intranasal decongestants should be used acutely and not for more than 3 consecutive days to avoid rhinitis medicamentosa (rebound) Integrated Pharmacotherapy 3 14 Allergic Rhinitis Corticosteroids The general pharmacology and chemistry of corticosteroids was covered in the IP 2 unit Adrenal and Pituitary Gland Disorders. You should be able to describe the general mechanism by which all corticosteroids work and recognize the chemical structure of a steroid drug. Review the Adrenal and Pituitary Gland Disorders notes if needed. Intranasal Corticosteroids For allergic rhinitis, corticosteroids are delivered directly to the nasal tissue via a nasal spray. In nasal tissue of a patent with allergic rhinitis, corticosteroids reduce inflammation by: 1. blocking immune mediator release 2. suppressing neutrophil chemotaxis 3. reducing intracellular edema 4. causing mild vasoconstriction 5. inhibiting mast cell-mediated reactions Ophthalmic Corticosteroids Ophthalmic corticosteroids are useful for the temporary relief of severe symptoms of allergic conjunctivitis not controlled with other Corticosteroids available agents. Loteprednol (Lotemax®, Alrex®) has a reduced risk of Intranasal Corticosteroids causing an increase in intraocular pressure compared with other ocular Beclomethasone (Beconase AQ®, QNASL®) (Rx) corticosteroids; therefore, this is the only ophthalmic corticosteroid Budesonide (Rhinocort Aqua®) (Rx) recommended for allergic conjunctivitis. Contact lenses should be Ciclesonide (Omnaris®, Zetonna®) (Rx) removed when instilling these medications. Contact lenses can be Flunisolide (Nasarel®) (Rx) Fluticasone (Flonase®, Veramyst®, Flonase Allergy Relief) (Rx, OTC) reinserted 10 minutes after the drops have been placed in the affected eyes. Mometasone (Nasonex®) (Rx) Opthalmic antihistamines (due to their mast cell stabilizing effect) are Triamcinolone (Nasacort AQ®, Nasacort Allergy 24HR) (Rx, OTC) preferred. Ophthalmic Corticosteroids Loteprednol (Lotemax®, Alrex®) (Rx) Oral Corticosteroids Oral corticosteroids are rarely used for allergic rhinitis due to significant adverse effects (see the IP 2 Adrenal and Pituitary Gland Disorders notes for details). However, a short course (5-7 days) of oral corticosteroids may be appropriate for the treatment of very severe or intractable nasal symptoms. Adverse Effects Adverse effects of intranasal corticosteroids are mostly related to delivery of the drug to the nasal tissue, such as stinging and burning that often subsides after initial dosing. Additional adverse effects include nasal dryness, blood tinged secretions, and epistaxis. Monitoring for intraocular pressure, glaucoma, and cataracts is recommended for patients who use intranasal corticosteroids. Improper administration resulting in delivery of intranasal corticosteroids to the back of the throat may cause a persistent sore throat. As explained in the IP 2 Adrenal and Pituitary Disorders unit, chronic administration of supraphysiologic doses of systemic corticosteroids may lead to HPA axis suppression and symptoms similar to Cushing’s disease and immunosuppression. Intranasal and ophthalmic corticosteroid administration is not considered to be systemic drug delivery because very little of the drug reaches the systemic circulation. Accordingly, the risk for HPA axis suppression, drug-induced Cushing’s disease, and immunosuppression is not clinically significant. The take home point is to determine the route of administration for a chronically-administered corticosteroid before assuming a patient is immunosuppressed or at risk for drug-induced Cushing’s disease. THERAPEUTIC CONSIDERATIONS FOR CORTICOSTEROIDS Intranasal corticosteroids are often considered the most effective agents for allergic rhinitis. They are effective in preventing symptoms of nasal congestion, rhinorrhea, nasal itching, sneezing, and allergic conjunctivitis. Intranasal corticosteroids may also help with sleep apnea in patients with allergic rhinitis and sleep apnea. Intranasal corticosteroids should be recommended as initial treatment for patients with allergic rhinitis symptoms that affect their quality of life. Intranasal corticosteroids may also be considered for initial treatment for all patients with allergic rhinitis without a previous trial of antihistamines and/or decongestants. The onset of initial therapeutic efficacy for intranasal corticosteroids occurs between 3 and 12 hours, but peak effects may take up to 3 weeks to occur. Therefore, intranasal corticosteroids should be used before allergen exposure in patients with seasonal allergic rhinitis. Intranasal corticosteroids may be used on a PRN basis, but continuous use is more effective. Integrated Pharmacotherapy 3 15 Allergic Rhinitis Mast Cell Stabilizers Mast cell stabilizers are medications that decrease the ability of mast cells to release histamine (mast cell degranulation). The medicinal chemistry and pharmacology of mast cell stabilizers will be covered in the IP 4 Asthma unit. Mast cell stabilizers are available in intranasal and ophthalmic dosage forms. Contact lenses should be removed when instilling these medications. Contact lenses can be reinserted 10 minutes after the drops have been placed in the eye. Avoid wearing contact lens if eyes are red. Adverse Effects The most significant adverse effects of intranasal mast cell stabilizers are nasal stinging and sneezing. The most significant adverse effect of ophthalmic mast cell stabilizers is ocular burning. THERAPEUTIC CONSIDERATIONS FOR MAST CELL STABILIZERS Intranasal mast cell stabilizers are effective for treating nasal congestion, rhinorrhea, nasal itching, and sneezing. Ophthalmic mast cell stabilizers are effective tor treating allergic conjunctivitis, but they are considered second line to ophthalmic antihistamines for allergic conjunctivitis. Mast Cell Stabilizers Intranasal mast cell stabilizers are less effective compared to intranasal corticosteroids. Intranasal Mast Cell Stabilizers For seasonal allergic rhinitis, intranasal mast cell stabilizers should be used before the offending Cromolyn (NasalCrom®) (OTC) allergen’s season starts. The onset of therapeutic action is 4 to 7 days, but improvement may not be seen for 2 weeks or more. Ophthalmic Mast Cell Stabilizers Cromolyn (Crolom®) (Rx) For maximum efficacy, intranasal cromolyn (Nasalcrom®) should be administered QID. This frequent Lodoxamine (Alomide®) (Rx) dosing schedule makes intranasal mast cell stabilizers less attractive. Nedocromil (Alocril®) (Rx) Ophthalmic mast cell stabilizers are safe for both PRN use or continuous use. Therapeutic response Pemirolast (Alamast®) (Rx) may take several days to occur. Leukotriene Modifiers Leukotriene modifiers are indicated for the management of asthma, and the medicinal chemistry and pharmacology will be covered in the IP 4 Asthma unit. Montelukast (Singulair®) is an oral leukotriene modifier that is effective for treating rhinorrhea, nasal itching, sneezing, and allergic conjunctivitis. Montelukast is equal in efficacy to antihistamines, but less effective compared to intranasal corticosteroids. Additionally, the combination of oral antihistamines and montelukast is less effective compared to intranasal corticosteroids. The most significant adverse effects of montelukast are headache and serious neuropsychiatric adverse effects including but not limited to aggression, anxiousness, depression, disturbance in attention, sleep disturbances, suicidal thoughts and behavior (including suicide). The FDA box warning related to these neuropsychiatric adverse effects recommends monitoring for neuropsychiatric symptoms and immediately discontinuing montelukast if neuropsychiatric symptoms occur. Due to the potential for serious neuropsychiatric adverse effects and the availability of more effective and lower cost medications for allergic rhinitis, the role of montelukast is limited to patients with both allergic rhinitis and asthma and patients do not tolerate intranasal therapies. Anticholinergics Quaternary amine anticholinergics that do not distribute into the CNS are useful for management of asthma, and their medicinal chemistry and pharmacology will be covered in the IP 4 Asthma unit. Ipratropium (Atrovent®) is a quaternary amine anticholinergic that is effective for treating rhinorrhea. Ipratropium should be considered in patients who fail or cannot tolerate all other therapies available for rhinorrhea. It may be used in combination with either antihistamines or intranasal corticosteroids for additive effects. Ipratropium should be used with caution in patients with glaucoma or benign prostatic hypertrophy (BPH). The most significant adverse effects of intranasal ipratropium are nasal dryness, nasal congestion, and epistaxis. NSAIDs Ketorolac (Acular®) is an ophthalmic NSAID that is useful for temporary relief of ocular itching caused by seasonal allergic conjunctivitis. Subcutaneous Immunotherapy Subcutaneous immunotherapy (SCIT) is the gradual process of injecting increasing doses of antigens responsible for eliciting allergic symptoms in a patient with the goal of increasing tolerance to the allergen when natural exposure occurs. Antigens used for immunotherapy are selected based on the patient’s history and allergen test results (see Diagnostic Tests section). Immunotherapy diminishes IgE production, increases IgG production, changes T-lymphocytes, reduces inflammatory mediator release from sensitized cells, and diminishes tissue responsiveness. In general, very dilute solutions are given one to two times per week. The concentration is increased until the maximum tolerated dose Integrated Pharmacotherapy 3 16 Allergic Rhinitis is achieved. This maintenance dose is continued every 2 to 6 weeks, depending on clinical response. Best results are usually obtained when injections are given year round rather than seasonally. The clinical benefits of SCIT may persist for years after discontinuing therapy. A disadvantage of SCIT is that it requires significant time from a patient compared to other therapies for allergic rhinitis. Table 7 can be used to identify patients who would or would not be good candidates for SCIT. Adverse Effects The most significant adverse effects of SCIT include mild local reactions (e.g., induration and swelling at the site of the injection), generalized urticaria, bronchospasm, laryngospasm, vascular collapse, and anaphylactic reactions. Sublingual Immunotherapy Sublingual immunotherapy (SLIT) is also available for some specific allergens. Oralair® contains a mixture of extracts from the pollens of five grasses: Kentucky Blue Grass, Orchard, Perennial Table 7. Rye, Sweet Vernal, and Timothy. Grastek® contains an extract Good Candidates for Subcutaneous Immunotherapy of Timothy Grass. Ragwitek® contains an extract of ragweed. Patients with a strong history of severe symptoms unsuccessfully controlled Patients must start therapy before grass pollen season begins (i.e., by avoidance and pharmacotherapy at least 16 weeks before the season for Oralair® and at least 12 Patients who have been unable to tolerate the adverse effects of properly weeks before the season for Grastek® and Ragwitek®. Odactra® managed drug therapy contains allergen extract to treat house dust mite-induced allergy Patients committed to the necessary regular office visits required to symptoms and is taken year round. complete this long course of therapy Patients who have evidence of specific IgE antibodies to clinically relevant The first dose of SLIT should be administered in a medical facility allergens under the supervision of a physician or other healthcare provider Poor Candidates for Subcutaneous Immunotherapy with experience in the diagnosis and treatment of anaphylaxis. Patients with any medical condition that would compromise the ability to The patient should be observed in the medical facility for 30 tolerate an anaphylactic reaction (e.g., uncontrolled asthma or unstable minutes after administration of the SLIT dose. Subsequent doses cardiovascular disease) may be administered by the patient at home. Patients should be Patients with impaired immune systems instructed to place the tablet under the tongue, wait 1 minute after Patients with a history of nonadherence to therapy tablet dissolves before swallowing, and do not eat or drink for minutes after administering the tablet. Patients should be prescribed autoinjectable epinephrine and educated on appropriate use. If patients have oral lesions (e.g., oral lichen planus, mouth ulcers, thrush, or wounds), SLIT should be temporarily discontinued until the oral lesions have completely healed. Contraindications to SLIT relate to a decreased ability to survive a systemic allergic reaction and/or increased risk of adverse effects after epinephrine administration, which include uncontrolled asthma, a history of a severe reaction to any form of immunotherapy, a history of a severe local reaction to SLIT, a history of eosinophilic esophagitis, unstable angina, recent myocardial infarction, arrhythmia, uncontrolled hypertension. Advantages of SLIT over SCIT include no need for injections and administration at home. Disadvantages of SLIT compared to SCIT include treatment of fewer allergens and a shorter tolerance to allergens after discontinuing therapy (6 to 12 months compared to years). Adverse Effects The most significant adverse effects of sublingual immunotherapy include oral pharyngeal adverse effects (e.g., itching of the mouth, throat irritation) and systemic allergic reactions. Drug Elimination Drug elimination is less important for drug administered by the nasal route, as much of the drug remains in nasal tissue and is eliminated in the mucus. Therefore, only orally administered allergic rhinitis drugs will be covered here. Antihistamines Most first generation antihistamines are extensively metabolized by CYP450, mostly by the 2D6 isoform and somewhat by the 3A4 isoform. Most have active metabolites as well. As a result, the effective elimination half-life of antihistamine activity is the elimination half-life of the parent antihistamine and active metabolites. For most antihistamines, this adds up to an effective elimination half-life Integrated Pharmacotherapy 3 17 Allergic Rhinitis of greater than 8 hours, meaning that the undesirable CNS adverse effects cannot be eliminated entirely by having the patient take the antihistamine at bedtime. For example, the half-life of diphenhydramine and its active metabolite nordiphenhydramine (see Figure 13) is about 9 hours and the elimination half-life of clemastine is approximately 21 hours. Second generation antihistamines are also extensively metabolized, but mostly by CYP3A4 (see loratadine and desloratadine in Figure 11 on page 12). In general, their elimination half-lives are shorter than that of first generation antihistamines. However, given their lack of CNS penetration and activity, the shorter elimination half-life is not an important advantage. Systemic Decongestants Phenylephrine undergoes extensive first-pass metabolism resulting in poor oral bioavailability. This, in turn, limits the effectiveness of orally-administered phenylephrine. About 3% of Figure 13. N-Demethylation of Diphenhydramine a phenylephrine dose is excreted unchanged. On the other hand, pseudoephedrine has very little first-pass metabolism and about 90% of the dose is excreted unchanged. Given both drugs are absorbed sufficiently, CYP2D6 H CYP3A4 the difference in first-pass metabolism helps explain why O CH2 CH2 N O CH2 CH2 N pseudoephedrine is associated with greater clinical efficacy CH3 than phenylephrine. Drug Interactions Diphenhydramine Nordiphenhydramine (Active) Antihistamines Second generation antihistamines carry a strong warning from the FDA about possible drug-drug interactions with other drugs metabolized by CYP3A4. The warning is that other medications may compete for CYP3A4 metabolism and decrease the metabolism of second generation antihistamines, resulting in increased levels of second generation antihistamines in the body that may possibly cause cardiac arrhythmias. This warning is largely due to terfenadine (Seldane®), the first second generation antihistamine to be marketed in the U.S. When combined with other medications that inhibited CYP3A4, terfenadine levels increased and caused several fatal cases of cardiac arrhythmias. Terfenadine was withdrawn from the market, and its active metabolite, fexofenadine, was subsequently marketed (the risk of drug interactions is much less with fexofenadine because it undergoes less CYP3A4 metabolism). The above drug-drug interaction was an example of a pharmacokinetic drug interaction (i.e., a drug-drug interaction that alters the pharmacokinetics of a drug). Antihistamines may also be involved in pharmacodynamic drug-drug interactions due to their general CNS depressant effects (e.g., drowsiness, sedation). This type of interaction may occur when an antihistamine is combined with another CNS depressant, such as ethanol or a benzodiazepine, resulting in excessive CNS depression. For which class of antihistamines would this type of phamacodynamic drug-drug interaction be of greatest risk? Complementary Medicines Based on existing evidence from Natural Medicines Comprehensive Database, there are no complementary medicines that are considered effective or likely effective for the treatment of allergic rhinitis. Butterbur and Tinospora cordifolia are considered possibly effective and possibly safe. Butterbur Butterbur (see Figure 14) may decrease plasma histamine and leukotrienes and may decrease priming of mast cells in response to contact with allergens. Butterbur naturally contains unsaturated pyrrolizidine alkaloids (UPAs or PAs), and some are hepatotoxic, pneumotoxic, and carcinogenic. Therefore, “PA-free” or “UPA-free” (e.g., Petadolex) products are preferred. Additionally, products Integrated Pharmacotherapy 3 18 Allergic Rhinitis with at least 7.5 mg of petasin and 7.5 mg of isopetasin per 50 mg tablet/capsule is most similar to the Figure 14. Butterbur product studied in clinical trials that suggested comparable efficacy to cetirizine (Zyrtec®) or fexofenadine (Allegra®). The effective dosing regimen is 50 to 75 mg PO BID. Patients with allergies to ragweed should avoid using butterbur because allergic reactions to butterbur have been reported in patients with allergies to plants in the Asteracea/Compositae family (e.g., ragweed, marigolds, chrysanthemums, daisies). Tinospora Cordifolia Tinospora cordifolia (see Figure 15) seems to have immunostimulatory effects and decreases the release of histamine from mast cells. Some evidence shows that taking a specific extract (i.e., Tinofend) 300 mg PO TID decreases allergic rhinitis symptoms. Tinospora cordifolia is overall well tolerated. THERAPEUTIC APPLICATIONS OF EVIDENCE BASED MEDICINE FOR ALLERGIC RHINITIS Figure 15. Tinaspora cordifolia Effective management of allergic rhinitis includes avoiding allergens, management of coexisting conditions, medications for allergic rhinitis, and/or allergen immunotherapy. If it is possible to anticipate the onset of symptoms associated with seasonal exposure to pollen or sporadic exposure to other triggers, early administration of medications (i.e., before exposure or the development of symptoms) may lessen the symptoms from exposure to allergens. Selection of an initial medication is individualized and guided by age, frequency of symptoms, severity of symptoms, and spectrum of symptoms (e.g., sneezing and rhinorrhea versus congestion only), allergen exposure pattern (e.g., seasonal versus perennial), comorbidities, cost, response to previous treatment, patient preference, and adherence to therapy. The spectrum of symptoms of allergic rhinitis includes nasal congestion, rhinorrhea, nasal itching, sneezing, and allergic conjunctivitis. Figure 16 on page 20 illustrates how each symptom can be treated with the available drug classes for allergic rhinitis. Medications may be required only on an as needed basis for episodic allergic rhinitis or on a daily basis for perennial allergic rhinitis. Table 8 includes the initial treatment options for common clinical scenarios. When a patient is adherent to a medication, but not fully Table 8. Initial Treatment for Common Clinical Scenarios responding, adding another medication class or switching to Clinical Scenario Treatment Options another class of medication should be considered (Table 9). Intranasal corticosteroid Combination therapy with an intranasal corticosteroid and Dominant concern is nasal Intranasal antihistamine an intranasal antihistamine may be considered after trials of congestion Intranasal decongestant monotherapy have failed to control symptoms. Alternatively, Intranasal cromolyn sodium for patients with more severe symptoms, the combination of an Oral antihistamine (2nd gen) intranasal antihistamine and an intranasal corticosteroid may be Intermittent sneezing, nasal Intranasal antihistamine considered as initial therapy. Because of the increased volume itching, and rhinorrhea Intranasal cromolyn sodium of medication when using 2 separate nasal sprays concurrently, patients should be instructed to wait several minutes between the Intranasal corticosteroid use of each nasal spray to optimize drug delivery. To improve Intranasal antihistamine adherence, there are two combination nasal sprays that include More severe symptoms Combination of intranasal corticosteroid and intranasal antihistamine an antihistamine and a corticosteroid: 1) azelastine/fluticasone Immunotherapy (Dymista®) and 2) olopatadine/mometasone (Ryaltris®). Table 9. Options for Switching or Changing Therapy Based on Initial Treatment Initial Treatment Discontinue Add (first step) Add (second step) Do Not Add Intranasal Intranasal decongestant (3 INAH Oral antihistamine corticosteroid days or less) INCS and/or Intranasal decongestant or Oral antihistamine oral antihistamine N/A INAH cromolyn sodium Intranasal INCS Opthalmic antihistamine N/A antihistamine Integrated Pharmacotherapy 3 19 Allergic Rhinitis  Figure 16. AR Treatment Algorithm Allergic rhinitis (AR) Intermittent AR Persistent AR _4 days/week _4 consecutive weeks/year Integrated Pharmacotherapy 3 20 Allergic Rhinitis Special Considerations During Pregnancy The most critical time for concern about potential congenital malformation because of medication use is the first trimester, when organogenesis is occurring. SCIT may be continued during pregnancy but without dose escalation. SLIT may be used very cautiously (and only if clearly needed) in pregnancy or breastfeeding because there is limited data on safety of SLIT in this patient population. Intranasal corticosteroids (budesonide being the preferred INCS), first generation and second generation antihistamines (except hydroxyzine), and sodium cromolyn may be used during pregnancy. Oral decongestants should be avoided during the first trimester. Intranasal decongestants, when used on a short-term basis, may have a better safety profile than oral agents for first trimester use, but studies in pregnancy have not been conducted. OPPORTUNITIES FOR FUTURE RESEARCH (FYI ONLY) Strategies for modulating cytokine production and/or function are likely to yield major advances in the future. These include: 1) inhibiting a specific proinflammatory cytokine; 2) monoclonal antibodies targeted to cytokines or their receptors; 3) soluble cytokine receptors (e.g., IL-4 receptors); 4) administering specific anti-inflammatory cytokines; 5) general TH2 cytokine inhibitors; and 6) redirecting the immune response to alter the TH1/TH2 balance using DNA vaccination and immunostimulatory sequences. Another potential future strategy is subcutaneous anti-IgE therapy which is currently approved for the treatment of asthma and has been studied in patients with allergic rhinitis. Immunotherapy directed at hay fever administered as a transdermal patch is being studied. Last Modified: January 9, 2025 9:02 PM Integrated Pharmacotherapy 3 21 Allergic Rhinitis APPENDIX A: AUTONOMIC RECEPTOR TISSUE AND ORGAN EFFECTS Sympathetic Activity Parasympathetic Activity Organ or Tissue Major Receptors Effect Major Receptors Effect a1 contracts ------- ------- Vascular Smooth Muscle b2 relaxes ------- ------- Heart Sinoatrial (SA) node Mostly b1 Some b2 increase rate M2 decreases rate Contractile Cells Mostly b1 Some b2 increases force M2 decreases force Respiratory Tract Nasal vasculature a1, a2 contracts ------- ------- Bronchial smooth muscle b2 relaxes M1, M3 contracts Gastrointestinal Tract Smooth muscle walls a2 b2 relaxes M3 contracts Smooth muscle sphincters a1 contracts M3 relaxes Secretions ------- ------- M3 increases Genitourinary Tract Bladder wall b2 relaxes M3 contracts Sphincter a1 contracts M3 relaxes Uterus (pregnant) a1, a2 contracts M3 contracts Uterus (pregnant) b2 relaxes ------- ------- Eye Pupillary dilator (radial) muscle a1 contracts ------- ------- Pupillary constrictor muscle ------- ------- M3 contracts Ciliary muscle ------- ------- M3 contracts Ciliary epithelium b1 b2 secretion of ------- ------- aqueous humor Metabolic Functions Liver a1, a2, b2 gluconeogenesis ------- ------- Liver a1, a2, b2 glycogenolysis ------- ------- Fat cells b3 lipolysis ------- ------- Kidney b1 Renin release ------- ------- Integrated Pharmacotherapy 3 22 Allergic Rhinitis