------------------------------------------------------------------------------- TITLE: PHARMACOLOGIC MANAGEMENT OF ALLERGIC RHINITIS AND SINUSITIS SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: October 19, 1994 RESIDENT PHYSICIAN: Carl S. Schreiner, M.D. FACULTY: Brian P. Driscoll, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. ------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." INTRODUCTION Allergic rhinitis and sinusitis rank among the most common and the most misunderstood of the upper respiratory diseases. This misunderstanding is most evident in the areas of topical corticosteroid and systemic antihistamine therapy. The relationship between allergic rhinitis and sinusitis is complicated by the fact that allergy can predispose to sinusitis. Although the pharmacologic treatment of allergic rhinitis and sinusitis often overlap, the potential for mistreatment exists. Thus, a thorough knowledge of the pathophysiology and related pharmacology of both diseases is needed to assure proper management of these illnesses. PATHOPHYSIOLOGY Allergic rhinitis is defined as nasal inflammation that is a result of an allergen-specific Gell and Coombs Type 1-IgE immunologic reaction. Crosslinking between allergen molecules and IgE antibodies bound on mast cells result in the release of the chemical mediators (histamine, tryptase, leukotrienes, prostaglandins) contained in the mast cell. The early allergic response (2 to 5 minutes after antigen exposure) results from the release of these mediators and is characterized by sneezing, itching, and rhinorrhea. The late phase response, due to mucosal infiltration of basophils and eosinophils, is characterized by congestion (often unresponsive to decongestants and antihistamines) and occurs 4 to 10 hours after exposure. The most significant pathophysiologic event that produces sinusitis is mucosal edema around the sinus ostium. Inflamed mucosa from allergies can block ostial drainage, creating stasis of sinus secretions and hypoxia of the involved sinus. Ciliary and mucous gland dysfunction lead to thickened secretions and stasis. Infection from relatively harmless bacteria occurs and a spiral of infection, mucosal edema and more blockage may ensue. This cascade of events relates how allergic rhinitis can lead to sinusitis. Inadequate treatment of acute sinusitis without disruption of this cycle appears to often lead to chronic sinusitis, which is less well understood and more difficult to treat. Local predisposing causes of sinusitis include apical dental infections, barotrauma (causing edema at the sinus ostium), or alterations in mucocilliary transport from inspiration of cold or some medications. Management goals for treatment of sinusitis include control of infection, reduction of tissue edema, facilitation of drainage, and maintenance of ostial patency. NORMAL NASAL PHYSIOLOGY Sympathetic fibers reach the nasal mucosa via the cervical sympathetic trunk and the internal carotid cervical plexus. The deep petrosal branch of this plexus unites with the greater superficial petrosal branch to form the vidian nerve. These fibers then pass through the sphenopalatine ganglion without synapsing and travel along vessels to the nasal mucosa; specifically around arterioles, venous sinusoids, and seromucous glands within the subepithelium. When stimulated, sympathetic nerve terminals release norepinephrine, which binds to and activates two types of adrenergic receptors, Alpha 1 and Alpha 2. Alpha 1 receptors tend to be concentrated on postcapillary venules, which act as capacitance vessels, and decrease mucosal blood volume when stimulated. Alpha 2 adrenergic receptors are concentrated on precapillary arterioles and decrease mucosal capillary blood flow when activated. Sympathetic innervation to the nose is regulated to some extent by the hypothalamus. Continuous sympathetic tone creates a certain level of vasoconstriction, which is further oscillated by the brain stem to produce the nasal cycle. Parasympathetic fibers exit the facial nerve at the geniculate ganglion in the greater superficial petrosal nerve, which again unites with the deep petrosal nerve to form the vidian nerve. These fibers then synapse in the sphenopalatine ganglion and postsynaptic fibers are distributed to the glandular epithelium through all branches of the sphenopalatine ganglion. Parasympathetic fibers contain acetylcholine and vasoactive intestinal peptide (VIP). Nasal secretions appear to be primarily mediated by acetylcholine, whereas vasodilation is controlled by VIP. PHARMACOLOGIC THERAPY TOPICAL DECONGESTANTS PHARMACOLOGY - Topical decongestants act as potent alpha- adrenergic agonists that constrict nasal mucosa, decreasing edema and rhinorrhea. Alpha 1 receptors populate postcapillary capacitance venules and when stimulated, decrease blood and mucosal volume. Alpha 2 receptors constrict precapillary arterioles. Prolonged Alpha 2 constriction and mucosal ischemia is theorized as a mechanism for rebound hyperemia. SIDE EFFECTS - Rebound hyperemia occurs after extended use (5-7days) and prolonged use leads to rhinitis medacamentosa. Desensitization due to down-regulation of receptors may occur over time. Topical decongestants are safe in pregnancy but the risk of habitation may be more increased in pregnancy. EFFICACY - Topical decongestants are safe and effective for nasal congestion and rhinorrhea for up to three days. They are often effective in "opening up" nasal passages to allow topical steroids or cromolyn to access the mucosa. SPECIFIC DRUGS Ephedrine (Primatene Mist) is now only used as an OTC bronchodilator Phenylephrine (Neo-Synephrine, Alconefrin) - Alpha 1 agonist. Short half life requires q 3-4hr dosing Oxymetolazine (Afrin, Dristan) - Alpha 2 agonist. Longer-acting preparation requiring only bid dosing. ORAL DECONGESTANTS PHARMACOLOGY - Pharmacology is similar to topical decongestants but systemic administration increases potential side effects. Desensitization or rebound hyperemia has not been reported with oral dosing. SIDE EFFECTS - Blood pressure elevation has caused concerns in the past but several recent controlled studies have shown pseudoephedrine and PPA to be safe at recommended doses. In 1989, Kroenke showed that PPA affects blood pressure no more than placebo in stable hypertension. Alpha-adrenergic side-effects include urinary retention, nervousness, and insomnia. In glaucoma and patients on tricyclics or MAO inhibitors, doses should be lowered to avoid exacerbation of Alpha effects. EFFICACY - Oral decongestants act on tissues deep in the osteomeatal complex, where topical decongestants may not reach. Many studies suggest that oral decongestants combined with antihistamines or mucolytics may be more beneficial in allergic rhinitis. SPECIFIC DRUGS Pseudoephedrine (Sudafed) - 60 mg dosing shows erratic blood levels unless dosed around-the-clock q 6hr. Extended release (120 mg bid) allows better compliance and more constant blood levels. Studies have shown no teratogenicity in pregnancy. Phenylpropanolamine (combined with guaifenesin in Entex)- Found in many OTC diet pills due to side effect of anorexia. (25mg q 4hr or sustained release: 75mg bid). Has been associated with birth defects with use in the first trimester of pregnancy. MUCOLYTICS PHARMACOLOGY - Guaifenesin reduces the viscosity of secretions and increases respiratory tract secretions, increasing the efficiency of the cough reflex and ciliary action SIDE EFFECTS - Guaifenesin acts as an emetic at high doses and requires only slightly subemetic doses to be effective. Taking with food may help. EFFICACY - Although the efficacy of mucolytics in general is poorly documented, guaifensen has been found to be the safest and most effective mucolytic currently available. A 1992 study from Laryngoscope found it to be effective in HIV-infected patients with symptoms of nasal congestion and thick postnasal drainage. SPECIFIC DRUGS Guiafenesin (Robitussin) - 2400mg day in q 4hr doses is most effective if tolerated. Combined with a decongestant in Entex. MAST CELL STABILIZERS PHARMACOLOGY - Cromolyn is the prototype mast cell stabilizer and its inhibition of the degranulation process has been shown to prevent the release of histamine and leukotrienes from sensitized mast cells. Cromolyn has no intrinsic antihistamine or antiinflammatory action, but it does offer the advantage of acting on both the acute and late phases of the allergic reaction. SIDE EFFECTS - Local side effects are rare and include sneezing (10%), nasal irritation (4%), and epistaxis (<1%). No septal perforations or systemic side effects have been reported. EFFICACY - As stated above, cromolyn acts on both phases of the allergic reaction and therefore may be used prophylactically or in an acute reaction. Its most beneficial effects may be for application before anticipated antigen exposure. Effectiveness depends on adequate mucosal contact and cromolyn is not effective for nasal polyps. SPECIFIC DRUGS Cromolyn sodium (Nasalcrom) is the only mast cell stabilizer available for topical nasal use and is supplied as a metered-dose pump spray. Treatment of existing symptoms requires q 4hr dosing. Less frequent dosing may be needed for prophylactic use. Nedocromil sodium has not been approved by the FDA for nasal use. It is a mast cell stabilizer but is not structurally related to cromolyn and appears to have additional antiinflammatory actions. Although deemed a more potent drug, dosing will likely be one spray by metered-dose inhaler qid for 8 weeks with the possibility of decreasing the dose to bid when the desired effect is achieved. TOPICAL STEROIDS PHARMACOLOGY - Although the exact mechanism of action of topically applied nasal corticosteroids is not clearly defined, dampening of immune responses is felt to occur through vasoconstriction, suppression of membrane permeability, and mediator inhibition. These effects offer obvious benefit for allergic rhinitis, but their use in sinusitis is more complicated. Reduction of edema at the osteomeatal complex is the goal of topical corticosteroid use in sinusitis but inhibition of the body's natural immune response to infection should preclude their use during an acute infection. SIDE EFFECTS - In general, the newer topical steroids are safer, longer acting and less irritating to the nasal mucosa. The most common local side effects are nasal irritation, epistaxis, and sore throat. Most can be minimized by rinsing the nose with saline before application and directing the stream towards the medial canthus of the eye to avoid the septum. Rare but more serious complications include septal perforation, candidiasis, and cataracts. Systemic absorption at recommended doses is minimal, but at high doses generalized side effects are possible. Their safety in young children (<6years), pregnancy and patients over 65 is unknown. EFFICACY - Nasal corticosteroids require about 4 to 7 days of regular use before their therapeutic effect is established. They cannot be used on an " as-needed" basis; once begun, they should be continued for at least 2 weeks. In the case of allergic rhinitis, this means institution of therapy prior to the start of the allergic season and continuing administration at the lowest effective maintenance throughout the season. As stated above, in sinusitis, nasal steroids should be administered only after antibiotic therapy, because they may inhibit the inflammatory response needed to combat infection. Combination with topical decongestants or saline irrigation may increase mucosal contact, which is essential for therapeutic effect. Obstructing polyps may require intrapolyp steroid injections or surgery before topical steroids will be effective. Some have even advocated application while in the head- down, kneeling (Moffat's) position for large polyps. SPECIFIC DRUGS Dexamethasone was the first nasal steroid used. It is now rarely used due to systemic absorption. Although short doses at recommended doses (two puffs tid) is probably safe, adrenal suppression has been noted within 30 days. Beclomethasone is available as a powder suspension delivered by a fluorocarbon propellant (Vancenase Pockethaler, Beconase aerosol), or as an aqueous solution dispensed by a pump spray (Vancenase AQ, Beconase AQ). Aqueous delivery is more soothing and may case less burning, dryness and epistaxis but powdered delivery is low-pressure and more comfortable to some patients. Hypothalamic-pituitary adrenal suppression has not been demonstrated in adults until doses of 1600ug, providing a 5 fold margin of safety. One canister last about one month and costs about $37. Triamcinolone acetonide (Nasacort) is the newest nasal steroid available in the U.S. It is dispensed by a fluorocarbon delivery system and has the advantage of only once daily dosing (2 puffs). A single dose of 64 puffs (3200ug) was required to suppress cortsol levels, providing an 8-16 fold safety margin. Cost is about $43 a month. Flunisolide (Nasalide) is contained in a propylene glycol vehicle, which accounts for the complaint of nasal stinging in about 45% of patients. Cortisol suppression occurs at only 700ug providing only a 3.5 margin of safety. Budesonide and Fluocortin are currently only available in Europe and are said to be more potent and safer than current preparations mainly due to rapid first-pass metabolism. Both are currently undergoing U.S. clinical trials. ANTIHISTAMINES PHARMACOLOGY - H1 receptor antagonists are reversible, competitive inhibitors of the actions of histamine on H1 receptors. Their actions depend on the site of histamine receptors and include decreased vascular permeability, decreased pruritis and smooth muscle relaxation. Recent evidence has shown that some second generation agents may also modify release of inflammatory mediators from IgE sensitized mast cell. Most first generation antihistamines cross the blood-brain barrier and cause sedation, which is an unacceptable side effect for many patients. Second generation antihistamines are lipophobic and poorly penetrate the CNS, causing less sedation. Both generations are well absorbed after oral administration and metabolized by the hepatic P-450 system. Maximum effect is noted several hours after peak serum concentrations and persist long after concentrations drop, apparently due to the production of active metabolites. This explains why they are not particularly effective after the immediate allergic reaction has begun. SIDE EFFECTS - First generation antihistamines have been proven to cause sedation, impaired cognition, and slowed reaction time and pose a problem for patients driving or operating machinery. Tachyphylaxis also occurs requiring and requires switching to another drug class. Also, anticholinergic affects of these agents can translate into symptoms of prostatitis, dystonia, and gastrointestinal symptoms. Second generation agents offer distinct advantages over the classic agents but are more expensive. Their sedation effect has not been shown to exceed placebo and they have little or no tachyphylaxis or anticholinergic affects. Contrary to previous conceptions, antihistamines are not contraindicated for use in patients who have both allergic rhinitis and asthma; in fact, terfenadine has been shown to reduce symptoms in asthma associated with exercise. Because of their anticholinergic actions, first generation antihistamines dry secretions and should not be used in acute sinusitis. Even though second generation antihistamines have minimal anticholinergic effects, they have no role in most cases of acute sinusitis. Terfenadine and astemizole have been associated with fatal arrhythmias in overdose and drug interactions and should be avoided in patients with impaired liver function, known arrhythmias, or taking macrolide antibiotics (erythromycin, Biaxin, Zithromax) or antifungal agents such as fluconazole and ketoconazole. EFFICACY - Several multicenter, double blind, placebo- controlled studies have shown that astemizole (Hismanal), chlorphenerimine (Clor-trimeton) and terfenadine (Seldane) are equally effective in reducing the symptoms of sneezing, watery rhinorrhea, and nasal itching and are statistically better than placebo. Ocular symptoms were reduced but less significantly. Numerous studies have shown that antihistamines have no effect on nasal congestion. Moderate to excellent symptom relief is achieved in 60-70% of patients with seasonal allergic rhinitis and 65-85% of those with perennial allergic rhinitis. Although the classic agents are unable to halt the allergic reaction once it has begun, emerging evidence suggests that the newer agents may offer additional clinical benefit by interfering with inflammatory mediator release. SPECIFIC DRUGS Classic Antihistamines Ethanolamines [Diphenhydramine (Benadryl), Clemastine (Tavist)] are potent H1 antagonists with strong sedative affects. Alkylamines [Chlorpheniramine(Chlor-trimetron), Brompheniramine (Dimetapp)] are the most frequently used and somewhat less sedating. They are often combined with decongestants. Piperazines [Hydroxyzine (Atarax, Vistaril)] are very sedating and used more for eczema. Phenothiazines [Promethazine (Phenergan), Trimeprazine (Temaril) Meclizine (Antivert)] have prolonged H1 blocking activity but are seldom used for allergy. Hydroxyzine is used for its tranquilizing and antiemetic effects or in chronic urticaria. Meclizine is used to treat vertigo. Piperidines [Cyproheptadine (Periactin)] is used to treat eczema Second-Generation (Nonsedating) Antihistamines Terfenadine (Seldane) is dosed at 60 mg bid with its onset of action in 1-3 hours. Time to maximum effect is faster than astemizole (4 hours) and lasts 8-12 hours. It has no effect on cognitive function and sedation equals placebo. One recent study has shown it highly effective for motion sickness and some airlines are considering approving its use by pilots. Large doses have caused tachycardia, QT prolongation, and fatal torsades de pointes has been reported with massive overdoses. One month supply costs about $62. Loratidine (Claritin) has been recently approved and is dosed 10mg daily. Efficacy and side effects are similar to terfenadine but it can be dosed once daily. One month supply costs about $67. Astemizole (Hismanal) is much longer acting with a half life of 18-20 days allowing once daily dosing (10mg qd). Its slower onset prevents intermittent use and it has been suggested for prophylactic use before the pollen season begins. Some advocate starting with higher doses (20-30mg) for the first three days to decrease the time to steady-state. Side effect profile and fatal arrhythmias with overdose are similar to terfenadine. Astemizole may cause appetite stimulation in some (3.6%) of patients and has an extremely long half life (10 days), making sporadic dosing inappropriate. Astemizole should be taken on an empty stomach because food decreases its absorption by 60%, although this figure has recently been disputed. One month supply costs about $55. Cetirizine is awaiting FDA approval and may be even less sedating than terfenadine, with similar efficacy. Levocabastine is a topical antihistamine under investigation as both a nasal spray and eye drops. It has been extensively evaluated in adults with good results and preliminary data shows it may be useful in children. Azelastine is currently being researched in topical and oral forms. The oral form is mildly sedating and causes dose- dependent taste disturbances. The topical form appears safe and effective for allergic rhinitis. ANTIBIOTICS OVERVIEW - Antibiotics deserve a full discussion and only commonly used oral agents will be mentioned here. Acute purulent sinusitis usually responds to an empiric 10 day course of antibiotics, often combined with decongestants and\or mucolytic. The problems more often faced by otolaryngologists are chronic sinusitis or sinusitis in the allergic patient. Nonencapsulated H. influenzae and Strep. pneumoniae account for more than half of all acute community-acquired sinusitis, Moraxella catarrhalis is the third leading organism followed by Strep. pyogenes, Staph. aureus, and alpha-hemolytic streptococci. Three classes of antibiotics cover the top three organisms; the aminopenicillins, trimethoprim- sulfonamide, and the newer cephalosporins. The relative prevalence of aerobic versus anaerobic organisms in sinusitis has been a subject of some controversy. In 1975, Evans cultured only 12% anaerobes, but his study mainly included cases of acute or subacute sinusitis. Since then, Frederick et al and Brook reported 52% and 88% anaerobes, respectively, in chronic sinusitis. Brooke also reported that 44% of Bacteroides species were Beta-lactamase producers. 6 to 10% of acute infections are anaerobic infections (often associated with dental infections) with Fusobacterium, Bacteroides, and peptostreptococcus being the major culprits. Chronic purulent sinusitis unresponsive to initial therapy suggests a resistant organism or an anaerobe. Agents not recommended include tetracycline, penicillin, erythromycin, and cephalexin, SPECIFIC DRUGS The aminopenicillins (ampicillin, amoxicillin) can still be considered for initial therapy but an estimated 20% of H. influenzae and probably an even higher percentage (up to 80%) of M. catarrhalis produce beta-lactamase. They do not cover S. aureus and have a tendency for rash formation, especially in infectious mononucleosis. Amoxicillin is better absorbed than ampicillin. Three weeks dosing costs about $6. Amoxicillin-clavulanate (Augmentin) is a suicide inhibitor of beta-lactamase enzymes and covers H influenzae, S. pneumoniae, M. catarrhalis, staph, and anaerobes. It is effective for adults and children but approximately 9% of patients develop gastrointestinal symptoms. Three weeks supply costs about $80 (250mg) or $115 (500mg). Cefuroxime (Ceftin) is a second generation cephalosporin that is a good choice if diarrhea with Augmentin develops. One disadvantage is that no liquid or chewable form exists. Three weeks supply costs about $94 (250mg) or $185 (500mg) Cefpodoxime (Vantin) has a similar scope as Ceftin but is available as a suspension. Three weeks supply costs about $75. ------------------------------------------------------------------------- BIBLIOGRAPHY Brook J. Bacteriology of chronic maxillary sinusitis in adults. Ann Otol Rhinol Laryngol 1989;98:426-8 Bailey, Byron J., ed. Head and Neck Surgery - Otolaryngology. Philadelphia, PA.: J.B. Lippencott, 1993 Reilly J. 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Amer Jour of Otolayn sep 1993;14;5:295-300 Affime M.B. three month evaluation of ECG effects of Loratadine in humans. Joun of allergy and chem immunol 1993;91:259 ---------------------------------END----------------------------------------