Adverse Effects of Medications for Rhinitis

Review article Supported by a grant from Zeneca Pharmaceuticals

Adverse effects of medications for rhinitis Henry Milgrom, MD*† and Bruce Bender, PhD*‡

Learning Objectives: Reading this article will reinforce the reader’s awareness of the adverse effects of medications used for the treatment of rhinitis. Data Sources: Articles on therapy of rhinitis and reports of associated side effects were reviewed. A MEDLINE database using subject keywords was searched from 1992 through 1997. Study Selection: Pertinent articles were chosen. A distinction was made in the text between controlled studies and case reports. Results: Antihistamines, decongestants, anticholinergic agents, and corticosteroids, alone or in combination are used in the treatment of rhinitis. Reported side effects include sedation, psychosis, impaired learning and memory, and cardiac arrhythmias. Conclusion: Rhinitis and its complications are important medical conditions. Adverse reactions are often difficult to diagnose and assess. Side effects may arise from the use of individual drugs or from drug combinations. There is insufficient cause to abandon these medications, but physicians must be mindful of the inherent risks of the drugs that they prescribe and of others that their patients may be taking without the physicians’ knowledge or approval. Ann Allergy Asthma Immunol 1997;78:439– 46.

INTRODUCTION Medicines for allergic rhinitis, cough, and colds comprise the largest group of drugs on the market.1 These preparations of antihistamines, decongestants, and anticholinergic agents are available over the counter (OTC) and are frequently taken without the supervision of physicians. The reason for combining antihistamines and adrenergic agents in a single preparation is that the former control sneezing and rhinorrhea, while the latter control nasal obstruction. Additionally, central nervous system (CNS) stimulation by the decongestant may counteract the sedation caused by the antihistamine. While these preparations may be use* Department of Pediatrics, † Department of Medicine, and ‡ Department of Psychiatry, and National Jewish Center for Medicine and Research, University of Colorado Health Sciences Center, Denver, Colorado. Received for publication March 14, 1997. Accepted for publication March 31, 1997.

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ful in allergic rhinitis, their benefit in respiratory infections is highly questionable. Further, the potential of these drugs, alone or in combination, for producing adverse effects is inadequately recognized and may be particularly difficult to assess in patients taking rhinitis medications in addition to an asthma regimen. The literature on adverse effects of medications consists largely of case reports and case reviews that may be subjective and inaccurate. In some cases the reported adverse events may not be real, or may not be the result of medication. Even reports documenting an association between a drug and an adverse reaction frequently do not confirm a cause-and-effect relationship.2 Patients and their families may attribute side effects that arise from other sources, including the negative impact of the illness itself, to medications. Chronic respiratory disease has been associated with increased behavior dis-

orders in children and anxiety and depression in adults.3,4 Greatest reliance must be placed on the relatively small number of well-controlled, experimental studies such as those carried out with antihistamines. ANTIHISTAMINES Histamine receptors are increased in patients with nasal allergy. Histamine, acting on H1 receptors, causes sneezing and itching through stimulation of the sensory nerves, and rhinorrhea and congestion through vasodilation, increased vascular permeability, extravasation of proteins and reflex stimulation of glandular sections.5 Treatment with H1 antagonists suppresses these disease processes. The side effects of antihistamines may be categorized as central, those affecting the CNS; or peripheral, those affecting other organ systems. Firstgeneration antihistamines are highly lipophilic and readily cross the bloodbrain barrier. These agents can both stimulate and depress the CNS. Central excitation is the principal characteristic of drug overdose, but it may occur even in patients given recommended doses of medication. Milder manifestations such as restlessness, nervousness, and insomnia may progress to hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions. Other detrimental effects resulting from central actions include dizziness, tinnitus, lassitude, incoordination, blurred vision, diplopia, euphoria, and tremors.6 First generation antihistamines have been reported to cause drowsiness in 25% of adults7 (Fig 1). Evidence that the sedative effects are greater for women than men suggests that sex is an important factor

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for considerations in such studies, which tend to rely on male volunteers.8 Second-generation H1 antihistamines are lipophobic, and numerous studies have shown that they are unlikely to result in sedation or impairment of psychomotor performance in adults.9 –12 Reports that compared the effects of first-generation and secondgeneration antihistamines on the operation of motor vehicles demonstrated that patients taking second-generation antihistamines had fewer driving errors, shorter response times, smoother steering, less lane weaving, and greater speed and accuracy in covering a driving course.10 –13 One study, however, found that a nonsedating antihistamine given at twice the therapeutic dose also produced significant driving impairment.8 It is important to note that patients frequently fail to recognize impairment caused by antihistamines,14 and the correlation between their own perceptions and objective measures of sedation is poor. In two studies, subjects reported adverse effects despite the absence of treatment-related changes on tests of psychomotor skills,15,16 while in another subjects reported no sedation although impairment was demonstrated in the laboratory.17 In tests evaluating driving performance, the impairment caused by triprolidine SR, 10 mg bid, was similar to that caused by blood alcohol concentrations of 0.05 mg/dL that result from the consumption of two cocktails.18 Driving performance was assessed one hour and three hours after the administration of triprolidine. While subjects recognized that their driving was impaired at one hour, at three hours their performance had not improved but they no longer recognized this effect. In these studies drivers taking terfenadine or loratadine drove normally. It is of concern that central depression associated with the use of older H1 antagonists is enhanced by concurrent ingestion of alcohol or other CNS depressants.19 In contrast, combined administration of sympathomimetic decongestants and mildly sedating second-generation an-

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Figure 1. (A) Percentage change from baseline in P300 event-related potential 2.5 hours after dosing. Difference from placebo was significant only for diphenhydramine (P ⬍ .05). (B) Change in visual analogue scale for somnolence 2.5 hours after dosing. Differences from placebo were significant only for cetirizine, ketotifen, and diaphenhydramine (P ⬍ .05). From: Simons FER. et al. Ref. 63. (used with permission).

tihistamines has a net beneficial effect on driving performance.8 Although much research has been directed toward understanding the relative benefits of sedating and nonsedating antihistamines on adult cognition and performance, little is known about their effects in children.20 Given the importance of school performance, the question of whether the sedation of

classic antihistamines impedes children’s learning requires resolution. Vuurman and colleagues found that children with allergic rhinitis did not perform as well on tests of learning as healthy controls. Diphenhydramine further impaired performance in these children while loratadine resulted in improved learning.21 The same investigators subsequently found that

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adolescents and young adults who received acrivastine with pseudoephedrine had better scores on tests of learning than those treated with diphenhydramine.22 Simons et al evaluated P300 evoked potential in children treated with antihistamines and found that chlorpheniramine increased latency relative to placebo and terfenadine.23 The critical variable was the time elapsed before brain wave activity was recorded, corresponding to the speed of cognitive processing. Correctness of the answer was not considered and the results were unaffected by the subjects’ motivation and knowledge. Children may be particularly susceptible to the central side effects of antihistamines. Uncontrollable behavior and hallucinations have been documented in three children who had received triprolidine-pseudoephedrine.24 Another report described three children who were treated with large doses of topical diphenhydramine for varicella-zoster lesions that led to visual and auditory hallucinations.25 The most common peripheral side effects are loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea. In rare patients, H1 antagonists increase appetite and cause weight gain. This appears to be most often associated with cyproheptadine, ketotifen, and astemizole. Other side effects are caused by the anticholinergic properties of first-generation H1 antagonists. They include dryness of the mouth and respiratory passages that may sometimes aggravate cough, urinary retention or frequency, and dysuria.6 A syndrome similar to atropine poisoning, characterized by fixed dilated pupils, flushed face, sinus tachycardia, urinary retention, dry mouth, and fever has been described.6 Since 1990, evidence has accumulated that high serum concentrations of the second-generation drugs terfenadine and astemizole produce a potentially lethal form of ventricular tachycardia.26,27 This arrhythmia has been named torsade de pointes, French for, “twisting of the points”. It follows delayed ventricular repolarization shown

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by the prolongation of the QT interval or prominent U waves. Potential causes include drug overdose or concomitant administration of medications that inhibit the P450 cytochrome oxidase hepatic enzymes. Interacting drugs include the macrolides (erythromycin and troleandomycin) and imidazole antifungals (ketoconazole and itraconazole). Interactions are suspected with nefazodone (Serzone), a synthetically derived phenylpiperazine antidepressant, unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics or monoamine oxidase inhibitors; fluvoxamine (Luvox), a selective serotonin uptake inhibitor, unrelated to other serotonin uptake inhibitors or clomipramine; and ritonavir (Norvir), a human immunodeficiency virus-specific protease inhibitor.28 Concurrent administration of nefazodone, fluvoxamine or ritonavir with either terfenadins or astemizole is contraindicated. A single 430-mg dose of quinine may lead to elevated plasma concentrations of astemizole.28 Quinine in beverages (80 mg/32 oz) is unlikely to raise plasma concentrations of astemizole sufficiently to result in a clinical effect, however ingestion of double-strength grapefruit juice has been documented to cause prolongation of the QT interval in subjects taking terfenadine.28 Currently available evidence indicates that three newer second-generation drugs—loratadine, cetirizine, and fexofenadine— do not produce torsade de pointes. Adverse effects of antihistamines, whether mediated through central or peripheral H1 receptors, anticholinergic actions, or prolongation of QT interval, can be avoided through prudent selection of drugs. It is regrettable that patients, for reasons of routine or strict economy, continue to be treated with medications that cause these needless complications. SYMPATHOMIMETICS The vascular bed of the nose has rich sympathetic innervation that determines vascular congestion and nasal patency. Alpha1-adrenergic receptors are present in the venous capacitance

vessels and ␣2 receptors in the arterioles.29,30 Alpha-agonists are used extensively as nasal decongestants in patients with chronic or acute rhinitis. These drugs, which may be administered either orally or topically, reduce resistance to air flow by decreasing the blood volume in the nasal mucosa. Topical decongestants are useful in the treatment of rhinitis because of their selective action. Critical drawbacks are their loss of efficacy, rebound hyperemia, and the exacerbation of symptoms that occur with prolonged use or following discontinuation of the drug. Long-term administration of topical decongestants frequently causes more discomfort than it relieves. An extreme example is the irritating, painful condition known as rhinitis medicamentosa, mechanisms may be receptor desensitization and damage to the mucosa.31 Agonists that are selective for ␣1 receptors are less likely to induce mucosal damage.32 The risk of rhinitis medicamentosa is minimized by limiting the use of topical agents to fewer than ten days. Oral decongestants are less likely to cause rebound congestion but carry a greater risk of adverse systemic effects. These medications are associated with hypertension, cardiac arrhythmias, palpitations, tremor, and CNS effects including restlessness, insomnia, and psychiatric disorders.31 Pseudoephedrine and phenylpropanolamine (PPA) are less likely to produce these side effects than ephedrine. Sympathomimetic decongestants should be avoided in patients with hypertension and men with prostatic enlargement. Other contraindications include coronary heart disease, hyperthyroidism, glaucoma, and diabetes mellitus. The actions of sympathomimetic amines are enhanced by MAO inhibitors, and profound potentiation of pressor responses may occur.31 Phenylpropanolamine, a sympathomimetic drug closely related to ephedrine (phenylpropanol methylamine) and amphetamine (phenylpropane amine), is a component of more than 150 over-the-counter preparations. A report of 142 adverse drug reactions

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attributed to PPA includes acute hypertension, severe headaches, toxic encephalopathy, intracranial hemorrhages, seizures, and eight deaths. An overdose of PPA was taken in about one-third of the cases.33 Myocardial infarction has been linked to the use of PPA for weight loss.34 Phenylpropanolamine has been associated with acute psychoses,35,36 but it appears that over-the-counter combination products rather than PPA alone are the most likely causes.37,38 The possibility that adverse events are more likely to occur in vulnerable populations has not been systematically addressed; however, it appears that individuals with mood spectrum disorders, history of psychosis, children under the age of 6 years, and postpartum women are particularly at risk.35,37 An interaction with caffeine has been reported in cases of manic psychosis39 and acute memory loss with nominal aphasia.40 Eighty percent of cases of adverse reactions to PPA that were reported to the Swedish Adverse Drug Reaction Committee involved patients less than 15 years of age.41 Five patients, four of them children, manifested acute psychosis, including profound confusion and visual hallucination; the remainder experienced restlessness, irritability, and sleep disturbance. Aggressiveness was noted, particularly in younger children. The case of a healthy 3-yearold who developed a dystonic reaction attributed to cough syrup containing PPA was published recently.42 A 17year-old boy was admitted to a mental hospital three times within a few months with acute mania-like psychosis that was subsequently attributed to high doses of PPA and PPA with brompheniramine.41 Pseudoephedrine, another sympathomimetic agent, taken at an excessive dose, precipitated a bipolar disorder in a 13-year-old girl.43 In a prospective clinical trial of pseudoephedrine and triprolidine, 9 of 74 children developed irritability, dizziness, general malaise, and nightmares.44 Three children, aged 2.5 to 3.5 years, suffered severe visual hallucina-

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tions attributed to the same drug combination,24 and case summaries of 50 additional patients with CNS side effects were received by the authors following the publication of these findings.45 ANTICHOLINERGIC DRUGS Parasympathetic innervation controls vasodilation and the secretion of the serous glands that are abundant in the nasal mucosa. The most effective therapy for rhinorrhea that results from excessive secretion by these glands is achieved by anticholinergic agents. Inhalation of quaternary salts of atropine, such as ipratropium bromide, is not associated with significant side effects. The sensation of nasal dryness has been reported by some patients; but may be treated with a nasal saline spray. Oral cough and cold medicines that commonly contain anticholinergics as well as antihistamines, decongestants, and expectorants pose a cause for concern. Following the 1985 ruling by the US Food and Drug Administration that anticholinergics are not safe and effective for over-thecounter distribution, the use of these agents has ceased in over-the-counter preparations.46 In contrast, numerous combinations available by prescription still contain methscopolamine, atropine, hyoscyamine, scopolamine, or homatropine. The literature documenting psychiatric reactions caused by anticholinergic agents is limited to case reports; however, several controlled studies have evaluated specific behavioral changes following the administration of atropine in the laboratory. Visual perception, reaction time, coordination, verbal memory, and motor steadiness showed impairment following the administration of atropine in normal male volunteers, with a greater deficit at a dose of 1.7 mg than at 0.85 mg.47 In another study, no side effects were detected at a dose of 1.5 mg, but an impairment was documented on tests of visual discrimination, calculation, and memory when subjects received 3.0 mg and increased when the dose was raised to 6.0 mg. The subjects also

reported dose-related symptoms that included nausea, confusion, blurred vision, restlessness, sleepiness, and feeling “high” that originated one and onehalf hours after ingestion and disappeared seven to nine hours later.48 Excessive doses of atropine may result in acute psychosis.49 A review of 212 cases of stramonium overdose reported visual hallucinations in 50% of cases, and disorientation, hyperactivity, combativeness, and amnesia in 10% to 21%.50 Adverse events, however, such as auditory and visual hallucinations and amnesia are not limited to cases of overdose and have been reported even in association with the use of mydriatic eye drops.51–53 CROMOLYN SODIUM OR NEDOCROMIL SODIUM Nasal cromolyn sodium and nedocromil sodium are free of side effects other than local irritation. Both preparations are clinically less effective than nasal corticosteroids. Treatment with cromolyn sodium is prophylactic; it offers minimal relief to symptomatic patients. The requirement for QID administration poses compliance problems. Nedocromil sodium is not available for nasal administration in the United States. CORTICOSTEROIDS Corticosteroids delivered by depot injection or by oral or topical administration are used in the treatment of allergic rhinitis. Support for the use of depot injections exists in the older literature54,55 and, interestingly, a recent review has produced a paucity of reports repudiating this practice.56,57 The use of intramuscular corticosteroids is continued by general practitioners, who argue that this form of therapy is free of side effects. Nevertheless, because of the availability of highly effective topical medications that need to be administered only once a day, there is little justification for systemic corticosteroids in the treatment of rhinitis. The risk of adverse effects from systemic corticosteroids depends on the total dose and the duration of treatment. Oral corticosteroid therapy

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should be short term (usually not more than 2 weeks) and should be used only when other therapies fail. Contraindications to systemic steroids are glaucoma, herpes keratitis, diabetes mellitus, psychiatric disorders, advanced osteoporosis, severe hypertension, and tuberculosis or other chronic infections. Systemic steroids should not be administered to children or to pregnant women.55 The efficacy of intranasal corticosteroids is beyond dispute.58 The concerns about using these drugs are based on negative attitudes toward any corticosteroid therapy held by some patients and the potential for the risk of adverse effects. Irritation and sneezing immediately after administration are frequent but largely inconsequential complaints.58 Dryness of the nasal mucosa and epistaxis occur commonly but usually can be successfully addressed through dose reduction, change of formulation, and application of an ointment to the nares.58 Septal perforation as a consequence of nasal corticosteroids has been reported very rarely probably due to repeated direction of the sprays against the septum.59 Recent studies have shown dose-related suppression of serum cortisol and changes in peripheral lymphocyte markers and osteocalcin levels by short-term use of nasal budesonide and fluticasone propionate.60,61 While there is little reason to question the safety of intranasal corticosteroids in adults, their use in children and in pregnant women is still open to question. Although pregnancy does not constitute a specific contraindication, a recent editorial concluded that cromolyn should be used as the initial treatment for patients with daily symptoms and antihistamines for those with intermittent symptoms.62 SUMMARY Serious side effects, including sedation, psychosis, impaired learning and memory, and cardiac arrhythmias have been linked to the treatment of allergic rhinitis. Millions of patients receive medications to control rhinitis but little is known about their impact on mood,

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behavior, and learning. Adverse reactions are often difficult to diagnose because the onset of symptoms may be delayed and the symptoms may persist beyond the discontinuation of the inciting agent. Furthermore, patients may ascribe side effects to medications that arise from other sources, including the adverse impact of the illness itself. Additionally, patients may be taking medications prescribed by others or purchased over the counter. As physicians, we must be aware of the inherent risks of the drugs that we prescribe and of others that may be administered to our patients without our knowledge or approval.

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Psychiatry 1994;16:358 – 60. 36. Stroe AE, Hall J, Amin F. Psychotic episode related to phenylpropanolamine and amantadine in a healthy female [Letter]. Gen Hosp Psychiatry 1995;17:457– 8. 37. Lake CR, Masson EB, Quirk RS. Psychiatric side effects attributed to phenylpropanolamine. Pharmacopsychiatry 1988;21:171– 81. 38. Sackier JM. Adverse reaction to antihistamine-decongestant [Letter]. Ann Allergy Asthma Immunol 1995;74: 356. 39. Lake CR. Manic psychosis after coffee and phenylpropanolamine. Biol Psychiatry 1991;30:401– 4. 40. Puar HS. Acute memory loss and nominal aphasia caused by phenylpropanolamine. South Med J 1984;77: 1604 –5. 41. Norvenius G, Widerlov E, Lonnerholm G. Phenylpropanolamine and mental disturbance [Letter]. Lancet 1979;2:1367– 8. 42. Joseph MM, King WD. Dystonic reaction following recommended use of a cold syrup. Ann Emerg Med 1995;26: 749 –51. 43. Dalton R. Mixed bipolar disorder precipitated by pseudoephedrine hydrochloride. South Med J 1990;83:64 –5. 44. Bain D. Can the clinical course of acute otitis media be modified by systemic decongestant or antihistamine treatment? Br Med J 1983;287:654 – 6. 45. Sills JA, Nunn AJ, Sankey RJ. Visual hallucinations in children receiving decongestants [Letter]. Br Med J (Clin Res Ed) 1984;288:1912–3. 46. Fed Reg 1985;50:46582–7. 47. Seppala T, Visakorpi R. Psychophysiological measurements after oral atropine in man. Acta Pharmacol Toxicol (Copenh) 1983;52(1):68 –74. 48. Higgins S, Lamb R, Henningfield J. Dose-dependent effects of atropine on behavioral and physiologic responses in humans. Pharmacol Biochem Behav 1989;34:303–11. 49. Brizer DA, Manning DW. Delirium induced by poisoning with anticholinergic agents. Am J Psychiatry 1982; 139:1343– 4. 50. Gowdy JM. Stramonium intoxication: review of symptomatology in 212 cases. JAMA 1972;221:585–7. 51. Freund M, Merin S. Toxic effects of scopolamine eye drops. Am J Ophthal

mol 1970;70:637–9. 52. Shihab ZM. Psychotic reaction in an adult after topical cyclopentolate. Ophthalmologica 1980;181:228 –30. 53. Khurana AK, Ahluwalla BK, Rajan C, Vohra AK. Acute psychosis associated with topical cyclopentolate hydrochloride. Am J Ophthalmol 1988;105:91. 54. Borum P, Gronborg H, Mygind N. Seasonal allergic rhinitis and depot injection of a corticosteroid. Allergy 1987;42:26 –32. 55. Laursen LC, Faurschou P. Pals H, et al. Intramuscular betamethasone dipropionate versus oral prednisolone in hay fever patients. Allergy 1987;42: 168 –72. 56. Dahl PR, Zalla MJ, Winkelmann RK. Localized involutional lipoatrophy: a clinicopathologic study of 16 patients. J Am Acad Dermatol 1996;35:523– 8. 57. Cherenko SM. Long-term asymptomatic abscess arising as a result of injections of corticosteroid hormones in a child with Addison’s disease. Klin Khir 1993;7– 8:68 –9. 58. Mygind N. Glucocorticosteroids and rhinitis. Allergy 1993:48:476 –90. 59. Soderberg-Warner ML. Nasal perforation associated with topical corticosteroid therapy. J Pediatr 1984;105: 840 –1. 60. Knutsson U, Stierma P, Marcus C, et al. Effects of intranasal glucorticoids on endogenous glucocorticoid peripheral and central function. J Endocrinol 1995;144:301–10. 61. Grahnen A, Eckernas SA, Brundin RM, Ling-Andersson A. An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers. Br J Clin Pharmacol 1995;38:521–5. 62. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–9. 63. Simons, FER, Fraser, TG, Reggin, JD, Simons, KJ. Comparison of the central nervous system effects produced by six H1-receptor antagonists. Clin Exper Allergy 1996;26:1092–7.

Requests for reprints should be addressed to: Henry Milgrom, MD National Jewish Medical & Research Center 1400 Jackson St Denver, CO 80206

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CME Examination No 007– 005 Questions 1–20, Milgrom H & B Bender. 1997;78:439 – 46 CME Test Questions 1. In patients with nasal allergies, histamine receptors: a. are repressed b. are increased in number c. are unaffected d. are delayed e. have not been clearly determined 2. First-generation antihistamines: a. are lipophilic and readily cross the blood-brain barrier b. are lipophobic and readily cross the blood-brain barrier c. are lipophilic and do not cross the blood-brain barrier d. are lipophobic and do not cross the blood-brain barrier e. none of the above 3. First generation antihistamines are known to sedate a. adults but not children b. children but not adults c. men less than women d. men more than women e. older adults more than younger adults 4. When sympathomimetic decongestants are combined with mildly sedating second-generation antihistamines, the net effect typically is a. increased sedation b. decreased driving performance c. reduced reaction time d. improvement in driving performance e. a, b, and c 5. Uncontrollable behavior and hallucinations in children taking triprolidine-pseudoephedrine a. occurred in about half children treated b. have not been established in controlled studies c. always ceased within four hours of last dose taken d. have been reported in girls but not boys e. have been reported only in teenagers

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6. Torsade de pointes has been associated with a. astemizole b. alpha-adrenergic agonists c. bromide phenylpropanolamine d. ipratropium bromide e. scopolamine 7. Cromolyn sodium has been associated with side effects including a. auditory and visual hallucinations b. sedation only c. syncope only d. local irrritation only e. diarrhea only 8. Anticholinergic agents a. are currently unavailable OTC b. are currently available OTC c. are never combined with expectorants d. are never combined antihistamines e. are no longer available in this country 9. Nasal corticosteroids a. are free of side effects b. can cause perforation of the nasal septum c. do not suppress serum cortisol d. can be used safely by pregnant women e. are no safer than oral corticosteroids 10. Second-generation antihistamines: a. are lipophilic and readily cross the blood-brain barrier b. are lipophobic and readily cross the blood-brain barrier c. are lipophilic and do not cross the blood-brain barrier d. are lipophobic and do not cross the blood-brain barrier e. none of the above 11. The principal characteristic of antihistamine overdose is: a. tinnitus b. lassitude c. sedation d. blurred vision e. central excitation

12. The most dangerous side effect of second-generation antihistamines is: a. urinary retention b. sedation c. central excitation d. ventricular arrhythmia e. seizure activity 13. First-generation antihistamines are associated with: a. sedation b. learning impairment c. impaired driving skills d. potentiation of the effects of alcohol e. all of the above 14. Adverse effects of antihistamines are mediated through: a. central H1 receptors b. peripheral H1 receptors c. anticholinergic activity d. prolongation of QT interval e. all of the above 15. Which of the following does not increase the serum concentration of terfenadine and astemizole? a. erythromycin b. troleandomycin c. ketoconazole d. itraconazole e. ipratropium bromide 16. The drawback(s) to treatment of rhinitis with topical sympathomimetics is/are: a. loss of efficacy b. rebound hyperemia c. rhinitis medicamentosa d. receptor desensitization e. all of the above 17. Oral decongestants are contraindicated in: a. coronary heart disease b. hyperthyroidism c. glaucoma d. hypertension e. all of the above 18. Nasal administration of quaternary salts of atropine may lead to: a. urinary retention b. nasal dryness c. impaired visual perception d. acute psychosis

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e. memory impairment 19. Cromolyn sodium and nedocromil sodium are: a. effective by BID dosing b. associated with significant side effects c. used primarily as prophylaxis

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d. effective for treatment of acute symptoms e. associated with blurred vision 20. Systemic corticosteroids are: a. justifiable first-line therapy for allergic rhinitis b. free of side effects

c. shown to be safe for children and pregnant women d. currently used for allergic rhinitis e. appropriate therapy only for adult males

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY