New Directions in the Treatment of Asthma

NelN Directions in the Treatment of Asthma by Karen J. Tietze, PharmD, and Maya C. Smith, PharmD

Program PrevielN This article highlights new advances in the treatment of asthma including the changing roles of corticosteroids, cromolyn, beta-adrenergic agonists, theophylline, ipratropium bromide, methotrexate, and antihistamines. In addition, guidelines for counseling patients on the use of inhaled corticosteroids, metered-dose inhalers, and peak expiratory flow meters are provided.

tors triggers the release of mediators, such as histamine, thromboxanes, prostaglandins, and platelet-activating factor. These mediators lead to the development of airway inflammation, which now appears to be an important cause of airway hyperresponsiveness and bronchoconstriction, according to new evidence. 4-6 Airflow is limited not only by smooth muscle constriction of the airways but also by bronchial wall edema and by airway obstruction from

CE Credit

Introduction Conventional therapy for acute cases of asthma has included use of subcutaneous epinephrine, aerosolized adrenergic agonists, oxygen, and parenteral aminophylline. Conventional therapy for chronic asthma has included administration of beta-adrenergic agonists in a metered-dose inhaler and sustained-release theophylline. Corticosteroids were reserved for the treatment of severe cases of asthma or those unresponsive to other drug regimens. However, the availability of new products (such as the inhaled beta 2specific adrenergic agonists and inhaled corticosteroids) and new insights into the role of airway inflammation in the pathogenesis of asthma have stimulated a reassessment of the conventional therapy for asthma.

.~

CE "Credit: To obtain two (2) hours of contihuj~i~ducation credit for completing "New Directions in the Treatment of Asthma," complete the assessment exercise and . .gistration fonn and return it 0 APhA. A~ertificate0 will b~ "awarded upon achievaSsing grade;pf 70% or frn~cis~ >~uccessfully,

this

g artide within <+ of date of issue can

"New Directions in the Treatment of Asthma" is a selfstudy continuing education program for phannacists appearing in American Pharmacy, developed by the American Pharmaceutical Association. Objectives: After completing this article on new methods of treating asthma, the pharmacist should be able to: 1. Identify the advantages and disadvantages of the aerosol r'ou:ie of corticosteroid administration as compared with the oral and parenteral rputes in the treatment of

Pathophysiology Airway hyperresponsiveness to various stimuli characterizes asthma. 1-3 It can occur after exposure to allergenic factors, such as animal dander; airborne pollen, dust, and mold; or I).onallergenic factors such as chemical sensitizers, exercise, and inhalation of cold air. Exposure to these facAMERICAN PHARMACY

December 1991/904

Vol NS31, No. 12

mucous plugs, exudates of inflammatory cells, and desquamated airway epithelial cells? Asthma has two distinct phases. The early phase of asthma is characterized by bronchospasm whereas the late phase of asthma is characterized by airway inflammation, edema, increased mucous secretions, and the presence of inflammatory cellular debris in the airways.

Therapy Anti-inflammatory Agents Corticosteroids

The clinical use of corticosteroids in the treatment of asthma has changed dramatically over the past few years. Inhaled corticosteroids are being used earlier and more widely than systemic corticosteroids ever were. H- 10 Some clinicians have proposed using higher doses of inhaled corticosteroid, and some investigators are studying the use of intramuscular sustained-action corticosteroids in ambulatory patients. Corticosteroids reduce airway inflammation and desensitize the airways to allergens and inhaled irritants. In addition, these drugs appear to potentiate the response to betaadrenergic agonists. Because corticosteroids act indirectly by causing the production of end-effector proteins, a time delay occurs after administration of the corticosteroid and the clinically apparent steroid effect. The full physiologic effect may not occur for several weeks? Inhaled corticosteroids are used as prophylactic agents in the management of ambulatory patients with asthma. The first aerosolized corticosteroid, beclomethasone dipropionate (Beclovent-Allen & Hanburys; Vanceril-Schering) was introduced in the United States in 1972. Other available aerosolized products include flunisolide (Aero Bid-Forest) and triamcinolone acetonide (Azmacort-Rorer). Although some clinicians have suggested that aerosolized corticosteroids should be used in place of oral theophylline,S most clinicians use them in the early management of asthma in combination with beta-adrenergic agonists or theophylline, or bothY Corticosteroids in the longterm will help reduce bronchial hyperreactions, whereas theophylline does not. Aerosolized corticosteroids are preferred over systemic corticosteroids for the chronic prophylaxis of asthma because they have fewer side effects. Commonly used doses are not associated with adrenal suppression, growth suppression, osteoporosis, posterior subcapsular cataracts, respiratory infection, weight gain, hypertension, and hyperglycemia seen with the systemic agents . 12 However, aerosolized corticosteroids have some side effects, such as oral candidiasis. Also known as thrush, oral candidiasis VoL NS31, No. 12 December 19911905

occurs in one-third of patients using aerosolized corticosteroids,13 and appears to be associated with higher or more frequent doses of the drug. Drug depOSited on the oral mucosa changes the normal oropharyngeal microbial flora and allows Candida albicans, a yeast, to flourish. Oral candidiasis is characterized by painless creamy white curd-like patches in the mouth. The incidence of oral candidiasis can be minimized by haVing patients rinse their mouths or gargle with water after each dose of inhaled drug to remove the drug from the oral mucosa. Other techniques to minimize the amount of drug deposited in the mouth include tilting the head back when inhaling the drug , and using spacer devices. 14 Spacer devices are holding-chambers that attach to metered-dose inhalers. The device selectively removes large aerosolized medication particles that normally deposit in the mouth and throat while permitting the smaller particles to pass through the valve to the lung. One metered-dose inhaler, triamcinolone acetonide (Azmacort-Rorer), is marketed with its own spacer device. Another side effect of aerosolized corticosteroids is dysphonia, which affects up to one-half of patients . 1~ Deposition of the corticosteroid on the vocal cords appears to cause bilateral adductor muscle paresis from local steroid myopathy,16 thereby resulting in hoarseness. Oral candidiasis and dysphonia improve with time or after temporarily lowering the drug dose . Few patients require discontinuation of the drug because of these effects. New dosage regimens and schedules for inhaled corticosteroids are being studied. Many investigators have noted that high doses of aerosolized corticosteroids are associated with more optimal pulmonary function . 17 When beclomethasone was first introduced in the United States, the standard dosage was 2 puffs (100 ~g) 4 times daily. The standard dosage today is 4 puffs (200 ~g) twice daily, and the effectiveness of dosages up to 1200 ~g per day or more is being investigated.s Researchers are also studying the use of a Single large morning dose, which could increase patient compliance and decrease the risk of adrenal suppression. However, when such higher doses are used, the risk of side effects, including systemic side effects from absorbed drug, increases. Patient counseling is required for the optimal use of inhaled corticosteroids. Important points to review with the patient are the following: 1. Corticosteroid therapy is designed to prevent asthma attacks. The maximum benefit from the drug may not be apparent for several weeks. 2. The drug must be used prophylactically (it is not effective treatment of acute exacerbations). 3. Patients should not exceed the preSCribed dosage or discontinue the drug without consulting their physician. 4. The drug should be discarded according to the predetermined date. (By that time, enough will have been used so AMERICAN PHARMACY

that accurate doses cannot be guaranteed.) 5. When a bronchodilator is used together with the steroid, the bronchodilator should be administered 15 to 20 minutes before the steroid. 6. Changing from systemic to inhaled steroid therapy may unmask other atopic diseases (eczema, rhinitis, arthralgia, and nasal polyps). Table 1 shows the optimal metered-dose inhaler administration technique for aerosolized corticosteroids and aerosolized beta-adrenergic agonists.

Crornolyn

Cromolyn, an anti-inflammatory agent, inhibits the late phase of the allergic reaction and decreases airway hyperresponsiveness. 19 Interest in the use of cromolyn for the treatment of asthma greatly increased after the drug became available in a metered-dose inhaler formulation. Although cromolyn is now often used as a first-line anti-inflammatory agent, many physicians perceive it to be an alternative agent. Reasons for cromolyn's lack of popularity include patient noncompliance due to its frequent dosing schedule

Table 1.

Drug Administration Technique for Metered-Dose Inhalers .1~ Assemble the device, remove the cap, and shake the inhaler thoroughly.

2. Bre'athe out fully and s,l owly until the end of a quiet breath. 3. Hold the.inhaler in - ~pright inverted position (i.e., nozzle-end do~n). 4. Place the mouthpiece betw~en the lips or hold 3 cm to , 4 cm f~om th~ mouth. . 5. Hold the head upright and activate the inhaler at the ~ st~rt of a slow and deep inspiration. Breathe in a full breath. , .6. Held the breath for 10 seconds, or if less, as long as possible to give.tne drug particles time to disperse through the "airways and settle onto the respiratory mucosa. 7 .... Exhale slowly. .

Step 1

Step 2

8. Wait between doses (intervcrf ~:lepends on the drug , .~ beingadQ1inistered). 9. CI~an the plastic holder t~oroughly and frequently.

, When in~aling corti~osteroids,· als~: 1. Hold the moutiapiece 3 cm to 4 cm in ffont of a widely open mouth. This technique increases the distance fr.om the inhaler .and the back of the mouth and < reduces the amount of drug sprayed on- oropharyn" geal tissues,. thereby decreasing the risk for or~1 candidiasis. 18 "2. Slightly hyperextend the neck (tilt the head back) . 3. Rinse mouth with water or gargle after the last puff of . ' ea'ch dose. ' ,

Step3! 4

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Illustrations courtesy of Ventolin, Allen & HBnburys

, AMERICAN PHARMACY

December 1991/906

VoL NS31, No. 12

Table 2.

Physiologic Effects of Alpha- and Beta-Adrenergic Receptors Receptor

Target

Effect

Alpha

Blood vessels

Vasoconstriction

Alpha

Airways

Bronchoconstriction

Alpha

Pupillary dilator muscle

Mydriasis

Alpha

Urinary sphincter

Beta,

Heart

Beta 2

Airways

Urinary retention Increased heart rate, positive inotropic action Bronchodilation, decreased mediator release, increased ciliary activity, increased surfactant, antiedema effect

Beta 2

Blood vessels

Beta 2

Uterus Skeletal muscle Metabolic

Beta 2 Beta 2

Vasodilation Relaxation Tremor Increased levels of glucose, insulin, lactate, and free fatty acids; decreased potassi u m levels

Adapted from Reference 21.

drug administration. Other n~w treatment methods being developed include once-daily oral dosage forms and twice-daily aerosol formulations. In addition, investigators are studying drugs or delivery systems that increase the treatment's duration of action, and drugs with a high affinity for the lungs. However, until these new beta-adrenergic agonists are available, drug selection is based on the drug's receptor activity, the patient's tolerance for the drug's side effects, the drug's duration of action, and its dosage formulation. Theophylline

(four times per day) and the need for several weeks of therapy before benefits become apparent. 20

Bronchodilating Agents Beta-Adrenergic Agonists

Beta-adrenergic agonists have been used as bronchodilators in asthma treatment for centuries. These drugs improve airflow by relaxing bronchial smooth muscle. The adrenergic agonists specific to beta 2 receptors also decrease the release of mast cell mediators and improve lung function by increasing mucociliary clearance and surfactant (Table 2). Initially, investigators strove to develop beta-adrenergic agonists that had almost exclusive beta 2-agonist receptor activity to decrease the risk for side effects from alpha- and betal-adrenergic receptor activity (Table 2). Unfortunately, increasing a drug's selectivity for beta2 receptors does not eliminate the risk for side effects. The dose-limiting side effect of drugs with beta I-receptor activity is tachycardia, whereas the dose-limiting side effect of beta2-selective drugs is tremor. Other frequent side effects of beta 2-selective drugs include palpitations and nervousness. The availability of beta2-selective adrenergic agonists (listed in Table 3) has stimulated the study of alternative dosage regimens and drug-delivery methods. New treatment concepts include limiting the use of subcutaneous beta-adrenergic agonists in the management of acute asthma, increasing the doses of aerosolized drug in the management of acute asthma, raising the dose of drug used in metered-dose inhalers for acute and chronic asthma, and using auxiliary devices with metered-dose inhalers in place of aerosolized Vol. NS31, No. 12 December 1991/907

The role of theophylline and related methylxanthines such as aminophylline in the management of asthma has been debated for the past few years. 23-28 However, the comparative safety, efficacy, and cost of therapy of these agents have led some clinicians to recommend that the methylxanthines should be considered third- or fourth-line add-on agents whereas others believe that they should remain first-line agents. Theophylline, a drug with a narrow therapeutic index and considerable variability in metabolism, can have significant side effects and drug interactions. In a study of 116 consecutive cases of theophylline toxicity, factors that contributed to toxicity included patient error (290/0), physician or pharmacy error (21%), and impaired metabolism (210/0).29 A meta-analysis of 13 studies found no difference in outcome between aminophylline therapy and beta-adrenergic agonist therapy in the treatment of acute exacerbations of asthma; however, side effects occurred more frequently with aminophylline therapy.3o Additionally, the use of methylxanthines in combination with sympathomimetic agents may be associated with a small but potentially significant risk of cardiotoxicity.31-32 Methylxanthine therapy has other drawbacks as well. It does not reduce the inflammation associated with the pathogenesis of asthma as effectively as other agents and, because it requires serum theophylline monitoring, it costs more than therapy with inhaled corticosteroids. Because of these drawbacks, some clinicians believe that theophylline and related methylxanthines should be used only as add-on agents for patients who are receiving the maximum doses of inhaled corticosteroids and sympathomimetics without optimal benefit. Other clinicians, however, argue that although the effect of long-term treatment with theophylline on AMERICAN PHARMACY

Table 3.

Beta-Adrenergic Agonist Bronchodilators

Class

Trade Name

R~ot~r ActivjW Betaz Alpha Beta,

Maximum Bronchodilation (minutes)

Catechola~,ines

Epinephrine IsoproterenoJ Isoetharine

Numerous Medihaler-Iso (Riker) Bronkometer (Winthrop) Tornalate (Winthrop)

Bitolterol

++ +

++ ++ +

++ ++ ++

+/-

., 5

,6

./

5

2 2-3

+++

30-60

5-8

+ +/-

++ +++

30-60 60-120

3-5 4-6

Proventil (Schering) VentoHn (Allen & Hanburys)

+/-

+++

60-120

4-6

Maxair (Riker),

+/-

+++

30-60

5

Resorcinols Metaproterenol

Terbutaline '

>

Alupent (.Boehringer Ingelheim) Metaprel (Sandoz) Brethaire (elBA-Geigy)

Saligenin Albuterol

Pyridine Pirbuterol

Adapted from Reference 22.

bronchial hyperresponsiveness is uncertain, theophylline has some anti-inflammatory effect,33 and therefore should still be used as a first-line agent in the management of asthma. The development of methylxanthines with fewer side effects and better bronchodilating properties will add complexity to this issue. Anticholinergics

Ipratropium bromide (Atrovent-Boehringer Ingelheim) is a topically active quaternary amine derivative of atropine. Although ipratropium bromide is an effective first-line agent in the management of chronic obstructive pulmonary disease, betaz-adrenergic agonists appear to be better individual bronchodilators in asthma than ipratropium bromide. 34, 35 Whether ipratropium bromide is a beneficial addition to combination regimens is unclear. The disadvantages of inhaled ipratropium bromide include a .slower onset of action and lower peak bronchodilation than that achieved with beta-adrenergic agents. 36 Despite these drawbacks, some asthma patients do benefit from ipratropium therapy. It may be a useful adjunct for patients whose disease was not adequately controlled by beta-adrenergic bronchodilators, for those with exerciseinduced asthma in whom beta-adrenergic agonists or cromolyn has not prevented bronchoconstriction, and for those whose asthma is exacerbated by beta-adrenergic blockade. 37 AMERICAN PHARMACY

Miscellaneous Agents Methotrexate

Methotrexate became recognized as a possible treatment for asthma after a psoriatic steroid-dependent asthmatic was able to discontinue prednisone while taking ·methotrexate for the treatment of the psoriasis. 38 Although methotrexate, a folic acid antagonist, has anti-inflammatory and immunosuppressant activity in vivo,39 its mechanism of action in asthma treatment is unclear. Mullarkey et al. evaluated the short-term 40 and longterm41 effects of methotrexate in the treatment of patients with steroid-dependent asthma. Most patients were able to decrease the prednisone dose and some were able to discontinue prednisone. The initial methotrexate dose is usually 7.5 mg orally or intramuscularly per week. The dose may be titrated upward as tolerated, with weekly doses ranging from 15 mg to 50 mg. The total weekly dose is divided into three equal doses and given at 12-hour intervals. The optimal dose and duration of methotrexate therapy in asthma are undetermined. Also, whether asthma will flare if methotrexate therapy is tapered and discontinued is not known. Because of the potential for serious side effects and drug interactions, methotrexate therapy should be reserved for patients with severe steroid-dependent asthma unresponsive to conventional therapy. December 1991/908

VoL NS31, No. 12

Table 4.

Antihistamines

Antihistamines traditionally have not been used in the management of asthma. Although some patients with asthma do have higher than normal levels of histamine,42 the firstgeneration antihistamines have only moderate bronchodilating action,43 have relatively low antihistamine potency, lack specificity for histamine} receptors, cause central nervous system depression, and achieve low cellular concentrations in the lung.44 Additionally, the anticholinergic effects of firstgeneration antihistamines may dry and thicken pulmonary secretions, thereby worsening airway obstruction. The availability of the newer, highly potent, histamine} receptor selective antihistamines, such as terfenadine (Seldane-Merrell Dow) and astemizole (Hismanal- ]anssen), has stimulated a reevaluation of the role of these drugs in asthma treatment. Antihistamines increase the threshold for bronchoconstriction after histamine challenge,45 raise the threshold of reaction to other allergens,46 and appear to prevent rna t-cell activation, a proposed mechanism for exercise-induced asthma.47 The new er histamine} receptor selective antihistamines should not be considered specific therapy for asthma. Howantihistamines should not be withheld from ever, the patient with asthma who also have concomitant allergic disea e, uch as urticaria, rhinitis , and dermatoses. The American Academy of Allergy and Immunology recently recommended that antihistamine labeling should be changed to indicate that these agents are not contraindicated in patients with asthma.48 In the future, antihistamines may be approved agents for the treatment and prophylaxis of asthma in patients whose disease has an allergic component.

Technique for Using Peak Expiratory Flow Meters

1. Make sure the device is at the zero end of the scale. 2. Stand up. 3. Take a deep breath. 4. Close the lips around the mouthpiece. 5. Blowout as hard and as fast as possible.* 6. Record the peak expiratory flow rate. 7. Repeat the procedure two more times. 8. Record the highest of the three values in a diary. 9. Notify physician of changes according to a predetermined plan. * Do not cough into the device or block the device with the tongue . .

Peak Expiratory Flo\N Meters Measurement of peak expiratory flow rates (PEFR) has become an accepted self-monitoring tool for patients with asthma due to the availability of reliable, relatively inexpensive peak expiratory flow meters. The PEFR is the rate at which air is blown out of the lungs; low rates indicate the degree to which the airways are obstructed. Patients can use the peak flow meter at home to monitor the day-to-day response to therapy, to detect early changes in airway obstruction before symptoms are apparent, to determine when emergency care is needed, and to identify specific triggers of asthma. Home monitoring of PEFR with peak flow meters is most useful for patients w ho have moderateto-severe asthma, for patients who develop severe attacks with little warning, and for patients w ith significant diurnal variation. Although PEFR self-monitoring provides a useful objective measure of the day-to-day course of disease and the patient's response to therapy, it should not replace more VoL NS31, No. 12 December 1991/909

Illustration courtesy of Assess Peak Flow Meter, HEALTHSCAN Products Inc.

AMERICANPHARMACY

sophisticated office or hospital-based diagnostic procedures. Patients need to be taught how to use the device, how to record the information, and how to respond to changes in the flow rate (Table 4). Patients should take a full inspiration, followed by a maximum expiration, with their lips sealed around the mouthpiece. The procedure is repeated two more times and the best PEFR of the three is recorded. Patients are typically advised to measure the PEFR on awakening and at bedtime. The physician can use the recorded PEFR measurements to assess the severity of disease and as a guide for adjusting drug therapy. The patient and physician should have a predetermined plan of action for dealing with changes in the PEFR. For example, the patient may be instructed to take an additional dose of bronchodilator and notify the physician if the PEFR is less than 50010 of the patient's baseline despite .usual treatment.

Conclusion The therapeutic approach to asthma has undergone many changes recently, primarily because of the greater role assigned to airway inflammation in the pathogenesis of asthma. Trends include the increased use of inhaled corticosteroids; a reassessment of the role of theophylline; exploration of the use of agents such as cromolyn, ipratropium bromide, methotrexate, and antihistamines; and the use of patient-monitored PEFRs.

References 1. ATS. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis. 1987;136:225-44. 2. Holgate ST, Beasley R, Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci. 1987;73:561-72. 3. Boushey HA, Holtzman J, Sheller JR, et al. Bronchial hyperreactivity: state of the art. Am Rev Respir Dis. 1980;1 21:389-413. 4. Hargreave FE, Dolovich J, O'Bryne PM, et al. The origin of airway hyperresponsiveness. J Allergy Clin Immunol. 1986;78:825-32. 5. Nadel SA. Inflammation and asthma . J Allergy Clin Immunol. 1984;73:651-3. 6. Kaliner M . Hypotheses on the contribution of late-phase allergic responses to the understanding and treatment of allergic diseases. J Allergy Clin Immunol. 1984;73:311-5. 7. Morris HG. Mechanisms of glucocorticoid action in pulmonary disease. Chest. 1985;88(suppl): 1335--42S. 8. Clark TJH. Inhaled corticosteroid therapy: a substitute for theophylline as well as prednisolone? J Allergy Clin Immunol. 1985;76:330-4. 9. Reed CEo Aerosol steroids as primary treatment of mild asthma. N Engl J Med. 1991;325:425-6. 10. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a B2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med. 1991;325:388-92. 11. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. Am Rev Respir Dis. 1987;136:1174-8.

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12. Koning P. Inhaled corticosteroids--their present and future role in the management of asthma. J Allergy Clin Immunol. 1988;82:297-306. 13. Vogt FC. The incidence of oral candidiasis with use of inhaled corticosteroids. Ann Allergy. 1979;43:205-10. 14. Salzman GA, Pyszczynski DR. Oropharyngeal candidiasis in patients treated with beclomethasone dipropionate delivered by metered-dose inhaler alone and with Aerochamber. J Allergy Clin Immunol. 1988;81 :424-8. 15. Toogood JH, Jennings B, Greenway RW, et al. Candidiasis and dysph«;,nia complicating beclomethasone treatment of asthma. J Allergy Clm Immunol. 1980;65:145-53. 16. Williams AJ, Maghat MS, Stableforth DE, et al. Dysphonia caused by inhaled steroids: recognition of a characteristic laryngeal abnormality. Thorax. 1983;38:813-21. 17. Salmeron S, Guerin J-C, Godard P, et al. High doses of inhaled corticosteroids in unstable chronic asthma . Am Rev Respir Dis. 1989;140:167-71. 18. Reed CE. Aerosol glucocorticoid treatment of asthma. Am Rev Respir Dis. 1990;141 (suppl):S82~. 19. Griffin MP, MacDonald N, McFadden ER. Short- and long-term effects of cromolyn sodium on the airway reactivity of asthmatics. J Allergy Clin Immunol. 1983;71:331-8. 20. Reed CEo New therapeutic approaches in asthma. J Allergy Clin Immunol. 1986;77:537-43. 21. Svensson LA. Sympathomimetic bronchodilators: increased selectivity with lung-specific prod rugs. Pharm Res. 1985;4:15EHl2. 22. AMA Drug Evaluations, 5th ed. Chicago: American Medical Association, 1983. 23. Newhouse MT. Is theophylline obsolete? Chest. 1990;98:1-2. 24. Jenne JW. Theophylline is no more obsolete than "two puffs qid" of current beta 2 agonists. Chest. 1990;98:3-4. 25. Niewoehner DE. Theophylline therapy. A continuing dilemma. Chest. 1990;98:5. 26. Bukowskyj M, Nakatsu K, Munt PW. Theophylline reassessed . Ann Intern Med. 1984;101:63-73. 27. Lam A. Newhouse MT. Management of asthma and chronic airflow limitation. Are methylxanthines obsolete? Chest. 1990;98:44-52. 28. Rogers RM, Owens GR, Pennock BE . The pendulum swings again toward a rational use of theophylline. Chest. 1985;87:280-2. 29. Sessler CN. Theophylline toxicity: clinical features of 116 consecutive cases. Am J Med. 1990;88:567-76. 30. Littenberg B. Aminophylline treatment in severe, acute asthma. JAMA. 1988;259: 167~4. 31. Nicklas RA, Balazs T. Adverse effects of theophylline-beta agonist interactions. J Allergy Clin Immunol. 1986;78:806-11 . 32. Conradson T-B, Eklundh G, Olofsson B, et al. Cardiac arrhythmias in patients with mild-to-moderate obstructive lung disease . Chest. 1985;88:537-42. 33. Pauwels R, Van Renterghem D, Van Der Straeten M, et al. The effect of theophylline and enprofylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol. 1985;76:583-90. 34. Gross NJ, Skorodin MS. Anticholinergic, anti muscarinic bronchodilators. Am Rev Respir Dis. 1984;129:856-70. 35. Gross NJ. Ipratropium bromide. N EnglJ Med. 1988;319:486-94. 36. Ruffin RE, Fitzgerald JK, Rebuck AS. A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J Allergy Clin Immunol. 1977;59:136-41 . 37. Johns KA, Busse WW. Anticholinergic drugs: what role in asthma? J Respir Dis. 1989;10:35-50. 38. Mullarkey NF, Webb DR, Pardee NE. Methotrexate in the treatment of steroid-dependent asthma. Ann Allergy. 1986;56:347-9. 39. Stevens JE, Willoughby DA. The anti-inflammatory effect of some immunosuppressive agents. J Pathol. 1969;97:367-73. 40. Mullarkey MF, Blumenstein BA, Andrade WP, et al. Methotrexate in the treatment of corticosteroid-dependent asthma. N Engl J Med. 1988;318:603-7. 41. Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroid-dependent asthma. Ann Intern Med. 1990;112:577~1 .

42. Casale TB, Wood D, Richerson HB, et al. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. J Clin Invest. 1987;79:1197-203. December 1991/910

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43. Popa VT. Bronchodilating activity of an H, blocker, chlorpheniramine. J Allergy Clin Immunol. 1977;59:54-63. 44. Chai H. Antihistamines and asthma. Chest. 1980;78:420-2. 45. Rafferty P, Holgate ST. Terfenadine (Seldane) is a potent and selective hi;rtamine Hj receptor antagonist in asthmatic airways. Am Rev Respir DIs. 1987;135:181-4. 46. Chan TB, Shelton DM, Eiser NM. Effect of an oral H,-Receptor antagonist, terfenadine, on antigen-induced asthma . Br J Dis Chest. 1986;80:375-84. 47. McFadden ER, Lenner KAM, Strohl KP. Postexertional airway rewarming and thermally induced asthma: new insights into pathophysiology and possible pathogenesis. J Clin Invest. 1986;78:18-25. 48. Sly RM, Kemp JP. The use of antihistamines in patients with asthma. J Allergy Clin Immunol. 1988;82:481-2.

Self-Assessment Questions

Instructions: For each question blacken the letter corresponding to the answer you select as being the correct one. Please review

all your answers to be sure you have blackened the proper spaces. There is only one correct answer. 1. Asthma is characterized by: a. Narrowing of the airways b. Airway obstruction c. Airway hyperresponsiveness d. All of the above e. None of the ahove. 2. Which of the following factors has been recognized as an increasingly important pathogenic factor in asthma? a. Bronchial smooth muscle constriction b. Airway inflammation e. Mucosal gland hypertrophy d. Both a and c e. None of the ahove 3. Which of the following statements regarding corticosteroid therapy in the treatment of asthma is TRUE? a. Corticosteroids induce the accumulation of histamine on mast cells. h. Systemic corticosteroids are safer than inhaled cortice}steroids. e. Corticosteroids act by reducing airway inflammation. d. Corticosteroids are used only after theophylline therapy has failed. e. Peak physiologic effects from steroids occur 15 minutes after the dose. 4. Which of the following agents was the first aerosolized corticosteroid marketed in the United States? a. Flunisolide b. Triamcinolone c. Beclomethasone d. Budesonide e. Methylprednisolone 5. Which of the following side effects is commonly reported with usual doses of inhaled corticosteroids? a. Adrenal suppression b. Osteoporosis e. Weight gain d. Hyperglycemia e. Oral candidiasis 6. Which of the following statements regarding oral candidiasis is TRUE? a. Oral candidiasis causes painful lesions. b. Oral candidiasis appears as crusty yellow lesions. c. Patients taking frequent doses of corticosteroids are at a greater risk for developing oral candidiasis. d . Oral candidiasis develops from bilateral adductor vocal cord paralysis. e. Oral candidiasis improves with continued use of high doses of inhaled corticosteroids. Vol NS31, No. 12 December 1991/ 911

7.

To minimize the incidence of oral candidiasis and dysphonia from inhaled corticosteroids, the patient should be advised to: a. Rinse the mouth with water after each dose. b. Slightly hyperextend the neck when inhaling the drug. e. Discharge the dose into a closed mouth with the lips sealed around the mouthpiece. d . All of the above. e. Both a and b. 8. Which of the following sympathomimetic drugs is the most beta 2-selective drug marketed as a solution for inhalation? a. Epinephrine b. Isoetharine e. Albuterol d. Terbutaline e. Metaproterenol 9. The dose-limiting side effect of sympathomimetic drugs with betaj-adrenergic receptor activity is: a. Tremor b. Palpitations e. Nervousness d. Mydriasis e. Tachycardia. 10. The dose-limiting side effect of sympathomimetic drugs wtth beta 2-adrenergic receptor activity is: a. Tremor b. Palpitations c. Nervousness d. MydriaSiS e. Tachycardia. 11. Cromolyn is: a. A beta-adrenergic agonist b. An antihistamine derivative e. An anti-inflammatory agent d. Administered once daily e. A methylxanthine derivative. 12. Which of the following statements regarding methylxanthines is FALSE? a. Methylxanthines may cause dysphonia. h. Drug therapy is monitored with serum drug concentrations. e. Methylxanthines have a narrow therapeutic index. d. Many clinicians feel that the methylxanthines are thirdor fourth-line therapeutic agents. e. Methylxanthines have a less favorable side effect profile than sympathomimetics. 13. Ipratropium bromide may be a useful adjunct for: a. Patients in whom beta-adrenergic bronchodilators have not sufficiently controlled the disease. b. Patients with exercise-induced asthma in whom betaadrenergic agonists or cromolyn has not prevented bronchoconstriction. c. Patients whose asthma is exacerbated by beta-adrenergic blockade. d. All of the above. e. None of the above. 14. A typical methotrexate dosage regimen for the treatment of asthma is: a. 15 mg/day intravenously b. 75 mg/week intramuscularly c. 5 mg orally, 3 times per week d. 2.5 mg orally/ intramuscularly every 12 hours, for 3 doses per week e. 2.5 mg/day orally. 15. Which one of the follOWing drugs is a histamine j receptor selective antihistamine? a. Diphenhydramine b. Meclizine c. Astemizole d. Chlorpheniramine e. Dimenhydrinate

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AMERICAN PHARMACY