Pamela A.Simon, Pharm.D.
Spring 1998

Pediatric Asthma 

  1. Introduction
  2. Instructions & Feedbacks
    Define the Situation:
    1.1
    1.2
    1.3

    Identify the Problems:
    2.1

    State the Goals:
    2.2

    Generate Ideas:
    3.1
    3.2
    3.3
    3.4
    3.5

    Select the Best Ideas:
    3.6

This module is composed in a modified Guided Design format. Whereas classic Guided Design depends on the student to learn all of the material before beginning the case study lesson, this module includes some teaching along with the feedback portions of the case study. Still, it would be best for you to read the assigned and suggested readings BEFORE attempting to tackle this case study. When you work on this case study, try to answer each Instruction question completely before turning the page to obtain the Feedback. Feedback related specifically to the case study is italicized; material in standard font is teaching material included to enhance your learning of this topic.

As you progress, you may find that you have questions or do not understand some of the material. Please do not hesitate to contact me at (312) 996-0887 for assistance.

Learning Objectives

At the end of this module, the student will be able to:

1. define asthma;

2. name the four characteristics of the asthma of a specific patient which help to define the applicable treatment options;

3. categorize a given asthmatic patient as having intermittent, chronic, or indeterminate asthma;

4. list the treatment goals for an asthmatic child;

5. name the category of drugs that all asthmatic patients must have available to treat acute asthma symptoms and outline the optimal route/method of administration for an individual patient;

6. choose the best preventive regimen for a given patient with chronic asthma; and

7. recommend a treatment plan for an acute exacerbation of asthma.

Required Reading

1. Murphy CM, Coonce SL, Simon PA. Treatment of asthma in children. Clin Pharm 1991;10:685-703. (attached)

**Admittedly, this article is dated in terms of pharmacotherapeutics. However, the concepts presented in terms of the nuances of caring for children with asthma (i.e., drug administration and monitoring) are still valid and applicable to the provision of pharmaceutical care for these patients.

Strongly Suggested Reading

1. Self TH, Kelly HW. Asthma. In: Young LY, Koda-Kimble MA eds. Applied Therapeutics: The Clinical Use of Drugs, 6th ed. Vancouver, WA; Applied Therapeutics, Inc.:1995.

2. National Institutes of Health. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education Program Expert Panel Report 2, 1997. [This document can be downloaded from the National Heart, Lung and Blood Institute’s home page at http://www.nhlbi.nih.gov]


Introduction

A.C. is a 4 y/o WM with Hx of asthma who presents to Pediatric Pulmonary Clinic for evaluation. This is the first time you are seeing this patient in your clinic. A.C.'s mom states that he has had bronchitis and asthma since age 6 months.

Instruction 1.1 - DEFINE THE SITUATION

What types of information ABOUT ASTHMA, IN GENERAL, would be useful in evaluating a patient like A.C.?

 

Feedback 1.1 - Define the Situation

Pathophysiology

Asthma is an inflammatory disease that causes airway obstruction and increased airway responsiveness to a variety of stimuli. This obstruction is reversible (although not completely so in some patients) either spontaneously or with drug therapy.

Asthma manifests as a biphasic response: the early asthmatic response (EAR) and the late asthmatic response (LAR). In any given patient one or the other of these tissue responses may predominate, or in many patients both the early and late asthmatic responses occur (called a dual asthmatic response).

The EAR is characterized by immediate symptoms beginning within 10 minutes of exposure to a precipitant, peaking between 10 to 30 minutes, and resolving between 1 to 3 hours. The EAR is caused by tissue reaction to mediators released from mast cells, basophils, and other sensitized cells in the airways through processes mediated by IgE. The result is airway SMOOTH MUSCLE CONSTRICTION AND EDEMA. The EAR is reversed and/or prevented by b-agonists, theophylline, cromolyn sodium/nedocromil, leukotriene modifiers, and (indirectly) corticosteroids.

The LAR is characterized by delayed symptoms beginning between 3 to 4 hours after exposure to a precipitant, peaking in 4 to 8 hours, and resolving within approximately 24 hours. The LAR is caused by the cellular phase of the INFLAMMATORY REACTION in the airways (i.e., infiltration of a variety of inflammatory cells such as eosinophils, neutrophils, basophils, etc.). The LAR commonly contributes to chronic asthmatic symptoms and more severe presentations. The LAR is reversed and/or prevented by cromolyn sodium/nedocromil, corticosteroids, leukotriene modifiers, and possibly theophylline (controversial).

Definitions

1. Asthma - a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy

2. Intermittent asthma - presence of symptoms less than or equal to five days per month and extended symptom-free periods

3. Chronic asthma - presence of symptoms greater than 5 days per month for greater than three months and greater than 50% of the days in any one month

4. Indeterminate asthma - presence of symptoms for greater than or equal to five days per month for less than three months or less than 50% of the days in any one month and extended symptom-free periods

5. Steroid-dependent asthma - corticosteroid therapy required for control of symptoms

6. Status asthmaticus - an acute, severe exacerbation of asthma which is not relieved by usual treatment


Instruction 1.2 - DEFINE THE SITUATION

What types of SPECIFIC information ABOUT A.C. would be useful in evaluating this patient and in determining treatment options?

 

Feedback 1.2 - Define the Situation

1. Characterize the symptoms of this individual patient

Asthma may manifest as any or all of the following symptoms or signs.

(*These symptoms are the most common and are present in most asthmatic patients.)

Recall that asthma is also reversible. A history that symptoms reverse, either with time or medications, is important.

A.C.'s mother states that he usually coughs violently until he vomits and is very SOB. Symptoms usually resolve with rest. He is currently being treated with Metaproterenol (Alupent®) syrup 1 tsp. p.o. Q6H PRN [mom states that she gives this 2-3 times a day and it helps him] and TheoDur® Sprinkles 100 mg p.o. Q12H [at 8AM and 8PM].

2. Define the precipitating factors for this individual patient

Asthma can be precipitated by any of the following factors.

*Inhaled irritants (e.g., cigarette smoke, air pollution)

*Exercise (In ~10% of asthmatics exercise is their ONLY precipitating factor. These patients are often termed exercise-induced asthmatics [EIA].)

*Cold air

*Infections (Viral upper respiratory infections are the #1 precipitant in children. Sinusitis is also intimately related to asthmatic exacerbation in some patients. Patients may have been misdiagnosed as having pneumonia or bronchitis in the past, and therefore present with a history of recurrent lower respiratory infections.)

Emotional stress, laughing, crying

Allergens (Patients presenting with this precipitant often suffer with allergic rhinitis or conjunctivitis and/or eczema along with their asthma.)

pollen    
  -trees (spring) Generally pollinate about same time each year
  -grasses (early- to mid-summer)
  -weeds (late summer to fall)
mold spores    
  -outdoor (early spring to late fall [counts rise and fall depending on regional flora on which the molds grow, e.g., grains, orchards, forests]  
  -indoor (damp areas,e.g., basements, bathrooms) contribute to perennial symptoms
house dust mite  
animal/insect dander  

 

 

Drugs -ASA, NSAIDs (except, possibly, nonacetylated salicylates)

A.C.'s mother states that he gets asthma "attacks" every time he gets a cold. Mom also notes that he coughs when he laughs or cries, when someone smokes around him, or when he runs around a lot. He seems much worse in the spring and the fall as well. Review of A.C.'s social history indicates that he lives at home with his mom, dad, and 2 older sibs (6 y/o M and 10 y/o F); dad smokes all over the house.

3. Characterize the chronicity of symptoms [Categorizing the patient as having intermittent or chronic asthma will be important in determining proper drug therapy. The following are questions to ask the patient/parent.]

(It is sometimes hard to get an accurate history due to: (1) constraints of patient/parent memory, or (2) inability of the patient/parent to recognize symptoms as abnormal because they have been so longstanding, i.e. the family now considers incessant coughing to be "normal" for this particular child.)

A.C.'s mom states that he stops himself from play about 2-3 times/week due to coughing and SOB; he sits down and rests, then feels better. He wakes from his sleep due to coughing about 1-2 times/week. He has had 10-12 ER visits in his life. Usually, treatment in the ER is either "a shot" or "a breathing treatment" and he gets better and goes home. The longest that A.C. has gone without any symptoms of asthma is 1 week.

4. Assess severity

Document:

 

A.C. has been hospitalized twice in his life. Both times, the "breathing treatments" did not make him much better so he stayed in the hospital for about 5 days. He has never been in the ICU or intubated. Mom thinks that he has gotten prednisone 1 or 2 times in the past which helped.


Instruction 1.3 - DEFINE THE SITUATION

In addition to the history you have obtained from A.C. and his mother, what diagnostic testing is usually done in a patient of this kind?

 

Feedback 1.3 - Define the Situation

1. Physical examination

 

2. Spirometry

 

A. FVC (forced vital capacity): normal = 80% predicted for that individual

B. FEV1 (forced expiratory volume in one second): normal = 80% predicted

C. FEV1/FVC: normal = 75%

D. FEF25-75 (forced expiratory flow rate from 25% to 75% of vital capacity): should see a 25% or greater increase in FEF25-75 to at least 75% of predicted with a normal FVC after bronchodilator administration (a test of reversibility)

E. PEFR (peak expiratory flow rate): An easy way to monitor objective information for a given patient at home. Hand-held peak flow meters are available in almost any pharmacy and give good intrapatient information, i.e. good for comparing the patient to him/herself over time. Not good for comparing one patient to another because of large interpatient variability. Any patient with moderate to severe asthma and stoic patients in whom severity of airway obstruction does not correlate well with reported symptoms should be given a peak flow meter and should monitor PEFR regularly.)

3. Chest radiograph - Because asthma is, by definition, a completely reversible disease, the physician will want to document a normal chest X-ray.

4. PPD - if TB is common, this may be done routinely; if not, this may be done only if patient does not respond to initial therapy

5. Allergen sensitivity testing (This is done only if history indicates it is necessary. Must correlate skin test results with patient history.)

A. Skin testing: Conducted by introducing small quantities of allergen into the skin by pricking the skin in the immediate presence of diluted allergen extract. This is the preferred objective test because of its high sensitivity, relatively low cost, and rapid availability of results (i.e., positive skin test gives a wheal and flare response in 15-30 minutes.)

B. Radioallergosorbent test (RAST): A serum test for specific IgE antibodies. Because of its expense and the delay in obtaining results, it is generally reserved for patients with dermatographism, those patients who are unable to discontinue antihistamines (skin testing cannot be performed in patients on antihistamines; depending on the half-life of the drug, must be discontinued for 1 to 40 days prior to testing), or patients with extensive eczema or other skin lesions.

[NOTE: Patients who do not respond to antiasthmatic therapy often require additional diagnostic testing to investigate other diagnoses which may cause symptoms that mimic asthma, like congenital malformations of the respiratory, cardiovascular, or gastrointestinal systems; foreign body; immunodeficiency syndromes; cystic fibrosis; gastroesophageal reflux disease; or tuberculosis.]

 

On physical exam, A.C. is coughing frequently with inspiratory and expiratory wheezing in all lung fields and a prolonged expiratory phase. Intercostal retractions are present. BP = 98/60, HR = 100/min, RR = 28/min, and T = 97°F ax. Wt = 40 lbs, Ht = 40 in.

A.C.'s spirometry was abnormal at baseline: FEV1 = 55% predicted, FVC = 80% predicted. After bronchodilator, spirometry was improved, but not to normal values: FEV1 = 70% predicted, FVC = 80% predicted, FEF25-75 increased by 17%. Physical examination after bronchodilator reveals less coughing, but incomplete resolution of symptoms.

Skin testing revealed sensitivities to tree pollen, ragweed, cockroach dander, and cat dander. PPD is negative.

 


Instruction 2.1 - IDENTIFY THE PROBLEMS

List the medical problem(s) that need to be addressed in this case.

 

Feedback 2.1 - Identify the Problems

A.C.'s problem list includes:

1. Mild to moderate chronic asthma, currently with an acute exacerbation that is not completely bronchodilator responsive.

2. Probable subtherapeutic theophylline dosing [Current dose of 200 mg/day = 11 mg/kg/day. Appropriate starting dose for a 4 y/o is 22 mg/kg/day. NOTE: We can only say that it is probably subtherapeutic, because the recommended starting doses are based on population pharmacokinetic parameters. The only way to state that the dosing is, in fact, subtherapeutic is to measure the serum theophylline concentration.]


Instruction 2.2 - STATE THE GOALS

What are the treatment goals for A.C.?

 

Feedback 2.2 - State the Goals

The treatment goals for asthma are:

• interference with activities or sleep < once per week

• minimal need for PRN b2-agonist

• NO emergency visits

• NO drug side effects

 


Instruction 3.1 - GENERATE IDEAS

What NONPHARMACOLOGIC approaches to the treatment of the asthmatic patient are available?

 

Feedback 3.1 - Generate Ideas

Nonpharmacologic therapy:

• avoidance of airborne allergens (often difficult and impractical--restriction of activities is no longer necessary in the management of the asthmatic patient)

• avoidance of house dust mite (biggest source of exposure = bed/bedding because patient is exposed for 6 to 10 hours per night; launder pillows, pillowcases, blankets every month; plastic mattress cover; remove stuffed animals from bed)

• avoidance of animal dander (weigh the medical vs. the psychosocial issues for the patient; depending on the severity of the patient's asthma, can usually manage the patient's symptoms effectively without removing a family pet from the home environment)


Instruction 3.2 - GENERATE IDEAS

What category of drugs must every asthmatic have available for treatment of acute symptoms? What are the ideal characteristics of this group of drugs? What is the best route of administration?

 

Feedback 3.2 - Generate Ideas

All asthmatics must have a reliable method of administering inhaled b2-agonists for the treatment of acute asthma symptoms.

When choosing a specific agent, the ideal drug should be b2 specific, have an appropriate duration of action, and have appropriate dosage forms available for the individual patient's needs.

 

DRUG RECEPTORS STIMULATED DURATION OF ACTION [hrs]
  b2 b1 a  
Epinephrine +++ +++ +++ 1-2
Ephedrine ++ ++ +++ 3-5
Isoproterenol +++ +++ - 2-3
Isoetharine +++ ++ - 2-3
Bitolterol* +++ + - 4-6
Pirbuterol +++ + - 5
Metaproterenol +++ ++ - 3-5
Terbutaline +++ + - 4-6
Albuterol +++ + - 4-6
Salmeterol +++ + - 12

* A pro-drug; hydrolyzed in vivo to colterol.

 

b specificity

Limiting effects to stimulation of b2 receptors (not a or b1) will give the desired effect for the asthmatic patient and, to a certain extent, limit the unwanted side effects of this class of drugs.

Side effects/adverse reactions are the result of stimulation of adrenergic receptors other than the b2 receptors in the lung; injectable (SQ)>>PO>inhalation

• cardiac stimulation/tachycardia (result of b1 and b2 stimulation)

• muscle tremor (b2)

• nervousness, anxiety (CNS)

• tolerance

 

Methods of administering inhaled medication

1. Compressed air nebulizer

• easiest "technique" (just breath in and out), but least convenient (rather large device, requires AC power)

• generally necessary for children < 4 to 5 y/o

 

2. Metered-dose inhaler plus a spacing device

• a little more difficult to use than a nebulizer (requires that a child be able to breath in, hold breath, and blow out on command), but much more convenient

• usually appropriate for children 5 to 8 y/o

 

3. Metered-dose inhaler alone

• most difficult technique, but most convenient

• usually children > 8 y/o can be taught technique

 

Technique for use of a Metered-Dose Inhaler

1. Shake the canister well

2. Place the mouthpiece approximately 1 inch (two finger width) away from the mouth and open the mouth wide*

3. Exhale to the end of a normal breath

4. Actuate the canister at the beginning of a slow, deep inhalation (this is the critical step in metered-dose inhaler usage)

5. Hold the breath for at least 10 seconds

6. Exhale normally

7. Wait at least one minute before repeating

* Closing the lips gently around the canister is also acceptable and should be encouraged if the patient is unable to perform the open-mouth technique.

• Breath-activated Inhalers: AutohalerÔ [Maxair® (pirbuterol), budesonide] and E-Z-VÔ [albuterol, beclomethasone]. AutohalerÔ actuator is activated by an inspiratory flow rate of approximately 30 L/min (a velocity usually attainable even by patients with compromised lung function). In light of the considerable difficulty that most patients have with the proper usage of MDIs (particularly with the timing of the actuation with inspiration), these devices offer a simpler, and theoretically more effective, administration technique. Please refer to package instructions for proper administration technique. [Selected readings: (1) Fergusson RJ, Lenney J, McHardy GJR, Crompton GK. The use of a new breath-actuated inhaler by patients with severe airflow obstruction. Eur J Respir 1991;4:172-4. (2) Newman SP, Weisz AWB, Talaee N, Clarke SW. Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique. Thorax 1991;46:712-6.]

Salmeterol

Salmeterol is a selective b2-agonist with a long duration of action (up to 12 hours) and a slow onset of action when compared with other b-agonists like albuterol. It CANNOT, therefore, be used as a "rescue" medication for acute asthma symptoms (in fact, patients on salmeterol must have albuterol or another rapid acting b2-agonist available for immediate treatment). In single-dose and long-term studies (up to 12 months duration), salmeterol has been shown to produce significant bronchodilation for up to 12 hours. It has been shown to effectively prevent exercise-induced and nocturnal asthma.

The incidence of side effects from salmeterol is relatively low when the recommended dosage of 42 mcg BID is administered. Higher or more frequent doses produce significantly more side effects including tachycardia, muscle tremor, and CNS stimulation.

Of concern is the association between regular use of b-agonists and increased morbidity and mortality from asthma. In one study designed to compare the safety of salmeterol and albuterol, patients treated with salmeterol had a 3-times higher mortality rate than those treated with albuterol, but the study lacked sufficient power to detect a statistical difference between the groups. Considering these findings and the guidelines of the NHLBI for asthma management, salmeterol should only by used in patients concurrently treated with antiinflammatory drugs (e.g., cromolyn, nedocromil, or inhaled corticosteroids).

Safety and efficacy in children less than 12 years old have not been established. Based on limited data, it appears that salmeterol in doses of 25 to 50 mcg is well tolerated and efficacious in the pediatric population. Still, there is inadequate information to determine where salmeterol fits into the management of pediatric asthma.

[Suggested readings: (1) Meyer JM, Wenzel CL, Kradjan WA. Salmeterol: a novel, long-acting beta2-agonist. Ann Pharmacother 1993;27:1478-87. (2) Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034-7.]

 

Pharmaceutical Care

• The age guidelines for the various methods of administration are estimates. In each individual case, you, the pharmacist, must assess the ability of the patient to use a given method of administering inhaled b2-agonist. If you do not believe that the patient will be able to perform a given technique in such a way as to deliver the medication to the desired site of action, you must recommend that the next easiest method of administration be tried. This is regardless of patient age (there are many adults who cannot perform the technique for using a MDI alone and should be advised to use a spacer.) Then, the pharmacist must teach the patient the proper technique for using the chosen method of administration and, just as importantly, review this technique with the patient each time he/she is seen.

Also, you will find that patients may, under the best of conditions be able to use a MDI, but when acutely dyspneic cannot. These patients should have a nebulizer available for such occasions. It is much less expensive to dispense a nebulizer than to have the patient go to the ER for inhaled b-agonist treatments.

 

• It is equally dangerous for an asthmatic patient to overuse inhaled b-agonists as it is for them to be without such therapy. Excessive use of these agents has been associated with increased morbidity and mortality from asthma. The pharmacist must be alert to how much b-agonist is being used by a given patient and work with the patient's physician to optimize therapy if indicated. Use of more than one MDI of albuterol or a comparable drug per month is reason to alert the patient's physician.

[Selected readings: (1) Sears MR, Taylor DR, Print CG, Lake DC, Li Q, Flannery EM et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391-6. (2) Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockroft D et al. The use of b-agonists and the risk of death and near-death from asthma. N Engl J Med 1992;326:501-6. (3) Mullen ML, Mullen B, Carey M. The association between b-agonist use and death from asthma: a meta-analytic integration of case-control studies. JAMA 1993;270:1842-5. (4) Ernst P, Habbick B, Suissa S, Hemmelgarn B, Cockroft D, Buist AS et al. Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity? Am Rev Respir Dis 1993;148:75-9. (5) Suissa S, Ernst P, Boivin JF, Horwitz RI, Habbick B, Cockroft D et al. A cohort analysis of excess mortality in asthma and the use of inhaled b-agonists. Am J Respir Crit Care 1994;149:604-10.]

 

 

A.C. is being inappropriately treated with oral metaproterenol and it should be discontinued. Oral b-agonists should be reserved for use in a diagnostic maneuver for a patient in whom a history of reversibility has not yet been established.

A.C. needs a reliable method to administer b2-agonist for the treatment of acute symptoms. Since A.C. is 4 y/o, he may be able to master the technique of using a metered-dose inhaler plus a spacing device. You, as the pharmacist, must carefully assess the efficiency with which he is able to perform this technique. If, for any reason, you do not believe he will reliably get the medication delivered to the desired site of action with a metered-dose inhaler plus a spacing device, you must recommend that a nebulizer be prescribed.

Albuterol is an appropriate drug choice for A.C. because it is b2-specific, it has an appropriate duration of action of 4-6 hours, and it is available in either the MDI or nebulized dosage forms.

 

 


Instruction 3.3 - GENERATE IDEAS

How should A.C.'s acute exacerbation be managed?

 

Feedback 3.3 - Generate Ideas

Any patient with asthma symptoms that are not responding to usual treatment is in early status asthmaticus (please refer back to the definitions). The best time to intervene is at that point when usual therapy (e.g., inhaled b2-agonist) begins to fail--not to wait until symptoms become severe and emergency treatment is required.

 

Intervention or "Burst" Corticosteroid Dosing

• Need to use high enough dose of daily systemic steroids for intervention to minimize duration of need.

• Continue intervention course until free of symptoms and signs of airway obstruction incompletely responsive to inhaled bronchodilator--no longer and no shorter: do not prolong course with suboptimal dosage by 'tapering.'

• Doses:

< 1 year of age, 10 mg prednisone BID;

1-3 years of age, 20 mg prednisone BID;

3 years to puberty, 30 mg prednisone BID;

postpuberty, 40 mg prednisone BID.

Continue until completely clear + 2 days. Average duration is 7 days; rarely needed for more than 10 days. Only if "burst" therapy is required for >14 days, short taper is indicated.

• Harris et al. conducted a double-blind, randomized, placebo-controlled, parallel trial of high dose oral prednisone intervention in 41 patients > 6 years of age with acute exacerbation of asthma. Patients were randomized to either prednisone treatment (using above doses) or placebo if asthma symptoms were unresponsive to 2 treatments with albuterol 2 puffs (via MDI) and PEFR was < 20% of values when controlled. All of the 22 patients who received prednisone improved during the week of treatment; 1 patient had a subsequent exacerbation 5 days after D/Cing study medication. Of the 19 patients who received placebo, 8 required rescue intervention with prednisone (doses as above) in association with continued symptoms, increased frequency of MDI use, and decrease PEFR (p < 0.004). There were no clinically important adverse effects from the prednisone.

The authors suggest that this early intervention with high-dose oral prednisone can prevent emergency care and hospitalization, particularly in patients with a history of protracted course of emergency care.

• Side effects of "burst" dosing: increase in appetite, mild Cushingoid effects (roundness in face), no or only transient HPA axis suppression (except in patients who receive >4 bursts/year)

 

[Selected readings: (1) Weinberger M. Managing asthma. Baltimore; Williams & Wilkins, 1990. (2) Harris JB, Weinberger MM, Nassif E, Smith G, Milavetz G, Stillerman A. Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators. J Pediatr 1987;110:627-33.]

 

A.C. should be prescribed a prednisone burst because of the incomplete resolution of his symptoms (coughing) and the fact that his spirometry did not normalize after bronchodilator. He should receive prednisone 30 mg BID until completely clear plus 2 additional days, but should call you if he requires more than 7 days of therapy.

 


Instruction 3.4 - GENERATE IDEAS

What treatment options are available for the management of A.C.'s chronic asthma symptoms?

 

Feedback 3.4 - Generate Ideas

There are a number of treatment options for chronic asthma. The choice between these options depends on the severity of the patient's asthma and patient preference for administration.

 

CROMOLYN SODIUM, NEDOCROMIL SODIUM

Cromolyn and nedocromil are "antiinflammatory" drugs, in that they inhibit the release of the chemical mediators that initiate and prolong the late asthmatic reaction (which is characterized by inflammation). They prevent the release of mediators from mast cells induced by both immunologic (e.g., allergy) and nonimmunologic stimulation (e.g., exercise). They have no bronchodilatory effects. Their beneficial effects are seen in both children and adults.

The place of cromolyn and nedocromil in the therapy of asthma are for prophylactic treatment of mild to moderate chronic asthma. They must be used chronically to be effective (the full effect is usually delayed 4-6 weeks). Side effects from either of these drugs are rare.

 

INHALED CORTICOSTEROIDS

Corticosteroids have antiinflammatory effects that alter mediator response. In addition, this class of drugs increases b-adrenergic response, decreases arachidonic acid production, and decreases mucus production.

Chronic corticosteroids are indicated for chronic management of steroid-dependent asthma and are primary (first-line) therapy for moderate to severe chronic asthma (not necessarily classic steroid-dependent asthma). Inhalation is the preferred route of administration for these drugs (but, if necessary, at least one study indicates no difference in desired effects or side effects between inhaled and every other day oral corticosteroids).

The side effects of inhaled corticosteroids are mainly local and include dry or sore throat, dysphonia, and oropharyngeal candidiasis. These can be avoided by using a spacing device or rinsing out the mouth with water after inhaler use (be sure to advise spitting out the water as substantial absorption can occur from the GI tract).

At the highest inhaled doses, some of the systemic side effects of the corticosteroids can be seen. These include hyperglycemia, hypertension, HPA axis suppression, Cushingoid changes in appearance, posterior subcapsular cataracts, and osteoporosis. All of these side effects will be milder with even high doses of inhaled corticosteroids than with oral steroids.

Growth suppression due to chronic corticosteroid use is a topic of considerable discussion and concern. The question has been raised as to whether the growth suppression is due to chronic steroid use or to chronic, severe asthma. Some studies demonstrate no effect on growth from steroids; others in demonstrate a growth spurt when steroid therapy is initiated (possibly due to improved oxygenation). It is important to consider the age at which the children are studied, particularly in relation to the onset of puberty. The best study, which looks at children over the course of their illness and into adulthood, shows no difference in adult heights.

 

THEOPHYLLINE

Theophylline is a bronchodilator, but may also affect cellular inflammatory response. In the past, theophylline has been used as first-line, prophylactic treatment for chronic asthma. Bur the recent NHLBI guidelines have relegated theophylline's use to second or third line (added to inhaled corticosteroids).

When using theophylline, one must choose a sustained-release formulation which demonstrates sufficient extent of absorption, appropriate rate of absorption, limited peak-to-trough fluctuation in serum concentration over a 12-hour dosing interval, and minimal effect of food on the rate and extent of absorption. The two currently available products which best meet these characteristics are Slo-bid® capsules and Theo-Dur® tablets.

The following is a brief overview of theophylline pharmacokinetics (particularly as they apply to the drug's use in children):

• Vd = 0.45 liters/kg (range 0.3 to 0.7 liters/kg) in adults and older children; 0.6 and 0.7 liters/kg in term and preterm neonates, respectively approximately 40% bound to plasma proteins; protein binding decreases in neonates

• metabolized by the cytochrome P-450 component of the hepatic microsomal oxidative enzyme system; in older children and adults, metabolites are inactive and excreted by the kidney; in neonates, methylation to caffeine is more prominent and a larger portion is excreted unchanged in the urine

• clearance varies with age

 

Dosing should be initiated with a slow, upward titration over about one week

Upward titration schedule for theophylline

1. Calculate the total daily theophylline dose for the patient.

2. Give 1/2 to 2/3 of the total daily dose (not to exceed 400 mg/day) for 3 days.

3. Increase to 2/3 to 3/4 of the total daily dose (not to exceed 600 mg/day) for 3 days.

4. Increase to total daily dose (not to exceed 900 mg/day).

A serum theophylline concentration is obtained after the patient is on the total daily dose for at least 3 days; the therapeutic range for theophylline is 10-20 mcg/ml (the recent NHLBI guidelines indicate that the therapeutic range FOR ASTHMA is 5-15 mcg/ml).

 

Side effects/adverse reactions for theophylline may be minor ("caffeine-like" side effects including mild headache, mild nausea--these can be avoided with slow, upward titration) or serious (greater risk at serum concentration > 20 mcg/ml] and include tachycardia, cardiac arrhythmias, and seizures, all of which are potentially fatal).

Parents often have concerns about possible adverse effects of theophylline on behavior and school performance. Researchers in Iowa have compared scores on standardized performance tests (Iowa Basics) between asthmatic children on theophylline and their nonasthmatic siblings. They found no difference between these groups. Data from other short term tests conflict. Using this data, one can usually calm most parental fears. However, if the family is against the use of theophylline in a particular child, it is usually destined to failure (in spite of all the data in the world!) I also hesitate to recommend theophylline (if possible) for very active children who clearly do not need any more (even temporary) stimulation.

 


Instruction 3.5 - GENERATE IDEAS

What combinations of agents for chronic therapy have been shown to be effective?

 

Feedback 3.5 - Generate Ideas

Neither cromolyn sodium nor nedocromil sodium have been shown to be effective in combination with any other agent for chronic preventive care of asthma (i.e., combinations with inhaled steroids or theophylline are no more effective than either agent alone). Therefore, if treatment with cromolyn or nedocromil does not meet therapeutic goals for asthma care, these agents should be discontinued completely and a different drug started instead.

 

On the other hand, the combination of inhaled corticosteroids and theophylline has been demonstrated to be more effective than either agent alone in patients requiring combined therapy. Therefore, the NHLBI guidelines recommend adding theophylline to inhaled corticosteroids if treatment with steroids alone is not meeting the therapeutic goals for asthma care.

 

THERAPEUTIC PLANNING

Intermittent Asthma:

Inhaled b2-agonist PRN + Steroid "burst" PRN

 

Mild to Moderate Chronic Asthma:

Inhaled b2-agonist PRN + Cromolyn or Nedocromil + Steroid "burst" PRN

(if therapeutic goals not met) Inhaled b2-agonist PRN + Inhaled corticosteroids + Steroid "burst" PRN

(if therapeutic goals still not met) Inhaled b2-agonist PRN + Inhaled corticosteroids + Theophylline + Steroid "burst" PRN

 

Severe Chronic Asthma:

Inhaled b2-agonist PRN + Inhaled corticosteroids + Steroid "burst" PRN

(if therapeutic goals not met) Inhaled b2-agonist PRN + Inhaled corticosteroids + Theophylline + Steroid "burst" PRN

 

Seasonal Asthma:

Inhaled b2-agonist PRN + Cromolyn or Nedocromil or Inhaled corticosteroids and/or Theophylline (during chronic season) + Steroid "burst" PRN

 

NOTE: The leukotriene modifiers [zileuton (ZyfloÒ ), zafirlukast (AccolateÒ ), and soon montelukast) are a new class of agents. These drugs work by reducing the production (zileuton) or blocking the action (zafirlukast, montelukast) of the leukotriene inflammatory mediators LTD4 and LTE4. They improve pulmonary function; diminish asthma symptoms; and decrease the need for short-acting b -agonists, physician visits, and decrease the number of acute asthma exacerbations. Both of the currently available drugs can also cause serious side effects including hepatotoxicity (zileuton) and systemic eosinophilic vasculitis or Churg-Strauss syndrome (zafirlukast) which is potentially fatal. Both drugs also affect the cytochrome P-450 microsomal enzyme system and, therefore, can cause several drug interactions. NEITHER of these drugs is approved for use in patients less than 12 years of age. Also, the labeled indication for these drugs is in patients with mild persistent asthma as an alternative to low-dose inhaled corticosteroids—unfortunately, these drugs are often prescribed for severe, steroid-dependent asthmatics in a sort of "shot-gun" approach to therapy (in combination with several other therapies.) Because of the potential toxicity, lack of sufficient data, and potential for improper usage, these drugs should, in general, not be used in children.

 

 


Instruction 3.6 - SELECT THE BEST IDEAS

Select a therapeutic plan for A.C.'s asthma. (Hint: Include management of his acute exacerbation and chronic asthma. Review the Feedback for 3.1-3.5)

 

Feedback 3.6 - Select the Best Ideas

The therapeutic plan for A.C. should be:

1. Nonpharmacologic tx - decrease smoke exposure; encourage dad to stop smoking and assist him in finding a smoking cessation program (if he refuses to stop smoking, instruct family that he should smoke in only one room of the house where A.C. does not go)

2. D/C Alupent® and TheoDur® Sprinkles

3. Albuterol 2 puffs via Inhalaid® Q4H PRN [Note: if child is unable to master technique with MDI + spacer, recommend nebulizer]

4. Prednisone 30 mg p.o. Q 12 H for 5-7 days (until the patient is completely clear)

5. Cromolyn (Intal®) 2 puffs via Inhalaid TID

6. Patient education re: Inhalaid® use, indications for albuterol, when to call clinic (i.e., when albuterol fails to clear sx completely for 4 full hours), proper use of prednisone, potential side effects of meds, etc.

 

Doses of Some Drugs for Asthma

b -ADRENERGIC AGONISTS

Drug Formulation Initial Adult Dosage Initial Pediatric Dosage
Albuterol (ProventilÒ , VentolinÒ ) MDI (90 m g/puff) 2 puffs q4-6h PRN 2 puffs q4-6h PRN
  Neb. Soln. (5 mg/ml) 0.5 cc + 2-3 cc NS q4-6h PRN

Acute/severe exacerb.:

0.5-1 cc + 2-3 cc NS q 20 min X 3 doses, 2.5-10 mg q1-4h PRN OR 10-15 mg/hr continuously

 <20 kg: 0.25 cc + 2-3 cc NS q4-6h PRN

>20 kg: 0.5 cc + 2-3 cc NS q4-6h PRN

Acute/severe exacerb.:

0.15 mg/kg (min. dose 2.5 mg) + 2-3 cc NS q 20 min X 3 doses, then 0.15-0.3 mg/kg (up to 10 mg) q1-4h PRN OR 0.5 mg/kg/hr continuously
  syrup (2 mg/5 ml) or tablets (2 & 4 mg) 2-4 mg tid or qid 0.1 mg/kg (max. 2 mg) q6-8h PRN
Epinephrine subcutaneous (1:1000 = 1mg/cc) 0.3-0.5 mg q 20 min X 3 PRN 0.01 mg/kg (up to 0.5 mg) q 20 min X 3 PRN
Epinephrine, sustained action (SusphrineÒ ) subcutaneous (1:200) 0.5-0.75 mg q6h PRN 0.005-0.01 mg/kg q6h PRN
Terbutaline (BrethineÒ , BrethaireÒ , BricanylÒ ) subcutaneous

(1 mg/ml)

 0.25 mg (may be repeated once after 15-30 min., but not more than 0.5 mg in 4 hours) 0.01 mg/kg, up to 0.25 mg (may be repeated once after 15-30 min.)
  MDI (200 m g/puff) 2-3 puffs q4-6h PRN 2-3 puffs q4-6h PRN
  tablets (2.5 & 5 mg) 2.5-5 mg tid 1.25-2.5 mg tid
Bitolterol mesylate (TornalateÒ ) MDI (370 m g/puff) 2 puffs q4-6h PRN 2 puffs q4-6h PRN
Pirbuterol (MaxairÒ ) MDI (200 m g/puff) 2 puffs q46h PRN 2 puffs q4-6h PRN
Metaproterenol (AlupentÒ ) MDI (650 m g/puff) 2-3 puffs q3-4h PRN  
  Neb. Soln. (5%) 0.3 ml + 2-3 cc NS q6-8h PRN 0.01-0.02 ml/kg of 5% soln. (min. dose 0.1 ml; max. dose 0.3 ml) + 2-3cc NS q4-6 PRN
  syrup (10 mg/5 ml) or tablets (10 & 20 mg) 20 mg tid or qid <2 y/o: 0.4 mg/kg/dose tid or qid

2-6 y/o: 1.3 - 2.6 mg/kg/day divided q6-8h

6-9 y/o: 10 mg/dose given tid-qid

>9 y/o: adult dose
Salmeterol (SereventÒ ) MDI (25 m g/puff) 2 puffs Q12h Not recommended for children under 12 y/o

(1 puff Q 12 h in studies)
Ipratropium bromide (AtroventÒ ) Neb. Soln. (0.025%) 0.5 mg (2ml) q30 min X3 then q2-4h PRN (Mix with b -agonist) 0.25 mg (1ml) q30 min X3 then q2-4h PRN (Mix with b -agonist)

 

CORTICOSTEROIDS

Drug Formulation Initial Adult Dosage Initial Pediatric Dosage
Prednisone Oral - "Burst" therapy 40 mg Q12ha <1 yr old: 10 mg q12ha

1-3 yr old: 20 mg q12ha

3-13 yr old: 30 mg q12ha

>13 yr old: 40 mg q12ha
  Oral - Chronic 15-60 mg QOD <1 yr old: 10 mg QOD

1-3 yr old: 20 mg QOD

3-13 yr old: 30 mg QOD

>13 yr old: 40 mg QOD
Methylprednisolone sodium succinate (Solu-MedrolÒ ) Powder for injection with diluent (40 mg/cc and 125 mg/2cc) 40-125 mg q6h 2 mg/kg loading dose, then 0.5-1 mg/kg q6h
Beclomethasone dipropionate (BecloventÒ , VancerilÒ ) MDI (42 m g/puff) 2-4 puffs 2-4 times/day 1-2 puffs 2-4 times/day
(VancerilÒ 84 mcg Double Strength) MDI (84 m g/puff) 2 puffs bid  
Flunisolide (AeroBidÒ ) MDI (250 m g/puff) 2-4 puffs 2 times/day 2 puffs 2 times/day
Triamcinolone acetonide (AzmacortÒ ) MDI (100 m g/puff) 2-4 puffs 2-4 times/day 1-2 puffs 2-4 times/day

aTwice daily oral doses are usually sufficient for ambulatory patients.

 

 

MAST CELL STABILIZERS

Drug Formulation Initial Adult Dosage Initial Pediatric Dosage
Cromolyn sodium (IntalÒ ) Neb. Soln.

(20 mg/2 cc)

 20 mg qid (may be mixed with b -agonist) 20 mg qid (may be mixed with b -agonist)
  MDI (800 m g/puff) 2 puffs tid or qid 2 puffs tid or qid
Nedocromil sodium (TiladeÒ ) MDI (1,750 m g/puff) 2 puffs qid Not recommended for children < 12y/o.

METHYLXANTHINES

Drug Formulation Initial Adult Dosage Initial Pediatric Dosage
Theophyllineb (Theo-DurÒ , TheochronÒ , Slo-bid GyrocapsÒ , Theo-DurÒ sprinkles) several tablet and capsule dosages available First three daysc:

400 mg/day

Second three days c:

600 mg/day

Third three days d:

800 mg/day

 Total daily doseb, 1-9 y/o:

22 mg/kg/day ¸ q12h

Total daily doseb, 9-12 y/o:

20 mg/kg/day ¸ q12h

Total daily doseb, 12-16 y/o:

18 mg/kg/day ¸ q12h
Aminophylline liquid (105mg/5ml = 80 mg theophylline/5ml)     Total daily doseb <1 yr old term infant:

(0.2)(age in weeks) + 5 mg/kg/day ¸ q6h

bDosage must be slowly titrated over 9 days to avoid adverse effects. Total daily dose is divided into equal parts and given at intervals appropriate for rate of absorption: liquids and tablets q6h, most sustained-release products q12h (sometimes q8h required in children.)

cInitial dose should not be increased without serum concentration measurement in patients with COPD, liver dysfunction, cardiac failure, fever, or in those taking cimetidine.

dIf symptoms persist, measure serum concentration four hours after dose of sustained-release product to determine if larger doses can be given safely.

 

LEUKOTRIENE MODIFIERS

Drug Formulation Initial Adult Dosage Initial Pediatric Dosage
Zileuton (ZyfloÒ ) 300 mg and 600 mg tablets 600 mg qid Not recommended for children < 12y/o
Zafirlukast (AccolateÒ ) 20 mg tablet 20 mg bid Not recommended for children < 12y/o.

 

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The University of Illinois at Chicago Last modified: Dec 19, 1997