The increasing number of drugs available for the treatment of asthma in recent years imposes a considerable burden upon the physician who has to make a decision on the proper therapy for his patients. This review of drugs used in the treatment of asthma has been designed to help the pediatrician in these therapeutic choices.
ASTHMA DRUGS: MECHANISM OF ACTION
In order to make a rational choice in the drugs available for treatment of asthma, the physician needs to understand the mechanism of action of the drugs used in asthma therapy. The normal patency of the lumen of the tracheobronchial tree depends on an equilibrium between the effects caused by two opposing forces, the sympathetic and the parasympathetic nervous systems.
Stimulation of the sympathetic or adrenergic system produces a decrease of mucous gland production, a decrease in capillary permeability, and relaxation of bronchial smooth muscle. These effects increase airway patency. Stimulation of the parasympathetic or cholinergic system produces the opposite effect upon the bronchial glands, vasculature, and smooth muscles. There is increased mucus production, an increase in capillary permeability that results in edema of the mucosal wall, and contraction of the bronchial smooth muscles. This results in a narrowed airway with mucus plugging.
At the cellular level (Figure 1) stimulation of the sympathetic system acts on the /3-2 receptors of the tracheobronchial tree. The activated /3-2 adrenergic receptor, now identified as a membrane-bound enzyme, adenylate cyclase, accelerates the conversion of adenosine triphosphate (ATP), to cyclic adenosine monophosphate (cAMP) in the cell cytoplasm. It is the increase in the level of intracellular cAMP level that results in the svmpathomimetic effects upon the mucous glands, vasculature, and bronchial smooth muscle.
Stimulation of the parasympathetic system acts through the cholinergic receptors of the tracheobronchial tree. The activated cholinergic receptor, guanylate cyclase, also a membrane-bound enzyme, accelerates the conversion of guanosine triphosphate (GTP), to cyclic guanosine monophosphate (cGMP) in the cell cytoplasm. The increase in intracellular cGMP results in a parasympathetic response. The normal diameter of the tracheobronchial tree lumen thus depends upon the relative intracellular concentration of cAMP and cGMP.
Other important mechanisms include those by which cAMP is inactivated by adenyl phosphodiesterase to 5'AMP and cGMP is inactivated by guanyl phosphodiesterase to 5'GMP.
In experimental guinea pigs, a-adrenergic stimulation by norepinephrine produces bronchoconstriction. A similar effect has not been identified in humans, and there is some disagreement over whether α-sympathetic receptors exist in the human lung.
When antigen-antibody- induced chemical mediator is released from tissue mast cells and circulating basophils, it is also modulated by the relative intracellular concentrations of cAMP/cGMP (Figure 1). Drugs that increase the level of intracellular cAMP inhibit mediator release; drugs that increase intracellular cGMP increase mediator release. The mediators (particularly histamine and SRS-A) that are released because of this immunologic reaction cause effects similar to parasympathetic stimulation - increased capillary permeability (producing edema), smooth muscle contraction, and increased glandular secretion.
Intelligent pharmacologic management of asthma is designed to increase the relative amounts of intracellular cAMP. This can be achieved either by an increase in cAMP production by the use of /3-2 agonist drugs or by decreasing the breakdown of cAMP by the use of methylxanthines, which inhibit phosphodiesteration of cAMP. Although both adenyl phosphodiesterase and guanyl phosphodiesterase are inhibited by methylxanthines, it has been demonstrated recently that adenyl phosphodiesterase is 10 times more susceptible to the drug than guanyl phosphodiesterase. This may explain the preferential action of methylxanthines on the level of cAMP over that of the level of cGMP and therefore the effectiveness of methylxanthines in the treatment of asthma.1
Figure 1. Relationship between the effects of the sympathetic and parasympathetic nervous system on the patency of the tracheobronchial tree lumen and IgE-antigen-induced release of chemical mediators.
A decrease in the intracellular level of cGMP can be achieved by the use of such anticholinergic drugs as atropine. In this situation, there is relatively less cGMP than cAMP and thus a predominantly adrenergic effect on the airway patency.
Cromolyn sodium has been shown to inhibit mediator release from tissue mast cells and from basophils. The drug may inhibit the degran ulation of IgE-sensitized mast cells, which occur after exposure to specific antigens. Cromolyn sodium, however, has no effect on the sensitization of the cell and the subsequent union of specific antigen and antibody. The drug has no direct antagonistic effect on such chemical mediators as histamine or SRS-A, and thus it is not effective in modifying the allergic response once the mediators have been released. Cromolyn sodium has no anti-inflammatory or bronchodilatory activity.
Glucocorticosteroids, among other actions, appear to restore responsiveness of the β- receptor, adenylate cyclase, to adrenergic drugs. They are also potent anti-inflammatory agents. In the following article Dr. Sheldon C. Siegel presents a more complete discussion of the mode of action of these agents.
Theophylline has been long recognized as a potent bronchodilator effective in the relief of the signs and symptoms of asthma.
In the early 1950s, it was felt that theophylline was not soluble in water and thereby was erratically absorbed in the intestine and in the blood stream.2 Because of this belief, theophylline compounds were formulated as water-soluble salts or in alcohol solution, in an attempt to improve absorption either in the blood or in the gastrointestinal tract (Table 1). When the therapeutic dose is considered, it is important to recognize that only part of the theophylline salt is active (e.g., each 100 mg. of aminophylline represents only 85 mg. of theophylline, with 15 mg. of ethylenediamine). It is now recognized that anhydrous theophylline itself is well absorbed and that salts of this drug are not necessary. In addition, alcoholic solutions are no longer needed. Several pure anhydrous preparations are available currently in solution, tablet, and capsule form that have nearly 100 per cent bioavailability.3
The daily dose of anhydrous theophylline for most patients in the pediatric age group is between 18 and 24 mg./kg. of lean body weight.4 The optimal therapeutic dose, however, varies with each patient according to his metabolism of theophylline.
The half-life of theophylline in the blood in children and adolescents ranges from two to 10 hours, with an average of about four hours.5 Several factors are now known to affect the rate of theophylline metabolism, and they include age, other medications, and some specific organ diseases. Theophylline has a shorter half-life in children below the age of nine years than it does in older children or adults. A prolongation of drug half-life has been associated with the use of troleandomycin and erythromycin, and in patients with heart failure, liver, and kidney disease.6 A shortening of the half-life has been found in persons who are receiving phenobarbital and also in cigarette smokers. Recently a possible alteration in theophylline pharmacokinetics during acute respiratory viral illness has been reported.7
A direct relationship between bronchodilation and serum theophylline concentration has been well established.8 Progressive impjovement of pulmonary function is observed as serum theophylline concentration increases from S- to 20-/xg./ml. A further increase in the theophylline level is associated with an increased incidence of toxic effects of the drug.
The generally accepted therapeutic serum theophylline level ranges between 10 and 20 jug./ml. Patients must be monitored individually by blood theophylline determination and clinical response in order to determine the proper drug dose levels. Satisfactory therapy is based on giving a dose necessary to maintain an adequate blood level and good bronchodilation.
In status asthmaticus, where rapid effect of the drug is desired, aminophylline should be given intravenously in a dose of 4- to 6mg./kg. of lean body weight over a 30-minute period, in 30 to 50 cc. of ?5 Vi normal saline. This should be followed by 13-24 mg./kg./day of aminophylline in a continous drip. These doses rapidly achieve and maintain therapeutic serum theophylline levels in most children, but of course must be adjusted in the individual patient based upon prior medication and by blood theophylline monitoring.
When choosing oral theophylline preparations for asthmatic patients one should look for a single drug preparation with predictable and almost complete bioavailability, which is acceptable to the patient. We prefer a pure anhydrous theophylline preparation, thereby avoiding possible side effects from the nonactive part of the theophylline salt and the undesirable drug interactions of fixed drug combinations.
Quick release solutions that have short duration of action, chewable tablets, other tablets, and capsules are all available that meet these qualifications. They are satisfactory choices in situations where rapid onset of therapeutic blood levels are desirable. They should also be acceptable in some older children and adults who demonstrate low theophylline metabolism and need continous drug therapy to control their asthma. In most children, however, who require continuous oral bronchodilators, the use of timed-release theophylline preparations is desirable. These preparations allow smoother, more "straight-line" blood levels than the quickrelease preparations - especially in the child with a very rapid drug metabolic rate. The timed-release preparations are available in tablet and capsule form. This latter formulation makes it possible to give doses to small children who are unable to swallow tablets or capsules whole; the mother takes the capsule apart and sprinkles the contents on applesauce or pudding.
Possible side effects of all theophylline preparations include gastric irritation, nausea, vomiting, headache, syncope, hyperactivity, and occasional diarrhea. Theophylline poisoning can result in bloody diarrhea, seizures, shock, coma, and death. Both the toxic side effects and the therapeutic effects are related to the serum theophylline concentration. Serious toxicity usually does not occur at levels under 20 ug./ml., but minor side reactions may occur. Above 20 /xg/ml., the frequency of all side effects increases, especially above 40 µg./ml. After stopping theophylline administration, the toxic effects can be generally managed symptomatically while the drug is being eliminated by endogenous metabolic pathways. Recently it has been shown that charcoal hemoperfusion may be of help in the treatment of severe theophylline poisoning.9
Guided therapy, based on the serum theophylline level, is the ideal approach when managing the asthmatic using this drug - especially when treating status asthmaticus and using continuous dosing. Blood theophylline determinations are usually readily available in most communities; if not, serum samples may safely be mailed at room temperature to the nearest laboratory without risk of significant change in the serum theophylline level, provided this is done within 24 hours.
In spite of a somewhat narrow therapeutic range of action, theophylline remains one of the most important drugs in the management of asthma.
Sympathomimetic drugs are a group of medications that are widely used in the treatment of asthma. The name comes from their pharmacologic effect, for when these drugs are administered to the patient they "mimic" stimulation of the sympathetic nervous system.
Sympathetic or adrenergic nervous system activities are mediated through membranebound cell receptors in the effector organs. Ahlquist,10 in 1948, divided the adrenoreceptors into alpha and beta types based on their activities in response to natural and exogenous catecholamines. Lands,11 in 1967, studying the pharmacologic action of isoetharine in animals, noted the more selective action of the drug on the tracheobronchial tree than on the cardiovascular system, suggesting the existence of two subtypes of /3-adrenergic receptors. These subtypes are now designated /3-1 and /3-2. Stimulation of the /M adrenoreceptor results in a positive chronotropic (rate) and positive inotropic effect on the heart muscle. Stimulation of the /3-2 adrenoreceptor results in bronchial-muscle relaxation.
The ideal sympathomimetic drug to be used in the treatment of asthma, based on our knowledge of the activity of the drug on the different adrenergic receptors, would be a drug with maximum selectivity for the /3-2 receptor in the tracheobronchial tree. Activities of that drug mediated through the β- and α-receptors should be considered as "side effects."
Each year more and more sympathomimetic drugs are used throughout the world in the treatment of asthma. Figure 2 indicates the chemical structures of four that are available in the United States and considered to be important in the treatment of asthma. Epinephrine, isoproterenol, metaproterenol, and terbutaline are all derivatives of phenylethylamine. Epinephrine, which has only one methyl radical on the amine end of the molecule, produces stimulation of the ot-1, /3-1, and /3-2 receptors. Other sympathomimetic drugs can be considered as modification of this basic structure. The addition of more methyl radicals at this end of the molecule has been found to produce an increasing selectivity for stimulation of the /3-2 receptor, with a corresponding decrease in otaria /3-1 effects. The drugs listed in Figure 2 are arranged in order of increasing /3-2 specificity as one progresses down the list.
Figure 2. Chemical structures of commonly used sympathomimetic drugs
Epinephrine and isoproterenol have hydroxyl groups in the number 3 and number 4 position on the catechol end of the molecule. The enzyme, catechol-orthomethyl transferase (COMT), located in the liver and in the wall of the gastrointestinal tract, catalyzes the methylation of the hydroxyl group in position 3. Both drugs are rapidly degraded by COMT following oral administration. The change of one of the hydroxyl groups from number-4 to number-5 position, as is found in metaproterenol and terbutaline, makes these drugs resistant to COMT degradation, thus allowing them to be effectively given by mouth. This change also lengthens the half-life of these drugs when compared with epinephrine and isoproterenol.
Epinephrine hydrochloride (Adrenalin) has been used in the treatment of asthma since the work of Bayer and Dale in 1910. Bronchodilator response to epinephrine has been used as one of the classical signs in the diagnosis of bronchial asthma. Epinephrine hydrochloride 1:1,000 aqueous solution is usually administered by the subcutaneous route in doses of 0.005 to 0.01 mg./kg./dose, not exceeding 0.3 cc./dose in pediatric patients. Effective bronchodilation may occur, but the duration of action is short-lived, and the dose may be repeated once or twice at 20-to-30minute intervals, if needed. Longer activity of this drug (approximately four hours) can be obtained by using a 1:200 aqueous suspension of Adrenalin in thioglycolate (SusPhrine). This is usually administered to infants and children up to the age of 12 in a dose of 0.005 ml./kg. body weight, with the maximum single dose not to exceed 0.15 ml. for children weighing 30 kg. or less. It should be noted that approximately 20 per cent of the aqueous Adrenalin is released immediately from this drug suspension, equivalent in effect to aqueous epinephrine hydrochloride 1:1000.
The side effects of epinephrine on the central nervous system are related to its a-agonist action. The chronotropic and inotropic effects are related to the drug's /3-1 activity.
Ephedrine sulfate, an alkaloid derived either from the plant Ephedra equistina or produced synthetically, has been used since ancient times as an antiasthma drug. Although the drug has some direct bronchodilatory action, most of the effect of the drug in asthma is through its ability to release endogenous epinephrine. The drug has a- as well as /3-1 and /3-2 activities that limit its effectiveness, with side effects similar to those of epinephrine.
Until recent years, ephedrine was the only orally active sympathomimetic agent available in the United States. It is frequently used with theophylline in the so-called fixed combination asthma medications. The usefulness of ephedrine sulfate has declined in recent years with the advent of other more /32-specific drugs that produce better and more prolonged bronchodilation, and with recognition that "fixed combination" medications of ephedrine-theophylline did not provide optimal therapy.
The drug may still be valuable, however, in spite of these drawbacks, in certain patients who cannot tolerate the newer drug formulations. The drug is available in 25-mg. tablets and a syrup (12.5 mg./5 ml.). The usual dose is one tablet or one teaspoon three times daily, as needed, depending on the tolerance of the patient to the drug.
Isoproterenol is a catecholamine with potent /3-2 action. The drug has no a-adrenergic activity but has considerable /3-1 side effects. The drug is usually used by inhalation in the treatment of asthma. Administration by the oral route results in rapid breakdown by COMT and therefore is not recommended.
For inhalation it is available in a metered dose form that delivers 0.075 mg. per puff, the usual recommended dose being two inhalations q4h.
Inhaled isoproterenol may be quite effective in giving immediate subjective relief to mild bronchoconstriction. The drug, however, may only temporarily relieve the respiratory distress. Metabolic breakdown products of isoproterenol such as 3-methoxyisoproterenol have been shown to be bronchoconstrictive in some patients. In addition, it should be kept in mind that isoproterenol has considerable effect on the pulmonary vasculature in addition to its /3-2 effects upon the airways. In acute asthma, many pulmonary vessels are reflexly shut down as the alveoli, which they serve, become poorly ventilated. Inhalation of isoproterenol may initially cause rapid dilatation of the pulmonary vessels supplying still poorly ventilated alveoli and thereby resulting in a temporary shunting of unoxygenated blood and an overall drop in the patient's PaO2.
As important as these physiologic events are, there seems to be a psychological dependence on these small, easily used, and portable freon-propelled nebulizers, when used by some patients. At the least provocation, these patients use the nebulizer, at times to excess. Severe life-threatening asthma has progressed into the late stages of respiratory failure as the patient has overused his nebulizer instead of seeking medical attention. For these reasons, the physician should use great discretion when prescribing this form of treatment.
Isoproterenol also may be used intravenously in the treatment of severe status asthmaticus with impending respiratory failure as an alternative method to assisted ventilation.12,13 The starting dose is 0.1 µg./kg./min., which is increased by 0.1 µg./kg./min. every 15 minutes until there is a drop in arterial carbon dioxide pressure or signs of toxicity are found. The goal of this therapy is to achieve clinical improvement; in some patients, however, it is necessary to give sufficient isoproterenol intravenously to reach a heart rate of 180 before the beneficial effects are evident. This form of treatment should be used only in the child who gives no evidence of a cardiac problem.
Isoetharine (Bronkosol) represents a slight chemical modification of isoproterenol by the addition of an ethyl group into the second carbon of the side chain. This compound produces less bronchodilation than do comparable doses of isoproterenol. It is more /3-2 specific, however, than isoproterenol. Isoetharine is used infrequently in pediatrics, but when used, is given in an aerosol form. (In adults with hypertension, it may be a preferable aerosol because of its better /3-2 selectivity.) It is available in a 1 per cent solution. The usual nebulized dose is 0.25-0.5 ml. mixed in a 1:3 dilution with saline. The rate of administration must be adjusted to the patient.
Metaproterenol (Alupent, Metaprel) has been used in the treatment of asthma since 1961. Though similar to isoproterenol, the modification of the catechol ring (one of the hydroxyl groups is in the number 5, rather than the number 4 position) makes the drug resistant to degradation by the catecholorthomethyl transferase enzyme, thus prolonging its activity and making oral administration possible. The drug retains significant /3-1 activity, however, so that cardiac stimulation is not an uncommon side effect following oral administration. In addition, the orally administered drug produces central nervous system stimulation in some patients.
The drug is available in a metered-doseinhaler form, which delivers 0.6 /Ag. drug per puff. The recommended dose is two to three inhalations every three or four hours, with the total dosage per day not exceeding 12 puffs. Metaproterenol is also available for oral use in a syrup (10 mg./5 cc.) and tablets (10 and 20 mg.). The recommended dose is 10 mg. every six hours in patients between six and nine years of age, and 20 mg. every six hours in patients older than nine. Actual dosage, of course, will depend on individual response and the development of side effects.
Tachyphylaxis with regular oral metaproterenol therapy was not found in a study of 50 asthmatic children over a period of 90 days, pulmonary function testing being used as a measurement.12
Terbutaline sulfate (Bricanyl, Brethine) is the most selective /3-2 antiasthmatic drug currently on the United States market. It is available in a subcutaneous parental formulation (1.0 mg./ml.) and in tablets 2.5 mg. and 5.0 mg. The recommended oral dose for children in the 12- to 15 -year age group is 2.5 mg. three times a day. Older adolescents may receive as much as 5 mg. (0.0075/kg. body weight). Oral doses are not recommended at present for children below the age of 12. The subcutaneous dose, also not recommended for children below the age of 12 is 0.25 mg. (varying between 0.0035 to 0.01 mg./kg. body weight).
Following oral administration, a measurable change in flow rate is detected within 30 minutes, with a peak response usually occurring within 180 to 240 minutes. The duration of action ranges between five and seven hours, with some studies indicating significant bronchodilator action continuing for as long as eight hours.15
Although the possibility of tachyphylaxis has been suggested for terbutaline sulfate, it has not been conclusively demonstrated, even with regular oral administration. It may be possible that there will be additive effects in some patients when terbutaline and theophylline preparations are used, especially in those in whom therapeutic theophylline blood levels are difficult to achieve because of side effects to theophylline.
Subcutaneously administered terbutaline is valuable in the treatment of acute asthma. Because of its relative selectivity for the /3-2 receptor, it is the drug of choice in patients with hypertension or cardiac patients who must be treated for asthma. Although several injections (two or more) have been suggested by some investigators, the longer duration of action of the drug may limit its flexibility. In spite of side effects, epinephrine may still be advisable because of its safety and short duration of action.
Terbutaline has not been shown to produce more bronchodilation than a comparable dose of epinephrine. Sus-Phrine 1-200 should not be used following subcutaneous terbutaline administration because of the potential for serious side effects from two longacting preparations.
The most frequently reported side effect of terbutaline administration is skeletal-muscle tremor, especially noted when one is attempting finely coordinated muscle movements, such as writing. This is a /3-2 effect exerted directly on the skeletal muscle. It may occur in 10 to 20 per cent of the patients receiving the drug and is dose-related. It may severely limit the use of the drug in some patients. Tachyphylaxis has been observed in some patients after two weeks of regular terbutaline administration.
Physicians are somewhat limited in the use of terbutaline sulfate because the drug has not been officially approved in the United States for the treatment of children under 12 years of age. Also, liquid preparations and aerosols are not available.
Other selective /3-2 catecholamines, such as salbutamol, are being used throughout the world outside of the United States. Many of these drugs are similar in activity and side effects to terbutaline sulfate, but some would offer unique advantages in the management of asthma.
Cromolyn sodium (Intal) was synthesized in 1965. Investigation of cromolyn derivatives originated from the observation that khellin, which is a naturally occurring closely related substance, relaxed smooth muscle. Cromolyn sodium has no bronchodilatory effect but does prevent the release of chemical mediators from the mast cells, if administered before antigen or nonantigenic stimulation.
The drug is poorly absorbed by the GI tract - roughly only 0.5 per cent of the ingested dose is absorbed - and it does not appear to be active systemically. In the treatment of asthma, cromolyn sodium is administered prophylactically directly into the bronchial tree. It is inhaled as a powder, mixed with lactose through the use of a special turbodelivery system (Spinhaler).
Clinical results have been variable. Some patients have responded dramatically, but many have not benefited from use of the drug. In England, where cromolyn sodium was developed, it is not uncommon for the medication to be used as a primary prophylactic medication to prevent mild asthma. When used in this way, cromolyn sodium appears to be most effective, especially in atopic children and adolescents. In the United States, where other drugs are used primarily as prophylactic medications (especially theophylline preparations) cromolyn sodium has been used as adjuvant therapy and has largely given way to other medications. It is least effective in adult nonatopic asthmatics. It may, in some patients, decrease the need for concomitant steroid medication.16,17
In intractable asthmatic adults requiring regular medications, however, cromolyn sodium is not as helpful in the control of asthma as inhaled steroids and has not been observed to produce additional benefit when added to inhaled steroid treatment.
Cromolyn sodium has proved valuable as preexposure treatment in asthmatic patients known to be sensitive to a specific allergen (cat, mold) or chemical irritant (tobacco smoke, chemical, or particulate dust). It has also been shown that cromolyn sodium inhibits exercise-induced bronchospasm to some degree when given up to five minutes before exercise.
The dose for all ages is one capsule (20 mg.) by inhalation. The effect lasts approximately four hours. If used continuously, q.i.d. administration is preferred. The prophylactic benefit of the drug is usually observed within the first two to four weeks of administration. The drug should be used only prophylactically and will be irritating and ineffective if continued during an acute asthma attack. A bad taste or irritative effect in the mouth may be lessened by rinsing the mouth with water following inhalation. Although the drug produces no depression or stimulation and side effects are minor, a rare patient may have an allergic reaction to the medication, with development of eosinophilic pneumonia.
The use of anticholinergics for the treatment of asthma has received increasing attention in recent years.18'19 Subcutaneous administration of atropine sulfate has been used to treat asthmatics in the past, but the frequency of such side effects as central nervous system stimulation, mydriasis and cycloplegia, and depression of salivary secretions, has restricted its clinical application. Most of the side effects can be eliminated if atropine is given by inhalation.
A new drug not yet approved for use by the Food and Drug Administration appears to lack the deleterious effects of atropine while retaining some of its beneficial properties. This is the synthetic anticholinergic compound ipratropium bromide (Sch 1000, Atrovent). Its quaternary ammonium behavior prevents it from crossing the blood-brain barrier, thereby obviating effects on the central nervous system.18 Ipratropium bromide does not produce a detectable decrease in volume of salivary secretions when administered at therapeutic doses.19 Adverse eye side effects have been observed in about 1 per cent of the patients. The clinical bronchodilator effect of this drug starts about 30 minutes after inhalation begins, with peak action occurring in 60 to 120 minutes, and significant bronchodilator effect lasting for six or eight hours.
There are a number of drugs available for treatment of asthma in children and adolescents in the United States today. Theophylline, in spite of a somewhat narrow therapeutic range, remains one of the most important drugs in the management of asthma. Sympathomimetic drugs, by their direct action on the /3-adrenergic receptors, help the asthmatic by providing bronchial- muscle relaxation. Of these, terbutaline is the most selective /3-2 asthmatic drug now available in the U.S., and is the drug of choice for patients with hypertension or cardiac problems. Cromolyn sodium has no bronchodilatory effect, but does prevent the release of chemical mediators from mast cells, and has been effective in England as a primary prophylactic medication to prevent mild asthma. The use of anticholinergics has received increasing attention in recent years, but adverse side effects have restricted their clinical application for asthma. One new anticholinergic now being tested, ipratropium bromide, appears to have significant bronchodilator effect without the adverse side effects of other anticholinergics.
1. Frick, O. L. Immediate Hypersensitivity. In Fudenberg, H. H., et al., (eds.) Beste and Clinical Immunology, Second Edition. Los Altos, Calif.: Lange Medical Publications, 1978, p. 261.
2. Ritchie, J. M. The xanthines. In Goodman, L. S., and Gilman, A. (eds.). The Pharmacological Basis of Therapeutics, Fifth Edition. New York MacMillan Publishing Company, 1975, p. 373.
3. Weinberger, M., Hendeles, L., and Bighley, L. The relation of product formulation to absorption of oral theophylline. N. Engl. J. Med. 299 1978, 852-857.
4. Wyatt, R., Weinberger, M., and Hendeles, L. Oral theophylline dosage for the management of chronic asthma. /. Pediatr. 92 (1978), 125-130.
5. Ellis, E. F., Yaffe, S. J., and Levy, G. Pharmacokinetics of theophylline in children with asthma. Pediatria 58 (1973), 542-547.
6. Weinberger, M. Theophylline for treatment of asthma. /. Pediatr. 92 (1978), 1-7.
7. Chang, K. C, et al. Altered theophylline pharmacokinetics during acute respiratory viral illness. Lancet 1 (1978), 1132-1133.
8. Mitenko, P. A., and Ogilvie, R. I. Rational intravenous doses of theophylline. N. Engl. i. Med. 289 (1973), 600-603.
9. Ehlers, S. M., et al. Massive theophylline overdose - rapid elimination by charcoal hemoperfusion. i.?.?.?. 2*0 (1978), 474.
10. Ahlquist, R. P. A study of the adrenotropic receptors. Am. J. Physiol. 153 (1948), 586.
11. Lands, A. M., et al. Differentiation of receptor system activated by sympathomimetic amines. Nature 286 (1967), 597.
12. Wood, D. W., and Downes, J, J. Intravenous isoproterenol in the treatment of respiratory failure in childhood status asthmaticus. Ann. Allergy. 31 (1973), 607-609.
13. Parry, W. H., Martorano, F., and Cotton, E. K. Management of life- threatening asthma with intravenous isoproterenol infusions. Am. f. Dis. Child. 130 (1976), 39-42.
14. Brandon, M. L. Long-term metaproterenol therapy in asthmatic children. f.A.M.A. 235 (1976), 736-737.
15. Tashkin, D. P., et al. Double-Hind comparison of acute bronchial and cardiovascular effects of oral terbutaline and ephedrine. Chest 68 (1975), 155-161.
16. Bernstein, I. L., et al. A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allergy. /. Allergy Clin. Immunol. 50 (1972), 235-245.
17. Berman, B. A., et al. Cromolyn sodium in the treatment of children with severe, perennial asthma. Pediatrics 55. (1975), 621-629.
18. Borut, T. C, et al. Comparison of aerosolized atropine sulfate and Sch 1000 on exercise-induced bronchospasm in children. /. Allergy Clin. Immunol. 60 (1977), 127-133.
19. Chervinsky, P. Double-blind study of ipratropium bromide, a new anticholinergic bronchodilator. /. Allergy Clin. Immunol. 59 (1977), 22-30.