Pulmonary medications.

Key Words: Bronchodilator agents; Pharmacology; Pulmonary, general; Respiration; Ventilation.

The prescription of any pulmonary medication is founded on four basic goals: (1) promotion of bronchodilation or relief of bronchoconstriction, (2) facilitation of the removal of secretions from the lungs, (3) improvement of alveolar ventilation or oxygenation, and (4) optimization of the breathing pattern.[1-6] The relative importance of each of these goals depends on the specific disease process and the resultant respiratory problem(s). Consequently, pulmonary-active medications are typically grouped in accordance with their principal desired effect: bronchodilators, anti-inflammatory agents, decongestants, antihistamines, antitussives, mucokinetics, respiratory stimulants and depressants, and paralyzing and antimicrobial agents. Each of these groups will be reviewed, with emphasis placed on its impact on the specific problem.

Bronchodilators are the most often used drugs in the treatment of pulmonary disease.[1] Therefore, they will be considered before the other drug groups. First, however, a brief discussion of the mechanisms of bronchoconstriction, or airway narrowing, is presented to facilitate an understanding of the actions of bronchodilator drugs. The bronchial smooth muscle fibers of the lungs involuntarily constrict in response to various types of irritation. The resultant bronchoconstriction plays a major role in the pathophysiology of most obstructive pulmonary diseases. Bronchoconstriction can be attributed to any, or all, of three primary pathologic factors: abnormal bronchomotor tone (bronchospasm), inflammation, and mechanical obstruction.[2] With the elimination of overt mechanical obstruction, the control of bronchomotor tone and inflammation become the components of airway management in patients with pulmonary disease. Only after constricted airways are dilated can mucociliary transport, removal of secretions, and subsequent alveolar ventilation and oxygenation take place.[1.2]

Mechanisms of Bronchospasm

Normal bronchomotor tone is the result of a balance between adrenergic and cholinergic influences (Fig. 1).[3] When something (eg, disease, allergy) disrupts this balance, bronchospasm may result. The characteristic findings in acute bronchospasm are mucus production, vascular engorgement, and submucosal inflammatory edema. The mechanisms of bronchospasm can be illustrated using asthma as a model. In asthma, an imbalance in autonomic nervous system (ANS) activity causes a predominant parasympathetic influence, increasing bronchomotor tone and resulting in narrowing of bronchial and bronchiolar passages.[4]

Other receptors in the connective tissues of the airways (eg, receptors on mast cells) and the blood are also stimulated, and mediator substances are released. This response is called inflammation, and it plays a central role in the production of bronchospasm in the vast majority of respiratory disorders.[1,2,4] The mediator substances originate from the plasma, the adjacent cells, or the damaged tissue and are associated with at least eight major events: (1) changes in vascular flow and caliber; (2) changes in vascular permeability; (3) leukocytic (eg, neutrophils, monocytes, eosinophils, lymphocytes, basophils) exudation; (4) margination, or clustering of leukocytes along the capillary endothelial cells at the site of injury; (5) sticking, or adherence of the leukocytes to the endothelial surface at the site of injury; (6) emigration, or leukocytic insinuation between endothelial cells; (7) chemotaxis, or unidirectional migration of polymorphonuclear leukocytes from the bloodstream to the site of injury in response to released attractants; and (8) phagocytosis.[2.4,5] Although macrophages, leukocytes, and neutrophils assist in the elimination of an invading pathogen by means of phagocytosis, it is the action of the lymphocytes that is probably most critical. Lymphocytes have been identified as the "cornerstones of the immune process."[2,4]

Invading organisms (eg, bacteria) or other irritants that elicit an immune response are referred to as allergens or antigens. Antigens stimulate the different types of lymphocytes stored in the lymph nodes to produce two mediator substances: antibodies or sensitized lymphocytes (Fig. 2).[3] Antibodies are produced by the interaction of antigens and B lymphocytes in a process referred to as humoral immunity. Antibodies are also called immunoglobulins, because many reside in the gamma-globulin fraction of the blood.[4] Antibodies are generally grouped into five major classes: IgA, IgE, IgG, IgM, and IgD; the first four of these have been identified in respiratory secretions.[1,2,4] Sensitized lymphocytes (also called lympbokines) are produced through the interaction of antigens with T lymphocytes in a process referred to as cell-mediated immunity. Lymphokines are responsible for a variety of immunologic actions, including the activation of macrophages (by the production and release of macrophage-activating factor), inhibition of leukocyte migration (by the production and release of leukocyte inhibitory factor), and destruction of susceptible target cells lymphotoxic effect).[2,4]

The humoral immunologic response causes the release of chemical mediators from mast cells and leukocytes--a type I sensitivity reaction. This immediate reaction is apparently related to IgE antibody activity and occurs within 10 to 20 minutes. The cell-mediated immunologic response takes approximately 48 hours to develop, and is most likely due to the macrophagic release of specific enzymes that produce inflammation--type IV sensitivity reaction.[2,4] Type I inflammatory reactions are treated with rapidly acting agents such as glucocorticoids, whereas type IV reactions can be treated with less rapidly acting agents, which may have less profound side effects.

Principles of Bronchodilator Therapy

The primary goal of bronchodilator therapy is to influence the ANS via two opposing nucleotides: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (CGMP) (Fig. 3).[1,2,4,6] Cyclic adenosine monophosphate facilitates smooth muscle relaxation and inhibits mast cell degranulation, resulting in bronchodilation. Cyclic guanosine monophosphate facilitates smooth muscle contraction and may enhance mast cell release of histamine and other mediators, resulting in bronchoconstriction. Within the lungs, the effects of cAMP or cGMP can be attributed to

* cholinergic stimulation--muscarinic receptor stimulation, which increases cGMP and enhances bronchoconstriction, or

* adrenergic stimulation--[beta.sub.2]-receptor stimulation, which produces an increase in CAMP and bronchodilation, or [alpha.sub.1]-receptor stimulation, which results in a decrease in CAMP and facilitates bronchoconstriction.[7,8]

As noted, however, in asthma and possibly other pulmonary disorders, there appears to be a reduced sympathetic influence because of predominant parasympathetic activity.

The three main effects of parasympathetic activity are heart rate slowing, bronchial constriction, and increased exocrine gland secretion.[1-2,4] clearly, these effects may be deleterious to a patient with pulmonary disease. Consequently, autonomic-active agents are often used in the treatment of patients with pulmonary disease. Beta-adrenergic agonists, some prostaglandins. glucocorticoids (although not technically bronchodilators), and methytxanthines may be given to increase cAMP and thereby promote bronchodilation. Alpha-adrenergic antagonists, glucocorticoids, cholinergic antagonists, and cromolyn may be given to inhibit cGMP or enhance cAMP. The common autonomic-active bronchodilating agents--methylxanthines, cromolyn sodium, and corticosteroids--are listed in Table 1 and are discussed in the following section.

[TABULAR DATA 1 OMITTED]

Medications That Promote Brunchodilation

Medications that stimulate adrenergic receptors are frequently referred to as sympathomimetics (adrenergic), and those that inhibit adrenergic receptors are referred to as sympatholytics (antiadrenergic). Similarly, medications that stimulate the cholinergic receptors are referred to as parasympathomimetics (cholinergic), and those that inhibit cholinergic receptors are called parasympatholytics (anticholinergic). The actions and adverse effects of the principal bronchodilators, specifically, the autonomic-active agents (adrenergic sympathomimetics and parasympatholytics) and methylxanthines, will be reviewed next. Additionally, two types of anti-inflammatory medications--corticosteroids and cromolyn sodium--will also be considered in this section because of their positive effect on bronchial intraluminal diameter.

Sympathomimetics

Sympathomimetic drugs may be selective or nonselective in their activity. Selective medications react with specific receptors, whereas nonselective medications react with several receptors. As with all drugs, the response elicited by sympathomimetic agents depends on the relative intensity of the receptor reaction, the route of administration, and the dosage of the particular drug (Tab. 2). Recall that

* alpha-receptors are distributed within peripheral and bronchial smooth muscle, the myocardium, and mucosal blood vessels, but they are most abundant in the peripheral smooth muscles;

* beta-receptors are more abundant in cardiac tissue, although they are also present in mucosal blood vessels; and

* [beta.sub.2]-receptors predominate in the bronchial smooth muscles, although they are also found in peripheral smooth muscle and skeletal muscle.[4.6.8]

Epinephrine (adrenalin) and ephedrine typify general, nonselective sympathomimetics. Epinephrine has a short duration of action, demonstrating moderate alpha-receptor activity, strong [beta.sub.1]-receptor activity, and moderate [beta.sub.2]-receptor activity.[4,6] Ephedrine has a long duration of action, exhibiting mild alpha-receptor activity and moderate [beta.sub.1] and [beta.sub.2] activity. Thus, in the treatment of bronchoconstriction, peripheral vascular constriction and accelerated cardiac responses may result from the alpha-and [beta.sub.1]-receptor stimulation. Other adverse reactions include agitation, sweating, headache, and nausea. It should be noted that the route by which a particular medication is administered significantly influences the extent of any adverse reactions.[4,6] For example, sympathomimetic medications administered by an inhalational route produce less profound deleterious side effects than when they are administered systemically. Clearly, drugs that elicit no alpha-receptor activity and more specific [beta.sub.2]-receptor activity would be desirable for bronchodilator therapy. Unfortunately, however, no purely [beta.sub.2]-specific sympathomimetic medications have been identified. Isoproterenol, a drug with very weak alpha-receptor activity and strong [beta.sub.1]- and [beta.sub.2]-receptor activity, is the most commonly prescribed nonspecific betasympathomimetic. Selective stimulation of [beta.sub.2]-receptors is preferable, because [beta.sub.2]-specific agents would affect the lungs without affecting the heart. [Beta.sub.2]-specific agents produce bronchiolar dilatation by relaxing the bronchial smooth muscle through facilitation of increased cAMP levels. The most commonly prescribed [beta.sub.2]-specific-type sympathomimetics include isoetharine (Bronkosol, Bisorine, Bronkometer) and terbutaline (Brethaire, Bricanyl), which elicit weak [beta.sub.1]-receptor activity and moderate [beta.sub.2] activity, as well as albuterol (Proventil) and bitolterol (Tornalate), which elicit weak [beta.sub.1]-receptor activity and strong [beta.sub.2]-receptor activity.[8,9] Although the adverse effects of the currently available [beta.sub.2]-specific sympathomimetics are similar to, but usually less profound than, those of the nonspecific beta-sympathomimetics, their severity affects the dosage of the drug administered. The adverse effects that are associated with beta-sympathomimetic medications include tremor, palpitations, headache, nervousness, dizziness, nausea, and hygpertension.[4,9,10] In addition, nonspecific beta-sympathomimetic drugs may also elicit inotropic (enhanced myocardial contractility) and chronotropic (enhanced heart rate) effects.

Sympatholytics

Because alpha-adrenoreceptor stimulation produces both vasoconstriction and bronchoconstriction, the pharmacologic reduction of alpha-adrenergic activity via alpha-adrenoceptor antagonists is certainly warranted for patients with pulmonary disease.[11,12] Alpha-sympatholytic action inhibits the decrease of cAMP associated with an antigen-antibody reaction, allowing bronchodilation to occur. The most commnon side effects associated with alpha sympatholytic administration are nausea and dizziness.

Parasympatholytics

The lungs receive a rich supply of parasympathetic innervation through the vagus nerve.[13] The role of the parasympatholytics is similar to that of alpha-sympatholytics in that it is the lytic action (inhibitory effect) that produces the desired effect of bronchodilation.[4] Blocking parasympathetic stimulation prevents an increase in cGMP, thereby producing a relative increase in the amount of cAMP and promoting bronchial smooth muscle relaxation.[14-16] The agent most commonly used for this purpose was the muscarinic antagonist atropine. Because atropine is readily absorbed into the systemic circulation, however, it is frequently associated with adverse reactions, including central nervous system (CNS) stimulation with low dosages or depression with high dosages, delirium, hallucinations, and decreased gastrointestinal activity.[4,6] The newer drug, ipratropium (Atrovent), is administered by inhalation and is, therefore, poorly absorbed into the systemic circulation; consequently, it has fewer side effects.[17]

Methylxanthines

The intracellular level of cAMP can be enhanced if the process of its degradation by the enzyme phosphodiesterase can be inhibited. By blocking the inactivation of cAMP, bronchodilation is facilitated. The group of drugs that most significantly inhibits phosphodiesterase is the methylxanthines.[4,6] Methylxanthines are also believed to facilitate bronchodilation by means of prostaglandin inhibition, adenosine receptor blockade, enhancement of endogenous catecholamine levels, inhibition of cGMP, and enhancement of the translocation of intracellular calcium.[4,6] Although still inconclusive, there is evidence to suggest that these actions enhance diaphragmatic contractility, reduce patient complaints of dyspnea, and improve exercise tolerance and gas exchange.[18-24] The most commonly used methylxanthines are theophylline (Bronkodyl, Theo-Dur, Sio-phyllin) and aminophylline (Aminophyllin, Cardophyllin), which are associated with a variety of side effects, including increased myocardial work load, heightened susceptibility to ventricular and supraventricular dysrhythmias, and possibly diuresis. Fortunately, the identification of several phosphodiesterase isoenzymes is spurring the development of selective inhibitors that should minimize the systemic side effects associated with such nonselective inhibitors as theophylline and aminophylline.[25] The potential benefits and undesirable side effects associated with methylxanthines are summarized in Table 3.

Table 3. Known Deleterious and
Known or Suspected Beneficial Effects of
Methylxanthines
Deleterious
Effects           Beneficial Effects
Tachycardia       Bronchodilation
Hypertension      Increased diaphragmatic
                   strength/
                   endurance[18,21,22,24]
Palpitations       Improved ventilatory muscle
                   reserve[22]
Chest pain         Increased minute ventilation[22]
Agitation          Enhanced gas exchange[22]
Dizziness          Enhanced exercise
                   tolerance[19, 23]
Headache           Decreased sensation of
                   dyspnea[20]

Cromolyn Sodium (Disodium Cromoglycate)

Research in England in the 1960s on an extract of a Mediterranean plant resulted in the discovery of cromolyn sodium, which is known by the brand names Intal, Nalcrom, Nasalcrom, or Rynacrom. Cromolyn is used prophylactically in cases of chronic asthma because it prevents the immediate hypersensitivity reaction (also known as type I reaction). Immediate hypersensitivity reactions are mast cell controlled via the release of specific mediators (eg, histamine, lymphokines, bradykinin) that produce bronchoconstriction and a variety of other signs and symptoms (eg, mucus secretion, mucosal swelling, dyspnea). Cromolyn sodium does not prevent the activation of mast cells and the subsequent release of specific mediators that results from the coupling of IgE with an allergen.[4] The late phase reaction in an acute asthma episode (which can cause severe airway obstruction 4-6 hours after initial bronchoconstriction) can be prevented by cromolyn sodium.[26] Cromolyn prevents the influx of calcium ions into the mast cells, blocking the degranulation process of these cells and thereby inhibiting the further release of mediators that cause bronchoconstriction. Thus, although cromolyn has no effect on the mediators released from the antigen-antibody reaction of an acute asthma attack, it prevents later bronchoconstriction by impairing the release of mediators.[26] Cromolyn has few side effects, the most commnon being dry mouth and throat, airway irritation, and possible bronchospasm.

Glucocorticoids

The adrenal cortex synthesizes cholesterol and secretes two major corticosteroids: the mineralocorticoids and the glucocorticoids. Although there is some controversy as to the exact mechanism, glucocorticoids are postulated to suppress the process of IgE-mediated bronchoconstriction and to block or inhibit a variety of mediator substances.[1,2,4,27] Even though glucocorticoids are not classified as primary bronchodilators, they are known to have the following general effects that contribute to the enhancement of bronchial intraluminal diameter[6,27]:

* inhibition of the migration of leukocytes and mast cells

* reduction of stickiness and margination of polymorpholeukocytes

* potentiation of catecholamine activity

* reduction of tissue stores of histamine and other mediators

* suppression of kinin activity, resulting in constriction of the microvasculature

* stabilization of mast-cell membranes

* reduction of phosphoaiesterase activity

It is because of their profound anti-inflammatory actions, that glucocorticoids are considered by many to be the drugs of first choice during an acute attack of asthma.

The most commonly used glucocorticoids in the treatment of bronchoconstriction are identified in Table 4.1.[1,2,4] Although it influences all medications, the route of administration of corticosteroids is of particular importance because of the tremendous impact it plays in the incidence of side effects--the more localized the area of administration, the less likely the chance of systemic reaction. During episodes of severe bronchoconstriction, glucocorticoids are usually administered intravenously (eg, methylprednisolone). For prolonged use, however, an oral (prednisone) or inhalational (dexamethasone sodium phosphate, beclomethasone dipropionate, triamcinolone acetonide, flunisolide) route of administration is used.[28] The inhalational route is usually preferred because there are fewer side effects.

Table 4. Common Glucocorticoids
Drug Generic (Brand)             Route of
Name                             Administration
Prednisone (many)                Intravenous, oral
Hydrocortisone                   Intravenous, oral
(Solu-Cortef)
Methylprednisolone               intravenous
(Solu-Medrol)
Dexamethasone                    inhaler
(Decadron Respihaler)
Beclomethasone                   Inhaler
(Beclovent, Vanceril)
Triamcinolone (Azmacort)         Inhaler
Flunisolide (Aerobid)            Inhaler

Most of the adverse effects of glucocorticoid therapy are dosage dependent and take a few days or weeks to manifest themselves. Some side effects are unavoidable; reactions span the spectrum from merely unpleasant to dangerous. The primary side effects associated with steroid use include immunosuppression, gastrointestinal disturbance, emotional lability (vacillation between euphoria and depression), insomnia, osteoporosis, retardation of growth, muscle weakness and atrophy (particularly of pelvic and shoulder girdle musculature), hyperglycemia, sodium and water retention, and cushingoid effects.[1,2,4,6]

Current Controversies Regarding Bronchodilators and Anti-inflammatory Agents

Even a cursory review of the literature concerning asthma illustrates the complexity of the disease and a lack of consensus regarding the use of medications in the treatment of the various types of asthma.[29] Little consensus could be expected because there are virtually no data on which to base any comparisons of the efficacy of the numerous classes of drugs used in the treatment of asthma.[30] The same probably holds true for many of the drugs used to treat other kinds of lung disease.

Although the National Institutes of Health has developed and promulgated guidelines for patient care and pharmacologic therapy in the management of asthma,[31] there are several limitations to the guidelines. The primary limitation involves the method of defining the severity of asthma: frequency of acute episodes versus the intensity and duration of airway obstruction. Moreover, some authors[30] contend that the virtual absence of comparative data for different pharmacologic therapies fosters an environment in which the choices for the use of inhaled steroids, cromolyn, sympathomimetics, or specific [beta.sub.2]-agonists are made on the basis of personal preference and anecdotal communication between physicians and patients. Perhaps, physical therapists can take a part in limiting this dilemma by carefully documenting and reporting the functional ramifications associated with the withdrawal or titration of pharmacologic therapy in the treatment of patients with asthma.

Because mast-cell stabilization is believed to reverse or prevent the acute physiologic and clinical aspects of asthma, there is an ongoing quest to identify the most efficacious means of accomplishing such stabilization. Unfortunately, many investigations of the specific effects of cromolyn and corticosteroids are highly theoretical and lack a large base of supportive data.[32-34] In addition, the evidence suggesting that [beta.sub.2]-agonists are more potent mast-cell stabilizers than cromolyn[35] has not been widely substantiated. Nonetheless, [beta.sub.2]-agonists such as albuterol and terbutaline have been the most frequently prescribed drugs for the treatment of asthma since 1983.[30,31] Recently, however, inhaled [beta.sub.2]-agonists have been reported to facilitate bronchoconstriction in some patients with airway hyperresponsiveness, [36-43] and they have been implicated in the deaths of some patients.(44-47)

In response, the American Academy of Allergy and Immunology published a position statement on the use of inhaled [beta.sub.2]-adrenergic agonists in asthma.- These current recommendations call for the identification and nonprecipitous withdrawal of [beta.sub.2]-agonists from the treatment regimens of those patients (1) requiring "rescue treatment" for the symptoms of asthma with [beta.sub.2]-agonists more than three to four times within a 24-hour period or (2) using more than one canister (200 metered dose inhalations) of a [beta.sub.2]-agonist per month. These recommendations also call for the replacement of [beta.sub.2]-agonists with an inhated glucocorticoid or other nonbronchodilator medication. Investigators(49-53) have identified neonatal thrombocytopenia, elevated IgE levels,. and chromosome 11q as predisposing factors for adverse reactions.

Ancillary Pulmonary Medications

In addition to bronchodilators, several other drug groups are frequently used in the treatment of respiratory disorders: decongestants, antihistamines, antitussives, mucokinetics, respiratory stimulants and depressants, and paralyzing and antimicrobial agents. The drug grouping may provide clues regarding the nature of the problem for which it was taken, or vice versa. For example, a patient experiencing mucosal edema may complain of feeling "stuffed up" and the patient may be taking an over-the-counter decongestant or antihistamine.

Decongestants

The common cold, allergies., and many respiratory infections have in common the symptoms of "runny nose and stuffy head." Decongestants are used to treat this upper airway mucosal edema and discharge. The most common decongestants are alpha-adrenergic sympathomimetics, specifically [alpha.sub.1]-agonists.[54] These medications stimulate vasoconstriction by binding with the [alpha.sub.1]-receptors in the blood vessels of the mucosal lining of the upper airways. The desired result is a decreased congestion in the upper airways.

Decongestants are frequently combined (eg, with other ingredients. antihistamines) as constituents of commercially available nonprescription, over-the-counter preparations (Tab. 5). When used appropriately, these medications can be safe and affective. If a patient has a specific sensitivity or if the decongestant medication is improperly used, however, adverse effects may arise. Primary side effects include headache, dizziness, nausea, nervousness, hypertension, and cardiac irregularities (eg, palpitations).

Table 5.                      Common Decongestants
Drug                          Route of
Generic (Brand) Name          Administration
Ephedrine                     Oral
(Primatene [Tablets.sup.a])
Epinephrine                   Nasal spray
(Primatene Mist)
Oxymetazoline                 Nasal spray
(Neo-Synephrine
12-Hour)
Phenylephrine                 Nasal spray
(Neo-Synephrine)
Phenyl propanolamine          Oral
([Triaminic,.sup.a] [Contaca.sup.a])
Pseudoephedrine               Oral
(Sudafed)
[a]Decongestant combined with other ingredients.

Antihistamines

Treatment of the respiratory allergic responses associated with seasonal allergies (eg, hay fever) is one of the most common uses of antihistamines. Histamines play a role in the modulation of neural activity within the CNS and the regulation of gastric secretion by means of two types of receptors: [H.sub.1]- and [H.sub.2]-receptors, respectively.[55] The [H.sub.1]-receptors, primarily located in vascular, respiratory, and gastrointestinal smooth muscle, are specifically targeted for blockade by antihistamines in the treatment of asthma.[56,57] [H.sub.1]-antagonist drugs decrease the mucosal congestion, irritation, and discharge caused by inhaled allergens. Antihistamines may also reduce the coughing and sneezing often associated with common colds.

Some of the antihistamines commonly used to treat the symptoms of hay fever and other hay-fever-like allergies are listed in Table 6. Antihistamines are frequently combined with other ingredients, such as alpha-adrenergic sympathomimetics. The adverse effects most often attributable to antihistamines include sedation, fatigue, dizziness, blurred vision, loss of coordination, and gastrointestinal distress.

Table 6. Common Antibistamines
Drug                              Route of
Generic (Brand) Name              Administration
Brompheniramine                   Oral
([Dimetapp.sup.a])
Chlorpheniramine                  Oral
([Chlor-Trimeton,.sup.a]
[Sudafed,.sup.a][Coricidin.sup.a])
Dexbrompheniramine                Oral
([Drixoral.sup.a])
Dimenhydrinate                    Oral
(Dramamine)
Diphenhydramine                   Oral
(Benadryl)
Pheniramine ([Triaminic.sup.a])          Oral
Phenyltoloxamine                  Oral
([Sinutab.sup.a])
Triprolidine ([Actifed.sup.a])           Oral
[a]Antihistamine combined with other ingredients.

Antitussives

Coughs are such a common and troublesome symptom that there are more prescription drugs available for the treatment of coughs than for any other Symptom.[58] Used to suppress the ineffective, dry, hacking cough associated with minor throat irritations and the common cold, antitussive agents act to correct the irritation or block the receptors, or to increase the threshold of the cough center in the brain. They are generally indicated for only short-term use and are not indicated for coughs due to retained secretions.

Antitussives may be classified as topical anesthetics (eg, benzonatate [Tessalon]), nonnarcotics (eg, dextromethorphan [Congespirin for Children, Mediquell, Pertussin]), and narcotics (eg, codeine, morphine);. they are frequently combined with other ingredients and are offered under many brand names. The primary adverse effect of antitussive agents is sedation. Gastrointestinal distress and dizziness, however, may also occur. Common antitussives are listed in Table 7.

*Table 7.                  Common Antitussives
Drug
Generic
(Brand) Name               Classification
Benzonatate                Local anesthetic
(Tessalon)
[Codeinea.sup.a]           Increases threshold in
(many brand                cough center
names)
[Dextromethorphan.sup.a]   Increases threshold in
(many brand                cough center
names)
Diphenhydramine            Antihistamine
(Benadryl)
Hydrocodone                Increases threshold in
(Triaminic                 cough center
Expectorant
DH)
[a]Frequently combined with other ingredients
(ie, expectorants, decongestants).

Mucokinetics

Drugs that promote the mobilization and removal of secretions from the respiratory tract are called mucokinetic agents. There are four basic types of mucokinetic agents: mucolytics, expectorants, wetting agents, and surface active agents.

Mucolytic drugs disrupt the chemical bonds in mucoid and purulent secretions. decreasing the viscosity of the mucus and promoting expectoration. Administered by inhalation or direct intratracheal instillation, acetylcysteine (Mucomyst) is the principal mucolytic drug used today. Acetylcysteine's primary adverse effects include mucosal irritation, coughing, bronchospasm (especially in individuals with asthma), and nausea.

Expectorants increase the production of respiratory secretions, thus facilitating their ejection from the respiratory tract. Several expectorant drugs are available, among them are guaifenesin (Anti-Tuss, Robitussin), potassium iodide, and ammonium chloride. These drugs are often combined with others, and are available by many trade names (eg, Contac Cough and Sore Throat Formula, Triminicol Multi-Symptom Cold). Although expectorants are widely used outside the United States, and are sold over the counter in this country, there has been an ongoing debate over their efficacy.[1,19,60] Nonetheless, in an acute care setting, expectorants are often administered as an adjunct to vigorous bronchial hygiene techniques.

By humidifying and lubricating secretions, wetting agents make expectoration easier for the patient. The diluent of choice is half normal saline (0.45% NaCI), delivered by either continuous aerosol or intermittent ultrasonic nebulization.[61] Sterile water, however, is sometimes administered via a nebulizer as an airway irritant to induce coughing and facilitate the expectoration of sputum for subsequent laboratory testing. Although surface active agents may stabilize aerosol droplets, and thereby enhance their efficacy as carrier vehicles for nebulized drugs, the utility of these agents is debatable.[1,6]

Respiratory Stimulants and Depressants

Any agent that increases the output of the central respiratory centers may be considered a respiratory stimulant. Certainly, noxious stimuli, such as pain or verbal exhortation, may result in CNS excitation and thus elicit enhanced respiratory center activity. Medications such as sympathomimetics and methylxanthines also stimulate respiratory center activity and induce an increase in ventilation. Drugs that have a specific ability to cause central excitation with subsequently enhanced respiratory center activity are called analeptics. Unfortunately, analeptic drugs elicit dose-dependent levels of central stimulation that can ultimately result in convulsions. Therefore, the clinical use of analeptic medications is not without controversy, but few would argue that when respiratory failure has been aggravated by an injudicious intervention (eg, oxygen, narcotics), respiratory stimulants serve a purpose.[62,63]

Because it stimulates respiration more than it activates the cortical or spinal neurons, doxapram is one of the most widely accepted analeptics.[64] Administered intravenously, it is used to prevent a rise in arterial carbon dioxide pressure ([Paco.sub.2]) with oxygen therapy in acute ventilatory failure.[65-67] It is also used in patients with high-risk postoperative conditions to prevent respiratory depression.[68-70]

Some drugs (eg, sedatives, tranquflizers) are, to varying degrees, respiratory depressants. In general, patients with pulmonary disease should avoid the use of sedatives because they suppress the ventilatory drive. In some instances, however, intravenous morphine or diazepam (Valium) is given to patients who receive mechanical ventilation if anxiety or agitation is contributing to an increased work of breathing and hindering mechanical ventilation. The tranquilizer haloperidol (Haldol) may be prescribed for spontaneously breathing patients to control agitation because it has less respiratory depressant action than other tranquilizers or sedatives.[1] Many of the drugs used in the treatment of psychiatric disorders have varying degrees of sedative effect, depressing the CNS and possibly leading to respiratory depression in some patients.

Some antipsychotic drugs are associated with significant parasympatholytic effects, causing symptoms such as bronchoconstriction, dry mouth, blurred vision, constipation, and urinary retention.

Paralyzing Agents

Although tranquilizers can relieve muscle spasm, they do not prevent volitional muscle activity, and, in order to completely ablate muscular contraction during general anesthesia, the level of anesthesia must be profound--a situation not wholly desirable. Anesthetists and anesthesiologists, therefore, usually opt for lighter general anesthesia in conjunction with muscle-paralyzing agents to produce the desired degree of immobilization. Paralyzing agents are also used to facilitate endotracheal intubation or control laryngeal spasm; to treat diseases that cause neuromuscular hyper-activity (eg, tetanus, severe intractable seizure activity); and occasionally to prevent struggling, fighting, or excessive tachypnea in patients being mechanically ventilated. Table 8 presents the neuromuscular blocking agents frequently used clinically.

Antimicrobial Agents

Drugs used to combat small, unicellular organisms (eg, bacteria, viruses) that invade the body are often called antimicrobial agents or antibiotics. There are numerous pathogenic organisms, so it is quite likely that many patients receiving physical therapy will be taking one or more antimicrobial drugs. Unfortunately, the majority of antimicrobial agents may be as toxic to the host cells as to the infecting organisms.[6] The commonly used antimicrobial agents (Tab. 9) act by inhibiting cell-wall synthesis and function (eg, penicillins, cephalosporins, bacitracin, vancomycin, cycloserine, polypeptides, antifungal polyenes), protein synthesis (eg, aminoglycosides, chloramphenicol, macrolides, tetracyclines, lincomycins), or nucleotide formation (eg, rifampin, isoniazid). Antibacterial drugs may be classified as bactericidal (killing or destroying bacteria) or bacteriostatic (limiting growth and proliferation of bacteria). The bactericidal or bacteriostatic characteristics of a drug may depend on the dosage of the drug, some drugs (eg, erythromycin) being bacteriostatic at low dosages and bactericidal at higher dosages.

Penicillins are a mainstay in the treatment of respiratory infections. The semisynthetic penicillins have a broader spectrum of antibacterial activity than the natural penicillins.[28] The principal drawback to the use of penicillins is hypersensitivity, which manifests itself as skin rashes, hives, bronchoconstriction, or even anaphylactic reaction.

Cephalosporins are generally considered as alternatives to the penicillins, when penicillins are not tolerated by the patient or when they are ineffective. First-generation cephalosporins are used in the treatment of grampositive cocci and some gram-negative bacteria. Second-generation cephalosporins are similar in effectiveness against gram-positive cocci and are generally thought to be more effective against gram-negative bacteria. Third-generation cephalosporins are effective against the greatest number of gramnegative bacteria, but are of limited effectiveness against gram-positive cocci. Cephalosporins may elicit stomach cramps, diarrhea, nausea, and vomiting, and some patients may exhibit similar hypersensitivity reactions as to penicillins.

Aminoglycoside drugs have a wide spectrum of antibacterial activity; they are active against many aerobic gramnegative bacteria, against some aerobic gram-positive bacteria, and against many anaerobic bacteria.[4,6] Unfortunately, this wide spectrum of activity is associated with some toxicity.[71] Nephrotoxicity and ototoxicity are the primary toxic manifestations, especially in patients with particular susceptibility (eg, elderly patients, patients with liver or renal failure). The erythromycins also exhibit a broad spectrum of antibacterial activity, being effective against many gram-positive and some gram-negative bacteria.[4,6] The most common side effect of erythromycin administration is gastrointestinal distress (stomach cramps, nausea, vomiting, and diarrhea). When the tetracyclines were first introduced, they were effective against many gram-positive and gram-negative bacteria, as well as organisms such as Chlamydia, Rickettsia, and Spirochaeta. Because tetracyclines are generally bacteriostatic, however, many bacterial strains have developed resistance to tetracycline and its derivatives.[4,6]

There are not many effective drugs for the treatment of viruses in humans. Research into this area of pharmacology, however, is in a period of explosive discovery. Interferons represent just one of the areas of potential pharmacologic and physiologic benefit; advancements with vaccines is another. Fungal and protozoal infections have historically been associated with tropical and subtropical environments, or with less-developed areas of the world where sanitation and hygiene are inadequate. Recently, however, the incidence of these infections has become more prevalent because immunoinsufficiency, acquired (acquired immunodeficiency syndrome) or induced (post-organ transplantation), is more widespread. The use of antifungal and antiprotozoal agents, therefore, is becoming more common.

It is often very difficult to establish the causative agent in an acute pulmonary infection because transoral sputum is often contaminated, yielding mixtures of multiple organisms on culture. Nevertheless, the organisms Diplococcus pneumoniae and Haemophilus influenzae are generally thought to be the primary causative agents of infection of the respiratory mucosa in patients with chronic obstructive pulmonary dysfunction (COPD).[72,73] Precise diagnosis generally requires that sputum samples be obtained by transtracheal aspiration, bronchoscopy, or transpulmonary aspiration.

Other Agents

Oxygen should be considered a drug when it is breathed in concentrations higher than those found in the atmospheric air.-4 Regardless of its etiology, arterial hypoxemia (partial pressure of oxygen in arterial blood [[Pao.sub.2]] of <60 nun H is the most common indication for oxygen therapy. The therapeutic administration of oxygen can elevate the arterial oxygen tension and increase the arterial oxygen content (which shifts the oxyhemoglobin dissociation curve to the right), improving peripheral tissue oxygenation.[75] Additionally. the constriction of the central pulmonary vascular beds that is associated with hypoxia can be reduced.[76] Oxygen therapy, therefore. can be quite beneficial in the reduction of the abnormally high pulmonary arterial pressures seen with pulmonary hypertension. both at rest and with exercise.[77]

Supplemental oxygen is most commonly administered via nasal cannula at flow rates between 1 and 6 L/min. Systems for such low, gas flow rates are generally prescribed on the assumption that the patient is breathing at a relatively constant rate and depth (minute ventilation). When breathing patterns deviate from the norm, however, patients cannot be assured of receiving the intended fraction of inspired oxygen ([Fio.sub.2]). Therefore, when higher gas flow rates are indicated (eg, respiratory rate greater than 30 respirations per minute), or more accurate titrations of [Fio.sub.2] are required, oxygen is typically delivered by any one of several types of moderate- and high-flow face masks (providing oxygen concentrations of 400%-60%, or higher).[78] Table 10 summarizes the approximate oxygen concentrations achieved with different oxygen delivery devices. Care must always be exercised to avoid the potential for depression of the hypoxic drive to breathe in patients with chronically elevated [Paco.sub.2] levels (primarily patients with COPD).[78]

Table 10. Approximate Concentration
of Oxygen Delivered by Different
Delivery Devices
Delivery                Oxygen Flow
Device                  Rate (L/min)     [Mathematical Expression Omitted]
Low-flow systems
Nasal [cannula.sup.b]
                        1                0.24
                        2                0.28
                        3                0.32
                        4                0.36
                        5                0.40
                        6                0.44
Simple mask
                        5-6              0.35
                        6-7              0.45
                        7-10             0.55
High-flow
systems
Aerosol mask
                        10-12            0.35-[1.0.sup.c]
Venturi [mask.sup.d]
                        4                [0.24.sup.e]
                        4                [0.28.sup.e]
                        6                0.31
                        8                [0.35.sup.e]
                        8                [0.40.sup.e]
                        10               0.50
[a][Fio.sub.2] = fraction of inspired oxygen.
[b]Estimated [Fio.sub.2], assuming normal minute
ventilation.
[c]Depends upon the setting.
[d]Oxygen flow rates are minimums to be used
for indicated [Fio.sub.2] with device-specific orifice
sizes.
[e]The [Fio.sub.2] depends on the size of the orifice
or entrainment ports; these vary among manufacturers.

When used judiciously, oxygen therapy has few side effects. Dependent on the oxygen concentration and its duration of administration, however, oxygen toxicity can occur. In general, the pathological changes in the lungs associated with oxygen toxicity can be described in three phases: exudative, proliferative, and recovery.[79-81] In the exudative phase, there is damage to the alveolar-capillary membrane, which results in an increased permeability to water, electrolytes, and protein. Secondarily, the capillaries become plugged with platelets, and the interstitium is invaded by polymorphonuclear leukocytes. As lung damage progresses, the inflammatory response is intensified. In the proliferative phase, fibroblasts and type II epithelial cells proliferate in conjunction with interstitial collagen deposition. The recovery phase may result in complete healing or areas of fibrosis.

Since the accidental discovery, in 1980, of the important role the vascular endothelium plays in the regulation of vascular smooth muscle tone,[82] the identification of endothelium-derived relaxing factor (EDRF) in 1982,[83] and the discovery in 1986 that EDRF was indistinguishable from nitric oxide (NO),[84,85] numerous articles regarding the actions and effects of NO have been published. Although little is known about the biochemistry of NO, it is widely distributed in the body and plays an important role in the regulation of the circulation. In the body, (NO) is derived from L-arginine in a reaction catalyzed by NO synthase. Once produced, NO diffuses to the vascular smooth muscle cells where it activates the enzyme guanylate cyclase, leading to increased cGMP levels and to vascular smooth muscle relaxation.[86] In its ability to elicit the relaxation of vascular smooth muscle, NO resembles nitrovasodilators, such as nitroglycerin,[87] and has been termed the "endogenous nitrovasodilator."[87,88] For this reason, NO has been administered by inhalation for the treatment of pulmonary hypertension.89 93 Other potential therapeutic roles of NO include the treatment of endotoxic shock, adult respiratory distress syndrome, and hypertension in various disease states such as atherosclerosis and chronic renal failure.[86,94,95]

Although the side effects of NO are not completely understood, the marked oxidizing effects of nitrogen dioxide (the product of NO and oxygen) are known to (1) decrease alveolar permeability, (2) decrease [Pao.sub.2] and DLCO, (3) cause pulmonary edema, (4) cause loss of cilia and disintegration of bronchiolar epithelium, and (5) decrease pulmonary function tests (ie, forced expiratory volume in 1 second [FEV.sub.1]).[86] The few studies investigating the toxic effects of NO have shown that at concentrations of NO greater than 15 to 20 ppm, [Pao.sub.2] decreased 7 resistance to 8 mm Hg and airway resistance increased.[96,97]

The Effects of Pulmonary Medications on Exercise

The vast majority of pulmonary medications are used to promote bronchodilation and improve alveolar ventilation and oxygenation. These effects should improve an individual's ability to exercise and more effectively develop training effects. Because of the side effects of many pulmonary medications, hovever, exercise tolerance and the normal adaptations to habitual exercise conditioning may be retarded. The following section is not presented to discourage the use of these medications nor of exercise training; rather, it should highlight the important role exercise has for patients with pulmonary disease who are taking one or more pulmonary medications.

Habitual exercise performed at the proper intensity, duration, and frequency typically elicits both peripheral and central physiologic adaptations. The central adaptations include (1) improved ventilatory efficiency and (2) improved cardiac performance.[98-100] Peripheral adaptations include (1) an increase in the number and size of mitochondria, (2) improved extraction of oxygen from circulating blood by the exercising muscles, (3) increased muscle strength, (4) increased mitochondrial enzymatic activity, (5) proliferation of capillaries, (6) an increase in the mean transit time of blood through muscle capillaries, (7) a lowering of peripheral vascular resistance, and (8) an increased arteriovenous oxygen difference.[101-104] Moreover, these central and peripheral adaptations produce (1) a reduction in resting and submaximal heart rates, blood pressure, respiratory rate, and rating of perceived exertion (eg, Borg scale); (2) improved skeletal muscle and coronary blood flow; (3) increased exercise-induced lipolysis and translocation of lactate from muscle cells to the blood; and (4) improved oxygen consumption (lower levels of oxygen during submaximal exercise and higher levels at maximal exercise) and physical work capacity.[101-104]

Unfortunately, many of the favorable effects associated with habitual exercise are markedly delayed or absent in patients with pulmonary disease. In addition, many of the medications routinely used in the treatment of pulmonary disease mask or impede the beneficial effects of exercise. In particular, glucocorticoids have several deleterious effects on exercise performance and bodily function. The major deleterious manifestations of corticosteroids include cataracts, diabetes, peptic ulcers, emotional lability, ecchymoses, edema, osteoporosis, weight gain with cushingoid appearance, skeletal muscle myopathy (occurring in the proximal and possibly other muscle groups), and atrophy of type IIb muscle fibers.[l,4,6,105-110] It is of particular concern for patients with pulmonary disease that steroid myopathy and muscular atrophy have been identified not only in the peripheral skeletal muscles but also in the muscle fibers of the diaphragm.[111-113] The impact of glucocorticoids and other pulmonary medications on selected variables associated with exercise performance is summarized in Table 11.

All of the untoward effects associated with glucocorticoids are significantly dosage dependent. Moreover, the deleterious side effects of glucocorticoids may be reduced in their severity, or forestalled, with the implementation of a regular aerobic exercise regimen and proper nutritional support.[114,115] When anabolic steroids are used in conjunction with glucocorticoid therapy and exercise, trained patients with severe pulmonary disease have exhibited increased fat-free mass and improved ventilatory muscle strength and endurance in comparison with patients receiving only glucocorticoids.[115,116]

Because one of the major objectives of pharmacologic intervention and exercise therapy is the improvement of a patient's ability to breathe at rest and during activity, it is important to understand the impact of obstructive and restrictive pulmonary diseases on the pattern of breathing. Making this task difficult, however, is the fact that the exercise-related breathing patterns of patients with obstructive lung diseases have been described as falling somewhere between two extremes: rapid and shallow, or slow and deep.[117-119] This apparent lack of agreement stems from the fact that patients with obstructive lung disease must rely to a greater extent on breathing frequency to augment minute ventilation, because their tidal volumes tend to be significantly smaller than normal due to the disease process.[117] As a consequence, patients with obstructive lung disease reach their maximum minute ventilation at lower work loads than do asymptomatic individuals. Patients with obstructive pulmonary diseases are also hampered by a greater degree of alveolar and terminal respiratory unit hyperinflation compared with asymptomatic persons. This leads to larger residual volumes and smaller tidal volumes, further decreasing efficiency and increasing the work of breathing. It seems that the greater the severity of the obstructive lung disease (ie, the lower the [FEV.sub.1]). the longer it takes to achieve an increase in tidal volume.

Although patients with asthma and cystic fibrosis may demonstrate different pathological changes in the lung, the pattern of breathing during exercise is similar to that used by patients with chronic bronchitic and emphysemic obstructive lung disease.[120] The exercise-related pattern of breathing exhibited by patients with restrictive lung disease also appears to be similar to that of patients with obstructive lung disease. 121.122 Patients with restrictive lung disease appear to increase minute ventilation only minimally during exercise, and, as a result, there is a decrease in the total breathing cycle time due to a subsequent decrease in inspiratory time and a concomitant increase in inspiratory flow.[123] Because there is less opportunity to increase tidal volume and a greater degree of pulmonary hypertension in patients with restrictive lung disease, exercise tends to be terminated prematurely due to marked oxygen desaturation and dyspnea. Thus, like the patient with obstructive lung disease, the patient with restrictive lung disease tries to increase minute ventilation by increasing breathing frequency, but only slightly increases tidal volume.[77,24]

The appropriate and judicious use of supplemental oxygen can improve the metabolic activity and work capacity of skeletal muscle, as well as the breathing pattern, of patients with pulmonary disease who are hypoxic.[125,126] Additionally, the use of bilevel positive airway pressure (Bi-PAP*--a noninvasive ventflatory assistance device providing supplemental oxygen and positive airway pressure during both inspiration and expiration) at rest and during exercise has been shown to significantly increase arterial oxygen saturation levels and decrease the respiratory rates of patients with end-stage lung disease.[127] Careful prescription and titration of medications, as well as appropriate monitoring of the cardiorespiratory responses at rest and during exercise, can permit individuals with lung disease to participate to a greater extent in activities of daily living and exercise training programs.

Summary

In this article, we have discussed the principal groups of drugs used in the treatment of pulmonary dysfunction and their potential effects on exercise performance. The principal points that were addressed include

* normal bronchomotor tone is the result of a balance between the influences of the sympathetic and parasympathetic divisions of the ANS;

* bronchoconstriction is the result of abnormal bronchomotor tone (bronchospasm), inflammation, or mechanical obstruction;

* the primary goal of bronchodilator therapy is to manipulate the influences of the ANS via two opposing nucleotides: cAMP and cGMP;

* decongestants are used to treat the mucosal edema and increased production often associated with common colds, allergies, and many respiratory infections;

* antihistamines are often used alone, or combined with other ingredients, to control the production of mucus and the mucosal edema and irritation commonly associated with respiratory allergic responses;

* antitussives are used to suppress the ineffective, dry, hacking cough associated with minor throat irritations and the common cold;

* mucokinetics promote the mobilization and removal of secretions from the respiratory tract;

* analeptics are used to stimulate the CNS and enhance respiratory center activity;

* paralyzing agents are used to ensure the immobility of patients during surgical procedures, to facilitate endotracheal intubation, and to reduce the work of breathing in some patients receiving mechanical ventilation;

* antimicrobial agents are used to combat microorganisms that invade the body, either by killing them or by limiting their growth and proliferation;,

* oxygen is considered a drug when it is administered in concentrations higher than those found in the atmospheric air;

* NO is used for the treatment of pulmonary hypertension; and

* careful prescription and titration of medications, as well as appropriate monitoring of the cardiorespiratory responses at rest and during exercise, can permit individuals with lung disease to participate to a greater extent in activities of daily living and exercise training programs.

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LP Cahalin, PT, CCS, is Cardiopulmonary Physical Therapy Transplant Coordinator and Assistant Instructor, Massachusetts General Hospital and Institute of Health Professions, Boston, MA 02114 (USA). Address all correspondence to Mr Cahalin. HS Sadowsky, RRT. PT. CCS. is Associate Professor. Department of Physical Therapy. California State University,