Drug Administration Phase

The drug administration phase describes the method by which a drug dose is made available to the body. Administering drugs directly to the respiratory tract uses the inhalation route, and the dose form is an aerosol of liquid solutions, suspensions, or dry powders. The most commonly used devices to administer orally or nasally inhaled aerosols are the metered dose inhaler (MDI), the small volume nebulizer (SVN), and the dry powder inhaler (DPI). Reservoir devices, including holding chambers with one-way inspiratory valves and simple, nonvalved spacer devices, are often added to MDIs to reduce the need for complex hand-breathing coordination and to reduce oropharyngeal impaction of the aerosol drug (see Chapter 36).

The advantages of treatment of the respiratory tract with inhaled aerosols are as follows:

Disadvantages of the delivery of inhaled aerosols in treating respiratory disease include the number of variables affecting the delivered dose and lack of adequate knowledge of device performance and use among patients and caregivers.³

Pharmacokinetic Phase

The pharmacokinetic phase of drug action describes the time course and disposition of a drug in the body based on its absorption, distribution, metabolism, and elimination. Inhaled bronchoactive aerosols are intended for local effects in the airway. Undesired systemic effects result from absorption and distribution throughout the body. One method of limiting distribution of inhaled aerosols is use of a fully ionized drug rather than a nonionized agent. A fully ionized drug is not absorbed across lipid membranes, whereas a nonionized drug is lipid-soluble and diffuses across cell membranes and into the bloodstream. Examples are ipratropium and atropine sulfate. Ipratropium is a fully ionized quaternary ammonium compound that diffuses poorly across lipid membranes. Atropine is poorly ionized and diffuses well, distributing throughout the body. As a result, atropine produces systemic side effects such as mydriasis (dilation of the pupils) and blurring of vision. The effects of ipratropium are largely local to the airway, and systemic effects are nonexistent or minimal.

An inhaled aerosol distributes to the lung by inhalation and the stomach through swallowing of drug that deposits in the oropharynx. The therapeutic effect of the aerosol drug is caused by the portion in the airway. Systemic effects are due to absorption of the drug from the airway and gastrointestinal (GI) tract. The ideal aerosol would distribute only to the airway with none reaching the stomach. The lung availability-to-total systemic availability ratio (L/T ratio) quantifies the efficiency of aerosol delivery to the lung:

< ?xml:namespace prefix = "mml" />L/T ratio=Lung availability/(Lung+GI availability)

This concept, proposed by Borgström⁴ and elaborated by Thorsson,⁵ is illustrated in Figure 32-1, showing delivery of albuterol by inhalation using an MDI and a DPI.

Pharmacodynamic Phase

The pharmacodynamic phase describes the mechanisms of drug action by which a drug molecule causes its effects in the body. Drug effects are caused by the combination of a drug with a matching receptor. Drug signaling mechanisms include the following:

The mechanisms of drug action are briefly described for each class of bronchoactive drug.

Airway Receptors and Neural Control of the Lung

Pharmacologic control of the airway is mediated by receptors found on airway smooth muscle, secretory cells, bronchial epithelium, and pulmonary and bronchial blood vessels. There are sympathetic (adrenergic) and parasympathetic (cholinergic) receptors in the lung. The terminology for drugs acting on these receptors is based on the usual neurotransmitter that acts on the receptor. The usual neurotransmitter in the sympathetic system is norepinephrine, which is similar to epinephrine, also known as adrenaline (Adrenalin). The usual neurotransmitter in the parasympathetic system is acetylcholine. The receptors responding to these neurotransmitters are termed adrenergic and cholinergic. Agonists (stimulating agents) and antagonists (blocking agents) that act on these receptors are given the following classifications:

Because cholinergic receptors exist at autonomic ganglia and at the myoneural junction in skeletal muscle, the terms muscarinic and antimuscarinic distinguish cholinergic agents whose action is limited to parasympathetic sites. Neostigmine is a cholinergic (indirect-acting) drug that increases receptor stimulation at both the myoneural junction and the parasympathetic sites. By contrast, atropine is an antimuscarinic agent, which blocks the action of acetylcholine only at the parasympathetic sites. Table 32-1 summarizes receptors and their effects for the cardiopulmonary system. A more detailed description of the autonomic nervous system and receptor subtypes is provided by Katzung and colleagues.²

Indications for Use

The general indication for use of an adrenergic bronchodilator is the presence of reversible airflow obstruction. The most common use of these agents clinically is to improve flow rates in asthma (including exercise-induced asthma), acute and chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis (CF), and other obstructive airway states.

Mode of Action and Effects

Adrenergic bronchodilators can stimulate one or more of the following receptors, with the effects described:

Bronchodilation, through stimulation of beta-2 receptors, is the desired therapeutic effect. Both alpha-adrenergic and beta-adrenergic receptors are G protein–linked receptors. Figure 32-2 illustrates the mode of action for relaxation of airway smooth muscle when a beta-2 receptor is stimulated. The nature of the beta receptor and its activity is presented in detail in a review by Barnes.⁷

Adrenergic Bronchodilator Agents

Adrenergic bronchodilator agents represent the evolution of a drug class. Although all of these agents are adrenergic agonists, the differences among individual agents are due to their receptor preference (alpha-adrenergic, beta-1-adrenergic, beta-2-adrenergic) and their different pharmacokinetics as listed in Table 32-2. These differences determine the optimal clinical application of individual agents, as discussed subsequently. The adrenergic bronchodilators form three subgroups.

Short-Acting Noncatecholamine Agents

Because of their short duration of action and lack of beta-2 specificity, catecholamines were replaced with longer acting, beta-2-specific agents, including metaproterenol, pirbuterol, albuterol, and levalbuterol. Because their duration of action is approximately 4 to 6 hours, these drugs are more suited to maintenance therapy than catecholamines and can be taken on a four-times-daily schedule. However, their modest duration of action results in loss of bronchodilating effect overnight.

Single-Isomer Beta Agonists

Levalbuterol is approved as a single-isomer beta-2-selective agonist. Previous inhaled formulations of adrenergic bronchodilators all were synthetic racemic mixtures, containing both the (R)-isomer and the (S)-isomer in equal amounts. Levalbuterol is the pure (R)-isomer of racemic albuterol. Both stereoisomers of albuterol are shown in Figure 32-3 with the single-isomer (R-isomer) form of levalbuterol. Although the (S)-isomer is physiologically inactive on adrenergic receptors, there is accumulating evidence that the (S)-isomer is not completely inactive. Box 32-1 lists some of the physiologic effects of (S)-albuterol noted in the literature.^8–14 The effects noted antagonize the bronchodilating effects of the (R)-isomer and promote bronchoconstriction. In addition, the (S)-isomer is more slowly metabolized than the (R)-isomer.

Box 32-1   Effects and Characteristics of (S)-Isomer of Albuterol

• Increases intracellular calcium concentration in vitro⁸

• Activity is blocked by the anticholinergic atropine⁸

• Does not produce pulmonary or extrapulmonary beta-2-mediated effects⁹

• Enhances experimental airway responsiveness in vitro¹⁰

• Increases contractile response of bronchial tissue to histamine or leukotriene C₄ in vitro¹¹

• Enhances eosinophil superoxide production with interleukin-5 stimulation¹²

• Slower metabolism than (R)-albuterol in vivo¹³

• Preferential retention in the lung when inhaled by MDI (in vivo)¹⁴

Levalbuterol is available as a nebulization solution in three strengths: 0.31 mg/3 ml, 0.63 mg/3 ml, and 1.25 mg/3 ml. As a result of mixing of other inhaled agents, levalbuterol is also available as a concentrate of 1.25 mg/0.5 ml and an MDI. In a study by Nelson and associates,¹⁵ the 0.63-mg dose was found to be comparable to the 2.5-mg racemic albuterol dose in onset and duration. Side effects of tremor and heart rate changes were less with the single-isomer formulation. The 1.25-mg dose showed a higher peak effect on forced expiratory volume in 1 second (FEV₁) with an 8-hour duration compared with racemic albuterol. Side effects with this dose were equivalent to the side effects seen with racemic albuterol. An equivalent clinical response was seen with one-fourth of the racemic dose (0.63 mg) using the pure isomer, although the racemic mixture contains 1.25 mg of the (R)-isomer (half of the total 2.5-mg dose). A detailed review is available of levalbuterol and differences between the (R)-isomer and (S)-isomer of albuterol.¹⁶

Adverse Effects

Older adrenergic agents, such as isoproterenol, commonly caused tachycardia, palpitations, and an “adrenaline effect” of shakiness and nervousness. The newer, more beta-2-selective agents are safer and typically cause tremor as the main side effect. Other common side effects with the inhaled agents include headache, insomnia, and nervousness. Patients should be reassured that some tolerance to these effects does occur. Potential adverse effects with use of adrenergic bronchodilators include the following:

Inhalation results in fewer and less severe side effects than oral administration. Although tolerance develops to the bronchodilating effect, this is not a contraindication to use of the drugs, and relaxation of airway smooth muscle still occurs. Desaturation resulting from mismatching of with inhalation of the aerosol is not clinically significant and reverses quickly. Bronchospasm resulting from chlorofluorocarbon propellants can be prevented by changing to newer hydrofluoroalkane-propelled MDIs or a different aerosol delivery form.

The implication of beta-2-adrenergic agonists in deaths from asthma—termed the asthma paradox or the beta agonist controversy—remains debated.¹⁹ There is evidence of loss of a bronchoprotective effect with use of beta agonists, and patients should be cautioned to avoid asthma triggers.²⁰ The increased prevalence of asthma in general remains a troublesome and unresolved issue.

Assessment of Bronchodilator Therapy

Assessment of therapy with adrenergic bronchodilators should be based on the indication for the aerosol agent (presence of reversible airflow obstruction owing to primary bronchospasm or other obstruction secondary to an inflammatory response or secretions, either acute or chronic). With all aerosol drug therapy, basic vital signs (respiratory rate and pattern, pulse, breath sounds) should be assessed before and after treatment, especially for initial drug use, and the patient’s subjective reaction (complaints of breathing difficulty) should be assessed. Patients should be instructed in the correct use of the aerosol device used, with verification of correct use. Finally, the patient’s subjective reaction to the treatment should be monitored for any change in breathing effort. This assessment applies to all subsequent drug groups by aerosol and is not repeated for each class. The following specific actions are suggested to evaluate patient response to this class of drugs:

The following actions are suggested to evaluate patient response to long-acting beta agonists:

Note: Death has been associated with excessive use of inhaled adrenergic agents in severe acute asthma crises. Individuals using such drugs should be instructed to contact a physician or an emergency department if there is no response to the usual dose of the inhaled agent.

Because of the ongoing safety concerns of long-acting beta-2 agonists, the FDA is requiring changes on how long-acting beta-2 agonists are used in the treatment of asthma. As of June 2, 2010, the FDA suggests the following:

Indications for Use

Ipratropium bromide and tiotropium bromide are the only inhaled anticholinergic bronchodilators available in the United States. Table 32-3 lists the dosage forms and pharmacokinetics of ipratropium and tiotropium. Generally, anticholinergic agents have been found to be as effective as beta agonists in airflow improvement in COPD but less so in asthma. A nasal formulation of ipratropium is also available for relief of allergic and nonallergic perennial rhinitis, including the common cold.²¹

Mode of Action

As antimuscarinic agents, ipratropium and tiotropium act as competitive antagonists for acetylcholine at muscarinic receptors on airway smooth muscle. Part of the airflow obstruction in COPD may be due to vagally mediated, reflex cholinergic stimulation. Airway irritation and inflammation stimulate afferent sensory C-fibers in the airway, which synapse with efferent vagal (cholinergic) fibers to the airway and mucous glands. The muscarinic receptor subtype on smooth muscle and submucosal mucous glands is the M₃ receptor, which is a G protein–linked receptor. The effect of acetylcholine, the usual neurotransmitter, on the muscarinic (M₃) receptors on airway smooth muscle is bronchoconstriction. The M₁ receptor at the ganglionic junction enhances cholinergic nerve transmission. The M₂ receptor is an autoreceptor inhibiting further release of acetylcholine so that blockade can increase acetylcholine release and may offset the bronchodilating effect of antimuscarinics.²²

Ipratropium and tiotropium block the action of acetylcholine at the M₃ receptor in the airway, reversing bronchoconstriction secondary to cholinergic activity. Ipratropium is a nonselective muscarinic receptor blocker and has affinity for M₁, M₂, and M₃ receptors. Blockade of the M₂ receptor can theoretically reverse the bronchodilating effect of ipratropium or other nonselective muscarinic receptor antagonists because the autoinhibitory action of the M₂ receptor is blocked. Both ipratropium and tiotropium are quaternary ammonium compounds and are poorly absorbed after inhalation.

Tiotropium exhibits receptor subtype selectivity for M₁ and M₃ receptors. The drug binds to all three muscarinic receptors (M₁, M₂, and M₃) but dissociates much more slowly than ipratropium from the M₁ and M₃ receptors; this results in a selectivity of action on M₁ and M₃ receptors. In patients with COPD, tiotropium provides a bronchodilating effect for 24 hours with an adequate dose.²² Inhalation of a single dose gives a peak plasma level within 5 minutes, with a rapid decline to very low levels within 1 hour. The site of action of anticholinergic agents in reversing cholinergic-induced airflow obstruction is shown in Figure 32-4.

Adverse Effects

Ipratropium bromide and tiotropium bromide are fully ionized compounds that are not well absorbed and distributed throughout the body, whereas atropine sulfate is a tertiary ammonium compound that is easily absorbed into the bloodstream. As a result, atropine produces many systemic side effects when inhaled, even though it is delivered locally to the lung. Side effects include the local topical effect of dry mouth, pupillary dilation, lens paralysis, increased intraocular pressure, increased heart rate, urinary retention, and altered mental state. Because of its many side effects and the availability of ionized compounds such as ipratropium, the use of atropine sulfate by nebulization is not recommended. In contrast, the side effects of inhaled anticholinergics are largely limited to its local site of action (Box 32-2).

The amount of drug in the nebulizer dose of ipratropium is more than 10 times greater than the MDI dose (500 mcg vs. 34 mcg). If a patient receives approximately 10% of an inhaled aerosol to the lung, a much larger dose is given with an SVN. Although ipratropium is not contraindicated in subjects with prostatic hypertrophy, urinary retention, or glaucoma, the drug should be used with precaution and adequate evaluation for possible systemic side effects in these subjects. The eye must be protected from drug exposure with aerosol use owing to accidental spraying from an MDI or with nebulizer-mask delivery. There is less chance of eye exposure with the MDI formulation than the SVN solution; a holding chamber is recommended with MDI use.

Assessment

The assessment of bronchodilator therapy with an anticholinergic agent is the same as assessment for adrenergic agents. In addition, preexisting conditions of narrow-angle glaucoma, prostatic hypertrophy, or urinary retention warrant caution with continued evaluation.

N-Acetyl Cysteine

NAC is the N-acetyl derivative of the amino acid l-cysteine and is given either by nebulization or by direct tracheal instillation.

Mini Clini

Calculating Drug Doses

 Problem

The dose of ipratropium bromide (Atrovent) released from the valve of the MDI is 17 µg. With a usual dose of two actuations, this would release 34 µg total. The SVN solution is a vial of 2.5 ml of a 0.02% strength concentration, all of which is placed in the nebulizer. Does the nebulizer dose contain the same amount of drug as the two actuations from the MDI?

Discussion

The amount of drug in milligrams or micrograms can be calculated for the nebulizer solution, using the following formula for percentage strength:

%(as decimal)=Drug solute(in g)Total solution(in ml)

0.0002=xg2.5ml

xg=0.0002×2.5ml=0.0005g

Converting 0.0005 g to milligrams gives 0.5 mg, or 500 µg. Two actuations of the MDI release 34 µg, whereas the dose contained in the SVN is 500 µg (or >10 times more). The lower dose MDI is the reason that additional actuations of four or six are needed if a patient does not obtain relief. The SVN solution may also provide relief by giving a higher dose of the drug.

Dornase Alfa

Dornase alfa (Pulmozyme) is a genetically engineered clone of the natural human pancreatic DNase enzyme, which can digest extracellular DNA material. It is a peptide mucolytic and can reduce extracellular DNA and F-actin polymers. It is occasionally referred to as rhDNase (recombinant human DNase). It is designated as an orphan drug. Administration and dosage are given in Table 32-4.

Mode of Action

Dornase alfa is a proteolytic enzyme that can break down the DNA material from neutrophils found in purulent secretions (Figure 32-5). This agent has been shown to be more effective than acetylcysteine in reducing the viscosity of infected sputum in CF.²⁸

Other Mucoactive Agents

Bland aerosols of water, including distilled water and normotonic, hypertonic, and hypotonic saline, have traditionally been nebulized to improve mobilization of secretions in respiratory disease states. The mucus gel layer is relatively resistant to the addition or removal of water after it is formed. Bland aerosols have been found to increase secretion clearance and sputum production and cause productive coughing.²⁹ The effect is probably a vagally mediated reflex production of cough and mucus secretion. Bland aerosols are more properly considered expectorants rather than mucolytic agents. Clinicians must be alert to the possibility of bronchospasm with nonisotonic solutions, in particular, in patients with hyperreactive airways.

Sodium bicarbonate has been aerosolized and directly instilled into the airway in intubated subjects to reduce the viscosity of airway secretions. This agent is not approved for such use. The reduction in secretion viscosity is thought to be caused by the increase in topical airway pH, with degradation of bonding in the mucin polysaccharide.

Expectorants are mucoactive but stimulate the production and clearance of airway secretions rather than cause mucolysis. Examples of such agents include guaifenesin (also known as glyceryl guaiacolate), iodinated glycerol, and saturated solution of potassium iodide (SSKI). Guaifenesin is found in many over-the-counter cough and cold products.

Assessment of Mucoactive Drug Therapy

Assessment of drug therapy for respiratory secretions is difficult. FEV₁ is relatively insensitive to changes in mucociliary clearance. The rate of change in lung function over time is a better marker. In addition, during maintenance therapy, the volume of sputum expectorated varies from day to day and does not reflect effective therapy. The following assessments should be performed.

Indications and Purposes

The two general formulations of aerosolized glucocorticoids are orally inhaled and intranasal aerosol preparations. Orally inhaled preparations are listed in Table 32-5. The primary use of orally inhaled corticosteroids is for antiinflammatory maintenance therapy of persistent asthma⁶ and severe COPD.³¹ The use of intranasal steroids is for control of seasonal allergic or nonallergic rhinitis. Most agents in Table 32-5 are available as intranasal preparations, with the exception of the combination drugs.

Mode of Action

Glucocorticoids are lipid-soluble drugs that act on intracellular receptors. The complex action of steroids is illustrated in Figure 32-6.^32–34 Because steroid action involves modification of cell transcription, full antiinflammatory effects require hours to days. It is important for patients to understand that inhalation of an aerosolized steroid does not provide immediate relief as with an adrenergic bronchodilator. However, daily compliance with the inhaled medication is essential to controlling the inflammation of asthma. Oral corticosteroids may be needed initially to clear the airway or as “burst” therapy to control asthma exacerbations.

Adverse Effects

The type and severity of side effects seen with inhaled aerosolized corticosteroids are much less than with systemic use, as with other classes of aerosolized drugs. Box 32-3 lists systemic and local effects that can occur with inhaled steroids. The systemic effect of adrenal suppression is not usually seen with inhaled doses less than 800 mcg/day in adults or less than 400 mcg/day in children. Use of a reservoir device should be routine with inhaled steroids to prevent a swallowed portion adding to the systemic effect and to prevent the local effects of oral candidiasis and dysphonia. Growth retardation with use of inhaled steroids in asthma is controversial. Some investigators found no growth suppression even with high-dose inhaled steroids. Allen and colleagues³⁵ published a comprehensive review of inhaled steroids.

Special Considerations

The modes of action of all inhaled glucocorticoids are the same with one exception. Ciclesonide, a prodrug, is given as an inactive compound and is converted to an active metabolite, desisobutyryl-ciclesonide, by intracellular enzymes. Ciclesonide is available as an intranasal formulation (Omnaris) and a pressurized MDI (Alvesco).

Assessment of Drug Therapy

The basic actions to evaluate an aerosol drug treatment should be followed (see section on Assessment of Bronchodilator Therapy). As with other drug therapy, the indications for this class of drug should be present. The 2007 NAEPP and 2010 Global Initiative on Obstructive Lung Disease (GOLD) COPD guidelines are recommended for guidance.6,31 In addition, with inhaled corticosteroids, the following actions are suggested:

Indication for Use

The general indication for clinical use of nonsteroidal antiasthma agents is prophylactic management (control) of persistent asthma (Step 2 or greater asthma, using the classification in the 2007 NAEPP guidelines⁶). Step 2 asthma is defined as more than 2 days/week with but not daily symptoms and more than 2 nights/month with awakenings and FEV₁ of 80% or greater. Step 3 asthma is defined as daily symptoms and 3 to 4 nights/month with awakening and FEV₁ greater than 60% but less than 80%. Step 4 and above asthma is defined as symptoms throughout the day and night awakenings more than once a week and FEV₁ less than 60%. For children older than 12 years and adults, omalizumab is available for use in asthma above step 4.³⁶

The following are qualifications to the general indications for use of these agents:

All of the nonsteroidal antiasthma drugs described in this chapter are controllers, not relievers, and are used in asthma requiring antiinflammatory drug therapy (Box 32-4).

Mode of Action

Cromolyn sodium acts by inhibiting the degranulation of mast cells in response to allergic and nonallergic stimuli. This inhibition prevents release of histamine and other mediators of inflammation. These mediators cause bronchospasm and trigger an increasing cascade of further mediator release and inflammatory cell activity in the airway.³⁸

Zafirlukast and montelukast act as leukotriene receptor antagonists and are selective competitive antagonists of leukotriene receptors LTD₄ and LTE₄. Leukotrienes such as LTC₄, LTD₄, and LTE₄ (previously known as SRS-A) stimulate leukotriene receptors termed CysLT₁ to cause bronchoconstriction, mucus secretion, vascular permeability, and plasma exudation into the airway. The mode of action is shown in Figure 32-7. The drug inhibits asthma reactions induced by exercise, cold air, allergens, and aspirin.³⁹

Zileuton inhibits the 5-lipoxygenase enzyme that catalyzes the formation of leukotrienes from arachidonic acid (see Figure 32-7).⁴⁰ Omalizumab is a recombinant DNA–derived humanized antibody that binds to IgE. The agent inhibits the attachment of IgE to mast cells and basophils, reducing the release of chemical mediators of the allergic response.⁴¹

Adverse Effects

A potential adverse effect with any nonsteroidal antiasthma drug is inappropriate use. These agents are not bronchodilators and offer no benefit for acute airway obstruction in asthma. Using the NAEPP terminology, all of these agents are controllers rather than relievers.⁶

Table 32-7 summarizes information and comparative features of the three antileukotriene agents, including drug interactions, common side effects, and contraindications. The most common adverse reactions seen with omalizumab include injection site reaction, viral infections, respiratory tract infections, headache, sinusitis, and pharyngitis.

Assessment of Drug Therapy

The basic actions to evaluate an aerosol drug treatment should be followed (see section on Assessment of Bronchodilator Therapy). As with other drug therapy, the indication for this class of drug should be present.

Pentamidine Isethionate

Pentamidine isethionate (NebuPent) is an antiprotozoal agent that has been used in the treatment of opportunistic pneumonia caused by Pneumocystis jiroveci, which is the causative agent of pneumocystis pneumonia (PCP). PCP is seen in immunocompromised patients, especially patients with AIDS.

Ribavirin

Ribavirin (Virazole) is an antiviral agent used in the treatment of severe lower respiratory tract infections caused by respiratory syncytial virus (RSV). RSV is a common seasonal respiratory infection in infants and young children, which is usually self-limiting. The cost-effectiveness of ribavirin continues to be debated. Recommendations for use of the drug were published in a statement by the American Academy of Pediatrics.⁴⁴ Administration of the aerosol requires use of a special large-reservoir nebulizer called a small particle aerosol generator (SPAG). The mode of action of ribavirin is ascribed to the similarity of the drug to guanosine, a natural nucleoside. Substitution of ribavirin for the natural nucleoside interrupts the viral replication process in the host cell.

Inhaled Tobramycin

Patients with CF have chronic respiratory infection with Pseudomonas aeruginosa and other microorganisms. Such chronic infection causes recurrent acute respiratory infections and deterioration of lung function. With the exception of the quinoline derivatives such as ciprofloxacin, antibiotics such as the aminoglycosides (e.g., tobramycin), which are effective against Pseudomonas organisms, have poor lung bioavailability when taken orally. Consequently, these antibiotics must be given either intravenously or by inhalation. The aminoglycoside tobramycin has been approved for inhaled administration (TOBI) and is intended to manage chronic infection with P. aeruginosa in patients with CF. Goals of therapy are to treat or prevent early colonization with P. aeruginosa and maintain present lung function or reduce the rate of deterioration. The emergence of bacterial resistance was not seen in clinical trials with inhaled tobramycin.⁴⁵

Inhaled Aztreonam

Aztreonam was approved in December 1986 by the FDA as a monobactam, a synthetic bactericidal antibiotic; it is given as an IV solution. Inhaled aztreonam (Cayston) was approved in 2010 to improve pulmonary symptoms in patients with CF colonized with P. aeruginosa.⁵⁰ Inhaled aztreonam is not indicated for patients younger than 7 years old or patients with Burkholderia cepacia infection. This agent has been studied only in patients with FEV₁ greater than 25% or less than 75% of predicted. The agent is delivered by itself using the Altera Nebulizer System.

Colistimethate Sodium

Colistimethate sodium (colistin) is an antibiotic used to treat sensitive strains of gram-negative bacilli, particularly P. aeruginosa. Colistimethate sodium is available as an inhaled formulation in Europe as Promixin; this agent is not approved for inhalation by the FDA. However, nebulization of the parenteral formulation is commonly used in patients with CF. Falagas and colleagues⁵¹ published a review of IV and aerosolized colistimethate sodium.

Inhaled Zanamivir

Zanamivir is an inhaled powder aerosol (DPI). Despite the availability of zanamivir and the oral antiinfluenza agent oseltamivir (Tamiflu), prophylactic vaccination against influenza is still recommended, especially in high-risk individuals with cardiovascular or pulmonary disease. Zanamivir and oseltamivir represent a new class of antiviral agents termed neuraminidase inhibitors.

Mode of Action

The influenza virus attaches to respiratory tract cells by binding of viral surface hemagglutinin to the cell’s surface molecule of sialic acid (Figure 32-8). The viral particle also has an enzyme, neuraminidase, on its surface. When replicated viral particles are released from the host cell after infection, the viral neuraminidase cleaves the sialic acid on both the host cell surface and other viral particle surfaces so that mature virus can be released and spread. Without neuraminidase, influenza virus would clump together and to the host cell, preventing spread. Zanamivir and oseltamivir combine with the surface neuraminidase, preventing its action and the spread of viral particles.

As described in more detail in Chapter 38, nitric oxide (INOmax) is indicated in the treatment of neonates (>34 weeks’ gestational age) with hypoxic respiratory failure.⁵⁶ The patient should have evidence of pulmonary hypertension in which nitric oxide would improve oxygenation and decrease the need for extracorporeal membrane oxygenation. Off-label uses include reducing pulmonary artery pressure in the neonate.⁵⁷

Iloprost (Ventavis) inhalation is indicated for the treatment of pulmonary hypertension.⁵⁹ Iloprost inhalation is administered with the I-neb nebulizer.

Treprostinil (Tyvaso) is indicated for the treatment of pulmonary arterial hypertension to increase walking distance in patients with New York Heart Association class III symptoms.⁶⁰ It is administered using the Tyvaso Inhalation System, which is an ultrasonic, pulsed-delivery device.