Chapter 16 presents three groups of drugs that are used for the direct treatment or prevention of respiratory disease: α₁-proteinase inhibitors (APIs), used in the treatment of congenital α₁-antitrypsin deficiency; nicotine replacement and other agents used in smoking cessation; and pulmonary vasodilators, used for pulmonary hypertension states in newborns and for acute respiratory distress syndrome (ARDS) in adults. Two inhaled synthetic analogues of prostacyclin (PGI₂) for the treatment of pulmonary hypertension are described as well.

α₁-proteinase inhibitor (human)

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α₁-proteinase inhibitor is given intravenously to individuals with congenital α₁-antitrypsin deficiency and who exhibit panacinar emphysema at a young age.

α₁-proteinase inhibitor (α₁-PI, API) is also known as α₁-antitrypsin (α₁-AT) and is intended for therapy of congenital α₁-AT deficiency, which leads to emphysema. The product is prepared from pooled human plasma from normal donors, with purification and treatment to remove potentially infectious agents. The disease state is usually termed α₁-antitrypsin deficiency, and the deficient protein is termed α₁-proteinase inhibitor. The terms α1-antitrypsin and α1-proteinase inhibitor are used interchangeably, and refer to the same protein.

α1-antitrypsin deficiency

α₁-AT deficiency is a genetic defect that can lead to the development of severe panacinar emphysema. This autosomal recessive disorder is characterized by serum API levels less than 35% of normal and manifests as panacinar emphysema at age 30 to 50 years. API deficiency is estimated to account for approximately 2% of all cases of emphysema in the United States. It is estimated that there are 60,000 to 100,000 Americans with severe α₁-AT deficiency.¹^,² Studies done in the United States vary in their estimates of the prevalence among newborns of α₁-AT deficiency, ranging from 1 in 2857 to 1 in 5097.³ Among whites, the genetic disorder α₁-AT deficiency is as common as cystic fibrosis.⁴ In about 50% of cases of emphysema that result from API deficiency, there is accompanying chronic bronchitis with mucus hypersecretion, perhaps as a result of secretory cell metaplasia caused by unchecked proteases in the epithelial lining fluid.⁵ Emphysema caused by API deficiency is worse in the lower lung zones and can be markedly accelerated by cigarette smoking.¹

The basic pathology of emphysema resulting from API deficiency is an imbalance between proteases, especially neutrophil elastase (NE) and antiproteases, especially API. The main substrate for API is neutrophil elastase. The pathogenesis of emphysema is described as a process of alveolar wall destruction caused by insufficient protection from the protease neutrophil elastase, an enzyme that can cleave all forms of connective tissue and degrade elastic fiber in the lungs by solubilizing elastin. With inadequate API levels in the lung to balance the protease activity, emphysema occurs at a significantly earlier age than is normally seen. A presentation of severe emphysema at an unexpectedly young age, such as the third or fourth decade, leads to a high suspicion of a genetic defect causing inadequate API levels in the blood and subsequently in the lungs. The main role of another protease inhibitor, secretory leukocyte protease inhibitor (SLPI), which is secreted by bronchial glands and goblet cells, is to protect the airway epithelium against proteolytic injury. However, Wewers and associates ⁶ provided evidence that API (α₁-AT) is the predominant antiprotease protecting against neutrophil elastase.

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Individuals who are homozygous (have both recessive alleles) for the defective gene that expresses α₁-proteinase inhibitor (API) lack this enzyme to balance the action of neutrophil elastase (NE), another enzyme in the lung that solubilizes connective tissue, causing alveolar wall destruction.

Genetics

API is a 54-kDa glycoprotein, encoded by a single gene on chromosome 14. The alleles of the API gene can be categorized as follows:⁵

• API normal: Normal serum levels of normal-functioning API

• API deficient: Lower than normal serum concentrations of API with altered electrophoretic properties

• API null: Undetectable API levels in the serum

• API dysfunctional: Normal amounts of abnormally functioning API

Persons with normal alleles for API (designated by the letter M for the alleles) are termed PI*MM, for protease inhibitor with a pair of the normal alleles. They are homozygous for the normal allele. Normal values for serum API are 150 to 350 mg/dL based on comparison with a commercial standard preparation and 20 to 48 μM based on comparison with a purified laboratory standard. The commercially available preparations are about 40% higher compared with the purified laboratory standards. Results referenced to the commercial standard are expressed as milligrams per deciliter, whereas comparisons with the highly purified (true) standard are given in micromolar units. Commercial standard values can be converted to true standard values by multiplying the commercial value by 0.71.⁵^,⁶

About 95% of persons in the severely deficient category are homozygous for the Z allele and are designated as PI*ZZ. Serum levels of API in these individuals range from 2.5 to 7 μM, or a mean of about 16% of normal.⁵ The Z allele is rare in Asians and African Americans. Alleles that do not express API at all are quite rare, and such individuals are designated as PI type null-null. PI type null-null individuals have an absence of measurable API in the serum. Wewers and colleagues⁶ described the treatment of a patient with the null-null phenotype and no measurable API serum levels. They were able to show that intravenously administered augmentation therapy with α₁-AT (API) led to normal API levels in the blood and in the lung epithelial lining fluid.

The major risk factor for developing emphysema among PI*ZZ individuals seems to be cigarette smoking, in which emphysema appears much earlier than in nonsusceptible individuals, as previously noted. Other features seen with airflow obstruction in PI*ZZ individuals include a history of pneumonia, episodes of increased cough and sputum production, and a parental history of emphysema.²

Indication for drug therapy

API therapy is indicated for long-term replacement therapy in individuals with congenital deficiency of API, with clinically demonstrable panacinar emphysema. At present four agents are available: Augmentation therapy and maintenance are indicated only for patients who have established API deficiency.⁷ Results from controlled, long-term trials to show that long-term therapy halts the progression of emphysema are unavailable because of inherent difficulties in such trials, including the need for large numbers of patients.¹ API therapy has been provided only to adult subjects. Given the nature of the disease and the action of the drugs, the drugs cannot reverse damage or improve lung function. These drugs are extremely expensive, costing $25,000 to $40,000 per year for therapy. A cost-effectiveness analysis of Prolastin-C concluded that α₁-AT replacement therapy is cost-effective in individuals who have severe α₁-AT deficiency and severe chronic obstructive pulmonary disease (COPD).⁸

The American Thoracic Society (ATS) stated that API augmentation therapy should be used for patients with a serum concentration of API less than 11 μM, or 80 mg/dL.²^,⁹ API therapy is not indicated for patients with emphysema related to cigarette smoking who have normal or heterozygous phenotypes.⁵ It is not indicated for individuals with liver disease associated with API deficiency, unless they also have lung disease. ATS guidelines suggest using augmentation therapy if lung function studies become abnormal and if serial studies show deterioration.

Dosage and administration

TABLE 16-1

α₁-Proteinase Inhibitors Currently Available

BRAND NAME	STRENGTH (mg)
Aralast NP*	400 and 800 (active)
Prolastin-C*	500 and 1000
Zemaira*	1000^‡
Glassia^†	1000

^*Powder form; reconstitution must take place before administration.

^†Ready to use liquid; no reconstitution needed.

^‡Must be administered through a filter.

Warnings and adverse reactions

Because API agents are derived from human plasma, there is a risk of disease transmission. Although there was some variation in reactions to each API agent, fever, exacerbation, and flulike symptoms were most common.

RESPIRATORY CARE ASSESSMENT OF THERAPY OF α1-PROTEINASE INHIBITOR (HUMAN)

Respiratory care assessment of α₁-AT replacement therapy is directed primarily at lung function and the rate of change of airflow obstruction in patients.

Before treatment

• Pulmonary function testing of flow rates is used to monitor the degree of airflow obstruction over long-term use of the drug.

During treatment and short term

• Smoking status should be monitored, and individuals with α₁-AT deficiency who smoke should receive both education on the effect of smoking with this disease and direction to resources to aid in smoking cessation (drug therapy and behavior modification assistance).

Long term

• Overall pulmonary health should be assessed, based on frequency and severity of respiratory infections, cough, sputum production if present, and hospitalization rate.

General contraindications

• API agents are derived from human plasma; therefore, disease transmission is possible.

Smoking cessation drug therapy

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Smoking cessation agents include nicotine as a transdermal patch, chewing gum, nasal spray, or inhaler as substitute therapy for smoking cessation in individuals with a strong physical addiction and withdrawal symptoms from nicotine absorbed during smoking. A tapered dose regimen allows withdrawal with minimal symptoms and assists in reducing the craving for cigarettes. Bupropion, an antidepressant, and varenicline have been found to be helpful in smoking cessation.

Nicotine and lobeline are naturally occurring alkaloids that are capable of stimulating acetylcholine receptors at the autonomic ganglia of the sympathetic and the parasympathetic systems and cholinergic nicotinic receptors at skeletal muscle sites (see Chapter 5) and in the brain. The structures of these two agents are shown in Figure 16-1. The affinity of nicotine for ganglionic and neuromuscular receptor sites led to the use of the term nicotinic to distinguish these receptors from muscarinic receptors because all of these receptors use acetylcholine as a neurotransmitter.

Figure 16-1 Chemical structures of nicotine and lobeline, both of which are nicotinic agonists.

Lobeline is a plant derivative that has less potency than nicotine but a similar spectrum of action. Nicotine itself has greater affinity for ganglionic receptors than for skeletal muscle nicotinic receptors. The response to nicotine stimulation involves simultaneous discharge of the sympathetic and parasympathetic systems. The sympathetic effect predominates in the cardiovascular system, with hypertension, tachycardia, and peripheral vasoconstriction. Part of the sympathomimetic effect is mediated by nicotinic stimulation of receptors on the adrenal medulla, leading to release of epinephrine and norepinephrine. Nicotine produces a parasympathetic effect in the gastrointestinal and urinary tracts, with nausea, vomiting, diarrhea, and urination. Response to nicotine is dose-dependent, and increasing or toxic doses can produce a depolarizing blockade of receptors. Stimulation of neuromuscular receptors causes tremor and loss of hand steadiness.

In addition to stimulating nicotinic receptors at the autonomic ganglia, neuromuscular junctions, and adrenal medulla, nicotine binds to receptors in the central nervous system (CNS). This action causes respiratory stimulation, tremors, convulsions, nausea, and emesis. The last two effects are often seen when nicotine is first inhaled as tobacco smoke, although tolerance rapidly occurs. Nicotine is the chief alkaloid in tobacco products, and addiction to nicotine is the basis for tobacco dependence. In a seasoned smoker, within seconds of inhaling from a cigarette, the internal carotid arteries carry a large bolus of nicotine to the brain, where it binds to nicotine receptors.¹⁰ This binding causes secretion of dopamine, which causes a feeling of pleasure and cognitive arousal. Nicotine also increases levels of norepinephrine, β-endorphin, acetylcholine, serotonin, and other substances in the CNS, all of which increase the sensation of euphoria and well-being; enhance concentration, alertness, and memory; and decrease tension and anxiety. Sensitivity and responsiveness to nicotine in the CNS are genetically determined and constitute the basis for forming the physiologic addiction to nicotine. Without the proper genetic substrate, a smoker cannot become nicotine dependent. About 10% of smokers lack this substrate and are not physiologically dependent; 90% have the substrate and are nicotine addicted to various degrees.¹⁰

Cigarette smoking is a preventable cause of cardiovascular and lung disease and accelerates the rate of decline of lung function that occurs with aging, as shown in the Lung Health Study.¹¹ The Lung Health Study concluded that aggressive smoking intervention and cessation reduce the age-related decline in forced expiratory volume in 1 second (FEV₁) among middle-aged smokers. Withdrawal from the nicotine in tobacco products is difficult because the stimulatory and reward effects are lost, and physical symptoms occur. The latter include craving for nicotine, nervousness, irritability, anxiety, drowsiness, sleep disturbance, impaired concentration, and increased appetite with attendant weight gain. Nicotine replacement therapy, in various dosing formulations, is intended to aid with smoking cessation by allowing initial replacement and then gradual withdrawal of the nicotine found in tobacco. Because nicotine is well absorbed from the skin and mucosa, a transdermal patch, a chewable gum formulation, a nasal spray, and an inhaler have been developed.