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11 Drugs acting on the respiratory organs function-1

June 24, 2024

DRUGS ACTING ON THE RESPIRATORY ORGANS FUNCTION – 1. RESPIRATORY STIMULATORS. COUGH REMEDIES. EXPECTORANTS. (Aethymisolum, Sulfocamphocainum, Bemegridum, Саrbogenum, Codeini phospas, Glaucinum, Oxeladinum, Libexinum, herba Thermopsidis, Radix Althaeae, Mucaltinum, Trypsinum crystallisatum, Bromhexinum, Ambroxolum, Acetylcysteinum, Ambroxolum

DRUGS ACTING ON THE RESPIRATORY ORGANS FUNCTION – 2. BRONCHOLYTICAL PREPARATIONS. DRUGS USED FOR LUNG EDEMA MANAGEMENT (Orciprenalini sulfas, Salbutamolum, Fenoterolum, Ambroxolum, Ipratropii bromidum (Atrovent), Cromolinum-sodium, Ketotifenum, Beclometasoni dypropionas, Triamcinolonum, Strophantinum, Corgliconum, Hygronium, Pentaminum, Droperidolum, Furosemidum, Mannitum, Morphini hydrochloridum, Phenthanilum, Spiritus aethylicus)

Drugs acting on the respiratory organs function

Respiratory antiinflammatory agents

Background: Respiratory antiinflammatory agents interrupt the pathogenesis of bronchial inflammation. These drugs can either prevent or modulate an ongoing inflammatory reaction in the airways. Respiratory antiinflammatory agents are used in a variety of clinical conditions where respiratory inflammation is a component of the disease process, most commonly, in asthma and allergic rhinitis, but also as adjunct treatment of Pneumocysitis carinii pneumonia (PCP), pulmonary eosinophilic syndromes, croup, and sarcoidosis. Recently, ibuprofen has been shown beneficial in slowing the rate of decline in lung function in patients with cystic fibrosis.

History: In the recent past, sympathomimetic agents and/or methylxanthine derivatives were considered primary therapy for the treatment of asthma, while corticosteroids were often used as alternative therapy. In 1991, guidelines for the diagnosis and management of asthma were published by the National Asthma Education Program. This report described the pathophysiology of asthma including airway obstruction, airway inflammation, and airway hyperresponsiveness. Since then, corticosteroids have moved to the forefront in the treatment of asthma despite their generalized availability since the 1950s.

In the mid-1970s, the first inhaled corticosteroid (beclomethasone) was made available. Administering corticosteroids by inhalation limited the systemic adverse reactions associated with oral or parenteral therapy. Other inhaled corticosteroids have since been approved (e.g., budesonide, dexamethasone, flunisolide, fluticasone, triamcinolone).

Cromolyn sodium, approved in 1973, represented a drug with a new mechanism of action in the prevention of acute asthma. Nedocromil, an agent similar to cromolyn, was marketed in late 1992. Other antiinflammatory agents are being investigated in asthmatic patients who do not respond adequately to high systemic doses of corticosteroids. Cyclosporine has been found efficacious in the treatment of patients with severe glucocorticoid-dependent asthma. Adverse reactions may limit the role of oral cyclosporine but the development of an aerosol delivery method might be an effective alternative. Other investigational antiinflammatory agents with a potential role in the treatment of asthma include zileuton (Leutrol(r)) a 5-lipoxygenase inhibitor and zafirlukast (Accolate(r)) a leukotriene-receptor antagonist. Zafirlukast may also have a role in the treatment of allergic rhinitis and in the prevention of exercise-induced bronchoconstriction. Methotrexate, gold preparations, and hydroxychloroquine, although useful in other chronic inflammatory diseases, have not proven their efficacy in the chronic treatment of asthma. The use of these agents is also limited by their potential for serious adverse effects. As the understanding of the pathophysiology of asthma grows, the use of respiratory antiinflammatory agents will expand.

Systemic corticosteroids are the treatment of choice for a number of the pulmonary eosinophilic syndromes. Chronic eosinophilic pneumonia, acute bronchopulmonary aspergillosis, and allergic angiitis and granulomatosis can be effectively treated with systemic corticosteroids. Corticosteroids have been used and beneficial effects have been reported in the treatment of bronchocentric granulomatosis, although the role in therapy has not been clarified. Although parasitic eosinophilic pneumonia and mucoid impaction of bronchi should be treated with specific therapy aimed at the underlying cause, treatment could include the use of corticosteroids.

Corticosteroids have been studied for the treatment of croup, a common upper airway disease of children. Corticosteroids are effective in hospitalized children with moderate to severe disease, preventing the need for intubation or allowing early extubation. Since the natural course of croup varies greatly (i.e., children often show improvement within 24 hours without therapy), the role of corticosteroids, specifically nebulized budesonide, in children with less severe disease is not clear.

The role of corticosteroids in pulmonary sarcoidosis is also not clear, since the natural course of the disease is characterized by frequent remissions. Corticosteroids are generally used for progressive pulmonary impairment or respiratory symptoms. These agents appear to suppress granuloma formation and may result in symptomatic and roentgenogram improvement. There is no evidence that therapy will reduce residual pulmonary dysfunction.

Administration of inhaled corticosteroids can be aided by the use of chambers or spacers. These devices help decrease systemic absorption and subsequent adverse reactions of the corticosteroid. Most inhaled therapy is delivered via metered dose inhalers, although manufacturers have developed other methods such as the breath-actuated dry powder inhaler devices. Examples of these devices include the Rotahaler(r), Diskhaler(r), and the Turbuhaler(r). These devices require less coordination, but deep, forceful inspiration at high flow rates (>= 60 L/min) are needed for optimal drug delivery. Delivery methods of respiratory antiinflammatory agents will continue to progress and change. Chlorofluorocarbons are used as propellants in many metered-dose inhalers; unfortunately chlorofluorocarbons have been implicated in destroying the earth’s atmospheric ozone layer and their use must be discontinued. By January 1996, the phase-out of all chlorofluorocarbons in metered-dose inhalers should be completed.

Mechanism of Action: Mucosal inflammation is characterized by early- and late- phases. The early-phase results from IgE-mediated mast cell degranulation. It appears that both cromolyn and nedocromil are similar in their ability to antagonize antigen-induced mast cell degranulation. This, in turn, prevents the release of histamine and slow-reacting substance of anaphylaxis (SRS-A), mediators of type I allergic reactions. Cyclosporine also inhibits the degranulation of mast cells. Neither cromolyor nedocromil interfere with the binding of IgE to the mast cell or with the binding of antigen to IgE. Orally inhaled corticosteroid hormones may decrease IgE synthesis.

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The late-phase bronchospastic response of asthma is characterized by interstitial edema, mucous glycoprotein release, and eosinophil infiltration of the airways. Leukotrienes attract cellular infiltrates producing epithelial injury, abnormalities ieural mechanisms, increases in airway smooth muscle responsiveness, and airway obstruction. Corticosteroids (oral, parenteral, or inhaled) decrease arachidonic acid metabolism and decrease the amount of prostaglandins and leukotrienes synthesized. Corticosteroids increase the number of beta-adrenergic receptors on leukocytes and increase the responsiveness of beta-receptors of airway smooth muscle. Cromolyn also may reduce the release of inflammatory leukotrienes. It has been postulated that cromolyn produces these effects by inhibiting calcium influx, but its exact mechanism of action is unclear. The mechanism of nedocromil’s antiinflammatory effects is also unknown. Nedocromil prevents bronchoconstriction secondary to non-antigenic stimuli. Because cromolyn and nedocromil are not bronchodilators, antihistamines, or vasoconstrictors, their beneficial effects in the treatment of asthma are largely prophylactic.

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An exaggerated bronchoconstrictor response, airway hyperresponsiveness, can be induced by a variety of causes including cold air, allergens, environmental pollutants, or exercise. Cromolyn can reduce hyperreactivity of the bronchi, inhibiting asthmatic responses to antigenic challenge. Nedocromil appears to be equivalent to cromolyn in preventing exercise-induced asthma. Orally inhaled corticosteroids also reduce airway hyperresponsiveness.

Other agents affect leukotrienes and T-cell activity. Leukotriene biosynthesis inhibitors, such as zileuton (Leutrol(r)), directly inhibit 5-lipoxygenase, preventing the formation of cysteinyl leukotrienes and LTB₄. Zafirlukast (Accolate(r)) is an orally active leukotriene-receptor antagonist currently undergoing phase III investigation. It is a selective antagonist of cysteinyl-leukotriene receptors, inhibiting allergen-induced bronchoconstriction. Cyclosporine, anti-adhesion molecules, anti-cytokines, and anti-effector cells all affect T-cells at various stages of activity (synthesis, action, recruitment, survival, or removal).

During treatment of pneumocystis pneumonia (PCP), destroyed organisms release antigens which elicit an inflammatory response in the lungs, impairing pulmonary function. Oral or intravenous corticosteroids are beneficial as adjunct treatment of severe PCP. Corticosteroids can also prevent the early deterioration in patients with mild to moderate disease. Corticosteroids improve outcomes in patients with PCP when used for primary, secondary, or taper rescue therapy.

Corticosteroids are effective in those children with moderate to severe croup, avoiding intubation or allowing early extubation. The exact mechanism for these results is unknown, but corticosteroids may decrease subglottic edema by decreasing capillary permeability and dilatation. Intranasally administered corticosteroids have local antiinflammatory effects with minimal systemic effects. These agents will affect allergic and nonallergic/irritant-mediated inflammation. The exact mechanism of this antiinflammatory action of corticosteroids oasal mucosa is not known. Corticosteroids are also effective in the treatment of airway inflammation associated with cystic fibrosis, however, long-term administration to children is associated with growth retardation, glucose intolerance, and impairment of host defenses. Nonsteroidal antiinflammatory agents can inhibit the migration and aggregation of neutrophils and prevent the release of lysosomal enzymes and have been shown to be beneficial in cystic fibrosis.

Distinguishing Features: Corticosteroids were originally available as oral and parenteral agents. Because of a high incidence of adverse reactions, inhaled corticosteroids were developed. Several corticosteroids are now available for administration by inhalation and they may be compared in several different ways. Budesonide, although not available in the U.S., appears to have less systemic absorption, and possibly less systemic effects than the other orally inhaled corticosteroids. Budesonide and fluticasone appear to be substantially more potent than beclomethasone, flunisolide, or triamcinolone. In a head-to-head comparison, inhaled triamcinolone was found to cause significantly less coughing and less decrease in FEV₁ than inhaled beclomethasone. Orally inhaled beclomethasone, dexamethasone, and triamcinolone are administered 3-4 times daily, compared to flunisolide which has a prolonged dosage interval at 2 times daily. Although the manufacturer’s recommended dosing frequency may differ between agents, once or twice daily dosing for all may be acceptable in patients with mild asthma. Despite some of these clinical issues, patients may ultimately prefer one agent over another based on cost or even degree of aftertaste.

Airway inflammation is an important factor during an asthmatic episode. The guidelines for the diagnosis and management of asthma recommend the role of the various respiratory antiinflammatory agents. The severity of disease and patient age are factors which determine which therapy to initiate. Both adults and children with chronic mild asthma can effectively prevent asthma attacks with cromolyn. If the patient becomes symptomatic, the next step is the addition of a beta-agonist. Inhaled corticosteroids, although considered safer than systemic therapy, still have the risk of adverse effects. Long term therapy of inhaled corticosteroids in children is restricted because of the risk growth suppression, adrenal suppression, or osteoporosis. Cromolyn is first line therapy for prophylaxis because it is well tolerated, displaying only minor adverse reactions.

For the chronic treatment of moderate asthma, cromolyn continues to be the respiratory antiinflammatory agent of choice, with inhaled corticosteroids an acceptable option in adults only. If symptoms persist or progress in adults a short course of oral corticosteroids can be used. The next step in children is inhaled corticosteroids with or without cromolyn.

As the severity of the disease progresses, therapy becomes more intense. Inhaled corticosteroids are first line agents for both adults and children, with or without cromolyn or other agents. If not effectively controlling symptoms, short burst of oral corticosteroids or chronic alternate day therapy should be considered. If symptoms are severe enough in children, systemic corticosteroid therapy may be considered; risk-benefit should be weighed in this therapeutic decision. The use of intravenous corticosteroids is limited to the treatment of acute exacerbations of asthma in patients in the emergency room or in hospitalized patients.

Cromolyn is recommended for the prevention of exercise-induced asthma, it is not used for treatment of symptoms following exercise. The nasal solution is indicated for the treatment and prevention of allergic rhinitis. Nedocromil is only indicated for the maintenance of bronchial asthma. Nedocromil appears to be equivalent to cromolyn in preventing exercise-induced asthma, although cromolyn may be longer acting. Nedocromil was not available when the “guidelines” were written, but could be substituted when cromolyn is recommended. Nedocromil has similar safety and efficacy profiles when compared to cromolyn.

Topically administered, intranasal corticosteroids provide a direct local antiinflammatory effect with minimal systemic adverse reactions. The intranasally administered products are primarily used for the prevention and treatment of symptoms associated with seasonal or perennial rhinitis. Intranasal corticosteroids should be considered before administering systemic corticosteroids because of the risks associated with systemic therapy. The same corticosteroids administered by oral inhalation are also available for intranasal administration, as well as fluticasone. Budesonide is a corticosteroid that is available in Europe as an oral inhaler, but was approved in the U.S. in 1994 for nasal administration only.

There are few distinctions between the available nasal corticosteroid preparations. All of these products are indicated for use in allergic rhinitis. Dexamethasone is also beneficial for the treatment of polyps and beclomethasone helps prevent recurrence of nasal polyps following surgical removal. Triamcinolone and fluticasone are not recommended for use in children less than 12 years old, whereas the other nasal corticosteroid products should not be used in children younger than 6 years of age. Fluticasone, budesonide, and triamcinolone can all be administered once daily, but may be given in divided doses. Beclomethasone, dexamethasone, and flunisolide are administered at least twice daily up to 3-4 times a day.

Adverse Effects: Oral and parenteral corticosteroids are associated with major systemic adverse reactions; the type and severity of the adverse reactions are dependent on the duration and dose of therapy. Adverse reactions include metabolic changes, fluid retention, hypertension, osteoporosis, and adrenal suppression. Inhaled corticosteroids are associated with local effects including dysphonia, coughing, and oropharyngeal candidiasis. These adverse effects can be minimized by administration via chamber or spacer and by rinsing the mouth after each use. Systemic effects are still a concern with inhalation therapy; specific concerns include growth suppression in children, osteoporosis, and adrenal suppression. The topical-to-systemic potency ratios are similar among the inhaled corticosteroids (ratios = 0.05-0.1), but are considerably reduced compared to budesonide (ratio = 1.0). Budesonide may demonstrate an improved adverse reaction profile due to decreased systemic absorption and subsequent toxicities.

Cromolyn sodium and nedocromil are well tolerated, with minimal adverse effects being reported. Nedocromil produced similar GI and CNS effects as cromolyn. Bronchospasm, irritated or sore throat, dysgeusia, cough, and headache are the most common adverse effects from these agents. Oral inhalation preparations of cromolyn can contain lactose. Administration of cromolyn sodium to patients with lactose intolerance can cause nausea and vomiting, bloating, abdominal cramps, and flatulence. Nedocromil also causes nausea and vomiting in approximately 4% of patients.

Dysfunction of the respiratory system, which supplies the body with the oxygeeeded for metabolic activities in the cells and removes carbon dioxide, a product of cellular metabolism. The respiratory system includes the nose, mouth, throat, larynx, trachea, bronchi, lungs, and the muscles of respiration such as the intercostal muscles and the diaphragm. See also Respiration.

The lung has a great reserve capacity, and therefore a significant amount of disease usually must be present to produce clinical signs and symptoms. Shortness of breath (dyspnea) on exertion is the most common symptom of a respiratory disorder. Shortness of breath while at rest is indicative of severe respiratory disease and usually implies a severe abnormality of the lung tissue. If the respiratory system is so diseased that normal oxygenation of the blood cannot occur, blood remains dark, and a bluish color can be seen in the lips or under the fingernails; this condition is referred to as cyanosis. Other signs and symptoms of respiratory disorder can include fever, chest pain, coughing, excess sputum production, and hemoptysis (coughing up blood). Most of these signs and symptoms are nonspecific. See also Hypoxia.

Most diseases of the airways increase the resistance against which air is sucked in and pushed out of the lungs. Diseases of the nose usually have little influence since collateral respiration through the mouth compensates easily. Diseases of the throat, larynx, and trachea can significantly inhibit the flow of air into the lungs. Infections in the back of the throat, such as in diphtheria, can cause marked swelling of mucous membranes, resulting in air obstruction. Edema (swelling) of the mucosal lining of the larynx can also cause a reduction in air flow. Likewise, air flow can be inhibited in asthma, in which the smooth muscle in the trachea and bronchi episodically constricts. Chronic bronchitis results in inflammation of and excess mucus production by the bronchi and this also can lead to a reduction in air flow. Bronchiolitis, a condition that usually occurs in children and is often caused by a respiratory virus, results iarrowing and inflammation of small airways and a decrease in air flow.

Pneumonia, cancer, and emphysema are the most common lung diseases and are a major cause of morbidity and mortality in the United States. Of the four major types of lung cancer, approximately 90% can be attributed to the carcinogens present in cigarette smoke.

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Common Cold

The common cold—colloquially the flu, catarrh, or grippe (strictly speaking, the rarer infection with influenza viruses)— is an acute infectious inflammation of the upper respiratory tract. Its symptoms, sneezing, running nose (due to rhinitis), hoarseness (laryngitis), difficulty in swallowing and sore throat (pharyngitis and tonsillitis), cough associated with first serous then mucous sputum (tracheitis, bronchitis), sore muscles, and general malaise can bepresent individually or concurrently in varying combination or sequence. The term stems from an old popular belief that these complaints are caused by exposure to chilling or dampness. The causative pathogens are different viruses (rhino-, adeno-, parainfluenza v.) that

may be transmitted by aerosol droplets produced by coughing and sneezing.Therapeutic measures. First attempts of a causal treatment consist of zanamavir, an inhibitor of viral neuraminidase, an enzyme necessary for virus adsorption and infection of cells. However, since symptoms of common cold abate spontaneously, there is no compelling eed to use drugs. Conventional remedies are intended for symptomatic relief. Rhinitis. Nasal discharge could be prevented by parasympatholytics; however, other atropine–like effects would have to be accepted.

Therefore, parasympatholytics are hardly ever used, although a corresponding action is probably exploited in the case of H1 antihistamines, an ingredient of many cold remedies. Locally applied (nasal drops) vasoconstricting б-sympathomimetics decongest the nasal mucosa and dry up secretions, clearing the nasal passage. Long-term use may cause damage to nasal mucous membranes. Sore throat, swallowing problems. Demulcent lozenges containing surface anesthetics such as ethylaminobenzoate (benzocaine) or tetracaine may provide relief; however, the risk of allergic reactions should be borne in mind. Cough. Since coughing serves to expel excess tracheobronchial secretions, suppression of this physiological reflex is justified only when coughing is dangerous (after surgery) or unproductive because of absent secretions. Codeine and noscapine suppress cough by a central action. Mucous airway obstruction. Mucolytics, such as acetylcysteine, split disulfide bonds in mucus, hence reduce its viscosity and promote clearing of bronchial mucus. Other expectorants (e.g., hot beverages, potassium iodide, and ipecac) stimulate production of watery mucus. Acetylcysteine is indicated in cystic fibrosis patients and inhaled as an aerosol. Whether mucolytics are indicated in the common cold and whether expectorants like bromohexine or ambroxole effectively lower viscosity of

bronchial secretions may be questioned. Fever. Antipyretic analgesics acetylsalicylic

acid, acetaminophen, are indicated only when there is high fever. Fever is a natural response and useful in monitoring the clinical course of an infection. Muscle aches and pains, headache. Antipyretic analgesics are effective in relieving these symptoms. Asthma and COPD are common disorders (affecting 10 and 30 million individuals, respectively) and show several similarities in their clinical features. The goal of this lecture and the lecture on anti-inflammatory agents will be to highlight the fundamental pharmacological basis to manage the pathological changes associated with these diseases and to restore normal functionality.

Plant origin expectorants

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Althea officinalis

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Thermopsis

ASTHMA

The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of breath, chest tightness, and wheezing. In mild asthma, symptoms occur only occasionally but in more severe forms of asthma frequent attacks of wheezing and dyspnea occur, especially at night, and chronic activity limitation is common.

Asthma is characterized physiologically by increased responsiveness of the trachea and bronchi to various stimuli and by widespread narrowing of the airways. Its chronic pathological features are contraction of airway smooth muscle leading to reversible airflow obstruction, mucosal thickening from edema and cellular infiltration with airway inflammation, persistent airway hyperreactivity (AHR), and airway remodeling. The fundamental pathogenesis of asthma involves several processes. Chronic inflammation of the bronchial mucosa is prominent, with infiltration of activated T-lymphocytes and eosinophils. This results in subepithelial fibrosis and the release of chemical mediators that can damage the epithelial lining of the airways. Many of these mediators are released following activation and degranulation of mast cells in the bronchial tree. Some of these mediators act as chemotactic agents for other inflammatory cells. They also produce mucosal edema, which narrows the airway and stimulates smooth muscle contraction, leading to bronchoconstriction. Excessive production of mucus can cause further airway obstruction by plugging the bronchiolar lumen.. Approximately 5% of asthmatic patients remain poorly controlled. Despite considerable effort by the pharmaceutical industry, it has proven very difficult to develop new classes of therapeutic agents for asthma.

COPD (Сhronic obstructive pulmonary disorders

COPD is characterized by airflow limitation caused by chronic bronchitis or emphysema that is usually caused by tobacco smoking. This is usually a slowly progressive and largely irreversible process, which consists of increased resistance to airflow, loss of elastic recoil, decreased expiratory flow rate, and overinflation of the lung. COPD is clinically defined by a low FEV₁ value (see lecture on Pulmonary Function Testing) that fails to respond acutely to bronchodilators, a characteristic that differentiates it from asthma. The degree of broncodilatory response at the time of testing, however, does not predict the degree of clinical benefit to the patient and thus bronchodilators are given irrespective of the acute response obtained in the pulmonary function laboratory.

PATHOGENESIS OF ASTHMA AND COPD

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A rational approach to the pharmacotherapy of asthma and COPD depends on a fundamental understanding of the diseases’ pathogenesis. The conventional immunological model suggests asthma is a disease mediated by IgE antibodies bound to mast cells in the airway mucosa. After re-exposure to the antigen, antigen-antibody interaction on the surface of the mast cells triggers both the release of mediators stored in the cells’ granules and the synthesis and release of other mediators. The agents responsible for the early reactions, such as immediate brochoconstriction, are a physiologist’s and pharmacologist’s dream: they include histamine, tryptase, other neutral preoteases, leukotrienes C₄ and D₄, and prostaglandins. These agents cause muscle contraction and vascular leakage. Putative mediators for the more sustained bronchocontriction, cellular infiltration of the airway mucosa, and mucus hypersecretion of the late asthmatic reaction, which occurs 2-8 hours later, are cytokines produced by Th2 lymphocytes, especially GM-CSF and IL-4, 5, 9, and 13, which attract and activate eosinophils and stimulate IgE production by B lymphocytes.

Some of the features of asthma cannot be readily accounted for by the antigen challenge model. In many patients, bronchospasm can be provoked by non-antigenic stimuli such as distilled water, exercise, cold air, sulfur dioxide, and rapid respiration. Bronchoconstruction itself seems to result not simply from the direct effect of the released mediators but also from the activation of neural or humoral pathways.

PHARMAcotherapy of Athma AND COPD

Current therapeutically available agents for the treatment of asthma and COPD can be divided into two general categories: drugs that inhibit smooth muscle contraction, i.e. bronchodilators (adrenergic agonists, methylxanthines, and anticholinergics) and agents that prevent and/or reverse inflammation, i.e., the “long-term control medications” (glucocorticoids, leukotriene inhibitors and receptor antagonists, and mast cell-stabilizing agents or cromones). The latter will be discussed in the future lecture by Professor DeFranco on anti-inflammatory agents.

Aerosol Delivery of Drugs

Topical application of drugs to the lungs can be accomplished by use of aerosols. This approach should in theory produce high local concentrations in the lungs with a low systemic delivery, thus reducing systemic side effects. The critical delivery determinant of any particulate matter to the lungs is the size of the particle. Particles >10 mm are deposited primarily in the mouth and oropharynx; particles <0.5 mm are inhaled to the alveoli and exhaled without being deposited in the lungs. The most effective particles have a diameter of 1-5 mm. Other important factors for deposition are rate of breathing and breath-holding after inhalation. Even under ideal circumstances, only a small fraction of the aerosolized drug (~2-10%) is deposited in the lungs. A large volume spacer attached to metered-dose inhalers can markedly improve the ratio of inhaled to swallowed drug.

The hypothesis suggested by these studies—that asthmatic bronchospasm results from a combination of release of mediators and an exaggeration of responsiveness to their effects— predicts that asthma may be effectively treated by drugs with different modes of action.

Asthmatic bronchospasm might be reversed or prevented, for example, by drugs that reduce the amount of IgE bound to mast cells (anti-IgE antibody), prevent mast cell degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel blockers), block the action of the products released (antihistamines and leukotriene receptor antagonists), inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonists), or directly relax airway smooth muscle (sympathomimetic agents, theophylline).

The second approach to the treatment of asthma is aimed not just at preventing or reversing acute bronchospasm but at reducing the level of bronchial responsiveness. Because increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented both by reducing exposure to the allergens that provoke inflammation and by prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids.

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Bronchodilators

History: Bronchodilators consist of theophylline, beta₂-adrenergic agonists, and inhaled anticholinergics. Although theophylline was not approved for general use until 1940, caffeine, another xanthine with bronchodilatory actions, has been consumed for centuries. Theophylline, however, is a more potent bronchodilator than caffeine. In 1947, isoproterenol, a potent beta-agonist, was approved and for the next 25 years, these two drugs were the major bronchodilators used in clinical practice.

Subsequent to isoproterenol, metaproterenol was released in 1973, followed, over the next decade, by additional beta-agonists, each with increasing specificity for beta₂-receptors. The dominant beta-agonist bronchodilator in use today, albuterol, was approved in 1981. Albuterol is very specific for beta₂-receptors and has a longer duration of action than metaproterenol or isoproterenol. Salmeterol, released in 1994 has yet a longer duration of action than albuterol and may now become the preferred beta₂-agonist.

For many years, atropine was known to possess bronchodilatory properties, however, it was thought that antimuscarinic drugs were to be avoided in the treatment of asthma. In addition, atropine possessed significant unwanted adverse reactions. It has since been shown that antimuscarinic anticholinergics are indeed effective bronchodilators. Ipratropium bromide, released in 1986 and administered by inhalation, is the primary anticholinergic agent used for bronchodilation. Due to its quaternary ammonium structure, its systemic bioavailability is low. As a result, systemic side effects occur much less frequently with ipratropium than with atropine. In 1994, a new combination product containing ipratropium bromide and the beta₂-agonist albuterol was made available.

Since its release in 1940, theophylline has been the bronchodilator of choice for a number of bronchoconstrictive pulmonary diseases. Due to its toxicity profile and a better understanding of the disease processes involved, theophylline therapy has declined in the treatment of asthma. Glucocorticoids are now regarded as primary therapy in the treatment of asthma (see “Respiratory Antiinflammatory Agents” Overview).

The bronchial tree is one of the organs that receive dual sympathetic and parasympathetic innnervation. The predominant adrenoceptors in the bronchial tree are b_2, which cause relaxation. As mentioned below, a subtype of muscarinic cholinergic receptor, M3, mediates smooth muscle contraction in the lungs. Bronchodilators are a group of agents that cause rapid relaxation of bronchial smooth muscle. Three classes of bronchodilators are in current use: b-adrenergic agonists, theophylline, and anticholinergic drugs.

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Despite the new focus on inhaled glucocorticoids, traditional bronchodilators may still be necessary in many patients. Controversy exists regarding the role of theophylline in the therapy of asthma. Theophylline is generally recommended in patients with chronic bronchoconstrictive diseases requiring prolonged bronchodilation, in patients with noctural symptoms, or in patients requiring hospitalization for treatment of asthma. Efficacy for beta₂-agonists in asthma has been demonstrated, however, there is some evidence that prolonged use of beta₂-agonists may be associated with diminished control of asthma.

Beta-adrenergic Agonists

b-agonists produce bronchodilation by directly stimulating b₂-receptors in airway smooth muscle. Activation of b₂ receptors results in activation of adenyl cyclase via a stimulatory guanine-nucleotide binding protein [G protein (Gs)] and increases intracellular cyclic 3′5′-adenosine monophosphate (cAMP). This activates protein kinase A, which then phosphorylates several target proteins within the cell leading to relaxation of bronchial smooth muscle.

b₂ agonists have other beneficial effects including inhibition of mast cell mediator release, prevention of microvascular leakage and airway edema, and enhanced mucociliary clearance. The inhibitory effects on mast cell mediator release and microvascular leakage suggests that B₂ agonists may modify acute inflammation. b₂ agonists, however, have no effect on chronic inflammation.

b₂agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in b₂ selectivity. The selectivity of b₂ agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure. As shown in Table , b agonists are generally divided into short (4-6 h) and long (>12 h) acting agents.

Table Beta Agonists
Generic name	Duration of action	b2-selectivity
Short acting
Albuterol	4-6 h	+++
Levalbuterol	8 h	+++
Terbutaline	4-8 h	+++
Metaproterenol	4-6 h	++
Isoproterenol	3-4 h	++
Epinephrine	2-3 h	–
Long acting
Salmeterol	12⁺ h	+++
Formoterol	12⁺ h	+++

Short-acting b₂ adrenergic receptor agonists, such as albuterol are the preferred treatment for rapid symptomatic relief of dyspnea associated with asthmatic bronchoconstriction. With topical delivery, there are relatively few side effects with these agents at therapeutic doses.

At higher doses, these agents may lead to increased heart rate, cardiac arrhythmias, and CNS effects associated with b adrenergic receptor activation. Side effects such as these as well as muscle cramps and metabolic disturbances limit oral administration.

Mechanism of Action: There are three types of bronchodilators, each with its own unique mechanism of action. The beta₂-agonists and methylxanthine derivatives are considered functional or physiologic antagonists, that is, they cause airway relaxation regardless of the mechanism of constriction. Conversely, the anticholinergic agents only cause bronchodilation in cholinergic mediated bronchoconstriction.

Beta₂-agonists bind to beta₂ receptors on smooth muscle cells located throughout the airways. Stimulation of beta₂-receptor increases intracellular cyclic AMP (cAMP) which, in turn, mediates bronchodilation. Given at equipotent doses, the beta₂-agonists will produce the same intensity of response.

It was thought for years that the methylxanthine derivatives caused bronchodilation by inhibition of phosphodiesterase, preventing enzymatic breakdown of 3′,5′-cAMP; it was subsequently found that these actions only occur at very high doses. A number of new mechanisms have been proposed; 1) prostaglandin antagonism, 2) inhibition of calcium ion influx into smooth muscle, 3) stimulation of endogenous catecholamines, 4) inhibition of release of mediators from mast cells and leukocytes, and 5) adenosine receptor antagonism.

The currently available anticholinergic bronchodilators are non-selective muscarinic blockers. Antagonism of cholinergic receptors causes a reduction in cGMP. cGMP normally causes constriction of bronchial smooth muscle. Because these agents cause a non-selective muscarinic blockade there can be an increased release of acetylcholine, thus overcoming the blockade on the smooth muscle receptors. Bronchoselectively is increased when these agents are administered by inhalation therapy.

All the bronchodilators have an effect on the function of ciliated bronchial epithelium. The exception is ipratropium bromide which has no effect on ciliary action. Beta₂ agonists cause an increase in ciliary beating. Methylxanthine derivatives cause stimulation of mucociliary clearance. Conversely, atropine causes marked inhibition on ciliary beating and mucociliary clearance.

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The bronchodilators can also produce nonbronchodilatory effects. Beta₂-agonists can cause cardiostimulatory effects from their actions on the beta₂-receptors (chronotropic) and beta₁ receptors (chronotropic and inotropic). Excessive stimulation can lead to arrhythmias, hypertension, palpitations, and tachycardia. Methylxanthine derivatives also cause inotropic and chronotropic effects. Atropine can cause cardiac stimulation, producing tachycardia.

Stimulation of beta₂-receptors in skeletal muscle results in tremors and increased in strength of contraction while stimulation of beta₂-receptors in uterine smooth muscle causes tocolysis. Beta₂ stimulation activates Na+/K+/ATPase causing gluconeogenesis and increases insulin secretion. These three effects can contribute to hypokalemia by causing an intracellular shift of potassium. Beta₂ stimulation can produce a metabolic lactic acidemia.

Methylxanthine derivatives possess nonbronchodilatory effects which can produce positive effects on the respiratory tract. They have been shown to produce improved diaphragmatic strength, cause a reduction in fatigue, and improve central respiratory response to hypoxemia. Other, non-respiratory effects, include 1) stimulation of the CNS by adenosine antagonism and cerebral vasoconstriction, 2) lowering of esophageal sphincter pressure, 3) increased gastric acid secretion, and 4) a diuretic response, which quickly develops tolerance. Methylxanthine derivatives also cause an increace in mucus production, and an inhibition of histamine release from mast cells.

Systemic effects of atropine include dryness of secretions, blurred vision, and CNS stimulation. Ipratropium bromide does not possess any significant systemic effects.

Distinguishing Features: The beta₂-agonists produce the most effective bronchodilation compared to the methylxanthine derivatives and anticholinergic agents. The beta₂-agonists can further be differentiated by their beta-selectivity, oral activity, beta₂ potency, and duration of action.

Non-selective agents (e.g., isoproterenol, metaproterenol, and isoetharine) have both beta₁ and beta₂ activity. The beta₁ activity can produce cardiac stimulation resulting in arrhythmias and a positive inotropic effect. The beta₂-selective agents (albuterol, bitolterol, pirbuterol, terbutaline, and salmeterol) have limited beta₁ activity, therefore avoiding the cardiac stimulatory effects. Ethylnorepinephrine, ephedrine and epinephrine are bronchodilators but are seldom used for this purpose because of their alpha-receptor effects. Beta₁ activity and systemic beta₂ effects (e.g. tremors, hypokalemia) occurs after systemic absorption of the agent from the lungs. Both beta₁ and beta₂ effects become even more apparent and potentially serious when the agent is administered orally or parenterally. Metoproterenol, albuterol, pirbuterol, and terbutaline are available as oral preparations. Procaterol, an investigational beta₂-selective-agonist, is being studied in an oral formulation. Terbutaline, ethylnorepinephrine, ephedrine and epinephrine are available as parenteral products.

Salmeterol is the most potent beta₂ agonist on a molar basis while metaproterenol is the least potent beta₂ agonist. In general, when given in equipotent doses, these agents produce the same intensity of response.

Beta₂-agonists can be further differentiated according to their duration of action. Isoproterenol and isoetharine, the shortest acting, have a duration of bronchodilation of 0.5-2 hours, with protection against bronchoconstriction for only 0.5-1 hour. Metaproterenol has a duration of bronchodilation of 3-4 hours, with protection against bronchoconstriction for 1-2 hours. Albuterol, bitolterol, pirbuterol, and terbutaline have an intermediate duration of bronchodilation of 4-8 hours, with protection against bronchoconstriction for 2-4 hours. Bitolterol is given as a prodrug and is metabolized by esterases to its active drug, colterol. Salmeterol has the longest duration of activity of 12 hours, with protection against bronchoconstriction for 12 hours. Procaterol, an investigational beta₂-agonist, has a duration of action of 8-12 hours, similar to salmeterol.

There are a number of methylxanthine derivatives which produce bronchodilation. These include theophylline, caffeine, and dyphylline. Oxtriphylline is a choline salt of theophylline. Theophylline is the most widely used oral methylxanthine derivative. Aminophylline (ie., a theophylline-ethylenediamine complex) is the preferred parenteral preparation.

Theophylline is available in a variety of different preparations. Liquid products and immediate release products generally need to be dosed every 4-6 hours. Theophylline is released over a 24 hour period from sustained-release products such as Theodur(r) and Slo-bid(r); these products can be dosed at intervals of 8-12 hours. The less frequent dosing interval may help improve compliance.

Aminophylline, used primarily for parenteral use, contain approximately 85% anhydrous theophylline. Oxtriphylline contains approximately 64% anhydrous theophylline. Theophylline is also available in a rectal preparation. Although rectal administration is generally not recommended due to erratic bioavailability, it has been used to treat Cheyne-Stokes respirations.

There are two anticholinergic agents commonly used for bronchodilation, atropine and ipratropium bromide. When administered intravenously, they produce similar physiologic effects, including tachycardia, inhibition of salivation, and bronchodilation. When administered via inhalation therapy, there are some distinct differences. Ipratropium bromide has low systemic bioavailability due to its quaternary ammonium structure, producing low or no systemic side effects. Atropine has high systemic absorption, producing undesirable systemic side effects. Ipratropium bromide lacks appreciable effects on the CNS and causes a greater inhibitory effect on ganglionic transmission.

Adverse Reactions: Adverse reactions of the beta₂ agonists are usually minor. As the absorption of the agent from the lung into the blood stream increases, systemic effects become more prominent. This is also true of oral and parenteral administration of the beta₂ agonists. Cardiovascular side effects can be serious and include palpitations, tachycardia, hypertension, and arrhythmias, and are associated with beta₁ stimulation. Local respiratory effects include cough, wheezing, dyspnea, bronchospasm, throat dryness or irritation, and pharyngitis. Salmeterol has a high incidence of respiratory side effects (e.g. upper respiratory tract infections, nasopharyngitis) compared to the other beta₂-agonists. Beta₂ activity in the skeletal muscle can produce tremors. Beta₂ agonists also cause vasodilation which can subsequently cause dizziness, headache, flushing, and sweating. CNS side effects include shakiness, nervousness, tension, excitement, and insomnia. Other effects include unusual or bad taste, anorexia, hypokalemia, lactic acidemia, and gluconeogenesis.

Methylxanthine derivatives, specifically theophylline, have a very narrow therapeutic range. Serious toxicities, such as seizures, permanent neurologic deficits, and death, can occur before minor side effects are seen; this is the reason for serum concentration monitoring. Other serious effects include tachycardia, arrhythmias, tachypnea, and behavioral disturbances in children secondary to CNS stimulation. Minor side effects include nausea and vomiting, anorexia, diarrhea, restlessness, irritability, insomnia, and headache. Diuresis is seen early in therapy, but tolerance tends to develop. Relaxation of the detrusor muscle can cause difficulty in urination in men with enlarged prostates. Metabolic alterations include hyperglycemia and hypokalemia.

The two most commonly used anticholinergic agents used for bronchodilation are atropine and ipratropium bromide. Ipratropium bromide has a very favorable side effect profile. Xerostomia is its most predominant effect and because of low bioavailability it generally lacks systemic effects. Atropine causes both local and systemic side effects. It causes dryness of secretions, blurred vision, cardiac stimulation and CNS stimulation.

Theophylline

The methylxantine theophylline shares a similar structure to the dietary xanthine caffeine. Many salts of theophylline have been marketed, the most common being aminophylline, which is the ethylenediamine salt. Theophylline has been in clinical use since the 1930s. It is a weak, non-selective inhibitor of phosphodiesterase (PDE). There are at least 10 PDE family members, all of which catabolize cyclic nucleotides in the cell. PDE inhibition results in increased concentrations of cAMP and cGMP. Another hypothesized mechanism of action is adenosine receptor inhibition, which may prevent the release of mediators from mast cells.

The dose of theophylline required to yield therapeutic concentrations varies among subjects, largely because of differences in clearance. Increased clearance is seen in children and in cigarette and marijuana smokers. Concurrent administration of phenobarbitol or phenytoin increases activity of cytochrome P-450 (CYP), which results in increased metabolic breakdown. Reduced clearance is also seen with certain drugs that interfere with the CYP system, such as cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, and zafirlukast. Viral infections and vaccinations may also reduce clearance.

Unwanted side effects may be seen at higher plasma concentrations, although they may occur in some patients even at low concentrations. The most common side effects are anorexia, nausea and vomiting, headache, abdominal discomfort, and restlessness.

Anticholinergic Drugs

Human airways are innervated by a supply of efferent, cholinergic, parasympathetic autonomic nerves. Motor nerves derived from the vagus form ganglia within and around the walls of the airways. This vagally derived innervation extends along the length of the bronchial tree but predominates in the large and medium-sized airways. Postganglionic fibers derived from the vagal ganglia supply the smooth muscle and submucosal glands of the airways as well as the vascular structures. Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands.

Three pharmacologically distinct subtypes of muscarinic receptors exist within the airways: M1, M2, and M3 receptors. M1 receptors are present on peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves. M2 receptors are present on the postganglionic nerves; they are activated by the release of acetylcholine and promote its reuptake into the nerve terminal. M3 receptors are present on smooth muscle. Activation of these M3 receptors leads to a decrease in intracellular cAMP levels resulting in contraction of airway smooth muscle and bronchoconstriction.

Atropine is the prototype anticholinergic bronchodilator. Ipratropium is a quaternary amine, which is poorly absorbed across biologic membranes. Atropine and ipratropium antagonize the actions of Ach at parasympathetic, postganglionic, effector cell junctions by competing with Ach for M3 receptor sites. This antagonism of Ach results in airway smooth muscle relaxation and bronchodilation.

Ipratropium is given exclusively by inhalation from a metered-dose inhaler or a nebulizer. Inhaled ipratropium has a slow onset (about 30 minutes) and a relatively long duration of action (about 6 hours). Recently, tiotropium (trade name: Spiriva), a structural analog of ipratropiem, has been approved for treatment of COPD. Like iprotropiem, tiotropiem has high affinity for all mucscarinic receptor subtypes but it dissociates from the receptors much more slowly than ipratropium, esp. M3 receptors. This permits once a day dosing. It is formulated for use with an oral inhalator.

Clinical trials of anticholinergic therapy have generally failed to show significant benefit in asthma. This relative lack of efficacy in asthma contrasts with COPD, in which anticholinergic agents are among the most effective therapies.

FUTURE PHARMACOLOGICAL DIRECTIONS FOR ASTHMA AND COPD

Injury and repair cycle of the airway epithelium in asthma. Complete repair requires glycosylation as a means of regulation of essential elements. Aberrant glycosylation would result in a defect in the mechanisms of repair, the accumulation of epithelial damage and persistent airway inflammation. Modified from Davies [D. E Davies, The bronchial epithelium: translating gene and environment interactions in asthma.Curr Opin Allergy Clin Immunol, 20016771].

Vasoactive intestinal peptide analogs

Vasoactive intestinal peptide (VIP) is a potent relaxant of constricted human airways in vitro but it is degraded in the airway epithelium and ineffective in asthmatic patients. A more stable cyclic analogue of VIP (Ro-25-1553) has a more prolonged effect in vitro ad in vivo and is effective in asthmatic patients by inhalation.

Prostaglandin E₂

PGE agonists that are selective for lung receptor subtypes are being considered for exploration as bronchodilator/anti-inflammatory drugs.

Atrial natriuretic peptides (ANP)

Intravenous infusion of ANP produces a significant bronchodilator response and protects against bronchoconstriction induced by inhaled broncoconstrictors such as methacholine. ANP, however, is a peptide and subject to rapid enzymatic degradation. A related peptide, urodilatin, is less susceptible to degradation and has a longer duration of action. It is as potent as salbutamol when given intravenously.

Phosphodiesterase 4 (PDE4) inhibitors

Based on the actions of theophylline, there has been interest in developing PDE4 inhibitors. In animal models of asthma, PDE4 inhibitors reduce eosinophil infiltration and airway hyperresponsiveness to allergens. The PDE4 inhibitor cilomilast has been clinically tested in COPD, but the drug causes emesis, which is a common side effect with this drug class (this could be due to inhibition of PDE4D). There is hope that selective inhibitors of PDE4B might have more therapeutic potential.

Pharmacogenomics

Current data suggest that the 16^th amino acid position of the b₂ adrenergic receptor is associated with a major, clinically significant pharmacogenomic effect, namely down regulation of the receptor and responsiveness of patients using b-agonists. Investigations of the effect of this and other polymorphisms on the response to long-acting b-agonists is currently being conducted.

The airways in asthma undergo significant structural remodeling. Medium-sized airways from a normal and severe asthmatic patient were sectioned and stained using Movat’s pentachrome stain. The epithelium (Ep) in asthma shows mucous hyperplasia and hyper secretion (blue), and significant basement membrane (Bm) thickening. Smooth muscle (Sm) volume is also increased in asthma. Bv = blood vessel. Scale bar = 100μm.

CHALLENGES FOR THE PHARMACOLOGICAL TREATMENT OF PULMONARY HYPERTENSION

As you know from a previous lecture, pulmonary arterial hypertension (PAH) is hemodynamically defined as an elevated mean pulmonary artery pressure (>25 mm Hg) with a normal pulmonary capillary or left atrial pressure (<15 mm Hg), which can be caused by an isolated increase in pulmonary arterial pressure or by increases in both pulmonary arterial and pulmonary venous pressure. Until recently, management of PAH was generally ineffective in alleviating symptoms or improving survival. The asymptomatic aspects of PAH, the complexity of differential diagnosis, involvement of coexistent cardiopulmonary disease, and the relatively small patient population all represent challenges for the development of pharmacologic therapy for PAH. Nonetheless, during the past decade substantial improvements have occurred in our understanding of the pathogenesis of PAH with new treatments being tested and approved.

BRIEF REVIEW OF PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL FUNCTION AND PHARMACOLOGICAL TARGETS for PAH

The pulmonary vascular bed is a high-flow, low-resistance circuit that can accommodate the entire cardiac output at a pressure that is normally less than 20% of the pressure in the systemic circulation. The pulmonary circulation has a remarkable capacity to regulate its vascular tone to adapt to physiologic changes. Vasoactive regulation plays an important role in the local regulation of blood flow in relation to ventilation (V/Q matching). Hypoxic pulmonary vasoconstriction results from inhibition of pulmonary vascular smooth muscle K⁺ channel conductance, leading to cellular depolarization and an influx of Ca²⁺ ions through voltage-gated calcium channels. Although contraction of vascular smooth muscle narrows pulmonary vessels, the signal for this contraction originates in the pulmonary endothelium.

In PAH, there is media thickening and hypertrophy, resulting in development of a muscle layer in an arteriole. The resulting chronic vasoconstriction and fibroblast proliferation leads to the initiation of remodeling in the intimal and medial layers of the arteriole.

The central role of the endothelium in regulating vascular smooth muscle action was first convincingly revealed with the discovery of endothelium-derived relaxing factor (EDRF) in the 1980s by Furchgott and others using isolated vascular smooth muscle preparations. In these experiments, they found vasodilation following acetylcholine or carbachol treatment but paradoxical vasoconstriction when the vascular endothelium was stripped or removed from the preparation. This short-lived vasodilator substance was called endothelium-derived relaxing factor (EDRF) because it promoted relaxation of pre-contracted smooth muscle preparations. EDRF was subsequently discovered to be nitric oxide (NO). Products of inflammation and platelet aggregation (e.g., serotonin, histamine, bradykinin, purines, and thrombin) exert all or part of their actions by stimulating the production of NO. NO diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase to generate cGMP that leads to smooth muscle relaxation. In addition to NO, the endothelial cell produces other vasodilators, including prostacycline (PGl₂). The endothelial cell also produces vasoconstrictors, such as endothelin 1 (ET-1) and thromboxane A₂(TXA₂), and catalyzes the conversion of angiotensin I to angiotensin II. ET-1 is the most potent known vasoconstrictor; it causes prolonged vasoconstriction and increases vascular tone and pulmonary vascular resistance (PVR), and this is mediated by ET receptors. These vasoactive molecules act on local vascular smooth muscle, mostly in a paracrine fashion, although TXA₂ also stimulates platelet aggregation, which can result in in situ thrombosis and increased PVR. While many other endothelium-derived vasoactive molecules and growth factors have been implicated as potentially important in pulmonary vasoconstriction and remodeling leading to pulmonary hypertension, only those molecules that are currently therapeutic targets in pulmonary hypertension will be emphasized here.

PHARMACOLOGY OF PULMONARY HYPERTENSION

No other area of pharmacology provides you with a wider array of delivery modalities. There are underlying physiological issues that limit the pharmacological options in PAH. First, pulmonary hypertension results from loss of normal cross-sectional area of the pulmonary vasculature, and this loss of capacitance may limit right ventricular cardiac output. Although the mechanism is different, the physiologic effect is similar to that of aortic stenosis. Designing feasible approaches to increase the cross-sectional area of the pulmonary vasculature is difficult. Second, limiting right ventricular cardiac output, limits left ventricular cardiac output, because the left ventricle cannot pump more blood than it receives. The reduction in biventricular cardiac output underlies the unique difficulties in the treatment of pulmonary hypertension. Patients with pulmonary hypertension frequently have low systemic blood pressure and cannot tolerate agents that lead to systemic vasodilation. Endothelial cells in both the pulmonary and systemic circulations share many of the same receptors and produce the same vasoactive molecules, so agents that might dilate the pulmonary vasculature, often act more prominently on the systemic vasculature. There are, however, differences in receptor type and density and in the quantitative production of vasoactive molecules in different vascular beds. Exploiting these differences therapeutically has been the goal of modern therapy.

Preparations Available

Sympathomimetics Used in Asthma

Albuterol (generic, Proventil, Ventolin, others)

Inhalant: 90 g/puff aerosol; 0.083, 0.5% solution for nebulization

Oral: 2, 4 mg tablets; 2 mg/5 mL syrup

Oral sustained-release: 4, 8 mg tablets

Albuterol/Ipratropium (Combivent, DuoNeb)

Inhalant: 103 g albuterol + 18 g ipratropium/ puff; 3 mg albuterol + 0.5 mg ipratropium/3 mL

solution for nebulization

Bitolterol (Tornalate)

Inhalant: 0.2% solution for nebulization

Ephedrine (generic)

Oral: 25 mg capsules

Parenteral: 50 mg/mL for injection

Epinephrine (generic, Adrenalin, others)

Inhalant: 1, 10 mg/mL for nebulization; 0.22 mg epinephrine base aerosol

Parenteral: 1:10,000 (0.1 mg/mL), 1:1000 (1 mg/mL)

Formoterol (Foradil)

Inhalant: 12 g/puff aerosol; 12 g/unit inhalant powder

Isoetharine (generic)

Inhalant: 1% solution for nebulization

Isoproterenol (generic, Isuprel, others)

Inhalant: 0.5, 1% for nebulization; 80, 131 g/puff aerosols

Parenteral: 0.02, 0.2 mg/mL for injection

Levalbuterol (Xenopex)

Inhalant: 0.31, 0.63, 1.25 mg/3 mL solution

Metaproterenol (Alupent, generic)

Inhalant: 0.65 mg/puff aerosol in 7, 14 g containers; 0.4, 0.6, 5% for nebulization

Pirbuterol (Maxair)

Inhalant: 0.2 mg/puff aerosol in 80 and 300 dose containers

Salmeterol (Serevent)

Inhalant aerosol: 25 g salmeterol base/puff in 60 and 120 dose containers

Inhalant powder: 50 g/unit

Salmeterol/Fluticasone (Advair Diskus)

Inhalant: 100, 250, 500 g fluticasone + 50 g salmeterol/unit

Terbutaline (Brethine, Bricanyl)

Inhalant: 0.2 mg/puff aerosol

Oral: 2.5, 5 mg tablets

Parenteral: 1 mg/mL for injection

Aerosol Corticosteroids (See Also Chapter 39: Adrenocorticosteroids & Adrenocortical

Antagonists.)

Beclomethasone (QVAR, Vanceril)

Aerosol: 40, 80 g/puff in 200 dose containers

Budesonide (Pulmicort)

Aerosol powder: 160 g/activation

Flunisolide (AeroBid)

Aerosol: 250 g/puff in 100 dose container

Fluticasone (Flovent)

Aerosol: 44, 110, and 220 g/puff in 120 dose container; powder, 50, 100, 250 g/activation

Fluticasone/Salmeterol (Advair Diskus)

Inhalant: 100, 250, 500 g fluticasone + 50 g salmeterol/unit

Triamcinolone (Azmacort)

Aerosol: 100 g/puff in 240 dose container

Leukotriene Inhibitors

Montelukast (Singulair)

Oral: 10 mg tablets; 4, 5 mg chewable tablets; 4 mg/packet granules

Zafirlukast (Accolate)

Oral: 10, 20 mg tablets

Zileuton (Zyflo)

Oral: 600 mg tablets

Cromolyn Sodium & Nedocromil Sodium

Cromolyn sodium

Pulmonary aerosol (generic, Intal): 800 g/puff in 200 dose container; 20 mg/2 mL for nebulization

(for asthma)

Nasal aerosol (Nasalcrom):* 5.2 mg/puff (for hay fever)

Oral (Gastrocrom): 100 mg/5 mL concentrate (for gastrointestinal allergy)

Nedocromil sodium (Tilade)

Pulmonary aerosol: 1.75 mg/puff in 112 metered-dose container

*OTC preparation.

Methylxanthines: Theophylline & Derivatives

Aminophylline (theophylline ethylenediamine, 79% theophylline) (generic, others)

Oral: 105 mg/5 mL liquid; 100, 200 mg tablets

Oral sustained-release: 225 mg tablets

Rectal: 250, 500 mg suppositories

Parenteral: 250 mg/10 mL for injection

Theophylline (generic, Elixophyllin, Slo-Phyllin, Uniphyl, Theo-Dur, Theo-24, others)

Oral: 100, 125, 200, 250, 300 mg tablets; 100, 200 mg capsules; 26.7, 50 mg/5 mL elixirs, syrups,

and solutions

Oral sustained-release, 8–12 hours: 50, 60, 75, 100, 125, 130, 200, 250, 260, 300 mg capsules

Oral sustained-release, 8–24 hours: 100, 200, 300, 450 mg tablets

Oral sustained-release, 12 hours: 100, 125, 130, 200, 250, 260, 300 mg capsules

Oral sustained-release, 12–24 hours: 100, 200, 300 tablets

Oral sustained-release, 24 hours: 100, 200, 300 mg tablets and capsules; 400, 600 mg tablets

Parenteral: 200, 400, 800 mg/container, theophylline and 5% dextrose for injection

Other Methylxanthines

Dyphylline (generic, other)

Oral: 200, 400 mg tablets; 33.3, 53.3 mg/5 mL elixir

Parenteral: 250 mg/mL for injection

Oxtriphylline (generic, Choledyl)

Oral: equivalent to 64, 127, 254, 382 mg theophylline tablets; 32, 64 mg/5 mL syrup

Pentoxifylline (generic, Trental)

Oral: 400 mg tablets and controlled-release tablets

Note: Pentoxifylline is labeled for use in intermittent claudication only.

Antimuscarinic Drugs Used in Asthma

Ipratropium (generic, Atrovent)

Aerosol: 18 g/puff in 200 metered-dose inhaler; 0.02% (500 g/vial) for nebulization

Nasal spray: 21, 42 g/spray

Antibody

Omalizumab (Xolair)

Powder for SC injection, 202.5 mg

Common Cold

bronchial secretions may be questioned. Fever. Antipyretic analgesics acetylsalicylic

ASTHMA

COPD (Сhronic obstructive pulmonary disorders

PATHOGENESIS OF ASTHMA AND COPD

A rational approach to the pharmacotherapy of asthma and COPD depends on a fundamental understanding of the diseases’ pathogenesis. The conventional immunological model suggests asthma is a disease mediated by IgE antibodies bound to mast cells in the airway mucosa (Figure 1). After re-exposure to the antigen, antigen-antibody interaction on the surface of the mast cells triggers both the release of mediators stored in the cells’ granules and the synthesis and release of other mediators. The agents responsible for the early reactions, such as immediate brochoconstriction, are a physiologist’s and pharmacologist’s dream: they include histamine, tryptase, other neutral preoteases, leukotrienes C₄ and D₄, and prostaglandins. These agents cause muscle contraction and vascular leakage. Putative mediators for the more sustained bronchocontriction, cellular infiltration of the airway mucosa, and mucus hypersecretion of the late asthmatic reaction, which occurs 2-8 hours later, are cytokines produced by Th2 lymphocytes, especially GM-CSF and IL-4, 5, 9, and 13, which attract and activate eosinophils and stimulate IgE production by B lymphocytes.

PHARMAcotherapy of Athma AND COPD

Aerosol Delivery of Drugs

Topical application of drugs to the lungs can be accomplished by use of aerosols. This approach should in theory produce high local concentrations in the lungs with a low systemic delivery, thus reducing systemic side effects. A schematic diagram of the fate of therapeutic agents delivered by inhaler devices is shown in Figure 3. The critical delivery determinant of any particulate matter to the lungs is the size of the particle. Particles >10 mm are deposited primarily in the mouth and oropharynx; particles <0.5 mm are inhaled to the alveoli and exhaled without being deposited in the lungs. The most effective particles have a diameter of 1-5 mm. Other important factors for deposition are rate of breathing and breath-holding after inhalation. Even under ideal circumstances, only a small fraction of the aerosolized drug (~2-10%) is deposited in the lungs. A large volume spacer attached to metered-dose inhalers can markedly improve the ratio of inhaled to swallowed drug.

Bronchodilators

Beta-adrenergic Agonists

b-agonists produce bronchodilation by directly stimulating b₂-receptors in airway smooth muscle. Activation of b₂ receptors results in activation of adenyl cyclase via a stimulatory guanine-nucleotide binding protein [G protein (Gs)] and increases intracellular cyclic 3′5′-adenosine monophosphate (cAMP) (Figure 4). This activates protein kinase A, which then phosphorylates several target proteins within the cell leading to relaxation of bronchial smooth muscle.

Table Beta Agonists
Generic name	Duration of action	b2-selectivity
Short acting
Albuterol	4-6 h	+++
Levalbuterol	8 h	+++
Terbutaline	4-8 h	+++
Metaproterenol	4-6 h	++
Isoproterenol	3-4 h	++
Epinephrine	2-3 h	–
Long acting
Salmeterol	12⁺ h	+++
Formoterol	12⁺ h	+++

Short-acting b₂ adrenergic receptor agonists, such as albuterol (Figure 5) are the preferred treatment for rapid symptomatic relief of dyspnea associated with asthmatic bronchoconstriction. With topical delivery, there are relatively few side effects with these agents at therapeutic doses.

Systemic effects of atropine include dryness of secretions, blurred vision, and CNS stimulation. Ipratropium bromide does not possess any significant systemic effects.

Theophylline

Anticholinergic Drugs

FUTURE PHARMACOLOGICAL DIRECTIONS FOR ASTHMA AND COPD

Vasoactive intestinal peptide analogs

Prostaglandin E₂

PGE agonists that are selective for lung receptor subtypes are being considered for exploration as bronchodilator/anti-inflammatory drugs.

Atrial natriuretic peptides (ANP)

Phosphodiesterase 4 (PDE4) inhibitors

Pharmacogenomics

CHALLENGES FOR THE PHARMACOLOGICAL TREATMENT OF PULMONARY HYPERTENSION

BRIEF REVIEW OF PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL FUNCTION AND PHARMACOLOGICAL TARGETS for PAH

The central role of the endothelium in regulating vascular smooth muscle action was first convincingly revealed with the discovery of endothelium-derived relaxing factor (EDRF) in the 1980s by Furchgott and others using isolated vascular smooth muscle preparations. In these experiments, they found vasodilation following acetylcholine or carbachol treatment but paradoxical vasoconstriction when the vascular endothelium was stripped or removed from the preparation. This short-lived vasodilator substance was called endothelium-derived relaxing factor (EDRF) because it promoted relaxation of pre-contracted smooth muscle preparations. EDRF was subsequently discovered to be nitric oxide (NO). Products of inflammation and platelet aggregation (e.g., serotonin, histamine, bradykinin, purines, and thrombin) exert all or part of their actions by stimulating the production of NO (Figure 1). NO diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase to generate cGMP that leads to smooth muscle relaxation. In addition to NO, the endothelial cell produces other vasodilators, including prostacycline (PGl₂). The endothelial cell also produces vasoconstrictors, such as endothelin 1 (ET-1) and thromboxane A₂(TXA₂), and catalyzes the conversion of angiotensin I to angiotensin II. ET-1 is the most potent known vasoconstrictor; it causes prolonged vasoconstriction and increases vascular tone and pulmonary vascular resistance (PVR), and this is mediated by ET receptors (Figure 2 & 3). These vasoactive molecules act on local vascular smooth muscle, mostly in a paracrine fashion, although TXA₂ also stimulates platelet aggregation, which can result in in situ thrombosis and increased PVR. While many other endothelium-derived vasoactive molecules and growth factors have been implicated as potentially important in pulmonary vasoconstriction and remodeling leading to pulmonary hypertension, only those molecules that are currently therapeutic targets in pulmonary hypertension will be emphasized here.