11 Drugs Affecting Respiratory System

DRUGS AFFECTING RESPIRATORY SYSTEM (ANTIHISTAMINES, DECONGESTANTS, ANTITUSSIVES, AND EXPECTORANTS; BRONCHODILATORS AND OTHER RESPIRATORY AGENTS)

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.

 

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

Althea officinalis

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

         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.

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.  Cellular mediators and cytokines in COPD are seen in Figure 2.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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. A schematic diagram of the fate of therapeutic agents delivered by inhaler devices. 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.

 

   Nebulizer

 

Bronchodilators

 

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.

 

 

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.

         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.

b₂ agonists 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 (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. 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.

 

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

 

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.

 

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.

 

The respiratory system helps meet the basic humaeed for oxygen. Oxygen is necessary for the oxidation of food-stuffs, by which energy for cellular metabolism is produced. When the oxygen supply is inadequate, cell function is im-paired; when oxygen is absent, cells die. Permanent brain damage occurs within 4 to 6 minutes of anoxia. In addition to providing oxygen to all body cells, the respiratory system also removes carbon dioxide, a major waste product of cell metabolism. Excessive accumulation of CO₂ damages or kills body cells.

The efficiency of the respiratory system depends on the qual-ity and quantity of air inhaled, the patency of air passageways, the ability of the lungs to expand and contract, and the ability of O₂ and CO₂ to cross the alveolar–capillary membrane. In addition to the respiratory system, the circulatory, nervous, and musculoskeletal systems have important functions in respira-tion. Additional characteristics of the respiratory system and the process of respiration are described in the following sections.

 

Respiration

Respiration is the process of gas exchange by which O₂ is obtained and CO₂ is eliminated. This gas exchange occurs be-tween the lung and the blood across the alveolar–capillary membrane and between the blood and body cells. More specifically, the four parts of respiration are:

• Ventilation—the movement of air between the atmos-phere and the alveoli of the lungs

• Perfusion —blood flow through the lungs

• Diffusion—the process by which O₂ and CO₂

are trans-ferred between alveoli and blood and between blood and body cells

• Regulation of breathing by the respiratory muscles and nervous system

 

Respiratory Tract

The respiratory tract is a series of branching tubes with pro-gressively smaller diameters. These tubes (nose, pharynx, larynx, trachea, bronchi, and bronchioles) function as air pas-sageways and air “conditioners” that filter, warm, and hu-midify incoming air. Most of the conditioning is done by the ciliated mucous membrane that lines the entire respiratory tract, except the pharynx and alveoli. Ciliaare tiny, hair-like projections that sweep mucus toward the pharynx to be ex-pectorated or swallowed. The mucous membrane secretes mucus, which forms a protective blanket and traps foreign particles, such as bacteria and dust.

When air is inhaled through the nose, it is conditioned by the nasal mucosa. When the nasal passages are blocked, the mouth serves as an alternate airway. The oral mucosa may warm and humidify air but cannot filter it.

 

 

Pharynx, Larynx, and Trachea

Air passes from the nasal cavities to the pharynx (throat). Pharyngeal walls are composed of skeletal muscle, and their lining is composed of mucous membrane. The pharynx con-tains the palatine tonsils, which are large masses of lymphatic tissue. The pharynx is a passageway for food, fluids, and air. Food and fluids go from the pharynx to the esophagus, and air passes from the pharynx into the trachea.

The larynx is composed of nine cartilages joined by liga-ments and controlled by skeletal muscles. It contains the vocal cords and forms the upper end of the trachea. It close on swallowing to prevent aspiration of food and fluids into the lungs. The trachea is the passageway between the larynx and the main stem bronchi. It is a cartilaginous tube lined with cili-ated epithelium and mucous-secreting cells. Cilia and mucus help to protect and defend the lungs.

 

Lungs

The lungs begin where the trachea divides into the right and left mainstem  bronchiand contain the remaining respiratory structures. They are divided into five lobes, each with a secondary bronchus. The lobes are further subdivided into bron-chopulmonary segments supplied by smaller bronchi. The bronchopulmonary segments contain lobules, which are the functional units of the lung (the site where gas exchange takes place). Each lobule is supplied by a bronchiole, an arteriole, a venule, and a lymphatic vessel.

Blood enters the lobules through a pulmonary artery and exits through a pulmonary vein. Lymphatic structures surround the lobule and aid in the removal of plasma proteins and other particles from interstitial spaces. The mainstem bronchi branch into smaller bronchi, then into bronchioles. Bronchioles are approximately the size of a pencil lead and do not contain cartilage or mucus-secreting glands. The walls of the bronchioles contain smooth mus-cle, which is controlled by the autonomic nervous system.

Stimulation of parasympathetic nerves causes constriction; stimulation of sympathetic nerves causes relaxation or dilation. The epithelial lining of the bronchioles becomes thinner with progressive branchings until only one cell layer is apparent. The bronchioles give rise to the  alveoli, which are grape-like clus-ters of air sacs surrounded by capillaries. The alveoli are composed of two types of cells. Type I cells are flat, thin epithelial cells that fuse with capillaries to form the alveolar–capillary membrane across which gas ex-change occurs. Oxygen enters the bloodstream to be trans-ported to body cells; CO₂ enters the alveoli to be exhaled from the lungs. Type II cells produce surfactant, a lipoprotein substance that decreases the surface tension in the alveoli and aids lung inflation. The alveoli also contain macrophages that help to protect and defend the lungs. The lungs are encased in a membrane called the pleura, which is composed of two layers. The inner layer, which adheres to the surface of the lung, is called the visceral pleura. The outer layer, which lines the thoracic cavity, is called the parietal pleura. The potential space between the layers is called the pleural cavity. It contains fluid that allows the layers to glide over each other and minimizes friction.

The lungs expand and relax in response to changes in pres-sure relationships (intrapulmonic and intrapleural pressures). Elastic tissue in the bronchioles and alveoli allows the lungs to stretch or expand to accommodate incoming air. This abil-ity is called compliance. The lungs also recoil (like a stretched rubber band) to expel air. Some air remains in the lungs after expiration, which allows gas exchange to continue between respirations. In addition to exchanging O₂ and CO₂, the lungs synthesize, store, release, remove, metabolize, or inactivate a variety of biologically active substances. These substances, which may be locally released or carried in blood or tissue fluids, partici-pate in both physiologic and pathologic processes. Specific sub-stances that may be released from the lungs include biogenic amines (eg, catecholamines, histamine, serotonin), arachi-donic acid metabolites (eg, prostaglandins, leukotrienes), angiotensin-converting enzyme, and heparin. The amines are important in regulating smooth muscle tone (ie, constriction or dilation) in the airways and blood vessels. Prostaglandins and leukotrienes are important in inflammatory processes.

Angiotensin-converting enzyme converts angiotensin I to angiotensin II, which is important in regulating blood pres-sure. Heparin helps to dissolve blood clots, especially in the capillaries, where small clots are trapped. The lungs also process peptides, lipids, hormones, and drugs and inactivate bradykinin.

 

Lung Circulation

The pulmonary circulatory system transports O₂ and CO₂. After oxygen enters the bloodstream across the alveolar–capillary membrane, it combines with hemoglobin in red blood cells for transport to body cells, where it is released. Car-bon dioxide combines with hemoglobin in the cells for return to the lungs and elimination from the body. The lungs receive the total cardiac output of blood and are supplied with blood from two sources, the pulmonary and bronchial circulations. The pulmonary circulation pro-vides for gas exchange as the pulmonary arteries carry un-oxygenated blood to the lungs and the pulmonary veins return oxygenated blood to the heart. The bronchial arter-ies arise from the thoracic aorta and supply the air passages and supporting structures. The bronchial circulation also warms and humidifies incoming air and can form new ves-sels and develop collateral circulation wheormal vessels are blocked (eg, in pulmonary embolism). The latter ability helps to keep lung tissue alive until circulation can be restored.

Capillaries in the lungs are lined by a single layer of ep-ithelial cells called endothelium. Once thought to be a pas-sive conduit for blood, it is now known that the endothelium performs several important functions. First, it forms a bar-rier that prevents leakage of water and other substances into lung tissue. Second, it participates in the transport of respi-ratory gases, water, and solutes. Third, it secretes vasodi-lating substances such as nitric oxide and prostacyclin.

Nitric oxide also regulates smooth muscle tone in the bronchi, and prostacyclin also inhibits platelet aggregation. When pulmonary endothelium is injured (eg, by endotoxins or drugs such as bleomycin, an anticancer drug), these func-tions are impaired.

Nervous System

The nervous system regulates the rate and depth of respira-tion by the respiratory center in the medulla oblongata, the pneumotaxic center in the pons, and the apneustic center in the reticular formation. The respiratory center is stimulated primarily by increased CO₂ in the fluids of the center. (However, excessive CO₂ depresses the respiratory center.)

When the center is stimulated, the rate and depth of breath-ing are increased, and excessive CO₂ is exhaled. A lesser stimulus to the respiratory center is decreased oxygen in arterial blood.

The nervous system also operates several reflexes impor-tant to respiration. The cough reflex is especially important because it helps protect the lungs from foreign particles, air pollutants, bacteria, and other potentially harmful substances. A cough occurs wheerve endings in the respiratory tract mucosa are stimulated by dryness, pressure, cold, irritant fumes, and excessive secretions.

 

Musculoskeletal System

The musculoskeletal system participates in chest expansion

and contraction. Normally, the diaphragm and external inter-costal muscles expand the chest cavity and are called muscles of inspiration. The abdominal and internal intercostal muscles are the muscles of expiration.

 

SUMMARY

 

Overall, normal respiration requires:

1. Atmospheric air containing at least 21% O₂.

2. Adequate ventilation. Ventilation, in turn, requires patent airways, expansion and contraction of the chest, expansion and contraction of the lungs, and mainte-nance of a normal range of intrapulmonic and intra-pleural pressures.

3. Adequate diffusion of O₂ and CO₂ through the alveolar–capillary membrane. Factors influencing diffusion in-clude the thickness and surface area of the membraneand pressure differences between gases on each side ofthe membrane.

4. Adequate perfusion or circulation of blood and sufficient hemoglobin to carry needed O₂. In addition, normal breathing occurs 16 to 20 times per minute and is quiet, rhythmic, and effortless. Approximately 500 mL of air is inspired and expired with a normal breath (tidal volume); deep breaths or “sighs” occur 6 to 10 times per hour to ventilate more alveoli. Fever, exercise, pain, and emotions such as anger increase respirations. Sleep or rest and various medications, such as antianxiety drugs, seda-tives, and opioid analgesics, slow respiration.

 

DISORDERS OF THE RESPIRATORY SYSTEM

The respiratory system is subject to many disorders that in-terfere with respiration and other lung functions. These dis-orders may be caused by agents that reach the system through inhaled air or through the bloodstream and include respiratory tract infections, allergic disorders, inflammatory disorders, and conditions that obstruct airflow (eg, excessive respiratory tract secretions, asthma, and other chronic obstructive pulmonary diseases).

 

 

Injury to the lungs by various disorders (eg, anaphylaxis, asthma, mechanical stimulation such as hyperventilation, pulmonary thromboembolism, pulmonary edema, acute respiratory distress syndrome) is associated with the release of histamine and other biologically active chemical mediators from the lungs.

These mediators often cause inflammation and constriction of the airways. The ciliated epithelial cells of the larger airways, the type I epithelial cells of the alveoli, and the capillary endothelial cells of the alveolar area are especially susceptible to injury. Once injured, cellular functions are impaired (eg, decreased mu-cociliary clearance).

Common signs and symptoms of respira-tory disorders include cough, increased secretions, mucosal congestion, and bronchospasm. Severe disorders or inadequate treatment may lead to cell necrosis or respiratory failure.

 

DRUG THERAPY

In general, drug therapy is more effective in relieving respira-tory symptoms than in curing the underlying disorders that cause the symptoms. Major drug groups used to treat respi-ratory symptoms are bronchodilating and anti-inflammatory agents, antihistamines, and nasal decongestants, antitussives, and cold remedies.

 

 

 

 

 

Drugs for Asthma and Other Bronchoconstrictive Disorders

 

OVERVIEW

The drugs described in this chapter are used to treat respira-tory disorders characterized by bronchoconstriction, inflam-mation, mucosal edema, and excessive mucus production (asthma, bronchitis, and emphysema). Asthma is emphasized because of its widespread prevalence, especially in urban populations. Compared with whites, African Americans and Hispanics have a higher prevalence and African Americans have a higher death rate from asthma.

However, the differ-ences are usually attributed to urban living and lesser access to health care rather than race or ethnic group. Occupational asthma (ie, asthma resulting from repeated and prolonged exposure to industrial inhalants) is also a major health prob-lem. Persons with occupational asthma often have symptoms while in the work environment, with improvement on days off and during vacations. Symptoms sometime persist after termination of exposure. Asthma may occur at any age but is especially common in children and older adults. Children who are exposed to allergens and airway irritants such as to-bacco smoke during infancy are at high risk for development of asthma.

 

Asthma

Asthma is an airway disorder characterized by bronchocon-striction, inflammation, and hyperreactivity to various stim-uli. Resultant symptoms include dyspnea, wheezing, chest tightness, cough, and sputum production. Wheezing is a high-pitched, whistling sound caused by turbulent airflow through an obstructed airway. Thus, any condition that produces sig-nificant airway occlusion can cause wheezing. However, a chronic cough may be the only symptom for some people.

Symptoms vary in incidence and severity from occasional episodes of mild respiratory distress, with normal function-ing between “attacks,” to persistent, daily, or continual res-piratory distress if not adequately controlled. Inflammation and damaged airway mucosa are chronically present, even when clients appear symptom free. Acute symptoms of asthma may be precipitated by numer-ous stimuli, and hyperreactivity to such stimuli may initiate both inflammation and bronchoconstriction. Viral infections of the respiratory tract are often the causative agents, especially in infants and young children whose airways are small and easily obstructed.

Asthma symptoms may persist for days or weeks after the viral infection resolves. In about 25% of patients with asthma, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate an attack. Some patients are aller-gic to sulfites and may experience life-threatening asthma at-tacks if they ingest foods processed with these preservatives (eg, beer, wine, dried fruit).

The Food and Drug Administra-tion (FDA) has banned the use of sulfites on foods meant to be served raw, such as open salad bars. Patients with severe asthma should be cautioned against ingesting food and drug products containing sulfites or metabisulfites.

Gastroesophageal reflux disease (GERD), a common dis-order characterized by heartburn and esophagitis, is also as-sociated with asthma. Asthma that worsens at night may be associated with nighttime acid reflux. The reflux of acidic gastric contents into the esophagus is thought to initiate a va-gally mediated, reflex type of bronchoconstriction. (Asthma may also aggravate GERD, because antiasthma medications that dilate the airways also relax muscle tone in the gastro-esophageal sphincter and may increase acid reflux.) Addi-tional precipitants may include allergens (eg, pollens, molds, others), airway irritants and pollutants (eg, chemical fumes, cigarette smoke, automobile exhaust), cold air, and exercise.

Acute episodes of asthma may last minutes to hours. Bronchoconstriction (also called bronchospasm) involves strong muscle contractions that narrow the airways. Airway smooth muscle extends from the trachea through the bron-chioles. It is wrapped around the airways in a spiral pattern, and contraction causes a sphincter-type of action that can completely occlude the airway lumen.

Bronchoconstriction is aggravated by inflammation, mucosal edema, and exces-sive mucus and may be precipitated by the numerous stimuli described above. When lung tissues are exposed to causative stimuli, mast cells release substances that cause bronchoconstriction and inflammation. Mast cells are found throughout the body in connective tissues and are abundant in tissues surrounding capillaries in the lungs. When sensitized mast cells in the lungs or eosinophils in the blood are exposed to allergens or irritants, multiple cytokines and other chemical mediators (eg, acetylcholine, cyclic guanosine monophosphate [GMP], histamine, interleukins, leukotrienes, prostaglandins, and serotonin) are synthesized and released. These chemicals act directly on target tissues of the airways, causing smooth mus-cle constriction, increased capillary permeability and fluid leakage, and changes in the mucus-secreting properties of the airway epithelium.

Bronchoconstrictive substances are antagonized by cyclic adenosine monophosphate (cyclic AMP). Cyclic AMP is an intracellular substance that initiates various intracellular ac-tivities, depending on the type of cell. In lung cells, cyclic AMP inhibits release of bronchoconstrictive substances and thus indirectly promotes bronchodilation. In mild to moder-ate asthma, bronchoconstriction is usually recurrent and reversible, either spontaneously or with drug therapy. In ad-vanced or severe asthma, airway obstruction becomes less re-versible and worsens because chronically inflamed airways undergo structural changes (eg, fibrosis, enlarged smooth muscle cells, and enlarged mucous glands), called “airway remodeling,” that inhibit their function Chronic Bronchitis and Emphysema

Chronic bronchitisand emphysema, commonly called chronic obstructive pulmonary disease (COPD), usually develop after long-standing exposure to airway irritants such as cigarette smoke. In these conditions, bronchoconstriction and inflam-mation are more constant and less reversible than with asthma. Anatomic and physiologic changes occur over several years and lead to increasing dyspnea and activity intolerance. These conditions usually affect middle-aged or older adults.

 

DRUG THERAPY

Two major groups of drugs used to treat asthma, acute and chronic bronchitis, and emphysema are bronchodilators and anti-inflammatory drugs. Bronchodilators are used to prevent and treat bronchoconstriction; anti-inflammatory drugs are used to prevent and treat inflammation of the airways. Reducing inflammation also reduces bronchoconstriction by decreasing mucosal edema and mucus secretions that narrow airways and by decreasing airway hyperreactivity to various stimuli.

Bronchodilators

Adrenergic drugs stimulate beta₂-adrenergic receptors in the smooth muscle of bronchi and bronchioles. The receptors, in turn, stimulate the enzyme adenyl cyclase to increase production of cyclic AMP. The increased cyclic AMP produces bronchodilation. Some beta-adrenergic drugs (eg, epinephrine) also stimulate beta₁-adrenergic re-ceptors in the heart to increase the rate and force of con-traction. Cardiac stimulation is an adverse effect when the drugs are given for bronchodilation. These drugs are con-traindicated in clients with cardiac tachydysrhythmias and severe coronary artery disease; they should be used cau-tiously in clients with hypertension, hyperthyroidism, dia-betes mellitus, and seizure disorders.

Epinephrinemay be injected subcutaneously in an acute attack of bronchoconstriction, with therapeutic effects in ap-proximately 5 minutes and lasting for approximately 4 hours. However, an inhaled selective beta₂ agonist is the drug of choice in this situation. Epinephrine is also available without prescription in a pressurized aerosol form (eg, Primatene).

Almost all over-the-counter aerosol products promoted for use in asthma contain epinephrine. These products are often abused and may delay the client from seeking medical attention. Clients should be cautioned that excessive use may produce hazardous cardiac stimulation and other ad-verse effects.

Albuterol, bitolterol, levalbuterol, and pirbuterol are short-acting beta₂-adrenergic agonists used for prevention and treatment of bronchoconstriction. These drugs act more selectively on beta₂ receptors and cause less cardiac stimula-tion than epinephrine. Most often taken by inhalation, they are also the most effective bronchodilators and the treatment of first choice to relieve acute asthma.

Because the drugs can be effectively delivered by aerosol or nebulization, even to young children and patients on mechanical ventilation, there is seldom a need to give epinephrine or other nonselective adrenergic drugs by injection. The beta₂ agonists are usually self-administered by metered-dose inhalers (MDIs). Although most drug references still list a regular dosing schedule (eg, every 4 to 6 hours), asthma ex-perts recommend that the drugs be used wheeeded (eg, to treat acute dyspnea or prevent dyspnea during exercise). If these drugs are overused, they lose their bronchodilating effects because the beta₂-adrenergic receptors become un-responsive to stimulation. This tolerance does not occur with the long-acting beta₂ agonists. Formoterol and salmeterol are long-acting beta₂ -adrenergic agonists used only for  prophylaxis of acute bronchoconstriction. They are not effective in acute attacks because they have a slower onset of action than the short-acting drugs (up to 20 minutes for salmeterol). Effects last 12 hours and the drugs should not be taken more frequently. If additional bronchodilating medication is needed, a short-acting agent (eg, albuterol) should be used.

Isoproterenol is a short-acting bronchodilator and cardiac stimulant. When used for treatment of bronchospasm, iso-proterenol is given by inhalation, alone or in combination with other agents.

Metaproterenol is a relatively selective, intermediate-acting beta₂-adrenergic agonist that may be given orally or by MDI.

 

It is used to treat acute bronchospasm and to prevent exercise-induced asthma. In high doses, metaproterenol loses some of its selectivity and may cause cardiac and central ner-vous system (CNS) stimulation.

Terbutaline is a relatively selective beta₂-adrenergic ago-nist that is a long-acting bronchodilator.

 

 

When given subcuta-neously, terbutaline loses its selectivity and has little advantage over epinephrine. Muscle tremor is the most frequent side effect with this agent.

 

Anticholinergics

Anticholinergics block the action of acetyl-choline in bronchial smooth muscle when given by inhalation. This action reduces intracellular GMP, a bronchoconstrictive

substance.

Ipratropium was formulated to be taken by inhalation for maintenance therapy of bronchoconstriction associated with chronic bronchitis and emphysema. Improved pul-monary function usually occurs in a few minutes. Ipra-tropium acts synergistically with adrenergic bronchodilators and may be used concomitantly. It improves lung function about 10% to 15% over an inhaled beta₂agonist alone. Ipra-tropium may also be used to treat rhinorrhea associated with allergic rhinitis and the common cold. It is available as a nasal spray for such usage. Ipratropium is poorly absorbed and produces few systemic effects. However, cautious use is recommended in clients with narrow-angle glaucoma and

prostatic hypertrophy. The most common adverse effects are cough, nervousness, nausea, gastrointestinal upset, headache, and dizziness.

 

Xanthines

The main xanthine used clinically is theophylline. Despite many years of use, the drug’s mechanism of action is un-known. Various mechanisms have been proposed, such as in-hibiting phosphodiesterase enzymes that metabolize cyclic AMP, increasing endogenous catecholamines, inhibiting cal-cium ion movement into smooth muscle, inhibiting prosta-glandin synthesis and release, or inhibiting the release of bronchoconstrictive substances from mast cells and leuko-cytes. In addition to bronchodilation, other effects that may be beneficial in asthma and COPD include inhibiting pulmonary edema by decreasing vascular permeability, in-creasing the ability of cilia to clear mucus from the airways, strengthening contractions of the diaphragm, and decreas-ing inflammation. Theophylline also increases cardiac out-put, causes peripheral vasodilation, exerts a mild diuretic effect, and stimulates the CNS. The cardiovascular and CNS effects are adverse effects. Serum drug levels should be monitored to help regulate dosage and avoid adverse ef-fects. Theophylline preparations are contraindicated in clients with acute gastritis and peptic ulcer disease; they should be used cautiously in those with cardiovascular dis-orders that could be aggravated by drug-induced cardiac stimulation.

Theophylline was formerly used extensively in the pre-vention and treatment of bronchoconstriction associated with asthma, bronchitis, and emphysema. Now, it is considered a second-line agent that may be added in severe disease in-adequately controlled by first-line drugs. Numerous dosage forms of theophylline are available.

Theophylline ethylene-diamine (aminophylline) contains approximately 85% the-ophylline and is the only formulation that can be given intravenously (IV). However, IV aminophylline is not rec-ommended for emergency treatment of acute asthma because studies indicate little, if any, added benefit in adults or children. Oral theophylline preparations may be used for long-term treatment. Most formulations contain anhydrous theophylline (100% theophylline) as the active ingredient, and sustained-action tablets (eg, Theo-Dur, Theobid) are more commonly used than other formulations. Theophylline is metabolized in the liver; metabolites and some unchanged drug are excreted through the kidneys.

 

Anti-inflammatory Agents

Corticosteroids

Corticosteroids are used in the treatment of acute and chronic asthma and other bronchoconstrictive dis-orders, in which they have two major actions. First, they sup-press inflammation in the airways by inhibiting the following processes: movement of fluid and protein into tissues; migra-tion and function of neutrophils and eosinophils; synthesis of histamine in mast cells; and production of proinflammatory substances (eg, prostaglandins, leukotrienes, several inter-leukins, and others).

Beneficial effects of suppressing airway inflammation include decreased mucus secretion, decreased edema of airway mucosa, and repair of damaged epithelium, with subsequent reduction of airway reactivity. A second action is to increase the number and sensitivity of beta₂-adrenergic receptors, which restores or increases the effectiveness of beta₂-adrenergic bronchodilators. The number of beta₂ recep-tors increases within approximately 4 hours, and improved re-sponsiveness to beta₂ agonists occurs within approximately 2 hours. In acute, severe asthma, a systemic corticosteroid in rela-tively high doses is indicated in patients whose respiratory dis-tress is not relieved by multiple doses of an inhaled beta₂ agonist (eg, every 20 minutes for 3 to 4 doses). The cortico-steroid may be given IV or orally, and IV administration offers no therapeutic advantage over oral administration. Once the drug is started, pulmonary function usually improves in 6 to 8 hours. Most patients achieve substantial benefit within 48 to 72 hours and the drug is usually continued for 7 to 10 days. Multiple doses are usually given because studies in-dicate that maintaining the drug concentration at steroid re-ceptor sites in the lung is more effective than high single doses.

High single or pulse doses do not increase therapeutic effects; they may increase risks of developing myopathy and other ad-verse effects, however. In some infants and young children with acute, severe asthma, oral prednisone for 3 to 10 days has relieved symptoms and prevented hospitalization.

In chronic asthma, a corticosteroid is usually taken by in-halation, on a daily schedule. It is often given concomitantly with one or more bronchodilators and may be given with another anti-inflammatory drug such as a leukotriene mod-ifier or a mast cell stabilizer. In some instances, the other drugs allow smaller doses of the corticosteroid. For acute flare-ups of symptoms during treatment of chronic asthma, a systemic corticosteroid may be needed temporarily to re-gain control.

In early stages of the progressive disease, patients with COPD are unlikely to need corticosteroid therapy. In later stages, however, they usually need periodic short-course therapy for episodes of respiratory distress. Wheeeded, the corticosteroid is given orally or parenterally because effec-tiveness of inhaled corticosteroids has not been established in COPD. In end-stage COPD, patients often become “steroid-dependent” and require daily doses because any attempt to re-duce dosage or stop the drug results in respiratory distress. Such patients experience numerous serious adverse effects of prolonged systemic corticosteroid therapy.

Corticosteroids should be used with caution in clients with peptic ulcer disease, inflammatory bowel disease, hyper-tension, congestive heart failure, and thromboembolic dis-orders. However, they cause fewer and less severe adverse effects when taken in short courses or by inhalation than when taken systemically for long periods of time.

Beclomethasone, budesonide, flunisolide, fluticasone, and  triamcinolone are topical corticosteroids for inhalation. Topical administration minimizes systemic absorption and adverse effects. These preparations may substitute for or allow reduced dosage of systemic corticosteroids. In people with asthma who are taking an oral corticosteroid, the oral dosage is reduced slowly (over weeks to months) when an inhaled corticosteroid is added. The goal is to give the lowest oral dose necessary to control symptoms.

Beclomethasone, flu-nisolide, and fluticasone also are available iasal solutions for treatment of allergic rhinitis, which may play a role in bronchoconstriction. Because systemic absorption occurs in clients using inhaled corticosteroids (about 20% of a dose), high doses should be reserved for those otherwise requiring oral corticosteroids.

Hydrocortisone, prednisone,and methylprednisolone are given to clients who require systemic corticosteroids. Prednisone is given orally; hydrocortisone and methylpred-nisolone may be given IV to patients who are unable to take an oral medication.

 

Leukotriene Modifiers

Leukotrienes are strong chemical mediators of bronchocon-striction and inflammation, the major pathologic features of asthma. They can cause sustained constriction of bronchi-oles and immediate hypersensitivity reactions. They also in-crease mucus secretion and mucosal edema in the respiratory tract. Leukotrienes are formed by the lipoxygenase pathway of arachidonic acid metabolism in response to cellular injury. They are designated by LT, the letter B, C, D, or E, and the number of chemical bonds in their structure (eg, LTB4, LTC4, and LTE4, also called slow releasing sub-stances of anaphylaxis or SRS-A, because they are released more slowly than histamine).

Leukotriene modifier drugs were developed to counteract the effects of leukotrienes and are indicated for long-term treatment of asthma in adults and children. The drugs help to prevent acute asthma attacks induced by allergens, exercise, cold air, hyperventilation, irritants, and aspirin or NSAIDs. They are not effective in relieving acute attacks. However, they may be continued concurrently with other drugs during acute episodes. The leukotriene modifiers include three agents with two different mechanisms of action. Zileuton inhibits lipoxy-genase and thereby reduces formation of leukotrienes; mon-telukast and  zafirlukast are leukotriene receptor antagonists. Zileuton is used infrequently because it requires multiple daily dosing, may cause hepatotoxicity, and may inhibit the metabolism of drugs metabolized by the cytochrome P450 3A4 enzymes. Zafirlukast and montelukast improve symp-toms and pulmonary function tests (PFTs), decrease night-time symptoms, and decrease the use of beta₂ agonist drugs.

They are effective with oral administration, can be taken once or twice a day, can be used with bronchodilators and corti-costeroids, and elicit a high degree of patient adherence and satisfaction. However, they are less effective than low doses of inhaled corticosteroids.

Montelukast and zafirlukast are well absorbed with oral administration. They are metabolized in the liver by the cy-tochrome P450 enzyme system and may interact with other drugs metabolized by this system. Most metabolites are ex-creted in the feces. Zafirlukast is excreted in breast milk and should not be taken during lactation. The most common ad-verse effects reported in clinical trials were headache, nau-sea, diarrhea, and infection.

Zileuton is well absorbed, highly bound to serum albu-min (93%), and metabolized by the cytochrome P450 liver enzymes; metabolites are excreted mainly in urine. It is contraindicated in clients with active liver disease or sub-stantially elevated liver enzymes (three times the upper limit of normal values). When used, hepatic aminotrans-ferase enzymes should be monitored during therapy and the drug should be discontinued if enzyme levels reach five times the normal values or if symptoms of liver dysfunction develop. Elevation of liver enzymes was the most serious adverse effect during clinical trials; other adverse effects include headache, pain, and nausea. In addition, zileuton in-creases serum concentrations of propranolol, theophylline, and warfarin.

 

Mast Cell Stabilizers

Cromolynand nedocromil stabilize mast cells and prevent the release of bronchoconstrictive and inflammatory sub-stances when mast cells are confronted with allergens and other stimuli. The drugs are indicated only for prophylaxis of acute asthma attacks in clients with chronic asthma; they are not effective in acute bronchospasm or status asthmati-cus and should not be used in these conditions. Use of one of these drugs may allow reduced dosage of bronchodilators and corticosteroids. The drugs are taken by inhalation. Cromolyn is available in a metered-dose aerosol and a solution for use with a power-operated nebulizer. A nasal solution is also available for pre-vention and treatment of allergic rhinitis. Nedocromil is available in a metered-dose aerosol. Mast cell stabilizers are contraindicated in clients who are hypersensitive to the drugs. They should be used with caution in clients with impaired renal or hepatic function. Also, the propellants in the aerosols may aggravate coronary artery dis-ease or dysrhythmias.

 

Herbal and Dietary Supplements

Numerous preparations are promoted to relieve symptoms of asthma and patients with asthma are increasingly using alter-native and complementary therapies. Some herbs have a phar-macologic basis for effect. However, most are less potent or more toxic than traditional asthma medications. For example, caffeine is a xanthine and therefore has bronchodilating effects similar to, but weaker than, those of theophylline. Caffeine-containing products, including coffee and tea, may slightly enhance bronchodilation. However, they also increase the adverse effects associated with adrenergic bronchodilators

or theophylline (eg, symptoms of excessive cardiac and CNS stimulation such as tachycardia, dysrhythmias, insomnia, ner-vousness). Ephedra (ma huang), an adrenergic-type product, may also have bronchodilating effects. However, it also causes excessive cardiac and CNS stimulation, and deaths have been reported. It is not recommended for any use by anyone. In general, herbal and dietary therapies in asthma, as in other disorders, have not been studied in controlled clinical trials and should be avoided. Because asthma can result in death in a matter of minutes, patients should be counseled not to use dietary or herbal supplements in place of pre-scribed bronchodilating and anti-inflammatory medica-tions. Delays in appropriate treatment can have serious, even fatal, consequences

 

PRINCIPLES OF THERAPY

Drug Selection and Administration

Choice of drug and route of administration are determined largely by the severity of the disease process and the client’s response to therapy. Some guidelines include the following:

1. A selective, short-acting, inhaled beta₂-adrenergic ag-onist (eg, albuterol) is the initial drug of choice for acute bronchospasm.

2. Because aerosol products act directly on the airways, drugs given by inhalation can usually be given in smaller doses and produce fewer adverse effects than oral or parenteral drugs.

3. Ipratropium, the anticholinergic bronchodilator, is most useful in the long-term management of COPD. It is ineffective in relieving acute bronchospasm by itself, but it adds to the bronchodilating effects of adrenergic drugs.

4. Theophylline is used less often than formerly and is now considered a second-line drug. When used, it is usually given orally in an extended-release for-mulation for chronic disorders, such as COPD. IV aminophylline is no longer used to treat acute asthma attacks.

5. Cromolyn and nedocromil are used prophylactically; they are ineffective in acute bronchospasm.

6. Because inflammation has been established as a major component of asthma, an inhaled corticosteroid is being used early in the disease process, often with a broncho-dilator or mast cell stabilizer. In acute episodes of bron-choconstriction, a corticosteroid is often given orally or IV for several days. In chronic disorders, inhaled corticosteroids should be taken on a regular schedule. These drugs may be effective when used alone or with relatively small doses of an oral corticosteroid. Optimal schedules of administration are not clearly established, but more frequent dosing (eg, every 6 hours) may be more effective than less frequent dosing (eg, every 12 hours), even if the total amount is the same. As with systemic glucocorticoid therapy, the recommended dose is the lowest amount required to control symptoms. High doses suppress adrenocortical function, but much less than systemic drugs. Small doses may impair bone metabolism and predispose adults to osteoporosis by decreasing calcium deposition and increasing calcium resorption from bone. In children, chronic administra-tion of corticosteroids may retard growth. Local ad-verse effects (oropharyngeal candidiasis, hoarseness) can be decreased by reducing the dose, administering less often, rinsing the mouth after use, or using a spacer device. These measures decrease the amount of drug deposited in the oral cavity. The inhaled drugs are well tolerated with chronic use.

7. A common regimen for treatment of moderate asthma is an inhaled corticosteroid on a regular schedule, two to four times daily, and a short-acting, inhaled beta₂-adrenergic agonist as needed for prevention or treatment of bronchoconstriction. For more severe asthma, an inhaled corticosteroid is continued and both a short-acting and a long-acting beta₂ agonist may be given. A leukotriene modifier may also be added to the regimen to further control symptoms and reduce the need for corticosteroids and inhaled bronchodilators.

8. Multidrug regimens are commonly used and one ad-vantage is that smaller doses of each agent can usually be given. This may decrease adverse effects and allow dosages to be increased when exacerbation of symp-toms occurs. Available combination inhalation prod-ucts include Combivent (albuterol and ipratropium) and Advair (salmeterol and fluticasone). Advair, which was developed to treat both inflammation and bron-choconstriction, was more effective than the individ-ual components at the same doses and as effective as concurrent use of the same drugs at the same doses. In addition, the combination reduced the corticosteroid dose by 50% and was more effective than higher doses of fluticasone alone in reducing asthma exacerbations. The combination improved symptoms within 1 week. Additional combination products are likely to be mar-keted and may improve patient compliance with pre-scribed drug therapy.

Dosage Factors

Dosage of antiasthmatic drugs must be individualized to attain the most therapeutic effects and the fewest adverse effects. Larger doses of bronchodilators and corticosteroids (inhaled, systemic, or both) are usually required to relieve the symptoms of acute, severe bronchoconstriction or status asthmaticus. Then, doses should be reduced to the smallest effective amounts for long-term control. Dosage of theophylline preparations should be based mainly on serum theophylline levels (therapeutic range is 5 to 15 mcg/mL; toxic levels are 20 mcg/mL or above). Blood for serum levels should be drawn 1 to 2 hours after immediate-release dosage forms and about 4 hours after sustained-release forms. In addition, children and cigarette smokers usually need higher doses to maintain therapeutic blood levels because they metabolize theophylline rapidly, and clients with liver disease, congestive heart failure, chronic pulmonary disease, or acute viral infections usually need smaller doses because these conditions impair theoph-ylline metabolism. For obese clients, theophylline dosage should be calculated on the basis of lean or ideal body weight because theophylline is not highly distributed in fatty tissue.

Toxicity of Antiasthmatic Drugs

Signs and symptoms of overdose and toxicity are probably most likely to occur when clients with acute or chronic bronchoconstrictive disorders overuse bronchodilators in their efforts to relieve dyspnea. General management of acute poisoning includes early recognition of signs and symp-toms, stopping the causative drug, and instituting other treatment measures as indicated. Specific measures include the following:

• Bronchodilator overdose.With inhaled or systemic adrenergic bronchodilators, major adverse effects are excessive cardiac and CNS stimulation. Symptoms of cardiac stimulation include angina, tachycardia, and palpitations; serious dysrhythmias and cardiac arrest have also been reported. Symptoms of CNS stimula-tion include agitation, anxiety, insomnia, seizures, and tremors. Severe overdoses may cause delirium, collapse, and coma. In addition, hypokalemia, hyperglycemia, and hypotension or hypertension may occur. Manage-ment includes discontinuing the causative medications and using general supportive measures (emesis, gastric lavage, or activated charcoal may be useful with oral drugs). For cardiac symptoms, monitor blood pressure, pulse, and electrocardiogram. Cautious use of a beta-adrenergic blocking drug (eg, propranolol) may be in-dicated. However, a nonselective beta blocker may induce bronchoconstriction.

• Theophylline overdose.Signs and symptoms include anorexia, nausea, vomiting, agitation, nervousness, insomnia, tachycardia and other dysrhythmias, and tonic-clonic convulsions. Ventricular dysrhythmias or con-vulsions may be the first sign of toxicity. Serious adverse effects rarely occur at serum drug levels below 20 mcg/mL. Overdoses with sustained-release preparations may cause a dramatic increase in serum drug concentrations much later (12 hours or longer) than the immediate-release preparations.

Early treatment helps but does not prevent these delayed increases in serum drug levels. In patients without seizures, induce vomiting unless the level of consciousness is impaired. In these patients, precautions to prevent aspiration are needed, especially in children. If overdose is identified within an hour of drug ingestion, gastric lavage may be helpful if unable to induce vomiting or vomiting is contraindicated. Ad-ministration of activated charcoal and a cathartic is also recommended, especially for overdoses of sustained-release formulations. In patients with seizures, treatment includes securing the airway, giving oxygen, injecting IV diazepam (0.1 to 0.3 mg/kg, up to 10 mg), monitoring vital signs, maintaining blood pressure, providing adequate hydra-tion, and monitoring serum theophylline levels until below 20 mcg/mL. Also, symptomatic treatment of dys-rhythmias may be needed.

• Leukotriene modifiers and mast cell stabilizers. These drugs seem relatively devoid of serious toxicity. There have been few reports of toxicity in humans and little clinical experience in managing it. If toxicity oc-curs, general supportive and symptomatic treatment is indicated.

 

Use in Children

The American Academy of Pediatrics endorses the clinical practice guidelines established by the National Asthma. In gen-eral, antiasthmatic medications are used in children and adolescents for the same indications as for adults. With adrenergic bronchodilators, recommendations for use vary according to route of administration, age of the child, and specific drug formulations. However, even infants and young children can be treated effectively with aerosolized or neb-ulized drugs. In addition, some oral drugs can be given to children as young as 2 years and most can be given to chil-dren 6 to 12 years of age. With theophylline, use in children should be closely monitored because dosage needs and rates of metabolism vary widely. In children younger than 6 months, especially premature infants and neonates, drug elimination may be prolonged because of immature liver function. Except for pre-term infants with apnea, theophylline preparations are not recommended for use in this age group. Children 6 months to 16 years of age, approximately, metabolize theophylline more rapidly than younger or older clients. Thus, they may need higher doses than adults in proportion to size and weight. If the child is obese, the dosage should be calculated on the basis of lean or ideal body weight because the drug is not highly distributed in fatty tissue. Long-acting dosage forms are not recommended for children younger than 6 years of age. Children may become hyperactive and dis-ruptive from the CNS-stimulating effects of theophylline. Tolerance to these effects usually develops with continued use of the drug. Corticosteroids are being used earlier in children as in adults and inhaled corticosteroids are first-line drugs for treat-ment of persistent bronchoconstrictive disorders. The effec-tiveness and safety of inhaled corticosteroids in children older than 3 years of age is well established; few data are available on the use of inhaled drugs in those younger than 3 years. Major concerns about long-term use in children include de-creased adrenal function, growth, and bone mass. Most are given by inhalation, and dosage, type of inhaler device, and characteristics of individual drugs influence the extent and severity of these systemic effects. Adrenal insufficiency is most likely to occur with sys-temic or high doses of inhaled corticosteroids. Dose-related inhibition of growth has been reported in short and inter-mediate studies but long-term studies have found few, if any, decreases in expected adult height. Inhaled corticosteroids have not been associated with significant decreases in bone mass but more studies of high doses and of drug therapy in adolescents are needed. Bone growth should be monitored closely in children taking corticosteroids. Although inhaled corticosteroids are the most effective anti-inflammatory medications available for asthma, high doses in children are still of concern. The risk of high doses is especially great in children with other allergic conditions that require topical corticosteroid drugs. The risk can be decreased by using the lowest effective dose, administration techniques that mini-mize swallowed drug, and other antiasthmatic drugs to re-duce corticosteroid dose.

Leukotriene modifiers have not been extensively studied in children and adolescents. With montelukast, the 10-mg film-coated tablet is recommended for adolescents 15 years of age and older and a 4-mg chewable tablet is recommended for children 2 to 5 years of age. Safety and effectiveness of zafirlukast in children younger than 12 years have not been established.

Cromolyn aerosol solution may be used in children 5 years of age and older, and nebulizer solution is used with children 2 years and older. Nedocromil is not established as safe and effective in children younger than 12 years of age.

Use in Older Adults

Older adults often have chronic pulmonary disorders for which bronchodilators and antiasthmatic medications are used. As with other populations, administering the medications by in-halation and giving the lowest effective dose decrease adverse effects. The main risks with adrenergic bronchodilators are excessive cardiac and CNS stimulation. Theophylline use must be carefully monitored because drug effects are unpredictable. On the one hand, cigarette smoking and drugs that stimulate drug-metabolizing en-zymes in the liver (eg, phenobarbital, phenytoin) increase the rate of metabolism and therefore dosage requirements. On the other hand, impaired liver function, decreased blood flow to the liver, and some drugs (eg, cimetidine, erythromycin) impair metabolism and therefore decrease dosage require-ments. Adverse effects include cardiac and CNS stimula-tion. Safety can be increased by measuring serum drug levels and adjusting dosage to maintain therapeutic levels of 5 to 15 mcg/mL. If the client is obese, dosage should be based on lean or ideal body weight because theophylline is not highly distributed in fatty tissue. Corticosteroids increase the risks of osteoporosis and cataracts in older adults. Leukotriene modifiers usually are well tolerated by older adults, with pharmacokinetics and effects similar to those in younger adults. With zafirlukast, however, blood levels are higher and elimination is slower than in younger adults. Zileuton is contraindicated in older adults with underlying hepatic dysfunction.

Use in Renal Impairment

Bronchodilating and anti-inflammatory drugs can usually be given without dosage adjustments in clients with im-paired renal function. Beta agonists may be given by in-halation or parenteral routes. Theophylline can be given in usual doses, but serum drug levels should be monitored. Most corticosteroids are eliminated by hepatic metabolism, and dosage reductions are not needed in clients with renal impairment. No data are available about the use of mon-telukast, and no dosage adjustments are recommended for zafirlukast or zileuton. Cromolyn is eliminated by renal and biliary excretion; the drug should be given in reduced doses, if at all, in clients with renal impairment.

Use in Hepatic Impairment

Montelukast and zafirlukast produce higher blood levels and are eliminated more slowly in clients with hepatic impair-ment. However, no dosage adjustment is recommended for clients with mild to moderate hepatic impairment. Zileuton is associated with hepatotoxicity and contraindicated in clients with active liver disease or aminotransferase elevations of three times the upper limit of normal or higher. Recommenda-tions to avoid hepatotoxicity include measuring hepatic aminotransferases (eg, alanine aminotransferase) before start-ing zileuton, once a month for the first 3 months of therapy, every 2 to 3 months for the remainder of the first year, and periodically thereafter. The drug should be discontinued if symptoms of liver dysfunction develop (eg, right upper quad-rant pain, nausea, fatigue, pruritus, jaundice, or flu-like symp-toms) or aminotransferase levels increase to more than five times the upper limit of normal. Cromolyn is eliminated by renal and biliary excretion; the drug should be given in reduced doses, if at all, in clients with hepatic impairment.

Use in Critical Illness

Acute, severe asthma (status asthmaticus) is characterized by severe respiratory distress and requires emergency treatment. Beta 2 agonists should be given in high doses and as often as every 20 minutes for 1 to 2 hours (by MDIs with spacer devices or by compressed-air nebulization). However, high doses of nebulized albuterol have been associated with tachycardia, hypokalemia, and hyperglycemia. Once symptoms are con-trolled, dosage can usually be reduced and dosing intervals ex-tended. High doses of systemic corticosteroids are also given for several days, IV or orally. If the patient is able to take an oral drug, there is no therapeutic advantage to IV administration. When respiratory function improves, efforts to prevent fu-ture episodes are needed. These efforts may include identify-ing and avoiding suspected triggers, evaluation and possible adjustment of the client’s treatment regimen, and assessment of the client’s adherence to the prescribed regimen.

Home Care

All of the drugs discussed in this chapter are used in the home setting. A major role of the home care nurse is to assist clients in using the drugs safely and effectively. Several studies have indicated that many people do not use MDIs and other in-halation devices correctly. The home care nurse needs to ob-serve a client using an inhalation device when possible. If errors in technique are assessed, teaching or reteaching may be needed. With inhaled medications, a spacer device may be useful, especially for children and older adults, because less muscle coordination is required to administer a dose. Adverse effects may be minimized as well. For clients with asthma, especially children, assess the en-vironment for potential triggers of acute bronchospasm, such as cigarette smoking. In addition, assist clients to recognize and treat (or get help for) exacerbations before respiratory distress becomes severe. With theophylline, the home care nurse needs to assess the client and the environment for substances that may affect metabolism of theophylline and decrease therapeutic effects or increase adverse effects. In addition, the nurse needs to reinforce the importance of not exceeding the prescribed dose, not crushing long-acting formulations, reporting adverse effects, and keeping appointments for follow-up care.

 

Medications

Medications used to treat asthma are divided into two general classes: quick-relief medications used to treat acute symptoms; and long-term control medications used to prevent further exacerbationю

 

 

Fast–acting

Salbutamol metered dose inhaler commonly used to treat asthma attacks.

• Short-acting beta₂-adrenoceptor agonists (SABA), such as salbutamol (albuterol USAN) are the first line treatment for asthma symptomsю

• Anticholinergic medications, such as ipratropium bromide, provide additional benefit when used in combination with SABA in those with moderate or severe symptoms. Anticholinergic bronchodilators can also be used if a person cannot tolerate a SABA.

 

 

• Older, less selective adrenergic agonists, such as inhaled epinephrine, have similar efficacy to SABAs. They are however not recommended due to concerns regarding excessive cardiac stimulation.

 

Long–term control

 

 

Fluticasone propionate metered dose inhaler commonly used for long-term control.

• Corticosteroids are generally considered the most effective treatment available for long-term controlю Inhaled forms such as beclomethasone are usually used except in the case of severe persistent disease, in which oral corticosteroids may be needed. It is usually recommended that inhaled formulations be used once or twice daily, depending on the severity of symptoms.

• Long-acting beta-adrenoceptor agonists (LABA) such as salmeterol and formoterol can improve asthma control, at least in adults, when given in combination with inhaled corticosteroids. In children this benefit is uncertain. When used without steroids they increase the risk of severe side-effects and even with corticosteroids they may slightly increase the risk.

• Leukotriene antagonists (such as montelukast and zafirlukast) may be used in addition to inhaled corticosteroids, typically also in conjunction with LABA. Evidence is insufficient to support use in acute exacerbations. In children under five years of age, they are the preferred add-on therapy after inhaled corticosteroids.

• Mast cell stabilizers (such as cromolyn sodium) are another non-preferred alternative to corticosteroids.

Delivery methods

Medications are typically provided as metered-dose inhalers (MDIs) in combination with an asthma spacer or as a dry powder inhaler. The spacer is a plastic cylinder that mixes the medication with air, making it easier to receive a full dose of the drug. A nebulizer may also be used. Nebulizers and spacers are equally effective in those with mild to moderate symptoms however insufficient evidence is available to determine whether or not a difference exists in those severe symptomatology.

Adverse effects

Long-term use of inhaled corticosteroids at conventional doses carries a minor risk of adverse effects. Risks include the development of cataracts and a mild regression in stature.

Others

When asthma is unresponsive to usual medications, other options are available for both emergency management and prevention of flareups. For emergency management other options include:

• Oxygen to alleviate hypoxia if saturations fall below 92%.

• Magnesium sulfate intravenous treatment has been shown to provide a bronchodilating effect when used in addition to other treatment in severe acute asthma attacks.

• Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases.

• Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases.

• Methylxanthines (such as theophylline) were once widely used, but do not add significantly to the effects of inhaled beta-agonists. Their use in acute exacerbations is controversial.

• The dissociative anesthetic ketamine is theoretically useful if intubation and mechanical ventilation is needed in people who are approaching respiratory arrest; however, there is no evidence from clinical trials to support this.

For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs bronchial thermoplasty may be an option. It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies. While it may increase exacerbation frequency in the first few months it appears to decrease the subsequent rate. Effects beyond one year are unknown. Evidence suggests that sublingual immunotherapy in those with both allergic rhinitis and asthma improve outcomes.

 

Alternative medicine

Many people with asthma, like those with other chronic disorders, use alternative treatments; surveys show that roughly 50% use some form of unconventional therapy. There is little data to support the effectiveness of most of these therapies. Evidence is insufficient to support the usage of Vitamin C. Acupuncture is not recommended for the treatment as there is insufficient evidence to support its use. Air ionisers show no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.

“Manual therapies”, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, have insufficient evidence to support their use in treating asthma. The Buteyko breathing technique for controlling hyperventilation may result in a reduction in medications use however does not have any effect on lung function. Thus an expert panel felt that evidence was insufficient to support its use.

The prognosis for asthma is generally good, especially for children with mild disease. Mortality has decreased over the last few decades due to better recognition and improvement in care. Globally it causes moderate or severe disability in 19.4 million people as of 2004 (16 million of which are in low and middle income countries). Of asthma diagnosed during childhood, half of cases will no longer carry the diagnosis after a decade. Airway remodeling is observed, but it is unknown whether these represent harmful or beneficial changes. Early treatment with corticosteroids seems to prevent or ameliorates a decline in lung function.

As of 2011, 235–300 million people worldwide are affected by asthma, and approximately 250,000 people die per year from the disease. Rates vary between countries with prevalences between 1 and 18%. It is more common in developed than developing countries. One thus sees lower rates in Asia, Eastern Europe and Africa. Within developed countries it is more common in those who are economically disadvantaged while in contrast in developing countries it is more common in the affluent. The reason for these differences is not well known. Low and middle income countries make up more than 80% of the mortality.

While asthma is twice as common in boys as girls, severe asthma occurs at equal rates. In contrast adult women have a higher rate of asthma than men and it is more common in the young than the old.

Global rates of asthma have increased significantly between the 1960s and 2008 with it being recognized as a major public health problem since the 1970s. Rates of asthma have plateaued in the developed world since the mid-1990s with recent increases primarily in the developing world. Asthma affects approximately 7% of the population of the United States and 5% of people in the United Kingdom. Canada, Australia and New Zealand have rates of about 14–15%.

 

 

 

REFERENCES

 

Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Brunton, Lazo & Porter Eds., 11^th Edition. McGraw Hill. 2006. “Pharmacotherapy of Asthma”. pp. 717-736. Comprehensive and good citations.

 

Basic & Clinical Pharmacology. Lange. Katzung, Ed.,  9^th Edition. McGraw Hill. 2004. “Drug Used in Asthma” pp.319-335.  Reasonable and comprehensive.

 

Pharmacology. Lippincott’s Illustrated Reviews. Howland & Mycek, Eds. 3^rd Edition. Lippincott Williams & Wilkins. 2006. “Drugs Affecting the Respiratory System”. pp. 315-322. A bit telegraphic but good illustrations.

 

Principles of Pharmacology. Golan, Tashijian et al. Eds., Lippincott Williams & Wilkins. 2005. “Integrative Inflammation Pharmacology: Asthma” pp. 695-705. Good case studies.

 

P. J. Barnes. New Drugs for Asthma. Nature Reviews Drug Discovery. 3: 831-844. 2004.

 

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