Abstract
Pulmonary pharmacology is focused primarily on medications that effect the conducting airways of the lung responsible for gas exchange at the alveoli. The maintenance of patent airways occurs naturally in health but reduced luminal area can be acutely life threatening in disease states. The anesthesiologist is frequency confronted with patients suffering from asthma, chronic obstructive pulmonary disease or cystic fibrosis since over 10% of the population suffer from these diseases with bronchoconstrictive potential. Furthermore, instrumentation of the airway, which is a frequent component of airway management, can induce bronchoconstrictive reflexes. The reversal of acute bronchoconstriction relies heavily on inhaled agonists for the β2-adrenoceptor or antagonists of muscarinic receptors, but can also be facilitated by a number of anesthetic agents, particularly inhaled volatile anesthetic agents. The chronic maintenance of conducting away patency is largely achieved by avoiding lung inflammation which induces airway smooth muscle hypercontractile responses, airway epithelial damage and mucus production, airway nerve hyperexcitability and chronic airway remodeling causing fixed airway narrowing. These chronic effects are attenuated by a variety of inhaled corticosteroids and selective antagonists of leukotriene signaling. Emerging therapies for avoidance of airway inflammation include monoclonal antibodies targeting specific cytokines, cytokine receptors and immunoglobulins common in allergic lung inflammation.
Keywords
bronchoconstriction, bronchodilator, beta-adrenoceptor, cyclic AMP, muscarinic receptor, inflammation
Chapter Outline
Methylxanthines and Phosphodiesterase Inhibitors
Leukotriene Receptor Inhibitors and 5-Lipoxygenase Inhibitors
Anesthetic Agents as Bronchodilators
The most widely used medications in pulmonary medicine are those delivered via inhalation for small airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Using the lung as a vehicle for drug delivery is well known to anesthesiologists who routinely deliver volatile anesthetics to the lungs for systemic distribution.
This chapter examines in detail pharmacologic approaches to the pulmonary system relevant to anesthesia; pulmonary pharmacology is discussed in the preceding chapter ( Chapter 29 ). Three classes of medications are inhaled for therapeutic treatment of chronic lung diseases, including β 2 -adrenoceptor agonists, anticholinergics (muscarinic receptor antagonists), and steroids. Although combinations of β 2 -adrenoceptor agonists and steroids are now the most widely used therapies in bronchoconstrictive diseases, this was not always so. In 1896 medical textbooks advocated the smoking of “asthma cigarettes” made from the dried leaf or fruiting tops of the Datura stramonium plant, commonly known as jimson weed, devil’s trumpet, or thorn apple. This plant contains tropane alkaloids such as atropine, hyoscyanine, and scopolamine that function as anticholinergics that would relieve reflex-induced bronchoconstriction. Modern use of anticholinergics has evolved with the introduction of inhaled ipratropium bromide in the 1980s.
Methylxanthines were first recognized as having therapeutic effects for asthma when coffee was recommended as early as the 1860s and again in 1914 by Osler and McCrae. By the 1940s intravenous aminophylline was recognized as effective for asthma even though today the mechanisms for this beneficial effect are not clearly established. The likely mechanisms involve elevation of cyclic adenosine monophosphate (cAMP) in airway smooth muscle owing to phosphodiesterase (PDE) inhibition, antagonism of adenosine receptors, and/or systemic release of catecholamines. Nonetheless, the low therapeutic benefit versus toxicity ratio led to its elimination from first-line asthma therapies.
The β-adrenoceptor agonists (see Chapter 14 ) have been the mainstay of asthma maintenance and rescue therapy since the development of metered-dose inhalers (MDIs) in the 1950s, but in 1910 Melland described three cases of patients achieving dramatic relief of acute asthmatic symptoms by subcutaneous administration of epinephrine. Inhaled epinephrine and isoproterenol were the initial therapeutics directed at β 2 adrenoceptors, but because of increased asthma death rates agents that were more selective for β 2 adrenoceptors were introduced in the 1960s.
By the 1970s it was recognized that systemic steroids dramatically improved asthma maintenance therapy. But the devastating complications of long-term systemic steroid use led to the search for alternative therapies in patients with mild asthma and alternative routes of delivery of steroids for those with severe asthma. With the development of inhaled steroids, combination inhalers that combine selective β 2 -adrenoceptor agonists with steroids became the mainstay of asthma therapy and ultimately culminated in the combination of long-acting β 2 -adrenoceptor agonists (LABAs) with steroids. However, by the early 2000s it was recognized that LABAs alone are associated with increased asthma deaths. In 2009 this led to a warning from the U.S. Food and Drug Administration (FDA) that LABAs should not be used alone in the treatment of asthma, but should be used in combination with inhaled steroids. Studies continue to examine whether LABAs added to inhaled steroids are indeed superior to inhaled steroids alone. A study of more than 11,000 adult patients with 6-month follow-up demonstrated no increased risk of serious asthma-related events in patients receiving fluticasone only compared to those receiving fluticasone with salmeterol, and patients receiving fluticasone with salmeterol had a 21% lower incidence of severe asthma exacerbations. In a similar study of more than 6000 children, 4 to 11 years of age, salmeterol in a fixed-dose combination with fluticasone was associated with a risk of serious asthma-related events that was similar to the risk using fluticasone alone.
Many inflammatory diseases are now being treated with monoclonal antibodies directed against specific immunoglobulins, cytokines, or cytokine receptors, and asthma is no exception. The biologic therapies have emerged as specific subtypes of asthma are defined by their specific pathophysiologic mechanism(s) (endotypes). The clearest molecular phenotyping emerging is the T helper 2 (Th2) lymphocyte–dominated response with its associated cytokines (interleukin [IL]-4, IL-5, IL-13) and the more poorly characterized non-Th2 lymphocyte–dominated subtype that includes neutrophilic asthma.
β 2 -Adrenoceptor Agonists
Structure-Activity
All short-acting β 2 -adrenoceptor agonists ( Table 30.1 ) are small molecules with a molecular structure very similar to the endogenous nonselective agonist epinephrine ( Fig. 30.1 ). The LABAs salmeterol and formoterol have modified long side chains with additional aromatic moieties to increase their lipophilicity, which prolongs their duration at the site of action.
| Generic or Trade Name | Delivery Method | |
|---|---|---|
| Short-Acting Inhaled β 2 -Adrenoceptor Agonists | ||
| Albuterol | Generic Proair HFA Proventil HFA Ventolin HFA Accuneb | Nebulization MDI MDI MDI Nebulization |
| Levalbuterol | Xopenex | MDI and nebulization |
| Metaproterenol | Generic | Nebulization |
| Pirbuterol | Maxair | MDI |
| Short-Acting Inhaled β 2 -Adrenoceptor Agonists–Anticholinergic Combinations | ||
| Albuterol + ipratropium bromide | Generic Duoneb Combivent | Nebulization Nebulization MDI |
| Long-Acting Inhaled β 2 -Adrenoceptor Agonists | ||
| Formoterol | Foradil Aerolizer Perforomist | DPI Nebulization |
| Salmeterol | Serevent Diskus | DPI |
| Arformoterol | Brovana | Nebulization |
| Long-Acting Inhaled β 2 -Adrenoceptor Agonists–Corticosteroid Combinations | ||
| Salmeterol/fluticasone | Advair Diskus Advair HFA | DPI MDI |
| Formoterol/mometasone | Dulera | MDI |
| Formoterol/budesonide | Symbicort | MDI |
| Short-Acting Oral β 2 -Adrenoceptor Agonists | ||
| Albuterol | Generic VoSpire ER | Oral Oral |
| Metaproterenol | Generic | Oral |
| Terbutaline | Generic | Oral |
| Inhaled Anticholinergics | ||
| Ipratropium bromide | Generic Atrovent HFA | Nebulization MDI |
| Tiotropium bromide | Spiriva | DPI |
| Umeclidinium | Incruse Ellipta | DPI |
| Aclidinium | Tudorza Pressair | DPI |
| Long-Acting Inhaled β 2 -Adrenoceptor Agonist–Long-Acting Inhaled Muscarinic Receptors Antagonists Combinations | ||
| Vilanterol/umeclidinium | Anoro Ellipta | DPI |
| Formoterol/glycopyrrolate | Bevespi Aeorsphere | MDI |
| Indacaterol/glycopyrrolate | Utibron Neohaler | DPI |
| Olodaterol/tiotropium | Stiolto Respimat | MDI |
Mechanism and Metabolism
Among the hundreds of types of G-protein–coupled receptors (GPCRs) within cells, the biochemical understanding of β-adrenoceptor ligand binding, G-protein interactions, and mechanisms of receptor phosphorylation, desensitization, and internalization have served as the prototypical model for understanding their function. The effectiveness of β 2 -adrenoceptors in asthma and chronic obstructive pulmonary disease (COPD) results from their combined effect at reducing inflammatory cell activation and directly relaxing airway smooth muscle. The role of β 2 adrenoceptors in bronchodilation is largely due to the multiple signaling mechanisms activated within airway smooth muscle cells that all favor smooth muscle relaxation. Classically, β 2 adrenoceptors couple the G s -stimulatory G protein that activates adenylyl cyclase and synthesis of the second-messenger cAMP. cAMP activates several targets, including protein kinase A, that ultimately results in the opening of calcium ion (Ca 2+ )-activated potassium ion (K + ) channels and subsequent plasma membrane hyperpolarization, decreased intracellular entry of Ca 2+ , and decreased sensitivity of the smooth muscle contractile proteins to Ca 2+ .
The long-lasting effects of LABAs such as salmeterol and formoterol are thought to be accounted for by their binding to two sites within the β 2 adrenoceptor: the classic ligand binding site and an exosite on the receptor to which the hydrophobic tail binds irreversibly. A second mechanism proposed to contribute to the prolonged duration of drug effect is that their high lipophilicity allows them to dissolve within the lipid bilayer of the airway smooth muscle cell to serve as an agonist depot.
The majority (80%–100%) of albuterol is excreted in the urine; its primary metabolic route is sulfate conjugation by sulfotransferase 1A3. Salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP 3A4) with 25% eliminated in the urine and the majority in the feces. The xinafoate moiety of salmeterol xinafoate has no pharmacologic activity and is highly protein bound (>99%) with an elimination half-life of 11 days. Formoterol is metabolized by glucuronidation and O-demethylation by CYP 2D6 and CYP 2C. About 60% of oral or intravenous formoterol is excreted in the urine and the remainder in the feces.
Clinical Pharmacology
Pharmacokinetics, Pharmacodynamics, and Therapeutic Effects
Inhaled β 2 -adrenoceptor agonists are rapidly absorbed through the respiratory epithelium reaching the airway smooth muscle within a few minutes. The therapeutic effect of inhaled β 2 -agonists depends on local tissue concentrations that are not reflected in plasma drug concentrations. Regardless of the delivery device used, only about 10% of the inhaled dose actually reaches the peripheral airways to mediate bronchodilation. The mean time for a 15% increase in forced expiratory volume at 1 sec (FEV 1 ) was 6 minutes following two albuterol inhalations with a peak effect occurring at 55 minutes with a mean duration of 2.6 hours. A comparison of the racemic formulation to the levo (R−) enantiomer of albuterol given by nebulization to healthy volunteers demonstrated a shorter time to maximum plasma concentrations for the R-enantiomer (0.2 hours for R−, 0.3 hours for RS−) but a longer half-life (1.5 hours for RS−, 3.4 hours for R−). Limited pharmacokinetic data are available for salmeterol because plasma concentrations often cannot be detected even 30 minutes after a therapeutic dose of 50 µg. Salmeterol-induced airway relaxation is slow in onset, prolonged in duration, and resistant to washout. After inhalation of 400 µg of salmeterol, plasma concentrations of 0.2 and 2 µg/L were achieved at 5 and 15 minutes in healthy volunteers. In a separate study a second peak plasma concentration occurred 45 to 90 minutes after inhalation, likely reflecting gastrointestinal absorption of swallowed drug. LABAs can require up to 30 minutes to first achieve bronchodilator effects with a duration of 12 hours.
Adverse Effects
The β agonists can produce dose-related cardiovascular effects (arrhythmias, tachycardia), hypokalemia, and elevations of blood glucose. Acute adverse effects are more common with oral compared with inhaled β 2 agonists and most commonly include tachycardia, nervousness, irritability, and tremor. Changes in the plasma concentrations of potassium and glucose are seen at doses far exceeding those used clinically. Paradoxical bronchospasm has been reported with β agonists. An initial concern regarding an increased death rate in patients with asthma using salmeterol was raised in 1993 when 12 of 16,787 patients using salmeterol died, but this outcome was attributed to the severity of the patients’ illnesses at the time of study entry. The Salmeterol Multicenter Asthma study Research Trial (SMART), conducted at more than 6,000 sites enrolling more than 26,000 patients, was stopped after an interim data analysis revealed a small but significant increase in respiratory-related morbidity and mortality. A meta-analysis of 19 trials involving more than 33,000 patients also revealed an increased risk of hospitalization for asthma exacerbations, life-threatening asthma attack, or asthma-related death. Although the mechanism or mechanisms for these increased are unknown, speculations include the lack of antiinflammatory effect, downregulation of β 2 adrenoceptors, or incorrect use of these LABAs as rescue inhalers. These findings led to a black box warning by the FDA that LABAs should not be used as monotherapy, and should be used only in patients whose asthma symptoms are not adequately controlled by low- to medium-dose inhaled steroids or whose disease severity warrants two maintenance therapies. Subsequently the FDA initiated a clinical trial protocol in cooperation with academic experts and manufacturers of LABAs that consists of five clinical trials: four in adults and one in children. The initial studies are reassuring. showing no increased risk of serious asthma-related events in a trial involving more than 11,000 adults, and in a separate trial of more than 6,000 children randomly assigned to receive fluticasone alone or fluticasone combined with salmeterol for a 6-month period.
Drug Interactions
The β agonists can potentiate the hypokalemic effect of non–potassium-sparing diuretics. Serum levels of digoxin are reduced after the oral or intravenous administration of albuterol. The vascular effects of β agonists can be exacerbated by patients currently or recently taking monoamine oxidase inhibitors or tricyclic antidepressants. An increased risk of cardiovascular side effects can occur when salmeterol is used along with strong CYP 3A4 inhibitors.
Clinical Application
Common Applications
The use of LABAs in combination with inhaled steroids is an option for patients whose bronchospasm is not adequately controlled using monotherapy with low to medium doses of inhaled corticosteroids as recommended by the Global Initiative for Asthma (GINA) and an expert report from the National Institutes of Health. Conversely, use of inhaled LABAs without steroids is not approved by the FDA because of an increased rate of asthma deaths with this therapy. Short-acting β agonists are recommended as rescue therapy for break-through episodes of bronchospasm, and the frequency of use of rescue therapy is often used as an indicator of the adequacy of asthma maintenance therapy. Inhaled short-acting β agonists can be given to treat active wheezing in the preoperative or intraoperative period. They may also be administered prophylactically in patients at risk for bronchospasm, especially in those patients in whom intubation of the trachea is planned.
Rationale Drug Selection and Administration
The anesthesiologist will most commonly administer short-acting β 2 -adrenoceptor agonists (e.g., albuterol) by inhalation via nebulization or MDIs either preoperatively or intraoperatively. Either modality can be connected to the inspiratory circuit of the anesthesia machine, but effective drug delivery to the airway smooth muscle is variable. This is affected by timing of drug administration relative to inspiration, and the volume of dead space (tracheal tube dimensions and anatomic dead space of the upper trachea/bronchi). Many studies have addressed the efficacy of delivering inhaled β 2 agonists in mechanically ventilated patients. Nebulization is more effective than MDIs. A location 15 cm upstream from the tracheal tube on the inspiratory side of an anesthesia circuit was optimal in an in vitro model. The mode of mechanical ventilation and the humidity of the circuit are also important factors in delivery; a dry circuit and spontaneous breaths under continuous positive airway pressure enhance delivery compared with continuous mandatory volume, assist control, or pressure control ventilator settings. It is also possible to administer selective β 2 -adrenoceptor agonists parenterally (e.g., terbutaline). Emergency treatment of bronchospasm in the emergency room uses inhaled short-acting β 2 agonists and systemic corticosteroids. Rescue therapy from intractable bronchospasm can require intravenous epinephrine, but systemic administration of these therapies is associated with significant cardiovascular effects.
Anticholinergics
Structure-Activity
Inhaled anticholinergics (see Table 30.1 ) are a mainstay in the chronic management of COPD and also are a component of some asthma regimens. Ipratropium bromide (nebulization or MDI) and tiotropium bromide (dry powder inhaler) ( Fig. 30.2 ) antagonize the effects of acetylcholine released from airway parasympathetic nerves on M 3 muscarinic receptors on airway smooth muscle ( Fig. 30.3 ).
Mechanism and Metabolism
Acetylcholine released from parasympathetic nerves traveling within the vagus nerve innervate the lung to act on M 2 and M 3 muscarinic receptors on airway smooth muscle. The nerve terminals also express autoinhibitory M 2 muscarinic receptors that respond to released acetylcholine to inhibit further neurotransmitter release. The M 3 muscarinic receptor on airway smooth muscle is a G-protein–coupled receptor (G q ) that activates phospholipase C to generate diacylglycerol and inositol phosphates from membrane phospholipids. Diacylglycerol activates a number of targets, primarily protein kinase C isoforms. Inositol phosphates elevate intracellular Ca 2+ primarily via release from the sarcoplasmic reticulum. This entire signaling cascade is blocked upstream by ipratropium or tiotropium’s antagonism of cell surface airway smooth muscle muscarinic receptors (see Fig. 30.2 ). Inhaled ipratropium is metabolized to eight metabolites that have little to no anticholinergic activity and are excreted in approximately equal proportions in feces and urine.
Clinical Pharmacology
Pharmacokinetics, Pharmacodynamics, and Therapeutic Effects
Inhaled ipratropium (2 puffs, 18 µg/puff) has an initial onset of 15 minutes with a peak effect at 1 to 2 hours and duration of 3 to 6 hours. Tiotropium bromide (18 µg/capsule, 18 µg/day) has an onset of 30 minutes, a peak effect at 3 hours, and a duration of 24 hours. Only 7% of inhaled ipratropium is bioavailable; the elimination half-life is 3.5 hours by all routes of administration.
Inhaled anticholinergics are indicated for the relief of bronchoconstriction in COPD and asthma by blockade of the M 3 muscarinic receptor on airway smooth muscle. They can be used both prophylactically and as maintenance therapy. Their slower onset of action compared with inhaled β 2 agonists make them unacceptable as rescue therapy for acute exacerbations.
Adverse Effects
Anticholinergics inhibit mucosal secretions and thus dry mouth is common (antisialogogue effect). As with β agonists, paradoxical bronchospasm has been reported with ipratropium. Patients with COPD who are using ipratropium bromide have an increased risk of adverse cardiac events that occur less commonly with tiotropium. Inhaled anticholinergics increase the risk of acute urinary retention more than fourfold in men with benign prostatic hypertrophy as the result of effects on parasympathetic innervation to the detrusor muscles of the bladder. Inhaled ipratropium can also worsen acute narrow-angle glaucoma owing to its parasympathetic effects.
Clinical Application
Common Applications
Anticholinergics have been used to treat obstructive airway disease since the early use of the deadly nightshade (genus Atropa ) and asthma cigarettes. Although inhaled β 2 -adrenoceptor agonists with steroids are often initial therapy for the bronchoconstrictive diseases asthma and COPD, there is evidence of equivalence or even superiority of inhaled anticholinergics in the treatment of COPD. In the perioperative setting the choice of anticholinergic is mechanistically sound because the bronchoconstriction following airway irritation involves parasympathetic nerve release of acetylcholine onto M 3 muscarinic receptors on airway smooth muscle.
Instrumentation of the upper airway with an endotracheal tube or suction catheter is a potent stimulus for reflex-induced bronchoconstriction (see Fig. 30.1 ). This reflex originates in the airway wall where irritant nerve fibers travel in the vagal nerve to the nucleus of the solitary tract, which synapses via gamma-aminobutyric acid (GABA) A and glutamatergic receptors on airway-related vagal preganglionic neurons. The efferent outflow from this brainstem nucleus travels back down the vagus to release acetylcholine onto M 3 muscarinic receptors on airway smooth muscle. The M 3 muscarinic receptor via G q -coupling increases intracellular Ca 2+ , resulting in smooth muscle contraction and airway narrowing. Thus anticholinergic blockade of M 3 muscarinic receptors is an ideal target to attenuate reflex-induced bronchoconstriction.
Four inhaled antimuscarinics are available: the relatively quick-onset short-duration ipratropium bromide, the intermediate-duration aclidinium, and the longer-duration tiotropium bromide or umeclidinium. Ipratropium bromide is available in either nebulized or MDI formulations, making this an ideal preoperative or intraoperative treatment for a patient with bronchoconstriction induced by airway irritation. A newer inhaled anticholinergic drug, aclidiumium, produces bronchodilation for a similar duration as tiotropium with preclinical evidence of a reduced risk of anticholinergic heart rate effects.
Combination inhalers are now available for COPD that contain both a LABA and long-acting muscarinic receptor antagonist (LAMA). Studies in patients with COPD comparing the combination inhaler indacaterol/glycopyrrolate indicated improved lung function, dyspnea, symptoms, and health status compared with the use of either agent alone. A meta-analysis compared combination LABA/LAMA bronchodilators with either LAMA alone or LABA/inhaled corticosteroid combinations in COPD patients. The LABA/LAMA combination had greater efficacy and comparable safety profiles compared with the LAMA alone or the combined LABA/inhaled corticosteroid. In contrast, the addition of inhaled tiotropium to patients with asthma maintained with LABA/inhaled corticosteroid failed to show a benefit of adding a LAMA to LABA/inhaled corticosteroid maintenance therapy in this disease state.
Inhaled Corticosteroids
Structure-Activity
The specific structures of the inhaled corticosteroids on a steroidal backbone are illustrated in Fig. 30.4 . For a more detailed discussion of systemic corticosteroid pharmacology see Chapters 36 and 38 .
Mechanism and Metabolism
Corticosteroids interact with intracellular steroid receptors that translocate to the nucleus and interact with transcription factor complexes to regulate inflammatory protein synthesis. The stimulation of gene transcription (transactivation) correlates with negative side effects of corticosteroids, whereas repression of transcription factors (e.g., nuclear factor kappa B [NF-κB] and activator protein 1 [AP-1]) is responsible for antiinflammatory effects. Although steroids affect the inflammatory response of lymphocytes, eosinophils, neutrophils, macrophages, monocytes, mast cells, and basophils, particular attention has focused on the role of a subset of T lymphocytes in asthma. CD + Th2 cells that produce IL-4, IL-5, and IL-13 are particularly important in orchestrating the complex inflammatory events in asthmatic lungs and are inhibited by inhaled steroids. Mast cell and basophil numbers are increased and release of mediators (histamine, leukotrienes [LTs]) in asthmatic airways is enhanced. Although inhaled steroids also suppress these cells, more specific therapy with oral LT antagonists has allowed reduction in inhaled steroid use in some patients. Corticosteroids exhibit high first-pass metabolism by the liver via CYP 3A4 isoenzymes.
Clinical Pharmacology
Pharmacokinetics, Pharmacodynamics, and Therapeutic Effects ( Table 30.2 )
Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active monoester 17-beclomethasone monopropionate. The active metabolite has an affinity for the glucocorticoid receptor that is 25 times that of the parent compound. Ciclesonide is an inactive prodrug that is converted to an active metabolite desisobutyrylciclesonide in the lung. Much (40%–90%) of an inhaled corticosteroid is swallowed and therefore available for systemic absorption (and potential systemic side effects). Thus a low oral bioavailability of inhaled corticosteroids is desirable, ranging from 1% for fluticasone propionate to 26% for 17-beclomethasone monopropionate. In contrast to oral absorption, most drug deposited in the lung will be absorbed systemically and is not subjected to first-pass hepatic metabolism. Deposition and thus absorption from the lung is more a function of the efficiency of the delivery device than the properties of the drug itself. Fluticasone has only 1% oral bioavailability owing to first-pass metabolism but when delivered to the lung by dry powder inhalers or MDIs, total systemic bioavailability is 17% and 25%, respectively. The transition from chlorofluorocarbons- to hydrofluoroalkane (HFA)-powered MDIs has resulted in unanticipated improvement in the delivery of smaller particles deposited deeper in the lung with less oropharnygeal deposition and thus less systemic absorption (see “ Emerging Developments ”). Most of the inhaled corticosteroids are (~70%) bound to plasma proteins and have half-lives of 3 to 8 hours owing to high extraction and metabolism by the liver.
