© Springer International Publishing AG 2018Ehab Farag, Maged Argalious, John E. Tetzlaff and Deepak Sharma (eds.)Basic Sciences in Anesthesiadoi.org/10.1007/978-3-319-62067-1_12
12. Respiratory Pharmacology
Department of Cardiothoracic Anesthesiology and Critical Care, Cleveland Clinic, Cleveland, OH, USA
Ahmad Maher Adi
12.7 Mast Cell Stabilizer
12.7.1 Cromolyn Sodium
12.7.2 Nedocromil Sodium
12.9 Combination Therapy
12.11 Questions and Answers
KeywordsRespiratory pharmacologyPathological triadBronchodilatorsAnti-inflammatory modifier drugs
Medications used to manage the pulmonary “pathologic triad” include bronchodilators and anti-inflammatory medication. Bronchodilators include beta 2 adrenergic receptor agonists and cholinergic/muscarinic acetylcholine receptor antagonists. Anti-inflammatory medications include leukotriene modifier drugs, mast cell stabilizers, and immunoglobulin E blockers.
Bronchodilators are essential in the treatment of airway disorders. They are a mainstay treatment for the management of chronic obstructive lung disease (COPD) and are critical in the symptomatic management of asthma.
There is a uniform distribution of β(beta)-adrenoreceptors on the alveolar wall with 2:1 ratio of β(beta)1/β(beta)2 receptors.
β(beta) 2 adrenergic agonists should be used with caution in patients with hyperthyroidism and cardiovascular disease due to the potential for QT prolongation and arrhythmias.
Airway tone is mainly controlled by parasympathetic nerves carried by the vagus nerve.
There are 5 different subtypes of muscarinic acetylcholine receptors (M1-M5), which are expressed in almost every cell type of the airway and lung tissue, including airway and vascular smooth muscle, different glandular and surface epithelium cells, endothelial cells, and inflammatory cells.
Steroids are considered first-line medications in the treatment of asthma. Using the inhaled rather than intravenous forms can reduce their side effects.
Low-dose inhaled steroids in regular daily doses are highly effective in reducing asthma symptoms and reducing the risk of asthma-related exacerbations, hospitalization, and death.
Headache is a common side effect in patients receiving leukotriene-modifying drugs.
The use of the immunoglobulin E blocker omalizumab can reduce the requirements for steroids and improve quality of life in asthmatic patients with frequent asthma exacerbation. Its use is reserved for severe uncontrolled asthmatic patients despite best available therapy.
Combination therapy combines a medication from 2 or more classes. Combination therapy, by using a lower dose of medication from each class, can reduce systemic side effects.
The pathological triad of pulmonary disease consists of: bronchospasm, airway inflammation, and retained secretion. Respiratory pharmacology deals with agents used to treat this “pathological triad.” Medications used to treat these conditions can be divided into different categories based on their mechanism of action. They include bronchodilators, anticholinergics, corticosteroids, mucolytics, and decongestants just to name a few. Other agents used to treat pulmonary disease such as oxygen, antibiotics, local anesthetics, respiratory stimulants, and muscle relaxers are beyond the scope of this chapter.
Bronchodilators are essential in the treatment of airway disorders. They are the primary treatment for the management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma. Bronchodilators work through a direct relaxation effect on airway smooth muscle cells. Three major classes of bronchodilators exist at the present time: β(beta)2-adrenoreceptor (AR) agonists, cholinergic receptor antagonists, and xanthines. This chapter will discuss the first 2 treatments, which can be used individually or in combination, as is currently preferred in order to minimize systemic effects. Fast- and short-acting agents are best used for acute symptom relief, whereas long-acting agents are best for maintenance therapy. Treatment adherence has been improved by new formulations that allow once-daily administration.
Understanding the neurological innervation of the airway is key to understanding how bronchodilators work. Airway tone is mainly controlled by parasympathetic nerves carried by the vagus nerve. Postganglionic parasympathetic cholinergic and non-noradrenergic noncholinergic (NANC) fibers innervate airway smooth muscles (ASM), providing the dominant control of the muscle tone and airway caliber as well as airway glands and microvasculature.
There is no direct sympathetic innervation of ASM, but there is innervation of the airway vasculature. Acetylcholine (ACh) is the classic neurotransmitter of the parasympathetic nervous system at both the ganglionic and neuroeffector junctions, which then activate the cholinergic/muscarinic receptors.
Five different subtypes of muscarinic receptors (mAChRs) have been identified (M1-M5), and they are expressed in almost every cell type of the airway and lung tissue, including airway and vascular smooth muscle, different glandular and surface epithelium cells, endothelial cells, and inflammatory cells.
β(beta)-ARs are present in high concentrations in lung tissue and are divided into 3 types: β(beta)1, β(beta)2, and β(beta)3. The majority of pulmonary β(beta)-ARs are of the β(beta)2-AR subtype, localized in the ASM, epithelium, vascular smooth muscle, and submucosal glands. They are more prevalent in small airways than large airways but are also expressed on many inflammatory and immune cells, whereas β(beta)1-ARs are located in the gland and alveoli. There is a uniform distribution of β(beta)-ARs on the alveolar wall with a 2:1 ratio of β(beta)1/β(beta)2.
β(beta)2-ARs are coupled to Gs (part of the G protein-coupled receptors), where stimulation by β(beta)2-AR agonist activate the adenyl cyclase and increase cyclic adenosine monophosphate (cAMP) levels, which in turn increase protein kinase A (PKA) activity. This reduces the intracellular calcium level and activates large conductance potassium channels leading to relaxation of airway smooth muscle.
12.3 β(beta)-Adrenergic Receptors Agonists
Ephedrine from the plant ephedra equisetina was used for more than 2000 years for the short-term treatment of respiratory symptoms. The discovery of epinephrine and isoproterenol followed, but due to the fact that these drugs were non-selective alpha- and beta-adrenergic receptor agonists, they caused unwanted side effects and warranted the need of selective β(beta)-AR receptors agonist.
12.3.1 Short-Acting β(beta)2-Adrenergic Receptors Agonists
Short-acting β(beta)2-AR agonists (SABA) can be divided into 2 groups dependent on the duration of action using conventional doses: (1) very short acting, duration 1–2 h (isoproterenol and rimiterol); and (2) short acting, duration 3–6 h (fenoterol, albuterol, and terbutaline).
Albuterol has greater selectivity between β(beta)2 and β(beta)1-AR than any other product previously available. It also has negligible α(alpha)-AR activity. It causes maximum bronchodilation but with minimal cardiovascular responses compared to isoproterenol. After inhalation, its maximum effect can be seen in 15 min. However, albuterol weakly binds to the receptor and quickly diffuses to the microcirculation, which accounts for the short action of duration (4–6 h), but it is the drug of choice to relieve symptoms of bronchospasm. It also can be used intravenously if the inhalation response is reduced or absent.
Levalbuterol ([R]-Albuterol), an isomer of albuterol, can be used instead of albuterol. It may reduce hospitalization, have fewer adverse effects, and provide similar bronchodilators effects at reduced dose, but recent studies have questioned these benefits.
Fenoterol has a similar effect to albuterol, with β(beta)2-AR selectivity and minimal α(alpha)-AR stimulation. The only difference is that it can exhibit slightly longer duration of action. A 200 microgram dose was required to produce a maximal response.
Synthetic sympathomimetic amine has a greater specificity for β(beta)2-AR. Due to it structure, with a dihydroxybenzene group at the β(beta)-carbon atom, it has a longer duration of action (4–6 h).
Terbutaline is administered by aerosol inhalation. When given parenterally, it loses much of its selectivity, and cardiovascular effects similar to isoproterenol are observed. Compared to epinephrine, subcutaneous terbutaline can induce more bronchodilation for a longer period of time but with more side effects.
Bambuterol is an oral terbutaline prodrug with prolonged duration of bronchodilator action.
12.3.2 Long-Acting β(beta)2-Adrenergic Receptor Agonists
Long-acting β(beta)2-AR agonists (LABA) such as salmeterol and formoterol provide 12-h bronchodilation.
Salmeterol binds specifically to the β(beta)2-AR via albuterol “head group”—the molecule of which is >10,000 times more lipophilic than albuterol. The process of its diffusion to reach the active site of the β(beta)2-AR is slow (>30 min) and accounts for the slow onset of action on the airway smooth muscle (ASM). Salmeterol does not induce desensitization or internalization of receptors, which may also contribute to its long therapeutic duration of action.
Studies have shown that salmeterol is a partial agonist, which may attenuate the effects of β(beta)2-AR agonist with greater efficacy, thus raising the possibility of pretreatment with this drug.
The onset of action is approximately 10 min. Maximal bronchodilation may take hours to achieve.
Due to its structural molecule, formoterol has greater affinity to the β(beta)2-AR and has the highest bronchoselectivity among the LABA.
Formeterol has a faster onset of action compared to salmeterol and has been shown in a concentration dependent to inhibit antigen-induced mediator release from human lung fragments.
Formoterol has the same effect of salmeterol at a lower dose (50 microgram vs 12 microgram).
12.3.3 Ultra-Long-Acting β(beta)2-Adrenergic Receptors Agonists
Ultra-long acting β(beta)2-ARs were developed in an attempt to simplify the treatment to 1 dose daily so that patients can adhere to their treatment.
Indacaterol is a highly lipophilic drug that is retained in the lipid rafts of the plasma membrane, an area particularly rich in β(beta) receptors. This means that these receptors are repeatedly stimulated by this drug and for a long period of time, achieving an effect that lasts 24 h. Indacaterol has high intrinsic activity, which explains the rapid onset of action within 5 min of administration. Mild cough is the only significant side effect, which may lead to discontinuation of the treatment.
Multiple studies have shown the superiority of daily dose indacaterol over formoterol, salmeterol, and tiotropium bromide in improving trough forced expiratory volume 1 (FEV1). It also provides significant health-related quality of life.
Olodaterol is a potent β(beta)2 receptor agonist with high intrinsic activity. This ultra-LABA binds moderately to lipid rafts, although its dissociation half-life is about 18 h. It has a 2-stage profile of dissociation from β(beta)2 receptors. Its slow component has a dissociation half-life of 12 h. These 2 features explain the fact that the bronchodilator effect lasts 24 h.
Vilamterol has greater intrinsic activity than salmeterol and appears to be more potent than indacaterol. All doses of vilamterol were associated with low incidence of treatment-related side effects.
Carmoterol is over 100 times more selective for bronchial muscle than myocardial tissue. It displays a fast onset and long duration of action.
Carmoterol has better improvement of trough FEV1 than salmeterol, and it has no side effects.
12.3.4 Intravenous β(beta)2-Adrenergic Receptors Agonists
Many patients with acute exacerbation of asthma are non-responders to inhaled β(beta)-adrenergic agonists. Intravenous bedoradrine is a highly selective β(beta)2-AR agonist. In a recent study to show the efficacy of bedoradrine, there was no significant difference in % FEV1 at 3 h between the bedoradrine compared to the placebo groups. The dyspnea scores were significantly improved for patients treated with bedoradrine.
12.3.5 Side Effects of β(beta)2-Adrenergic Receptors Agonists
Because of the widespread distribution of β(beta)2-AR, a number of side effects are noted when β(beta)2-AR agonists are absorbed into the systemic circulation. The number of side effects is the greatest when β(beta)2-AR are administered orally or parenterally.