Airway Pharmacology



Airway Pharmacology


Douglas S. Gardenhire



Chapter Objectives


After reading this chapter you will be able to:


image Analyze three phases that constitute the course of drug action from dose to effect.


image Describe classes of drugs that are delivered via the aerosol route.


image Compare mode of action, indications, and adverse effects that characterize each major class of aerosolized drug.


image Compare available aerosol formulations, brand names, and dosages for each specific drug class.


image Select the appropriate drug class for a specific patient or clinical situation.


image Assess the outcomes for each class of aerosol drug therapy.



Key Terms




















The primary focus of respiratory care pharmacology is the delivery of bronchoactive inhaled aerosols to the respiratory tract for the diagnosis and treatment of pulmonary diseases. Although other drug classes are used in respiratory care, discussion in this chapter is limited to bronchoactive inhaled aerosols. Other drug classes are reviewed in pharmacology texts.1,2



Principles Of Pharmacology


The course of drug action from dose to effect comprises three phases: drug administration, pharmacokinetic, and pharmacodynamic phases. These three phases of drug action can be applied to drug treatment of the respiratory tract with bronchoactive inhaled agents.



Drug Administration Phase


The drug administration phase describes the method by which a drug dose is made available to the body. Administering drugs directly to the respiratory tract uses the inhalation route, and the dose form is an aerosol of liquid solutions, suspensions, or dry powders. The most commonly used devices to administer orally or nasally inhaled aerosols are the metered dose inhaler (MDI), the small volume nebulizer (SVN), and the dry powder inhaler (DPI). Reservoir devices, including holding chambers with one-way inspiratory valves and simple, nonvalved spacer devices, are often added to MDIs to reduce the need for complex hand-breathing coordination and to reduce oropharyngeal impaction of the aerosol drug (see Chapter 36).


The advantages of treatment of the respiratory tract with inhaled aerosols are as follows:



Disadvantages of the delivery of inhaled aerosols in treating respiratory disease include the number of variables affecting the delivered dose and lack of adequate knowledge of device performance and use among patients and caregivers.3



Pharmacokinetic Phase


The pharmacokinetic phase of drug action describes the time course and disposition of a drug in the body based on its absorption, distribution, metabolism, and elimination. Inhaled bronchoactive aerosols are intended for local effects in the airway. Undesired systemic effects result from absorption and distribution throughout the body. One method of limiting distribution of inhaled aerosols is use of a fully ionized drug rather than a nonionized agent. A fully ionized drug is not absorbed across lipid membranes, whereas a nonionized drug is lipid-soluble and diffuses across cell membranes and into the bloodstream. Examples are ipratropium and atropine sulfate. Ipratropium is a fully ionized quaternary ammonium compound that diffuses poorly across lipid membranes. Atropine is poorly ionized and diffuses well, distributing throughout the body. As a result, atropine produces systemic side effects such as mydriasis (dilation of the pupils) and blurring of vision. The effects of ipratropium are largely local to the airway, and systemic effects are nonexistent or minimal.


An inhaled aerosol distributes to the lung by inhalation and the stomach through swallowing of drug that deposits in the oropharynx. The therapeutic effect of the aerosol drug is caused by the portion in the airway. Systemic effects are due to absorption of the drug from the airway and gastrointestinal (GI) tract. The ideal aerosol would distribute only to the airway with none reaching the stomach. The lung availability-to-total systemic availability ratio (L/T ratio) quantifies the efficiency of aerosol delivery to the lung:


L/T ratio=Lung availability/(Lung+GI availability)


image

This concept, proposed by Borgström4 and elaborated by Thorsson,5 is illustrated in Figure 32-1, showing delivery of albuterol by inhalation using an MDI and a DPI.


image
FIGURE 32-1 Comparison of efficiency of aerosol delivery with MDI and DPI using the L/T availability ratio. (From Gardenhire DS: Rau’s respiratory care pharmacology, ed 8, St. Louis, 2012, Elsevier.)



Airway Receptors and Neural Control of the Lung


Pharmacologic control of the airway is mediated by receptors found on airway smooth muscle, secretory cells, bronchial epithelium, and pulmonary and bronchial blood vessels. There are sympathetic (adrenergic) and parasympathetic (cholinergic) receptors in the lung. The terminology for drugs acting on these receptors is based on the usual neurotransmitter that acts on the receptor. The usual neurotransmitter in the sympathetic system is norepinephrine, which is similar to epinephrine, also known as adrenaline (Adrenalin). The usual neurotransmitter in the parasympathetic system is acetylcholine. The receptors responding to these neurotransmitters are termed adrenergic and cholinergic. Agonists (stimulating agents) and antagonists (blocking agents) that act on these receptors are given the following classifications:



Because cholinergic receptors exist at autonomic ganglia and at the myoneural junction in skeletal muscle, the terms muscarinic and antimuscarinic distinguish cholinergic agents whose action is limited to parasympathetic sites. Neostigmine is a cholinergic (indirect-acting) drug that increases receptor stimulation at both the myoneural junction and the parasympathetic sites. By contrast, atropine is an antimuscarinic agent, which blocks the action of acetylcholine only at the parasympathetic sites. Table 32-1 summarizes receptors and their effects for the cardiopulmonary system. A more detailed description of the autonomic nervous system and receptor subtypes is provided by Katzung and colleagues.2



TABLE 32-1


Airway Receptors and Their Effects in the Cardiopulmonary System*


















































Location Receptor Effect
Heart Beta-1-adrenergic Increased rate, force
M2-cholinergic Decreased rate
Bronchiolar smooth muscle Beta-2-adrenergic Bronchodilation
M3-cholinergic Bronchoconstriction
Pulmonary blood vessels Alpha-1-adrenergic Vasoconstriction
Beta-2-adrenergic Vasodilation
M3-cholinergic Vasodilation
Bronchial blood vessels Alpha-1-adrenergic Vasoconstriction
Beta-2-adrenergic Vasodilation
Submucosal glands Alpha-1-adrenergic Increased fluid, mucin
Beta-2-adrenergic Increased fluid, mucin
M3-cholinergic Exocytosis, secretion


image


M2, M3, Subtypes of muscarinic (M) cholinergic receptors.


*Adrenergic and muscarinic cholinergic receptor subtypes are indicated.



Adrenergic Bronchodilators


Adrenergic bronchodilators represent the largest group of drugs among the aerosolized agents used for oral inhalation. Table 32-2 lists bronchodilators in this group, with their aerosol formulations, selected brand names, and dosages.



TABLE 32-2


Adrenergic Bronchodilator Agents Available in the United States


















































































































































Drug Brand Name Receptor Preference Adult Dosage Time Course (Onset, Peak, Duration)
Ultra-Short-Acting Adrenergic Bronchodilator Agents
Epinephrine Adrenalin Chloride Alpha, beta SVN: 1% solution (1 : 100), 0.25-0.5 ml (2.5-5.0 mg) 4 times daily Onset: 3-5 min
Peak: 5-20 min
Duration: 1-3 hr
  Primatene Mist   MDI: 0.22 mg/puff, puffs as ordered or needed
Racemic epinephrine microNefrin, Nephron, S-2 Alpha, beta SVN: 2.25% solution, 0.25-0.5 ml (5.63-11.25 mg) 4 times daily Onset: 3-5 min
Peak: 5-20 min
Duration: 0.5-2 hr
Short-Acting Adrenergic Bronchodilator Agents
Metaproterenol Alupent Beta-2 SVN: 0.4%, 0.6% solution, tid, qid Onset: 1-5 min
      Tab: 10 mg and 20 mg, tid, qid Peak: 60 min
      Syrup: 10 mg per 5 ml Duration: 2-6 hr
Albuterol Proventil HFA, Ventolin HFA, ProAir HFA, AccuNeb, VoSpire ER Beta-2 SVN: 0.5% solution, 0.5 ml (2.5 mg), 0.63 mg, 1.25 mg and 2.5 mg unit dose, tid, qid Onset: 15 minPeak: 30-60 minDuration: 5-8 hr
      MDI: 90 µg/puff, 2 puffs tid, qid
      Tab: 2 mg, 4 mg, and 8 mg, bid, tid, qid
      Syrup: 2 mg/5 ml, 1-2 tsp tid, qid  
Pirbuterol Maxair Autohaler Beta-2 MDI: 200 µg/puff, 2 puffs every 4-6 hr Onset: 5 min
Peak: 30 min
Duration: 5 hr
Levalbuterol Xopenex, Xopenex HFA Beta-2 SVN: 0.31 mg/3 ml 3 times daily, 0.63 mg/3 ml 3 times daily, or 1.25 mg/3 ml 3 times daily, concentrate 1.25 mg/0.5 ml, 3 times daily Onset: 15 min
Peak: 30-60 min
Duration: 5-8 hr
      MDI: 45 µg/puff, 2 puffs every 4-6 hr  
Long-Acting Adrenergic Bronchodilator Agents
Salmeterol Serevent Diskus Beta-2 DPI: 50 µg/blister twice daily Onset: 20 min
Peak: 3-5 hr
Duration: 12 hr
Formoterol Perforomist, Foradil Beta-2 SVN: 20 µg/2 ml unit dose, bid Onset: 15 min
      DPI: 12 µg/inhalation, bid Peak: 30-60 min
  Foradil Certihaler Beta-2 DPI: 8.5 µg/inhalation, bid Duration: 12 hr
Arformoterol Brovana Beta-2 SVN: 15 µg/2 ml unit dose, twice daily Onset: 15 min
Peak: 30-60 min
Duration: 12 hr


image



Indications for Use


The general indication for use of an adrenergic bronchodilator is the presence of reversible airflow obstruction. The most common use of these agents clinically is to improve flow rates in asthma (including exercise-induced asthma), acute and chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis (CF), and other obstructive airway states.






Mode of Action and Effects


Adrenergic bronchodilators can stimulate one or more of the following receptors, with the effects described:



Bronchodilation, through stimulation of beta-2 receptors, is the desired therapeutic effect. Both alpha-adrenergic and beta-adrenergic receptors are G protein–linked receptors. Figure 32-2 illustrates the mode of action for relaxation of airway smooth muscle when a beta-2 receptor is stimulated. The nature of the beta receptor and its activity is presented in detail in a review by Barnes.7


image
FIGURE 32-2 Mode of action by which a beta agonist stimulates the G protein–linked beta receptor to cause smooth muscle relaxation. Adrenergic agonists, such as albuterol or epinephrine, attach to beta receptors, which are polypeptide chains traversing the cell membrane seven times. This causes activation of the stimulatory G protein, designated GS, linked to the receptor. When stimulated, the receptor undergoes a conformational change, and the alpha subunit of the G protein attaches to adenyl cyclase. Activation of adenyl cyclase by the GS protein causes an increased synthesis of the second messenger, cyclic adenosine monophosphate (cAMP). This ultimately causes smooth muscle relaxation and bronchodilation. ATP, Adenosine triphosphate; COOH, carboxy terminus; GDP, guanosine diphosphate; GTP, guanosine triphosphate. (From Gardenhire DS: Rau’s respiratory care pharmacology, ed 8, St. Louis, 2012, Elsevier.)


Adrenergic Bronchodilator Agents


Adrenergic bronchodilator agents represent the evolution of a drug class. Although all of these agents are adrenergic agonists, the differences among individual agents are due to their receptor preference (alpha-adrenergic, beta-1-adrenergic, beta-2-adrenergic) and their different pharmacokinetics as listed in Table 32-2. These differences determine the optimal clinical application of individual agents, as discussed subsequently. The adrenergic bronchodilators form three subgroups.




Short-Acting Noncatecholamine Agents


Because of their short duration of action and lack of beta-2 specificity, catecholamines were replaced with longer acting, beta-2-specific agents, including metaproterenol, pirbuterol, albuterol, and levalbuterol. Because their duration of action is approximately 4 to 6 hours, these drugs are more suited to maintenance therapy than catecholamines and can be taken on a four-times-daily schedule. However, their modest duration of action results in loss of bronchodilating effect overnight.



Single-Isomer Beta Agonists

Levalbuterol is approved as a single-isomer beta-2-selective agonist. Previous inhaled formulations of adrenergic bronchodilators all were synthetic racemic mixtures, containing both the (R)-isomer and the (S)-isomer in equal amounts. Levalbuterol is the pure (R)-isomer of racemic albuterol. Both stereoisomers of albuterol are shown in Figure 32-3 with the single-isomer (R-isomer) form of levalbuterol. Although the (S)-isomer is physiologically inactive on adrenergic receptors, there is accumulating evidence that the (S)-isomer is not completely inactive. Box 32-1 lists some of the physiologic effects of (S)-albuterol noted in the literature.8–14 The effects noted antagonize the bronchodilating effects of the (R)-isomer and promote bronchoconstriction. In addition, the (S)-isomer is more slowly metabolized than the (R)-isomer.



Box 32-1   Effects and Characteristics of (S)-Isomer of Albuterol




image
FIGURE 32-3 (R)– and (S)-isomers of racemic albuterol. Levalbuterol is the single, (R)-isomer form of racemic albuterol and contains no (S)-isomer.

Levalbuterol is available as a nebulization solution in three strengths: 0.31 mg/3 ml, 0.63 mg/3 ml, and 1.25 mg/3 ml. As a result of mixing of other inhaled agents, levalbuterol is also available as a concentrate of 1.25 mg/0.5 ml and an MDI. In a study by Nelson and associates,15 the 0.63-mg dose was found to be comparable to the 2.5-mg racemic albuterol dose in onset and duration. Side effects of tremor and heart rate changes were less with the single-isomer formulation. The 1.25-mg dose showed a higher peak effect on forced expiratory volume in 1 second (FEV1) with an 8-hour duration compared with racemic albuterol. Side effects with this dose were equivalent to the side effects seen with racemic albuterol. An equivalent clinical response was seen with one-fourth of the racemic dose (0.63 mg) using the pure isomer, although the racemic mixture contains 1.25 mg of the (R)-isomer (half of the total 2.5-mg dose). A detailed review is available of levalbuterol and differences between the (R)-isomer and (S)-isomer of albuterol.16



Long-Acting Adrenergic Bronchodilators


The release of salmeterol offered the first long-acting adrenergic bronchodilator in the United States. In contrast to previous agents, the duration of action of salmeterol is about 12 hours. The pharmacokinetics of salmeterol makes it suitable for maintenance therapy, in particular, with nocturnal asthma. However, it is not well suited for relief of acute airflow obstruction or bronchospasm because its onset is longer than 20 minutes, with a peak effect occurring by 3 to 5 hours. Although this agent is a beta-2 agonist, its exact mode of action differs from previous beta-2 agonists, allowing persistent receptor stimulation over a prolonged period of hours. A more detailed discussion of the action of salmeterol can be found in a review by Johnson and colleagues.17


Formoterol is a second long-acting, beta-2-specific agent and is approved for general clinical use in the United States. The duration of effect is approximately 12 hours, but in contrast to salmeterol, the onset of action and peak effect of formoterol are rapid and similar to albuterol.18 Nonetheless, patients should be cautioned about the risk of accumulation and toxicity if formoterol is used as a rescue agent in the same way that shorter acting beta agonists, such as albuterol, are used. As with salmeterol, the extensive side chain or tail makes formoterol more lipophilic than shorter acting bronchodilators and is the basis for its longer duration of effect.


Arformoterol (Brovana), the single (R)-isomer of formoterol, is the newest long-acting beta agonist on the market. Arformoterol is available as a 2-ml unit dose vial inhalation solution delivering 15 mcg per dose. The recommended dosage is one unit dose twice daily. Arformoterol is indicated for the maintenance of bronchospasm in COPD, including chronic bronchitis and emphysema. In phase III trials, the manufacturer reported an increase in bronchodilation compared with placebo.


A new novel once-daily, long-acting beta-agonist, indacaterol, was approved in the United States in 2011 under the brand name of Arcapta Neohaler. It has been used mainly to treat asthma, and additional indications for COPD are being examined. Indacaterol is also being studied in combination with tiotropium bromide with successful preliminary outcomes.1



Adverse Effects


Older adrenergic agents, such as isoproterenol, commonly caused tachycardia, palpitations, and an “adrenaline effect” of shakiness and nervousness. The newer, more beta-2-selective agents are safer and typically cause tremor as the main side effect. Other common side effects with the inhaled agents include headache, insomnia, and nervousness. Patients should be reassured that some tolerance to these effects does occur. Potential adverse effects with use of adrenergic bronchodilators include the following:



Inhalation results in fewer and less severe side effects than oral administration. Although tolerance develops to the bronchodilating effect, this is not a contraindication to use of the drugs, and relaxation of airway smooth muscle still occurs. Desaturation resulting from mismatching of image with inhalation of the aerosol is not clinically significant and reverses quickly. Bronchospasm resulting from chlorofluorocarbon propellants can be prevented by changing to newer hydrofluoroalkane-propelled MDIs or a different aerosol delivery form.


The implication of beta-2-adrenergic agonists in deaths from asthma—termed the asthma paradox or the beta agonist controversy—remains debated.19 There is evidence of loss of a bronchoprotective effect with use of beta agonists, and patients should be cautioned to avoid asthma triggers.20 The increased prevalence of asthma in general remains a troublesome and unresolved issue.



Assessment of Bronchodilator Therapy


Assessment of therapy with adrenergic bronchodilators should be based on the indication for the aerosol agent (presence of reversible airflow obstruction owing to primary bronchospasm or other obstruction secondary to an inflammatory response or secretions, either acute or chronic). With all aerosol drug therapy, basic vital signs (respiratory rate and pattern, pulse, breath sounds) should be assessed before and after treatment, especially for initial drug use, and the patient’s subjective reaction (complaints of breathing difficulty) should be assessed. Patients should be instructed in the correct use of the aerosol device used, with verification of correct use. Finally, the patient’s subjective reaction to the treatment should be monitored for any change in breathing effort. This assessment applies to all subsequent drug groups by aerosol and is not repeated for each class. The following specific actions are suggested to evaluate patient response to this class of drugs:



• Monitor flow rates using bedside peak flowmeters, portable spirometry, or laboratory reports of pulmonary function before and after bronchodilator studies to assess reversibility of airflow obstruction.


• Assess arterial blood gases or pulse oximetry saturation, as needed, for acute states with asthma or COPD to monitor changes in ventilation and gas exchange (oxygenation).


• Note the effect of beta agonists on blood glucose (increase) and K+ (decrease) laboratory values, if using high doses, such as with continuous nebulization or emergency department treatments.


• In the long-term, monitor pulmonary function studies of lung volumes, capacities, and flows.


• Instruct asthmatic patients in the use and interpretation of disposable peak flowmeters to assess severity of asthmatic episodes and provide an action plan for treatment modification.


• Emphasize in patient education that beta agonists do not treat underlying inflammation and do not prevent progression of asthma, and additional antiinflammatory treatment or more aggressive medical therapy may be needed if there is a poor response to the rescue beta agonist.


• Instruct and then verify correct use of aerosol delivery device (SVN, MDI, reservoir, DPI).


• Instruct patients in use, assembly, and especially cleaning of aerosol inhalation devices.


The following actions are suggested to evaluate patient response to long-acting beta agonists:



Note: Death has been associated with excessive use of inhaled adrenergic agents in severe acute asthma crises. Individuals using such drugs should be instructed to contact a physician or an emergency department if there is no response to the usual dose of the inhaled agent.


Because of the ongoing safety concerns of long-acting beta-2 agonists, the FDA is requiring changes on how long-acting beta-2 agonists are used in the treatment of asthma. As of June 2, 2010, the FDA suggests the following:




Mini Clini


Assessing Beta Agonist Side Effects



image Problem


The respiratory therapist (RT) has administered an aerosol treatment of albuterol using an MDI with a holding chamber to a 67-year-old patient with newly diagnosed COPD who was admitted for an acute exacerbation and shortness of breath. When the RT returns for the second treatment that day, the patient informs the RT that he began to feel very shaky and nervous, beginning about 30 minutes after the previous treatment. He also noticed a tremor when he held his water cup and took a drink. His pulse during the earlier treatment was 84 beats/min. Clinical assessment shows that he is coherent, has good color, is not diaphoretic, and is in no respiratory distress. His respiratory rate is 16 breaths/min and regular, and his pulse is 82 beats/min and regular. Auscultation reveals mild wheezing and scattered rhonchi, with little change from earlier breath sounds. A mild tremor is apparent when he holds his hand out. On questioning, he states that he is now feeling better, and the “shakiness” has subsided a bit.



Discussion


This patient’s situation exemplifies a common reaction to inhaled adrenergic bronchodilators. Although albuterol is beta-2 preferential, it is still an epinephrine-like drug and can produce side effects secondary to sympathetic stimulation. The description of the symptoms is suggestive of common adrenergic side effects (tremor, shakiness). The timing of the symptoms coincides with the pharmacokinetics of albuterol (peak effect in 30 to 60 minutes). As presented in the case description, it is important to rule out other complications. The physical examination shows no changes from the earlier treatment in his vital signs.


It is important to caution patients about “normal” expected side effects and to reassure them that the side effects decrease with tolerance to the medication. In addition, the RT needs to be alert to the possibility that patients may have deteriorated or changed in their respiratory status.



image Rule of Thumb


Choosing an Aerosol Agent


An aerosol agent to treat the respiratory tract is chosen based on the indication for the agent or class of drugs and a corresponding presence of the indication in the patient.




Anticholinergic Bronchodilators


A second method of producing airway relaxation is through blockade of cholinergic-induced bronchoconstriction. An important difference between beta agonists and anticholinergic bronchodilators is the active stimulatory action of the former versus the passive blockade of the latter. A cholinergic blocking agent is effective only if bronchoconstriction exists secondary to cholinergic activity.



Indications for Use


Ipratropium bromide and tiotropium bromide are the only inhaled anticholinergic bronchodilators available in the United States. Table 32-3 lists the dosage forms and pharmacokinetics of ipratropium and tiotropium. Generally, anticholinergic agents have been found to be as effective as beta agonists in airflow improvement in COPD but less so in asthma. A nasal formulation of ipratropium is also available for relief of allergic and nonallergic perennial rhinitis, including the common cold.21



TABLE 32-3


Inhaled Anticholinergic Bronchodilator Agents*







































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Jun 12, 2016 | Posted by in RESPIRATORY | Comments Off on Airway Pharmacology

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Drug Brand Name Adult Dosage Time Course (Onset, Peak, Duration)
Ipratropium bromide Atrovent HFA HFA MDI: 17 µg/puff, 2 puffs 4 times daily Onset: 15 min
    SVN: 0.02% solution (0.2 mg/ml), 500 µg 3-4 times daily Peak: 1-2 hr
    Nasal spray: 21 µg or 40  µg, 2 sprays per nostril 2-4 times daily (dosage varies) Duration: 4-6 hr
Ipratropium bromide and albuterol Combivent MDI: Ipratropium 18 µg/puff and albuterol 90 µg/puff, 2 puffs 4 times daily Onset: 15 min
Peak: 1-2 hr
Duration: 4-6 hr
  DuoNeb SVN: Ipratropium 0.5 mg and albuterol 2.5 mg