Indication for short-acting agents

Short-acting β₂ agonists such as albuterol, levalbuterol, or pirbuterol are indicated for relief of acute reversible airflow obstruction in asthma or other obstructive airway diseases. Short-acting agents are termed “rescue” agents in the 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP EPR 3) guidelines.¹ Short-term acting agents may also be termed “relievers” as discussed in the Global Initiative for Asthma (GINA) guidelines.²

Indication for long-acting agents

Long-acting agents such as salmeterol, formoterol, and arformoterol are indicated for the maintenance of bronchodilation and control of bronchospasm and nocturnal symptoms in asthma or other obstructive diseases. NAEPP EPR 3 guidelines and GINA consider salmeterol, formoterol, and arformoterol “controllers”; the slow time to peak effect makes long-acting agents poor rescue drugs. In asthma, a long-acting bronchodilator is usually combined with antiinflammatory medication for control of airway inflammation and bronchospasm. Although formoterol has a rapid onset of action, similar to that of albuterol, its slower peak effect and prolonged activity make it a better maintenance drug than an acute reliever or rescue agent.

Indication for racemic epinephrine

Racemic epinephrine is often used, either as an inhaled aerosol or by direct lung instillation, for its strong α-adrenergic vasoconstricting effect to reduce airway swelling after extubation or during epiglottitis, croup, or bronchiolitis or to control airway bleeding during endoscopy.

Adrenergic bronchodilators as stereoisomers

Adrenergic bronchodilators can exist in two different spatial arrangements, producing isomers. Rotation around the β carbon on the ethylamine side chain of the basic molecular structure seen in Figure 6-1 produces two nonsuperimposable mirror images, termed enantiomers or simply isomers. Figure 6-2 illustrates epinephrine as a stereoisomer, showing the (R)-isomers and (S)-isomers as the mirror image of each other. Enantiomers have similar physical and chemical properties but different physiologic effects. The (R)-isomer, or levo isomer, is active on airway β receptors, producing bronchodilation, and on extrapulmonary adrenergic receptors. The (S)-isomer, or dextro isomer, is not active on adrenergic receptors such as β receptors, and until more recently the (S)-isomer was considered physiologically inert. The two mirror images of the isomers rotate light in opposite directions, and this is the basis for designating them as dextrorotatory (d, +) or levorotatory (l, −). Using their actual spatial configuration, the levo isomer and dextro isomer are referred to as the (R)-isomer (for rectus, right) and (S)-isomer (for sinister, left), respectively. Adrenergic bronchodilators such as epinephrine, albuterol, and salmeterol have been produced synthetically as racemic mixtures, or 50:50 equimolar mixes of the (R)-isomers and (S)-isomers. Natural epinephrine found in the adrenal gland occurs as the (R)-isomer, or levo isomer, only. Levalbuterol, released in 1999, represents the first synthetic inhaled solution available as the single (R)-isomer of racemic albuterol. Structures of the currently available inhaled β agonists to be discussed are shown in Figure 6-3. Only a single isomer form is shown, for simplification and clarity.

Keyhole theory of β₂ specificity

The theory that explains the shift from α activity to β₂ specificity has been termed the keyhole theory of β sympathomimetic receptors: The larger the side chain attachment to a catechol base, the greater the β₂ specificity. If the catecholamine structural pattern is seen as a keylike shape, then the larger the “key” (side chain), the more β₂ specific the drug. The increase in side chain substitutions can be seen in the drug structures presented in Figure 6-3, for the three catecholamines described and subsequent β₂-selective agents to be discussed.

Metabolism of catecholamines

Despite the increase in β₂ specificity with increased side chain bulk, all of the previously mentioned catecholamines are rapidly inactivated by the cytoplasmic enzyme COMT. This enzyme is found in the liver and kidneys and throughout the rest of the body. Figure 6-4, A, illustrates the action of COMT as it transfers a methyl group to the carbon-3 position on the catechol nucleus. The resulting compound, metanephrine, is inactive on adrenergic receptors. Because the action of COMT on circulating catecholamines is very efficient, the duration of action of these drugs is severely limited, with a range of 1.5 hours to at most 3 hours.

Catecholamines are also unsuitable for oral administration because they are inactivated in the gut and liver by conjugation with sulfate or glucuronide at the carbon-4 site. Because of this action, they have no effect when taken by mouth, limiting their route of administration to inhalation or injection. Catecholamines are also readily inactivated to inert adrenochromes by heat, light, or air (Figure 6-4, B). For this reason, racemic epinephrine is stored in an amber-colored bottle or a foil-protected wrapper. Nebulizer rainout (i.e., nebulized particles that condense and fall, under the influence of gravity) in the tubing may appear pinkish after treatment, and a patient’s sputum may even appear pink-tinged after using aerosols of catecholamines.

Extended-release albuterol

An extended-release form of albuterol is available as VoSpire ER. This is a 4-mg or 8-mg tablet taken orally with extended activity up to 12 hours. The extended activity of VoSpire ER is achieved with a tablet formulation that contains 2 mg of drug in the coating for immediate release and 2 mg in the core for release after several hours. VoSpire ER uses an osmotic gradient to draw water into the tablet, dissolve the albuterol, and gradually release active drug through a pinhole in the tablet. The 6-hour duration can be extended for 8 to 12 hours and mimics the effect of taking two doses.

Salmeterol

Salmeterol, a β₂-selective receptor agonist, is available in a dry powder formulation in the Diskus inhaler. Salmeterol xinafoate is a racemic mixture of two enantiomers, with the (R)-isomer containing the predominant β₂ activity.¹⁵

Formoterol

Formoterol is another β₂-selective agonist with a long-acting bronchodilatory effect of 12 hours in duration. A racemic mixture of (R,R)-formoterol and (S,S)-formoterol was approved by the FDA as Foradil for maintenance treatment of asthma in adults and children 5 years or older and for acute prevention of exercise-induced bronchospasm in adults and children 5 years or older. Formoterol is also indicated for the treatment of COPD and can be used in conjunction with other inhaled medications, such as inhaled corticosteroids, short-acting β agonist, and theophylline. Racemic formoterol is available as a dry powder aerosol for use with the Aerolizer dry powder inhaler (DPI). The current recommended dose for adults and children 5 years or older is 12 μg twice daily by Aerolizer.

Foradil Certihaler has more recently become available in the market in the United States for adults and children 5 years and older. The small DPI is breath actuated and delivers 8.5 μg of drug on each breath. It is recommended to be taken twice daily.

The use of liquid nebulization is still very popular with many patients and is a great alternative to MDI and DPI use. Perforomist is available in a liquid nebulization form of 20 μg/2 mL unit dose and is prescribed twice daily. Currently, it is approved only for use with COPD at present.

The chemical structure of formoterol is shown in Figure 6-8. As with salmeterol, the extensive side chain, or “tail,” makes formoterol more lipophilic than the shorter acting bronchodilators and is the basis for its longer duration of effect. The increased lipophilicity of salmeterol and formoterol allows the drugs to remain in the lipid cell membrane. Even if a tissue preparation containing the drugs is perfused or washed, the drug activity persists. Salmeterol is more lipophilic than formoterol, and this along with its anchoring capability may explain why salmeterol is less prone to being “washed away” than formoterol.¹⁸

Bronchodilator effect.

Similar to salmeterol, formoterol has a prolonged duration of bronchodilating effect of up to 12 hours. In contrast to salmeterol, the onset of action for formoterol is significantly faster. The time from inhalation to significant bronchodilation is similar to that of albuterol. It has been reported that 1 minute after inhalation of formoterol there is a significant increase in specific airway conductance (SG_AW).²⁰ The onset of bronchodilation is generally considered to be 2 to 3 minutes with formoterol compared with 10 minutes or longer with salmeterol. Figure 6-9 shows the dose-proportional response to inhaled (R,R)-formoterol, the single isomer isolated from the racemic mixture of (R,R)-formoterol and (S,S)-formoterol, compared with inhaled racemic albuterol.²¹ In a study by van Noord and colleagues²² comparing racemic formoterol, 24 μg; salmeterol, 50 μg; and albuterol, 200 μg, the increase in SG_AW (airway conductance) after 1 minute was 44%, less than 16%, and 44%. The time to maximal increase in airway conductance was 2 hours, 2 to 4 hours, and 30 minutes for the three drugs. The maximal increase was 135%, 111%, and 100%.^20,22

The efficacy of formoterol in relaxing airway smooth muscle (its maximal effect) is greater than that of albuterol, which is greater than that of salmeterol. The lower intrinsic efficacy of salmeterol would make it a better agent than formoterol for patients with cardiovascular disease.¹⁸

Arformoterol

Arformoterol is the latest β₂-selective agonist with a long-acting bronchodilatory effect of 12 hours in duration. Arformoterol is the single, (R,R)-isomer form of racemic formoterol, which is approved by the FDA as Brovana for maintenance treatment of COPD. The current recommended adult dose is 15 μg twice daily. Brovana is available in 2-mL unit-dose vials and is for nebulization only.

Indacaterol

Indacaterol is an ultra long-acting β agonist; at the time of this edition, it sits before the FDA awaiting approval. Indacaterol is approved in Europe as Onbrez Breezhaler. It is a dry powdered inhaler for COPD administered once daily. Once approved in the United States, it will carry the brand name Arcapta Neohaler. Indacaterol is currently being studied with other anticholinergic agents, which may produce a once-daily combination agent.

Antiinflammatory effects

Both the short-acting and the long-acting β agonists show antiinflammatory effects in vitro. Salmeterol, formoterol, and arformoterol inhibit human mast cell activation and degranulation in vitro, prevent an increase in vascular permeability with inflammatory mediators, and generally diminish the attraction and accumulation of airway inflammatory cells.¹⁸ Despite these in vitro antiinflammatory effects, salmeterol and formoterol have not been shown to inhibit accumulation of inflammatory cells in the airway or the increase in inflammatory markers in vivo. Neither drug is considered to have a sufficient effect on airway inflammation in patients with asthma to replace antiinflammatory drugs such as corticosteroids.

Clinical use

Long-acting β agonists are indicated for maintenance therapy of asthma that is not controlled by regular low-dose inhaled corticosteroids and for COPD needing daily inhaled bronchodilator therapy for reversible airway obstruction. National guidelines recommend the introduction of a long-acting β agonist in step 3 care of asthma (asthma not controlled by lower doses of antiinflammatory medications)¹ and use as deemed necessary for COPD.²³ Use of long-acting β agonists may prevent the need to increase the inhaled dose of corticosteroid. Several points should be noted in the clinical use of long-acting agents because of their differences from shorter acting β agonists.

The addition of a long-acting β₂ agonist to inhaled corticosteroids can lead to improved lung function and a decrease in symptoms.²⁵ A combination product of salmeterol and fluticasone in a Diskus inhaler (Advair Diskus) showed superior asthma control and better lung function than either drug taken alone.^26–29 Because of their prolonged bronchodilation, long-acting β₂ agonists taken twice daily have a greater area under the FEV₁ curve compared with short-acting agents taken four times daily. Figure 6-10 illustrates dose-response curves for albuterol and salmeterol. In contrast to albuterol, which tends to return to baseline in 4 to 6 hours, salmeterol provides a more sustained level of bronchodilation, giving a higher baseline of lung function.³⁰ The same effect has been found in comparing twice-daily salmeterol with four-times-daily inhaled ipratropium bromide, a shorter acting anticholinergic bronchodilator that is discussed in Chapter 7.³¹

Salpeter and associates,³² in a meta-analysis, reported that long-acting β₂ agonists increased the risk of asthma hospitalizations and deaths compared with placebo. Nelson and colleagues³³ also described an increase in death rate among patients using salmeterol; their findings reported the highest death rate among African Americans. These studies did not take into account the severity of asthma or whether the participants used other medications. Asthma in some participants may have been worse than in others. Concerning cotreatments, the studies could not account for other medications participants may have been taking or with what regularity they were taking them. The latter could have serious consequences if, for example, a participant stopped using inhaled corticosteroids that were prescribed to treat asthma. Any of these variables—asthma severity, presence of cotreatments, and patient adherence—could affect interpretation of data. Nevertheless, the labeling of these agents has been changed to warn that death can occur.

Because of the ongoing concerns of safety of long-acting β₂ agonists, the FDA is now requiring changes on how long-acting β₂ agonists are used in the treatment of asthma. As of June 2, 2010, the FDA now requires the following:

β-receptor and α₂-receptor activation

The mode of action of β agonists and the β receptors has been well characterized, although the activity of α receptors is not as well understood. The mode of action for relaxation of airway smooth muscle when a β₂ receptor is stimulated is illustrated in Figure 6-11. Adrenergic agonists such as albuterol or epinephrine attach to β receptors, which are polypeptide chains that traverse the cell membrane seven times and have an extracellular NH₂ terminus and an intracellular carboxy (COOH) terminus. This attachment causes activation of the stimulatory G protein, designated G_s. The actual binding site of a β agonist is within the cell membrane, inside the “barrel” or circle formed by the transmembrane loops of the receptor chain. The β agonist forms bonds with elements of the third, fifth, and sixth transmembrane loops. When stimulated by a β agonist, the receptor undergoes a conformational change, which reduces the affinity of the α subunit of the G protein for guanosine diphosphate (GDP). The GDP is replaced by GTP, and the α subunit dissociates from the receptor and the β-γ portion of the G protein to link with the effector system. The effector system for the β receptor is adenylyl cyclase, a membrane-bound enzyme. Activation of adenylyl cyclase by the α subunit of the G_s protein causes increased synthesis of the second messenger, cyclic adenosine 3’,5’-monophosphate (cAMP). cAMP may cause smooth muscle relaxation by increasing the inactivation of myosin light chain kinase, an enzyme that initiates myosin-actin interaction and subsequent smooth muscle contraction. An increase in cAMP also leads to a decrease in intracellular calcium.

A similar sequence of events is responsible for the action of α₂-receptor stimulation, which can inhibit further neurotransmitter release from the presynaptic neuron when stimulated by norepinephrine in a feedback, autoregulatory fashion (see Chapter 5). However, stimulation of α₂ receptors (not shown in Figure 6-11) results in activation of an inhibitory G protein, designated G_i, whose α subunit serves to inhibit the enzyme adenylyl cyclase, lowering the rate of synthesis for intracellular cAMP.

α₁-receptor activation

Stimulation of an α₁ receptor by an agonist such as phenylephrine or epinephrine (which has affinity for both α and β receptors) results in vasoconstriction of peripheral blood vessels, including vessels in the airway. The mode of action for this effect as mediated by the G protein–linked α₁ receptor is illustrated in Figure 6-12. Stimulation of the α₁ receptor causes a conformational change in the receptor, which activates the G protein designated G_q. With activation, GDP dissociates from the G protein; GTP binds to the α subunit of the G protein; and the α subunit dissociates from the β-γ dimer, to activate the effector phospholipase C (PLC). Activation of the effector, PLC, leads to the conversion of membrane phosphoinositides into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ stimulates release of intracellular stores of calcium into the cytoplasm of the cell, and DAG activates protein kinase C. Contraction of vascular smooth muscle results.

Salmeterol, formoterol, and arformoterol: mechanism of action

The action of salmeterol in providing sustained protection from bronchoconstriction differs to a degree from that of the previously described adrenergic bronchodilators. The difference in pharmacodynamics of salmeterol is reflected in its pharmacokinetics with a slower onset and time to peak effect and a longer duration of action compared with previous adrenergic agents.

The structure of salmeterol is shown in Figure 6-3, along with that of other β agonists for comparison. The drug is a modification of the saligenin albuterol, with a long nonpolar (i.e., lipophilic) N-substituted side chain. Salmeterol consists of a polar, or hydrophilic, phenyl ethanolamine “head,” with a large lipophilic “tail” or side chain. As a result of this structure, salmeterol is lipophilic, in contrast to most β agonists, which are hydrophilic and approach the β receptor directly from the aqueous extracellular space. In contrast, salmeterol, as a lipophilic molecule, diffuses into the cell membrane phospholipid bilayer and approaches the β receptor laterally, as shown in Figure 6-13. The lipophilic nonpolar side chain binds to an area of the β receptor referred to as the exosite, a hydrophobic region. With the side chain (“tail”) anchored in the exosite, the active saligenin “head” binds to and activates the β receptor at the same location as albuterol.

The binding properties of salmeterol, formoterol, and arformoterol differ from those of albuterol and other β agonists. Because the side chain of salmeterol is anchored at the exosite, the active “head” portion continually attaches to and detaches from the receptor site. This activity provides ongoing stimulation of the β receptor and is the basis for the persistent duration of action of salmeterol. This model of activity is supported by studies of the effect of β antagonists on the β-agonist action of salmeterol and molecular binding studies. If albuterol is attached to the β receptor, the smooth muscle relaxation can be fully reversed by a β-blocking agent such as propranolol or sotalol, indicating a competitive blockade. When the β-blocking agent is removed, there is no further relaxation of smooth muscle. The albuterol has been displaced, and the action of the drug is terminated. If salmeterol stimulates a receptor, a β antagonist such as propranolol would also reverse the effect of relaxation. However, when the propranolol is removed from the tissue, the relaxant effect of salmeterol is reestablished. This indicates that the salmeterol remains anchored in the receptor and is available to stimulate the β receptor continually after the blocking agent is removed.¹⁵

The prolonged activity of formoterol is also thought to be due to its lipophilicity, although formoterol is less lipophilic than salmeterol. Formoterol and arformoterol, which is moderately lipophilic, enter the bilipid cell membrane, where they are retained, with the lipid layer acting as a depot and giving a long-acting effect. At the same time, formoterol and arformoterol can approach the β receptor from the aqueous phase, giving it a rapid onset of action.²⁰

Inhalation route

All of the β-adrenergic bronchodilators marketed in the United States are available for inhalation delivery, using an MDI, a nebulizer (including intermittent positive-pressure breathing nebulization), or a DPI. Catecholamines must be given by inhalation because they are ineffective orally. Inhalation is the preferred route for administering β-adrenergic drugs for all of the following reasons:

The use of aerosol delivery during an acute attack of airway obstruction has been questioned. However, several studies have failed to show substantial differences between inhaled and parenteral β-adrenergic agents in acute severe asthma.^34,35 There is no reason to avoid these bronchodilators as inhaled aerosols during acute episodes.³⁶ The inhalation route targets the lung directly. Combining oral delivery with additional inhalation has been shown to produce good additive effects with albuterol.³⁷

The major difficulties with aerosol administration are the time needed for nebulization (5 to 10 minutes), the possible embarrassment of using an MDI in public or at school, and inability to use an MDI correctly. Difficulty in correctly using an MDI can be remedied by using spacer devices or, alternatively, by using a gas-powered handheld nebulizer. A DPI can eliminate problems associated with nebulizers and MDIs.

Oral route

The oral route has the advantages of ease, simplicity, short time required for administration, and exact reproducibility and control of dosage. However, In terms of clinical effects, this is not the preferred route. The time course of oral β agonists differs from that of inhaled β agonists. The onset of action begins in about 1.5 hours, with a peak effect reached after 1 to 2 hours and a duration of action between 3 and 6 hours.⁴³ Larger doses are required than with inhalation, and the frequency and degree of unwanted side effects increase substantially. Catecholamines are ineffective by mouth, as previously discussed. Noncatecholamine bronchodilators in the adrenergic group seem to lose their β₂ specificity with oral use, possibly because of the reduction of the side chain bulk in a first pass through the liver.⁴⁴ Patient compliance on a three- or four-times-daily schedule may be better than with a nebulizer. If this is the case with an individual patient and the side effects are tolerable, oral use may be indicated for bronchodilator therapy. The introduction of an oral tablet of albuterol with extended action properties (Repetab, Volmax) offers the possibility of protection from bronchoconstriction for longer than 8 hours. However, inhaled salmeterol and formoterol now offer a 12-hour duration. Either the extended-release tablet or a long-acting β agonist is advantageous in preventing nocturnal asthma and deterioration of flow rates in the morning.

Parenteral route

β-adrenergic bronchodilators have been given subcutaneously and intravenously, usually in the emergency management of acute asthma. Subcutaneously, epinephrine 0.3 mg (0.3 mL of 1:1000 strength), every 15 to 20 minutes up to 1 mg in 2 hours, and terbutaline, 0.25 mg (0.25 mL of a 1-mg/mL solution) repeated in 15 to 30 minutes, not exceeding 0.5 mg in 4 hours, have been used. Shim⁴⁵ suggested that for practical purposes both aerosolized and subcutaneous routes should be used to manage acute obstruction, although there may be little difference in effect with the two routes. No difference in effect between epinephrine and terbutaline has been found when given subcutaneously.

The intravenous route has been used most commonly with isoproterenol and with albuterol. Intravenous administration of these agents was thought to be useful during severe obstruction because these agents would be distributed throughout the lungs, whereas aerosol delivery would not allow them to penetrate the periphery. This assumption is questionable for both subcutaneous and intravenous bronchodilator therapy because aerosols do exert an effect with obstruction. Intravenous isoproterenol is not clearly advantageous as a bronchodilator, although this route is used for cardiac stimulation in shock and bradycardia. The dose-limiting factor is tachycardia. Intravenous therapy is a last resort and requires an infusion pump, cardiac monitor, and close attention. Pediatric dosages range from 0.1 to 0.8 μg/kg/min, and adult dosages range from 0.03 to 0.2 μg/kg/min, until bronchial relaxation or side effects occur.⁴⁵ The combination of myocardial stimulation and hypoxia can cause serious arrhythmias; intravenous isoproterenol should be avoided in acute asthma, in favor of β₂-specific agents. Albuterol has been given intravenously as a bolus of 100 to 500 μg or by infusion of 4 to 25 μg/min.⁴⁶ Although albuterol is more β₂ specific by aerosol than isoproterenol, the usefulness of intravenous administration compared with oral, aerosol, or subcutaneous administration is not clearly established.

Tremor

The annoying effect of muscle tremor with β agonists is due to stimulation of β₂ receptors in skeletal muscle. It is dose related and is the dose-limiting side effect of the β₂-specific agents, especially with oral administration. The adrenergic receptors mediating muscle tremor have been shown to be of the β₂ type.^47,48 As shown previously, this side effect is much more noticeable with oral delivery, which provides a rationale for aerosol administration of these agents. Tolerance to the side effect of tremor usually develops after days to weeks with the oral route, and patients should be reassured of this when beginning to use these drugs.

Cardiac effects

The older adrenergic agents with strong β₁-stimulating and α-stimulating effects were considered dangerous in the presence of congestive heart failure. The dose-limiting side effect with these agents is tachycardia. They increase cardiac output and oxygen consumption by stimulating β₁ receptors, leading to a decrease in cardiac efficiency, which is the work relative to oxygen consumption. Newer agents have a preferential β₂ effect to minimize cardiac stimulation. However, tachycardia may also follow use of the newer agents, and there is evidence that this is due to the presence of β₂ receptors even in the heart.⁴⁹ β₂ agonists cause vasodilation, and this can cause a reflex tachycardia. Despite this effect, agents such as terbutaline or albuterol can actually improve cardiac performance. Albuterol and terbutaline can cause peripheral vasodilation and increase myocardial contractility without increasing oxygen demand by the heart.³⁴ The net effect is to reduce afterload and improve cardiac output with no oxygen cost. These agents are therefore attractive for use with airway obstruction combined with congestive heart failure.

Seider and colleagues⁵⁰ reported that neither heart rate nor frequency of premature beats was significantly affected by inhaled terbutaline or ipratropium bromide (an anticholinergic bronchodilator) in 14 patients with COPD and ischemic heart disease. Although there are no written standards, most health care practitioners accept no more than a 20% change in pretreatment pulse after bronchodilator therapy has been initiated. This is why it is important to check the pulse rate before, during, and after bronchodilator therapy to evaluate cardiac response. If the pulse rate has increased more than 20% relative to the pretreatment pulse, stopping treatment with referral to the prescribing health care practitioner may be warranted to prevent unwanted cardiac effects.

Tolerance to bronchodilator effect

Adaptation to a drug with repeated use is a concern because use of the drug is actually reducing its effectiveness. With β agonists, there is in vitro evidence of an acute desensitization of the β receptor within minutes of exposure to a β agonist as well as a longer term desensitization. Figure 6-14 shows both an acute decrease in response during sustained exposure of the receptor to the agonist and a long-term decrease in maximal response with subsequent drug exposure. This decrease in bronchodilator response has been observed with short-acting and long-acting β agonists.

Exposure of cells with β receptors to isoproterenol causes a short-term, acute reduction in adenylyl cyclase activity and production of cAMP. The immediate desensitization is caused by an “uncoupling” of the receptor and the effector enzyme adenylyl cyclase.⁵¹ A model for desensitization of the β receptor is diagrammed in Figure 6-15. When stimulated by a β agonist, the β receptor goes into a low-affinity binding state (i.e., has reduced affinity for binding with a β agonist). Simultaneously, the β agonist causes an increase in cAMP, which increases protein kinase A, also referred to as β-adrenergic receptor kinase (β-ARK). β-ARK causes phosphorylation (transfer of phosphate groups [P]) of the hydroxyl groups (OH) on the carboxy-terminal portion of the β receptor. This phosphorylation induces binding of a protein named β-arrestin, which prevents the receptor from interacting with G_s and disrupts the coupling of G_s with the effector enzyme adenylyl cyclase. Removal of the β agonist allows the dissociation of β-arrestin and the phosphate groups from the receptor, and the receptor returns to a fully active state.

Long-term desensitization is considered to be caused by a reduction in the number of β receptors; this is termed downregulation. Both norepinephrine and albuterol have caused a reduction of almost 50% in vitro in the number of β-adrenergic receptors in airway smooth muscle of guinea pigs.⁵¹ Exposure of isolated human bronchus to isoproterenol or terbutaline produces similar desensitization.⁵² Long-term desensitization is also illustrated in Figure 6-14, as indicated by the lower peak response to subsequent administration of an adrenergic agonist.

Although use of an inhaled β agonist does cause a reduction in peak effect, the bronchodilator response is still significant and stabilizes within several weeks with continued use.¹⁸ Such tolerance is not generally considered clinically important and does not contraindicate the use of these agents. The same phenomenon of tolerance is also responsible for diminished side effects, such as muscle tremor, among patients regularly using inhaled β-agonist bronchodilators.

In addition to loss of receptors (downregulation) by exposure to a β agonist, altered β-receptor function may be caused secondary to inflammation. Increased levels of phospholipase A₂ (PLA₂) may destabilize membrane support of the β receptor, changing its function. Cytokines such as interleukin-1β (IL-1β) may cause desensitization, and platelet-activating factor (PAF) inhibits the relaxing effect of isoproterenol on human tracheal tissue.

Corticosteroids can reverse the desensitization of β receptors and are said to be able to potentiate the response to β agonists.⁵³ Corticosteroids have the following effects, in relation to β-agonist and β-receptor function:

β agonists may have a positive effect on corticosteroid function and activity. A review by Anderson²⁵ explored possible mechanisms for the beneficial interaction of β agonists and corticosteroids.

Loss of bronchoprotection

A distinction was found by Ahrens and colleagues⁵⁴ to exist between the bronchodilating effect and the bronchoprotective effect of β agonists. The bronchodilating effect of a β agonist can be measured on the basis of airflow change, as indicated by a change in FEV₁ or peak expiratory flow rate (PEFR). The bronchoprotective effect refers to the reaction of the airways to challenge by provocative stimuli such as allergens or irritants and is measured with doses of histamine, methacholine, or cold air. Ahrens and colleagues⁵⁴ found that the protective effect with agonists such as metaproterenol or albuterol declines more rapidly than the bronchodilating effect. Not only is there a difference in time between these effects, but also it was found that tolerance occurs with the bronchoprotective effect of a β agonist, just as with the bronchodilating effect. Results from a study by O’Connor and associates⁵⁵ are shown in Figure 6-16. The difference in dose of adenosine (AMP) and methacholine required to induce a 20% decline in FEV₁ (PC₂₀) after the inhalation of terbutaline compared with placebo is seen before and after 7 days of steady treatment with terbutaline. Airway response to challenge is seen to occur with a significantly lower dose of either AMP or methacholine in subjects with mild asthma, after 7 days of β-agonist exposure, showing tolerance to the protective effect of terbutaline. The development of tolerance to the bronchoprotective effect of the long-acting β agonist salmeterol was shown to occur both in the absence of corticosteroid therapy (by Bhagat and colleagues⁵⁶) and with concomitant inhaled corticosteroid treatment (by Kalra and associates⁵⁷). In a study by Rosenthal and associates,⁵⁸ after the first 4 weeks of regular treatment with salmeterol, there was no increase in bronchial hyperresponsiveness or loss of bronchoprotection. Sustained improvements were seen in pulmonary function and asthma symptom control.⁵⁸

The mechanism underlying the increase in bronchial hyperresponsiveness with use of β agonists is unclear. Evidence accumulating on the effects of the (S)-isomer of β agonists suggests a possible cause.⁵⁹ The same effects could conceivably be implicated in the reduction in maximal bronchodilator effect with repeated use.

Central nervous system effects

Commonly reported side effects of the adrenergic bronchodilators include headache, nervousness, irritability, anxiety, and insomnia, which are caused by CNS stimulation. Feelings of nervousness or anxiety may be due to the muscle tremor seen with these drugs, rather than to direct CNS stimulation. Excessive stimulation of the CNS, or at least symptoms of such, should be noted by clinicians and can warrant evaluation of the dosage used.

Fall in arterial oxygen pressure

A decrease in arterial oxygen pressure (Pao₂) has been noted with isoproterenol administration during asthmatic bronchospasm, as ventilation improves and the exacerbation is relieved. The same effect has subsequently been noted with newer β agonists such as albuterol and salmeterol.⁶⁰ The mechanism seems to be an increase in perfusion (i.e., blood flow) of poorly ventilated portions of the lung. It is known that regional alveolar hypoxia produces regional pulmonary vasoconstriction in an effort to shunt perfusion to lung areas of higher oxygen tension. This vasoconstriction is probably accomplished by α-sympathetic receptors.⁶¹

Administration of inhaled β agonists may reverse hypoxic pulmonary vasoconstriction by β₂ stimulation, increasing perfusion to underventilated lung regions.⁶² Preferential delivery of the inhaled aerosol to better ventilated lung regions increases the ventilation-perfusion mismatch. It has been noted that such decreases in Pao₂ are statistically significant but physiologically may be negligible.^60,63 Oxygen tension decreases most in subjects with the highest initial Pao₂. Decreases in Pao₂ rarely exceed 10 mm Hg, and the Pao₂ values tend to be on the flat portion of the oxyhemoglobin curve so that decreases in arterial oxygen saturation (Sao₂) are minimized. Oxygen tensions usually return to baseline within 30 minutes.

Metabolic disturbances

Adrenergic bronchodilators can increase blood glucose and insulin levels and decrease serum potassium levels. This is a normal effect of sympathomimetics. In diabetic patients, clinicians should be aware of a possible effect on glucose and insulin levels. Hypokalemia has also been reported after parenteral administration of albuterol and epinephrine.⁶⁴ The clinical importance of this side effect is controversial, and it would be of concern mainly for patients with cardiac disease or in interpreting serum potassium levels obtained shortly after use of adrenergic bronchodilators. The mechanism of the effect on potassium is probably activation of the sodium-potassium pump by the β receptor, with enhanced transport of potassium from the extracellular to the intracellular compartment. Such metabolic effects are minimized with inhaled aerosols of β-adrenergic agents because plasma levels of the drug remain low.

Propellant toxicity and paradoxic bronchospasm

The use of MDIs powered by CFC (e.g., Freon) can cause bronchospasm of hyperreactive airways. This reaction to the propellant was shown by Yarbrough and colleagues.⁶⁵ They found that 7% of 175 subjects who used an MDI with placebo and propellant experienced a decrease of 10% or more in FEV₁. The incidence was about 4% when using an MDI with metaproterenol and propellant, probably because the bronchodilating effect overcame the propellant effect. In most cases, bronchospasm lasts less than 3 minutes. There is apparently no noticeable difference in adverse reactions among patients using a CFC MDI and patients using an HFA MDI.⁶⁶ A dry powder formulation is an ideal alternative formulation to an MDI if sensitivity to propellants exists, assuming drug availability and adequate inspiratory flow rate. Use of a nebulizer instead of an MDI may also be considered if bronchospasm occurs in a patient. Finally, the oral route offers an alternative to the inhalation route of administration. Cocchetto and associates⁶⁷ reviewed the literature on paradoxic bronchospasm with use of inhalation aerosols.

Sensitivity to additives

An increasingly publicized problem for individuals with hyperreactive airways is sensitivity to sulfite preservatives, with resulting bronchospasm. Sulfites are used as preservatives for food and are used as antioxidants for bronchodilator solutions to prevent degradation and inactivation. Sulfites include sodium or potassium sulfite, bisulfite, and metabisulfite. When a sulfite is placed in solution, at warm temperature in an acid pH such as saliva, it converts to sulfurous acid and sulfur dioxide. Sulfur dioxide is known to cause bronchoconstriction in asthmatic patients. A solution of racemic epinephrine is known to contain sulfites as preservatives. There have been reports of coughing and wheezing and pruritus after use of sulfite-containing bronchodilators.

Other additives and preservatives that can potentially have an effect on airway smooth muscle include benzalkonium chloride (BAC), ethylenediamine tetraacetic acid (EDTA), and hydrochloric or sulfuric acid to adjust pH of the solution. Asmus and colleagues⁶⁸ recommended that only additive-free, sterile-filled unit-dose bronchodilator solutions be used for nebulizer treatment of acute airflow obstruction, especially if doses are given hourly or continuously. Clinicians should check aerosol formulations for BAC or EDTA, and if symptoms of bronchoconstriction occur, consider these as a possible cause.

Asthma morbidity and mortality

A complete analysis of the relationship between β agonists and worsening asthma based on the literature seems to indicate that there is not a class effect of these drugs causing deterioration of asthma.⁵⁹ Although it is unclear that β-agonist use increases risk of morbidity or death from asthma, asthma mortality is reported to be increasing in the United States and worldwide, despite more available treatment options, including β₂-specific and longer acting adrenergic bronchodilators.⁷⁹ There are several causes, not all involving β-agonist therapy, that may potentially lead to worsening asthma severity:

Discussion of the relationship of β-agonist use to asthma morbidity and mortality should review the use of β agonists in the context of the NAEPP guidelines. The 1991, 1997, 2002, and 2007 documents all stress that asthma is a disease of chronic airway inflammation. Treatment with regular β-agonist therapy in severe asthma (asthma requiring step 2 care or greater) does not address the underlying inflammatory process. In evaluating β-agonist therapy in asthma, one must evaluate concomitant antiinflammatory therapy (or the lack of it) and environmental management of the asthma.