Adrenergic (sympathomimetic) bronchodilators

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CHAPTER 6

Adrenergic (sympathomimetic) bronchodilators

Key terms and definitions

Adrenergic bronchodilator

Agent that stimulates sympathetic nervous fibers, which allow relaxation of smooth muscle in the airway. Also known as sympathomimetic bronchodilator or β2 agonist.

α-receptor stimulation

Causes vasoconstriction and vasopressor effect; in the upper airway (nasal passages), this can provide decongestion.

Asthma paradox

Refers to the increasing incidence of asthma morbidity, and especially asthma mortality, despite advances in the understanding of asthma and availability of improved drugs to treat asthma.

β1-receptor stimulation

Causes increased myocardial conductivity and increased heart rate as well as increased contractile force.

β2-receptor stimulation

Causes relaxation of bronchial smooth muscle, with some inhibition of inflammatory mediator release and stimulation of mucociliary clearance.

Bronchospasm

Narrowing of the bronchial airways, caused by contraction of smooth muscle.

Catecholamines

Group of similar compounds having sympathomimetic action; they mimic the actions of epinephrine.

Cyclic adenosine 3’, 5’-monophosphate (cAMP)

Nucleotide produced by β2-receptor stimulation; it affects many cells, but causes relaxation of bronchial smooth muscle.

Cyclic guanosine monophosphate (cGMP)

Nucleotide producing the opposite effect of cAMP; that is, it causes bronchoconstriction.

Downregulation

Long-term desensitization of β receptors to β2 agonists, caused by a reduction in the number of β receptors.

Prodrug

Drug that exhibits its pharmacologic activity when it is converted, inside the body, to its active form.

Sympathomimetic

Producing effects similar to those of the sympathetic nervous system.

Chapter 6 presents adrenergic drugs used as inhaled bronchodilators. The specific agents and the clinical indications for this class of drugs are summarized, along with their mechanism of action as mediated by β receptors. Structure-activity relationships of available agents are presented as a basis for their difference in receptor selectivity and duration of action. Differences among routes of administration are discussed, and side effects are reviewed. A brief summary of the debate over possible harmful effects with β-agonists is given.

Clinical indications for adrenergic bronchodilators

The general indication for use of an adrenergic bronchodilator is relaxation of airway smooth muscle in the presence of reversible airflow obstruction associated with acute and chronic asthma (including exercise-induced asthma), bronchitis, emphysema, bronchiectasis, and other obstructive airway diseases. Differences in the rate of onset, peak effect, and duration led to a distinction in use between short-acting and long-acting agents. Various recommendations and guidelines exist for the use of β agonists in chronic obstructive pulmonary disease (COPD) and asthma.

Specific adrenergic agents and formulations

Table 6-1 lists adrenergic bronchodilators currently approved for general clinical use in the United States as of the writing of this edition. Practitioners are urged to read package inserts on a drug before administration. These inserts give details of dosage strengths and frequencies, adverse effects, shelf life, and storage requirements, all of which are needed for safe application. Table 6-1 is not intended to replace more detailed information supplied by the manufacturer on each of the bronchodilator agents. There are three subgroups of adrenergic bronchodilators based on distinct differences in duration of action:

TABLE 6-1

Inhaled Adrenergic Bronchodilator Agents Currently 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, Primatene Mist α, β

Racemic epinephrine microNefrin, Nephron, S-2 α, β SVN: 2.25% solution, 0.25-0.5 mL (5.63-11.25 mg) qid Short-Acting Adrenergic Bronchodilator Agents Metaproterenol Alupent β2 Albuterol Proventil HFA, Ventolin HFA, ProAir HFA, AccuNeb, VoSpire ER β2 Pirbuterol Maxair Autohaler β2 MDI: 200 μg/puff, 2 puffs q4-6h Levalbuterol Xopenex, Xopenex HFA β2 Long-Acting Adrenergic Bronchodilator Agents Salmeterol Serevent Diskus β2 DPI: 50 μg/blister bid Formoterol Perforomist, Foradil β2   Foradil Certihaler β2 DPI: 8.5 μg/inhalation, bid Arformoterol Brovana β2 SVN: 15 μg/2 mL unit dose, bid

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DPI, Dry powder inhaler; MDI, metered dose inhaler; SVN, small volume nebulizer.

Catecholamines

The sympathomimetic bronchodilators are all either catecholamines or derivatives of catecholamines. A catecholamine is a chemical structure consisting of an aromatic catechol nucleus and a dialiphatic amine side chain. In Figure 6-1, the basic catecholamine structure is seen to be composed of a benzene ring with hydroxyl groups at the third and fourth carbon sites and an amine side chain attached at the first carbon position.

The terminal amine group (NH2) and the benzene ring are connected by two carbon atoms, designated as α and β, a notation not to be confused with α and β receptors in the sympathetic nervous system. Examples of catecholamines are dopamine, epinephrine, norepinephrine, isoproterenol, and isoetharine. The first three occur naturally in the body. Catecholamines, or sympathomimetic amines, mimic the actions of epinephrine more or less precisely, causing tachycardia, elevated blood pressure, smooth muscle relaxation of bronchioles and skeletal muscle blood vessels, glycogenolysis, skeletal muscle tremor, and central nervous system (CNS) stimulation.

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.

Epinephrine.

Epinephrine is a potent catecholamine bronchodilator that stimulates α and β receptors. Because epinephrine lacks β2-receptor specificity, there is a high prevalence of side effects such as tachycardia, blood pressure increase, tremor, headache, and insomnia. Epinephrine occurs naturally in the adrenal medulla and has a rapid onset but a short duration because of metabolism by catechol O-methyltransferase (COMT). It has been administered both by inhalation and by subcutaneous injection to treat patients with asthma exacerbation. It is also used as a cardiac stimulant, based on its strong β1 effects. Self-administered, intramuscular injectable doses of 0.3 mg and 0.15 mg are marketed to control systemic hypersensitivity (anaphylactic) reactions.

This drug is more useful for the management of acute asthma rather than for daily maintenance therapy because of its pharmacokinetics and side-effect profile. The parenteral form of epinephrine is a natural extract, consisting of only the (R)-isomer, or levo isomer. The synthetic formulation of epinephrine for nebulization, microNefrin or Nephron, is a racemic mixture of the (R)-isomer, or levo isomer, and (S)-isomer, or dextro isomer. The mode of action of racemic epinephrine is the same as with natural epinephrine, giving α and β stimulation. Because only the (R)-isomer is active on adrenergic receptors, a 1:100 strength formulation of natural epinephrine (injectable formulation) has been used for nebulization, whereas a 2.25% strength racemic mixture is used in nebulization. An epinephrine metered dose inhaler (MDI) is sold over-the-counter as Primatene Mist. The U.S. Food and Drug Administration (FDA) ruled in 2006 that Primatene Mist was not essential, which will lead to its removal from the market if the manufacturer does not convert to the hydrofluoroalkane (HFA) formulation by December 31, 2011.

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.

Resorcinol agents

Because the limited duration of action with catecholamines is unsuitable for maintenance therapy of bronchospastic airways, drug researchers sought to modify the catechol nucleus, which is so vulnerable to inactivation by COMT. As a result, the hydroxyl attachment at the carbon-4 site was shifted to the carbon-5 position, producing a resorcinol nucleus (see Figure 6-3). This change resulted in metaproterenol (named for the 3,5-attachments in the meta position). Because metaproterenol is not inactivated by COMT, it has a significantly longer duration of action of 4 to 6 hours compared with the short-acting catecholamine bronchodilators. Metaproterenol can be taken orally because it resists inactivation by sulfatase enzymes in the gastrointestinal tract and liver. For these reasons, the newer generation of resorcinols and other catecholamine derivatives is much better suited for maintenance therapy than the older catecholamine agents. Metaproterenol is slower to reach a peak effect (30 to 60 minutes) than epinephrine. The chlorofluorocarbon (CFC) version of metaproterenol was removed from the market on June 14, 2010.

Saligenin agents

A different modification of the catechol nucleus at the carbon-3 site resulted in the saligenin albuterol, referred to as salbutamol in Europe (see Figure 6-3). Albuterol is available in various pharmaceutical vehicles in the United States, including oral extended-release tablets, syrup, nebulizer solution, and MDI. As with the resorcinol bronchodilators, this drug has a β2-preferential effect; is effective via oral administration; and has a duration of up to 6 hours, with a peak effect in 30 to 60 minutes.

Pirbuterol

Pirbuterol is another noncatecholamine adrenergic agent currently available as pirbuterol acetate (Maxair) in an MDI formulation with a breath-actuated inhaler delivery device. The strength is 0.2 mg per puff, and the usual dose is 2 puffs. Pirbuterol is structurally similar to albuterol except for a pyridine ring in place of the benzene ring (see Figure 6-3). The onset of activity by aerosol is 5 to 8 minutes, with a peak effect at 30 minutes and a duration of action of approximately 5 hours. Pirbuterol is said to be less potent on a weight basis than albuterol and similar in efficacy and toxicity to metaproterenol.4 The side-effect profile is the same as with other β2 agonists. The CFC version of pirbuterol will not be able to be manufactured or sold after December 31, 2013.

Prodrug: bitolterol

Bitolterol (Tornalate) differs from the previous agents discussed in that the administered form must be converted in the body to the active drug. Because of this, bitolterol is referred to as a prodrug. The sequence of activation is shown in Figure 6-5.

The bitolterol molecule consists of two toluate ester groups on the aromatic ring at the carbon-3 and carbon-4 positions. These attachments protect the molecule from degradation by COMT. The large N-tertiary butyl substituent on the amine side chain prevents oxidation by monoamine oxidase (MAO). Bitolterol is administered as an inhalation solution, and once in the body the bitolterol molecule is hydrolyzed by esterase enzymes in the tissue and blood to the active bronchodilator colterol. The process of activation begins when the drug is administered and gradually continues over time, resulting in a prolonged duration or sustained-release effect of up to 8 hours. Onset and peak effect are similar to those of the noncatecholamine agent metaproterenol, administered by inhalation. The active form, colterol, is a catecholamine and is inactivated by COMT similar to any other catecholamine. The speed of this inactivation is offset by the gradual hydrolysis of bitolterol, to provide a prolonged duration of activity. The bulky side chain gives a preferential β2 effect to the active form, colterol.5

In animal studies, bitolterol given orally or intravenously selectively distributed to the lungs. The inhalation route in humans seems preferable to treat the lungs locally, and the hydrolysis of bitolterol to colterol proceeds faster in the lungs than elsewhere, giving a selective effect and accumulation in the lungs. Colterol is excreted in urine and feces as free and conjugated colterol and as metabolites of colterol. Although interesting from a pharmacologic viewpoint, bitolterol has been removed from market in the United States.

Levalbuterol: (R)-isomer of albuterol

Previous inhaled formulations of adrenergic bronchodilators were all synthetic racemic mixtures, containing 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 6-6. Although the (S)-isomer is physiologically inactive on adrenergic receptors, there is accumulating evidence that the (S)-isomer is not completely inactive. Barnes6 suggested, however, there is no difference between single isomer levalbuterol and racemic albuterol. Box 6-1 lists some of the physiologic effects of (S)-isomer of albuterol noted in the literature.713 The effects noted would antagonize the bronchodilating effects of the (R)-isomer of an adrenergic drug and promote bronchoconstriction. In addition, the (S)-isomer is more slowly metabolized than the (R)-isomer. Levalbuterol is the single (R)-isomer form of racemic albuterol and is available in an HFA-propelled MDI, with nebulization solution in three strengths: 0.31-mg, 0.63-mg, and 1.25-mg unit doses. Levalbuterol is also available as a concentrate, 1.25 mg in 0.5 mL. In a study by Nelson and associates,14 the 0.63-mg dose was found to be comparable to the 2.5-mg racemic albuterol dose in onset and duration (Figure 6-7).

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Figure 6-7 Mean percent change in forced expiratory volume in 1 second (FEV1) from baseline (week 0) to the end of treatment (week 4) with various doses of levalbuterol, racemic albuterol, and placebo (PBO). (From Nelson HS, Bensch G, Pleskow WW, et al: Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma, J Allergy Clin Immunol 102:943, 1998.)

Side effects of tremor and heart rate changes were less with the single-isomer formulation. The 1.25-mg levalbuterol 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. It is significant that an equivalent clinical response was seen with one-fourth the racemic dose (0.63 mg) when using the pure isomer, although the racemic mixture contains 1.25 mg of the (R)-isomer (one-half of the total 2.5-mg dose).

Long-acting β-adrenergic agents

The trend in adrenergic bronchodilators has been toward development from nonspecific, short-acting agents, such as epinephrine, to β2-specific agents with action lasting 4 to 6 hours, such as albuterol and levalbuterol. Longer acting agents offer the advantages of less frequent dosing and protection through the night for asthmatic patients. These agents include extended-release albuterol and newer drugs such as salmeterol (Serevent), formoterol (Foradil, Foradil Certihaler), and arformoterol (Brovana). Long-acting bronchodilators are contrasted with short-acting agents. Short-acting agents include albuterol, levalbuterol, and pirbuterol, although these agents at one time were considered longer acting compared with the ultra-short-acting catecholamines such as epinephrine.

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

Bronchodilator effect.

Salmeterol represents a new generation of long-acting β2-specific bronchodilating agents, whose bronchodilation profile differs from the agents previously discussed. The median time to reach a 15% increase in FEV1 above baseline (considered the onset of bronchodilation) in asthmatic subjects is longer with salmeterol than albuterol; it has been reported as between 14 and 22 minutes16,17 and generally is longer than 10 minutes.18 The slower onset of action with salmeterol is significant for its clinical application (discussed subsequently). The time to peak bronchodilating effect is generally 3 to 5 hours, and its duration of action in maintaining an FEV1 15% above pretreatment baseline is 12 hours or longer. At each point (onset, peak effect, and duration), salmeterol exhibits slower, longer times for effect compared with shorter acting bronchodilators such as albuterol.

With inhaled salmeterol xinafoate, an initial peak plasma concentration of 1 to 2 μg/L is seen 5 minutes after inhalation, with a second peak of 0.07 to 0.2 μg/L at 45 minutes; the second peak is probably due to absorption of swallowed dose. The drug is metabolized by hydroxylation, with elimination primarily in the feces.19 The increased duration of action of salmeterol is due to its increased lipophilicity, conferred by the long side chain. The “tail” of the molecule anchors at an exosite in the cell membrane, allowing continual activation of the β receptor. The mode of action is discussed more fully subsequently.