Medical Pharmacology: The Pharmacology of Long-Acting Beta-2 Adrenergic Agonists and Related Drugs.

β-Adrenergic Receptor Agonists

Long-Acting β₂-selective adrenergic receptor agonists:¹⁵²

Salmeterol (Serovent)
Salmeterol (Serevent) is classified as a β₂-selective adrenergic receptor agonist which exhibits a duration of action in excess of 12 hours.¹⁵²
- Compared to albuterol, salmeterol appears more β₂-adrenergic receptor selective by a factor of about 50.
- Comparably effective as a cholinergic, muscarinic antagonist ipratropium and more effective than oral theophylline, salmeterol administration is associated with improved quality of life and improved pulmonary function and provides symptomatic relief for COPD patients.
- Salmeterol effects are additive when administered along with inhaled ipratropium or oral theophylline.
Extended pharmacological activity associated with salmeterol reflects not only its highly lipophilic nature but also its binding to a specific site within the β₂ receptor.¹⁵²
- Salmeterol is metabolized by the hepatic microsomal drug metabolizing system, specifically by the cytochrome P450 form, CYP3A4; the metabolic product, α-hydroxy-salmeterol is excreted in the feces.
- Salmeterol's slow onset of pharmacological action disqualifies this agent for use in management of acute bronchospastic attacks, although salmeterol (or formoterol) may be appropriate for managing nocturnal asthma in those subset of patients remaining symptomatic despite receiving anti-inflammatory drugs and other more standard management approaches.
- Salmeterol administration may result in tachycardia, elevated plasma glucose, tremor, and a reduction in plasma K⁺ concentration (β₂-receptor mediated).
Moderate or severe, persistent asthma may be effectively managed by long-acting β-adrenergic receptor agonists in combination with an inhaled corticosteroid.¹⁵²
- However, results from a clinical research trial (SMART), Salmeterol Multicenter Asthma Research Trial have suggested that salmeterol therapy is associated with increased risk of fatal or near-fatal asthma incidence when compared to "usual therapy."
- One criticism of the SMART study was that only a minority of patients in the trial were taking inhaled corticosteroids; a second point is that patients taking both long-acting β-adrenergic receptor agonists and inhaled corticosteroids may not be at elevated risk for asthma mortality.¹⁵²
However, in February 2010 the US Food and Drug Administration (FDA) has required a change with respect to how long-acting inhaled medications, referred to as "Long-Acting Beta-Agonists (LABAs), be used in asthma treatment.¹⁶⁹
- The changes were based on FDA analysis of studies indicating increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric as well as an adult patients as well as death in some patients when LABAs were used in treatment of asthma.
- LABAs are approved as single-ingredient products (e.g. Serevent and Foradil) and is part of combination products containing inhaled corticosteroids (Advair and Symbicort) for treatment of both asthma and chronic obstructive pulmonary disease (COPD).
- The 2010, FDA recommendations apply only to LABAs use in treatment of asthma.
- The FDA indicates that to ensure safe use of these agents:
  - "The use of LABAs is contraindicated without the use of an asthma controller medications, such as an inhaled corticosteroid. Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone.
  - "LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.
  - "LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patient should then be maintained on asthma controller medication.
  - "Pediatric and adolescent patients require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA to ensure compliance with both medications."
The FDA is also requiring a risk management program named "Risk Evaluation and Mitigation Strategy (REMS) for these agents.¹⁶⁹
- REMS for LABAs include a revised Medication Guide written specifically for patients as well as a plan to educate healthcare professionals about appropriate use of LABAs.
- Furthermore, the FDA is requiring manufacturers to conduct additional clinical trials that further evaluate LABAs safety when used in combination with inhaled corticosteroids.
The FDA has concluded that LABAs benefits in improving asthma symptoms outweigh potential risks when used appropriately with an asthma controller medication in those patients who require addition of LABAs; furthermore, the FDA leaves that the safety measures will improve safe use of these agents.¹⁶⁹
- The FDA also has provided additional information for patients-including the following:
  - "Long-Acting Beta Agonists (LABAs) do not relieve sudden-onset asthma symptoms. Patients should always have a rescue inhaler, such as an albuterol inhaler, to treat sudden onset asthma symptoms.
  - "LABAs must never be taken alone for the treatment of asthma.
  - "Patients who need LABA plus an asthma controller medication that is not available as a combination product should work with their healthcare professionals to ensure that each individual medication is taken correctly.
  - "Patient should read the Medication Guide for LABAs.
  - "Patient should talk with their healthcare professional to learn the warning signs of worsening asthma.
  - "Patient should discuss any questions they have about the use of LABAs with their healthcare professional."
- The FDA has also provided additional information for healthcare professionals-including the following:¹⁶⁹
  - "Long-Acting Beta Agonists (LABAs) should not be started in patients with acutely deteriorating asthma.
  - "Discuss with patients and families the warning signs of worsening asthma and advise them to seek immediate medical attention should their condition deteriorate.
  - "LABAs do not relieve sudden-onset asthma symptoms. A rescue inhalers, such as an albuterol inhaler, should be prescribed to treat sudden asthma symptoms.
  - "Increase patients, families, and caregivers to read the Medication Guide that accompanies LABA prescriptions.
  - When possible, prescribed a combination inhaled corticosteroid-LABA product to pediatric and adolescent patients who need the addition of a LABA for better control of their asthma. Using a combination product will help ensure compliance with both of these medications."

**FDA Approved Medications Containing a Long-Acting Beta Agonist (LABA)**¹⁶⁹
Brand Name	LABA active ingredient	Corticosteroid active ingredient	FDA Approved Uses
Serevent Diskus	Salmeterol	None	Asthma, COPD, exercise-induced bronchospasm
Foradil Aerolizer	Formoterol	None	Asthma, COPD, exercise-induced bronchospasm
Foradil Certihaler*	Formoterol	None	Asthma
Advair Diskus	Salmeterol	Fluticasone	Asthma, COPD
Advair HFA	Salmeterol	Fluticasone	Asthma
Symbicort	Formoterol	Budesonide	Asthma, COPD
Brovana	Arformoterol	None	COPD
Perforomist	Formoterol	None	COPD

* not currently marketed in the U.S.

As noted above, the FDA decision to require REMS and class-labeling alteration to drug labels for LABAs was based on the Salmeterol Multi-center Asthma Research Trial (SMART), the Salmeterol Nationwide Surveillance study (SNS) and a meta-analysis conducted by the FDA in 2008 which was discussed at the joint Pulmonary Allergy Drugs, Drug Safety and Risk Management, and Pediatric Advisory Committees, held on December, 2008.¹⁶⁹

SMART is described as a large, randomized, 28-week, placebo-controlled trial which evaluated patients 12 years of age and older receiving standard asthma therapy and the addition of either salmeterol or placebo.
- A total of 26, 355 patients were evaluated in the study with results indicating that patients receiving salmeterol were in an increased risk for asthma-related death compared to patients receiving placebo.
- Subgroup analyses were also performed and this analysis suggested that asthma-related death in Caucasians and African Americans occurred at a higher rate in those patients using salmeterol compared to placebo. These results are summarized below:¹⁶⁹

**SMART Results**¹⁶⁹
SMART Patients	Asthma-Related Deaths in Salmeterol Group n (%*)	Asthma-Related Deaths in Placebo Group n (%*)	Relative Risk of Asthma-Related Death (95% Confidence Interval)	Excess Deaths Expressed per 10,000 Patients+ (95% Confidence Interval)
All Patients§ salmeterol: n = 13,176 placebo: n = 13,179	13 (0.10%)	3 (0.02%)	4.37 (1.25, 15.34)	8 (3, 13)
Caucasian Patients Salmeterol: n = 9,281 Placebo: n = 9,361	6 (0.07%)	1 (0.01%)	5.82 (0.70, 48.37)	6 (1, 10)
African American Patients Salmeterol: n = 2,366 Placebo: n = 2,319	7 (0.31%)	1 (0.04%)	7.26 (0.89, 58.94)	27 (8, 46)

^"* 28‑week estimate, adjusted according to actual lengths of exposure to study treatment to account for early withdrawal of patients from the study.
⁺ Estimate of the number of additional asthma‑related deaths in patients treated with salmeterol in SMART, assuming 10,000 patients received salmeterol for a 28‑week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.
^§ The Total Population includes Caucasian, African American, Hispanic, Asian, and "Other" and "not reported". No asthma‑related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or "Other" (salmeterol n = 230, placebo n = 224) subpopulations. One asthma‑related death occurred in the placebo group in the subpopulation whose ethnic origin was "not reported" (salmeterol n = 130, placebo n = 127)."

The SNS was a 16-week, double-blind study which compared additional salmeterol or albuterol to stand asthma therapy in 25,180 asthma patients 12 years of age and older.¹⁶⁹
- In this study there was an increase in the number of respiratory and asthma-related deaths in the salmeterol group (0.07%) compared to the albuterol group (0.02%).
- The FDA, as noted above also performed a meta-analysis of 110 studies evaluating the use of LABAs in 60,954 asthma patients.
- This meta-analysis used a composite endpoint to measure substantial asthma symptom worsening including asthma-related death, intubation, and hospitalization.
- Results of the meta-analysis suggested an increased risk for severe exacerbation of asthma symptoms in patients using LABAs compared to those not using LABAs.
- The largest risk difference per 1000 treated individuals was seen in children 4-11 years of age as noted below.
- The results of the meta-analysis appeared primarily driven by asthma-related hospitalizations; however, other meta-analysis evaluating safety of LABAs in the treatment of asthma have not shown a significant increase in the risk for severe asthma worsening events.

**Meta-Analysis Results: Number of Patients Experiencing an Event*¹⁶⁹**
Patient Population	LABA Patients experiencing an event	Non-LABA Patients experiencing an event	Risk Difference Estimate per 1000 treated patients	95% Confidence Interval
All Patients n = 30,148 LABA patients n = 30,806 non-LABA patients	381	304	2.80	1.11 – 4.49
Patients ages 12 to 17 years n = 3,103 LABA patients n = 3,289 non-LABA patients	48	30	5.57	0.21 – 10.92
Patients ages 4 to 11 years n = 1,626 LABA patients; n = 1,789 non-LABA patients	61	39	14.83	3.24 – 26.43

* Event defined as the composite endpoint (asthma-related death, intubation, and hospitalization)

The FDA in the 2010 timeframe concluded that there was insufficient data to decide whether using LABAs with an inhaled corticosteroid reduces or eliminates risk of asthma-related death and hospitalization.
- Furthermore, the FDA is requiring LABAs manufacturers to conduct studies that evaluate safety of LABAs when used in combination with inhaled corticosteroids.
- Also, the FDA concluded that there is a risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric as well as an adult patients as well as staff in some patients using LABAs for asthma treatment and therefore is requiring the REMS and class-labeling changes to improve product safety.¹⁶⁹
As a result of the above considerations, the FDA has placed a "black-box" labeling warning for salmeterol (Serevent), formoterol (Foradil) and arformoterol (Brovana).
- Moreover, the use of long-acting β2-adrenergic receptor agonists appear recommended only for patients in whom inhalational corticosteroids alone either are unable to establish good asthma control or for initial treatment.^152,170

Formoterol (Foradil)
- Formoterol (Foradil)
- Formoterol (Foradil) is classified as a long-acting β₂-selective adrenergic receptor agonist which causes bronchodilation shortly after inhalation (minutes).
- Bronchodilation may last for up to a half a day.
  - The agent exhibits noteworthy lipophilicity, which confers an important advantage of formoterol compared to other similar agents, that of particularly prolonged duration of action.
  - The extended duration of up to 12 hours may be of special therapeutic benefit in managing nocturnal asthma.
  - Lipophilic drugs tend to partition into cell membrane lipid bilayers, as well as other sites enriched in lipid; however, concentration of drug within cell membrane may provide a "reservoir", diffusion from which accounts for extended activation of β₂-receptors.
- Formoterol has been approved by the FDA for several applications, including asthma management, bronchospasm, COPD and for prophylaxis of exercise-induced bronchospastic reaction.
  - This latter use refers to formoterol administration prior to beginning exercise with the therapeutic intent of preventing bronchospasm due to this exercise.
  - Formoterol may also be used along with short-acting β₂-adrenergic receptor agonists, inhaled or systemic administration of glucocorticoids and theophylline.
    - An example of formoterol combined with a corticosteroid is mometasone/formoterol (Dulera) combination for asthma management.¹⁷¹
      - This combination is available in a single metered-dose inhaler (Dulera), approved for asthma treatment in patients 12 years old and older. It represents the third corticosteroid/long-acting beta 2-agonist (LABA) combination in the United States.
      - Other combinations are budesonide/formoterol (Symbicort) and fluticasone/salmeterol (Advair Diskus).
      - These combination agents are not suitable either for initial asthma treatment or acute management of asthma symptoms.
Arformoterol (Brovana)^152,¹⁷²
- Arformoterol (Brovana)
- Arformoterol (Brovana), a formoterol enantiomer (R, R), is also classified as a selective-long-acting β₂-adrenergic receptor agonist with twice the potency of the formoterol racemate.
  - This agent is FDA-approved for patients with bronchoconstriction associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
- Arformoterol represents the first drug in its category developed for inhalational use with a nebulizer.
  - Its mechanism of action is the same as for other β₂ agonists; arformoterol stimulates the cAMP pathway resulting in bronchial smooth muscle relaxation as well as inhibition of mast cell mediator release (inhibition of histamine in leukotriene release).
    - Arformoterol is metabolized following pulmonary absorption by direct conjugation (forming glucuronide or sulfate conjugates) and additionally (<17%) by O-demethylation principally mediated by two cytochrome P450 isoforms, CYP2D6 and CYP2C19.
    - There have been at least five human UGT (uridine diphosphoglucuronosyltransferase) isoforms identified that catalyze arformoterol glucuronidation (in vitro).
  - Following a nebulized arformoterol dose (15μg), bronchodilation, about 15% increase in FEV₁, was noted in about 7 min. with peak effects described in 1-3 hours.
    - Evaluation of patient response to arformoterol was assessed in two 12-week randomized, double-blind clinical trials conducted in 1456 COPD patients.¹⁷²
      - Three doses of arformoterol (15μg/twice daily; 25μg/twice daily and 50μg/ once daily) were compared with placebo and salmeterol, the latter being an active control administered by metered dose inhaler, 42μg/twice daily.¹⁷²
      - Based on results from the one published study involving 717 COPD patients, patients receiving 15μg/twice daily arformoterol improved compared to placebo, as measured by FEV₁ (+16.9% vs. +6%).
        
        Patients treated with salmeterol exhibited a +17.4% increase in FEV1. [The unpublished results correspond closely to these.]
      - At week 12 most patients (57-62%) exhibited clinically important improvements in dyspnea with arformoterol, a percentage comparable to that observed with salmeterol.¹⁷²
  - Adverse effects are those expectable following β-adrenergic receptor activation including skeletal muscle tremor, tachycardia, reduced plasma K⁺, increased plasma glucose and insomnia.

Adverse effects associated with β-adrenergic receptor agonists:¹⁵²
- Adverse effects associated with β₂-adrenergic receptor agonists are directly related to β-receptor activation. Patients with cardiovascular disease perhaps especially myocardial disease may be particularly sensitive to adrenergic activation.
- Administration of adrenergic receptor agonist by inhalation reduces systemic absorption and accordingly decreases systemic toxicities.β₂-adrenergic agonist administration may induce tremor, which, over time, often diminishes.
- The likelihood of tremor following oral administration is reduced if a lower drug dose is administered at first, followed by increasing drug dosages as tolerance to tremor develops.
- Anxiety, apprehension, and restlessness, sometimes therapy limiting, are also noted with these drugs.
- Tachycardia is commonly observed with administration of β-adrenergic receptor agonists, possibly a consequence of direct receptor activation (β₁-adrenergic receptor subtype).
  - Another possibility is that agents with β₂-adrenergic agonist activity may produce peripheral vasodilation which, by autonomic reflex mechanisms, cause tachycardia.
  - Tachycardia associated with an ongoing severe asthma attack may be reduced following administration of a β-receptor agonist, because of improved pulmonary function on one hand and resultant reduced anxiety, which reduces circulating catecholamines, on the other.
  - If tachycardia is considered a relatively benign arrhythmia, more serious arrhythmias may develop associated with β-adrenergic stimulation in patients with pre-existing coronary vascular disease or pre-existing arrhythmia.
- Adverse cardiovascular incidents are more likely in patients receiving monoamine oxidase inhibitors (MAO inhibitors), presumably administered as part of management of endogenous depression.

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