Autonomic pharmacology

β-Adrenergic Receptor Agonists

β₂-selective adrenergic receptor agonists: Overview

Previously, descriptions of pharmacological effects associated with "non-selective" β-adrenergic receptor agonists used to manage pulmonary diseases such as asthma or COPD necessarily include unwanted side effects often due to β₁ adrenergic receptor activation. Specifically, myocardial effects are particularly emphasized.
Understanding Asthma Health Matters: Asthma
- Other medications, which are relatively selective for β₂-adrenergic receptors, retain the benefits in management of asthma and COPD, while limiting adverse effects mediated by β1-adrenergic receptor activation.
- At higher doses β₂-selective adrenergic agonists are still able to activate β₁-receptors, again emphasizing the role of drug concentration in drug specificity.


Understanding Asthma	Health Matters: Asthma

Approaches to targeting β₂-pulmonary adrenergic receptors involves not only drug design but also drug delivery.

For example, administration of drug by aerosol targets β₂ pulmonary receptors, while limiting systemic drug. A further benefit of aerosol administration is rapid therapeutic response in most cases.

Factors that influence aerosol therapy efficacy include those that affect drug delivery to distal elements of the airway.

Accordingly, aerosol particle size and patient respiratory characteristics such as tidal volume, inspiratory flow rate, breath-holding duration and airway diameter represent important determinants.

The premise of β₂-agonist-mediated receptor activation (applying also to "non-selective" β-receptor agonists) is based on both smooth muscle relaxation and reduced airway resistance.

Additional therapeutic benefits associated with β-adrenergic receptor agonists likely include reduced pulmonary mast cell leukotriene and histamine release, reduced microvascular permeability, phospholipase A₂ inhibition and increased mucociliary activity.

Cultured Mast Cells¹⁶³

"Photo of cultured mast cells at 100X using an oil immersion lens and an olympus digital camera. The cells are stained with Tol Blue, and might appear slightly degranulated as they were activated using an artificial antigen during the course of an experiment."¹⁶³ Mast cell activation results in release of both characteristic granules and hormonal mediators.¹⁶⁴ Granules are enriched in histamine and other substances including serine proteases (e.g. tryptase), serotonin, proteoglycans (heparin). These substances are "preformed." Other elements released by mast cell activation include newly formed lipid mediators (eicosanoids), including prostaglandin D2, leukotriene C4 and platelet activating factor. Cytokines such as eosinophil chemotactic factor are also elaborated.¹⁶⁴

Airway hyper-responsiveness is probably related to airway inflammation, a suggestion supporting use of inhaled steroids as part of asthma management in many cases.
- Combination of long-acting β-adrenergic receptor agonists with anti-inflammatory agents represents a strongly endorsed therapeutic approach.

Short-acting β₂-adrenergic agonists:¹⁵²

Short-acting β₂-adrenergic agonists administered by inhalation represent drugs of choice for management of acute asthma presentations and for prevention of exercise-induced bronchospastic reactions.¹⁶⁵

Albuterol (Ventolin, a.k.a. Salbutamol outside the US) is a commonly used selective β₂-adrenergic receptor agonist that may be administered either orally or by inhalation.

Administration of albuterol can provide rapid relief of bronchospastic symptoms.

Following inhalation, bronchodilation may be apparent within 15 min. and last for about 3-4 hours.
- When comparing the non-selective adrenergic agonist isoproterenol to albuterol, at doses that produce comparable bronchodilation, albuterol will exhibit substantially less cardiac stimulation. This observation illustrates the relatively weaker albuterol β₁-receptor activating property compared to its effect at β₂ receptor sites.

Albuterol is typically administered as the racemate, a 50:50 mixture of (R)-and (S)-albuterol enantiomers. Pharmacological activity is mediated by the R-form, which exhibits about 100 times more affinity for the β-receptor compared to the S-form.^165,166

(R)-albuterol (top) and (S)-albuterol (bottom)¹⁶⁷

"Ball-and-stick model of the (R)-salbutamol (top) and (S)-salbutamol (bottom) molecules, both C₁₃H₂₁NO₃ ."¹⁶⁷ Primary source cited by (167): X-ray crystallographic data from J. M. Leger, M. Goursolle, M. Gadret et A. Carpy (April 1978). "Structure cristalline du sulfate de salbutamol [tert-butylamino-2 (hydroxy-4 hydroxyméthyl-3 phényl)-1 éthanol.0.5H₂SO₄]". Acta Cryst. B34 (4): 1203-1208.

Levalbuterol (Xopenex) is a formulation consisting of only the R-albuterol enantiomer.¹⁵²
- This agent is available in a CFC (chlorofluorocarbons)-free metered dose inhaler.
- Levalbuterol is classified the same as albuterol, as a β₂-selective adrenergic receptor agonist, and behaves comparable to albuterol with respect to both pharmacokinetic and pharmacodynamic characteristics.
Metaproterenol (Alupent) is structurally similar to terbutaline (Brethaire) and fenoterol and is classified as a "resorcinol" bronchodilator.¹⁵²
- These agents have hydroxyl groups at phenol positions 3 and 5 (resorcinol) as opposed to having hydroxyl groups at positions 3 and 4 (catechols).
- As a result of this difference in phenol ring hydroxlation, metaproterenol is not a substrate for methylation by catechol-O-methyltransferase, by contrast to catecholamines.
  - Resistance to COMT metabolism results in the absorption in the active form of about 40% of an orally ingested dose.
    - Excretory pathways involve conjugation reactions with glucuronic acid conjugates predominating.
- Metaproterenol, although classified as a β₂-selective adrenergic agonist, appears less selective compared to albuterol or terbutaline. Increased β₁-adrenergic receptor activation associated with metaproterenol results in a relatively higher incidence of cardiac stimulation.
  - This observation emphasizes the point that even drugs classified as β₂-selective can still activate β₁-adrenergic receptors in a clinically noteworthy manner.
- Following administration by inhalation, pharmacological actions may be noted within minutes and last several hours.
- Metaproterenol can be used for clinical management of:
  - asthma
  - obstructive airway disease, and
  - acute bronchospasm.¹⁵²

Pirbuterol (Maxair)¹⁵²:

Pirbuterol (Maxair) belongs to the short acting, relatively selective β₂-adrenergic receptor agonist category.
Structurally this agent resembles albuterol (see below)-notice the benzene ring as part of albuterol structure, but the corresponding pyridine ring with pirbuterol.
Pirbuterol (Maxair, left) and Albuterol (Ventolin, right)

Pirbuterol (pyridine ring, arrow) Albuterol (benzene ring, arrow)
Pirbuterol acetate is administered by inhalation, with dosing every 4-6 hours.

Pirbuterol (Maxair, left) and Albuterol (Ventolin, right)

Pirbuterol (pyridine ring, arrow)	Albuterol (benzene ring, arrow)

This agent is available utilizing a "breath-actuated" meter-dose inhaler which delivers medication triggered by initiation of inspiration by the patient.¹⁵²

3M Autohaler™^{,
168}

With pressurized metered dose inhalers, patients must press and breeze at the same time. Both steps are required to ensure effective dosing; however, some patients may find this coordination challenging and might benefit from a breath-actuated (activated) inhaler. The example model above is manufactured by 3M and is triggered by patient initiation of inspiration.¹⁶⁸

Terbutaline (Brethine)¹⁵²:
- Terbutaline (Brethine) is another β₂-selective adrenergic receptor agonist.
  - This drug's resorcinol ring prevents its metabolism by catechol-O-methyltransferase (COMT).
  - Although the inhalation route of administration is not marketed in the US, bronchodilation occurs following administration by parenteral routes or inhalation.
  - Pharmacological activity may be observed for 3-6 hours. Oral administration may delay onset for about 1-2 hours.
  - Terbutaline may be used both for management of acute bronchospasm as well as for long-term management of obstructive airway disorders.
    - Parenteral use of terbutaline in the emergent setting may be helpful in status asthmaticus treatment.
Fenoterol (Berotec)¹⁵²:
- Fenoterol (Berotec) is classified as a β₂-adrenergic receptor agonist.
  - Following inhalation, rapid onset of action is followed by 4-6 hours of pharmacological activity.
  - This agent has been withdrawn from certain markets (New Zealand) because of concerns of association between its administration and possible increase incidence of asthma-related death.
  - Abnormal cardiac rhythms and other cardiac effects are likely mediated by fenoterol activity at myocardial β₁-adrenergic receptors.

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