Beta-adrenergic receptors are transmembrane glycoprotein structures that elicit a response inside the cell when interacting with catecholamines. They belong to a major receptor family (R7G) containing other receptors responding to substances other than catecholamines, and these receptors are coupled with guanine nucleotide (GTP) binding proteins (G proteins). Beta receptors divide into three subtypes; beta-1 (B1), beta-2 (B2), and beta-3 (B3). Other adrenergic receptors are alpha-1 and alpha-2 receptors.
Beta 2 receptors are predominantly present on airway smooth muscles. They also exist on cardiac muscles, uterine muscles, alveolar type II cells, mast cells, mucous glands, epithelial cells, vascular endothelium, eosinophils, lymphocytes, and skeletal muscles.
Natural catecholamines are nonspecific in their effects on the body, as they can stimulate all types and subtypes of adrenergic receptors. However, different catecholamines and synthetic drugs have affinities towards different receptor subtypes. Therefore, some synthetic drugs are considered “selective” to a specific adrenergic receptor or a subtype while other compounds are not.
Natural hormones stimulate B2 receptors in the body as well as by synthetic compounds; Epinephrine (adrenaline) is the most effective natural catecholamine agonist of B2, while norepinephrine (noradrenaline) is less effective on it, and epinephrine is the hormone responsible for B2 receptor stimulation in the physiological state. Synthetic agonists were sought to selectively stimulate specific receptors, unlike natural hormones, which have a low selectivity profile so that adverse effects could be minimized. Beta receptors can be blocked by using synthetic drugs, but B2-selective blockers are yet to be found.
Beta-2 Receptor Agonists
These drugs are designed to mimic the natural effect of epinephrine and norepinephrine hormones on the body, thus called sympathomimetics, but to limit the stimulation to B2 receptors as much as possible to reduce adverse effects. They are mainly used in the management of respiratory disorders such as chronic obstructive pulmonary disease (COPD) and asthma.
B2 agonists further classify into short-acting, long-acting, and ultra-long-acting drugs.
Some FDA-approved short-acting B2 agonists (SABAs) are albuterol, levalbuterol, metaproterenol, and terbutaline, and they are prescribed for bronchospasm caused by COPD, bronchial asthma, or emphysema.
Long-acting B2 agonists (LABAs) are indicated as maintenance treatment of bronchoconstriction in patients with COPD, chronic bronchitis, and emphysema. FDA-approved LABAs include salmeterol, formoterol, and arformoterol.
Recently, clinical trials have started on ultra-long-acting B2 agonists (ULABAs) to find their effects as a long-term once-daily management method for COPD and asthma. Olodaterol is an example of an FDA-approved ULABA.
Beta-2 Receptor Antagonists (Blockers)
B2 antagonists are the compounds used to block the activation of B2 receptors. There are no FDA approved selective B2 antagonists. Butoxamine is a non-FDA approved B2-selective blocker used exclusively for research purposes as it has no clinical use.
B2 adrenergic receptors are coded on chromosome 5 and expressed predominantly in the smooth muscle cells of the airways. The receptor is composed of 8 alpha helices; three are extracellular, and five are intracellular. It is bound to and transmits its signals inside the cell through heterotrimeric G protein, specifically Gs protein. Gs protein consists of alpha, beta, and gamma subunits. B2 receptors are present in two forms; activated and inactivated, and there is an equilibrium between both forms in the body.
The activity of the B2 receptor is dependent on the alpha subunit of the Gs protein; it becomes activated when bound to GTP and inactivated when bound to GDP. Presumably, agonistic ligands of B2 receptors achieve their effects by stabilizing the Gs-GTP form so it would retain its intracellular activity, whereas B2 blockers arrest the receptor in Gs-GDP low-energy form hence preventing the reactivation of the receptor.
The pathway of B2 receptor action begins when an agonist activates the receptor, causing the alpha subunit of the Gs protein to detach and reattach to adenylate cyclase, stimulating it to catalyze the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) which acts as a second messenger within the cell. In turn, cAMP initiates two routes leading to smooth muscle relaxation, the first is through freeing the catalytic subunit of protein kinase A enzyme, whose function is to phosphorylate various enzymes contributing to the relaxation of airway smooth muscles, and the second is by reducing calcium concentration inside the cell by preventing its extracellular influx, inhibiting its outflow from intracellular storage, and initiating sequestration of calcium ions in the cytoplasm, thus preventing muscle contraction. The same mechanism is responsible for uterine relaxation and is responsible for the use of B2 agonists in tocolysis. B2 activation is also reported to increase the beating frequency of the cilia, decrease acetylcholine release, change vascular permeability, and modulate immune cell function. B2 activation is also responsible for glycogenolysis.
B2 adrenergic antagonists cause their effect by blocking the activation of B2 receptors, so all the processes mentioned above cease to continue. Theoretically, beta-blockers can cause exacerbation of symptoms in patients with asthma, because they restrict the protective bronchodilatory effect of the natural epinephrine.
B2 agonists are mostly given in inhaled forms-whether as a spray or nebulized to limit the systemic adverse effects and reduce the delivered dose to target only the respiratory system. They can also be given intravenously or intramuscularly in severe acute exacerbations of asthma, orally in cases of using LABAs or ULABAs in the long-term management of asthma or COPD, and subcutaneously.
SABAs rarely have any adverse effects when used in the usual doses, but higher and systemic doses can have similar outcomes to sympathetic stimulation on the body; the most common one is tremor. Other adverse effects include anxiety, palpitations, and tachycardia. Elevated SABA doses can also cause lactic acidosis, a decrease in serum potassium and magnesium levels, and hyperglycemia.
LABAs can cause cardiac dysrhythmias and muscle cramps in normal doses in long-term use, especially when taken as the sole management drug for asthma without steroids. There is evidence of tolerance in the case of long-term use of LABAs.
Systemic exposure to B2 agonists can cause systemic vasodilation, which may lead to hypotension and can trigger headaches. Hypotension may also cause hypoxemia due to ventilation/perfusion mismatching in the lung. The risk of myocardial infarction was found to be seven times higher in patients using beta-2 agonists compared to those who are not.
Regular B2 agonist use in the treatment of asthma in the absence of corticosteroids may deteriorate the chronic state of the disease, as long-term tolerance to the antagonistic effect of B2 agonists is documented.
B2 receptor-related side effects caused by beta-blockers include Raynaud phenomenon, hypoglycemia during exercise, muscle cramps, and increased airway resistance.
Hypersensitivity is a contraindication for any substance, including B2 agonists and beta-blockers. B2 agonists require caution for patients with arrhythmias and cardiac problems. Hypokalemia is a contraindication for B2 agonists, because they may lead to increased severity of the condition. Beta-blockers are not recommended for patients with bronchoconstrictive diseases such as asthma and COPD. They should be given with care to diabetic patients as it may increase the risk of hypoglycemic comas.
The therapeutic index of beta-2 agonists is different for each chemical, and both therapeutic and adverse effects of similar doses can be different among individuals according to multiple factors, such as the severity of the condition and the length of the drug’s use, as well as other medications taken by the patient.
The plasma concentration of B2 agonists correlates with the severity of the toxicity. Direct monitoring of B2 agonists is not a regular procedure in clinical practice, as their efficacy, as well as their toxicity, can be measured clinically or by using indirect tests, nevertheless, there are some recognized tests for measuring drug concentration in the bloodstream; such as gas chromatography or liquid chromatography with mass spectrometry, high-performance liquid chromatography, fluorimetric detectors, and electrochemical detectors. Monitoring techniques are primarily used before athletic competitions to check for their use as anabolic agents. Clinically, serum potassium and blood glucose require regular monitoring to manage any adverse effects early. Recurrence of asthma attacks is not an indicator of the efficacy of B2 agonists, as the main drug responsible for long-term effects is steroids.
B2 agonist toxicity can be accidental or intentional. The most dangerous complication caused by its toxicity is hypokalemia caused by the intracellular shift of potassium. The toxicity can also present as exaggerations of documented side effects, such as significant hypotension and presence of bounding pulse due to greater affection of the diastolic portion, supraventricular tachycardia or ventricular extrasystoles, tremors which can-rarely but possibly-reach the level of seizures, hyperglycemia and lactic acidosis, tachypnea, and pupillary dilation. Very high doses can lead to psychosis and hallucinations.
There are some causes related to B2 receptors for beta-blocker contraindication; the most important one is in patients with asthma as it would cause increased bronchial resistance, thus increasing symptoms of asthma and other bronchospastic diseases.
Asthma and COPD are common chronic diseases with multiple treatment guidelines throughout the world, but beta-2 agonists are an essential part of every guideline; this necessitates the thorough and accurate knowledge of different aspects related to them, including the significant adverse effects and contraindications. Practitioners should always respect the individual difference between patients’ responses to treatment, so customization of treatment regimen according to all of the previous factors is a must.
Beta-2 agonists are not the first-line management drug for asthma, and patients require education about when and how to use them properly, as multiple studies showed that tolerance to B2 agonists is rapid if used incorrectly.
Patients with chronic respiratory inflammatory diseases should receive care from a team of healthcare workers, including pulmonologists or allergists, pharmacists, and nurses, who should all have at least the basic knowledge about beta-2 receptors.
Cardiologists and obstetricians should identify the clinical relevance of drugs affecting B2 receptors, which their patients may be taking and adjust the medications they prescribe accordingly to improve efficacy and prevent adverse effects.
The general public needs more information about the dangerous outcomes of B2 agonists if used inappropriately or without medical advice such as its use as an anabolic drug, and emergency physicians and nurses should have the training to identify the clinical picture of these drugs’ overdose correctly.
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