Mechanisms of Bronchospasm at the Cellular Level On the surface of the smooth muscle in the bronchus and bronchiole are hundreds of cholinergic receptors, specifically muscarinic (M3), that respond to stimulation by acetylcholine. There are more muscarinic receptors in the central airways than in the peripheral, so there are more potential M3 receptors to be blocked in the central airways  Once the muscarinic receptor is stimulated: 1.  binds & activated enzyme guanylate cyclase 2.  this catalyzes the conversion of [guanylate triphosphate] GTP into cyclic -GMP [3, 5 guanosine monophosphate] 3.  cyclic –GMP results in an increase of free intracellular Ca++ which results in muscle contraction-Bronchospasm.   Mechanisms of Bronchodilation at the Cellular Level On the surface of the smooth muscle in the bronchus and bronchiole are hundreds of Beta II receptors. They increase in number as they reach the peripheral area. When stimulated by a catecholamine with Beta II action such as epinephrine, the following happens: 1.   Intracellular enzyme, adenylate cyclase, is activated. 2.   this catalyzes the conversion of ATP (adenosine triphosphate) into cyclic-AMP (3,5 adenosine monophosphate) 3.   cyclic-AMP triggers protein kinase A which reduces intercellular Ca ions and results in relaxation of bronchial smooth muscles.

Bronchodilators are medications used to help improve airflow into the lungs. They act to relieve symptoms such as shortness of breath during asthma attacks by relaxing the smooth muscle surrounding the airways.

This allows the airways to open, letting more air move in and out of the lungs. Apart from being effective in asthma, they also help improve the breathing of patients with lung diseases such as bronchitis, emphysema, pneumonia and bronchiolitis in young children. Bronchodilator medications belong to three main groups - beta 2 agonists (short and long acting), the xanthines and muscarinic receptor antagonists. The most commonly used group of bronchodilators are the beta 2 agonists, which are used primarily in patients with asthma, to dilate the smooth muscle surrounding our airways by targeting specific receptors. Short acting beta agonists act to provide acute, immediate, rescue relief from symptoms. Longer acting bronchodilators help control symptoms and prevent asthma attacks.  

Beta 2 Agonists

Beta 2 Agonists are a group of medications formulated to act on special receptors called beta-2 receptors, located predominantly on smooth muscle and mucous membrane in the lungs and smaller airways. They also act on cells called mast cells to prevent release of substances which play a role in asthma attacks. Additionally, they may help clear mucous from the lungs. As the airways dilate, any mucous present can move more freely and can be coughed out of the airways. There are two categories of beta 2 agonists used in asthma:

1.    Short/ Intermediate acting agents: (Salbutamol, Isoproterenol, Albuterol, Metaproterenol and Terbutaline) - these are usually administered via devices, to deliver the medication straight to the lungs (i.e. puffers, nebulizers, inhaler). They act within 30 minutes and last for about 4-6 hours. They are often used as needed, to control symptoms. They are quick acting agents, relieving asthma symptoms by opening the airways. They remain first line agents for relief of acute symptoms and can be effective for both exercise and allergens induced asthma. Care must be taken to ensure that beta agonists are combined with other types of treatment to provide the best control of your disease and symptoms, in the long run. They only act acutely and have no sustained actions on other factors involved in diseases such as airways inflammation, edema and mucous secretion. Increasing usage of beta agonists is a sign of unstable asthma, that needs to be better controlled. If you need to use your short acting beta agonist more than 2-3 times a week, you should seek your doctor about management of your asthma.

2.    Longer acting agents: (Salmeterol and Formoterol) - these are usually taken via the inhaled route, through the nose and mouth and last for about 12 hours. These medications are best taken on a regular basis, to provide the best control of your symptoms and can be used in conjunction with glucocorticoids to provide additional control. You can take beta agonists via different delivery systems, ranging from metered dose inhalers, nebulized solutions, oral liquids and tablets to dry powder inhalers. The route of delivery of the medication can play a role in determining how effective it is in treating your symptoms. It has been suggested that bronchodilator medications taken through the mouth or given as an injection into the veins is more effective than inhaled routes of delivery because this allows bypassing of mucous plugs that may block the airways. However, there is an increased risk of side effects associated with these modes of delivery. There have been clinical studies performed which compare beta agonists given by two different routes - nebulized (inhaled) and intravenously (through the veins). Some earlier studies suggested advantages with giving medications through the veins, but subsequent studies with medications such as terbutaline and albuterol have demonstrated equivalent or superior effects on lung function using the nebulized (inhalation) route. Another study involving 15 trials and 584 patients compared the outcomes achieved with the use of beta agonist therapy via the veins, for acute asthma. Intravenous therapy was not associated with improved outcomes in the study population or any identified subgroup.

Xanthines

There are three main active, naturally occurring methylxanthines - theophylline, theobromine and caffeine. Theophylline is the most commonly used xanthine in treatment of asthma, also used as aminophylline. Theophylline has a proven dilatory action on the airways, although it is less effective compared to the beta 2 adrenoceptor agonists. Several studies have shown that theophylline is both effective in relieving the acute attack and in the treatment of chronic asthma. Additional actions to dilating the airways seems to be implicated, as theophylline has effects on the later stages of asthma. Xanthines are most commonly used in severe airways obstruction, including cases of acute asthma, and also in maintenance treatment of severe asthma and lung diseases such as bronchitis and emphysema. The exact mechanism by which xanthines produce it's effects in asthmatic patients is still unclear. It is thought that they induce smooth muscle relaxation, via inhibition of a substance called phosphodiesterase.

This allows an increase in cyclic AMP which acts to counteract the inflammatory effects that occur in the later stages of asthma. Note that xanthines also have actions on other bodily systems including: the central nervous system, heart and major vessels, and kidney. These actions on other systems result in many of the side effects of the drugs. They have a stimulant effect on the central nervous system, resulting in increased alertness, tremor and nervousness. All the xanthines also exhibit a stimulant effect on the heart, causing dilation of blood vessels. They can also act on the kidney to increase urine output and flow. These drugs are only effective if the cause of your symptoms is due to smooth muscle contraction and airways constriction. Most xanthine medications are given orally, via slow release preparations. Aminophylline can also be given via the veins as a slow infusion, especially if you present in the emergency setting, with an acute, sustained asthma attack (also known as status asthmaticus). Overall, theophylline is used as a second line drug in asthma therapy, often in addition to steroids and other anti-asthmatic medications in patients whose asthma is not adequately controlled by other bronchodilators.

Muscarinic Receptor Antagonists

The muscarinic receptor antagonists are a group of bronchodilators that includes medications such as ipratropium and oxitropium. The drug used most commonly in treatment of asthmatics is ipratropium. There are sensory nerve endings present in the lining of our airways - when these are activated, they induce constriction and narrowing of the airways. Muscarinic receptor antagonists act to relax constriction of airways due to activation of these nerves by stimulation of the parasympathetic system. These medications have been shown to be particularly effective in allergic irritant asthma. As their name suggests, muscarinic receptor antagonists act to block muscarinic receptors, but they do not discriminate between the different types.

They can help decrease mucous secretion and may increase the lung's ability to clear airway secretions. Muscarinic receptor antagonists are given via inhaled delivery systems, (ie through the nose) because they are not well absorbed into the body's circulation. Their peak effect occurs about 30 minutes after administration, lasting for about 3-5 hours. Often, these medications are used with the beta 2 adrenoceptor antagonists. Ipatropium can also be used to dilate the airways in patients with chronic bronchitis and to treat spasm of the airways precipitated by beta 2 adrenoceptor antagonists. It has been shown to be as effective as inhaled beta 2 agonists in the treatment of stable lung disease. These medications are often employed in maintenance treatment of patients with lung disease such as bronchitis, emphysema, and severe asthma.

Effectiveness of Bronchodilator Use

To ensure that your disease is as effectively controlled as possible, there are different factors that you and your doctor must address. These include:

·         The severity of your disease.

·         Mode of medication delivery.

·         Your compliance with taking medications.

·         Side effects experienced from taking the drugs.

Asthma Severity: To determine severity of diseases such as asthma, your doctor may ask about issues such as what symptoms you experience, their frequency, number of exacerbations and hospitalizations, the effects that asthma has on your daily life, frequency of acute bronchodilator use and results of lung function tests. The main aims of asthma management are good long term control. Features that suggest good long term control include:

·         Minimal day time and night time symptoms (i.e. ability to carry out activities of daily living without too much interference, good exercise performance),

·         Good control with controller medications and minimal use of your bronchodilators.

·         Minimal hospitalizations for asthma exacerbations.

Mode of Medication Delivery: The inhaled route of delivery is the preferred route of drug administration for patients with asthma and other lung diseases. This offers the greatest and quickest deposition of drug straight into the lungs, resulting in the lowest effective dose and the least side effects. Inhaled medications can be given via nebulizers, metered dose inhalers or dry powder inhalers. For the most effective administration of inhaled medications, you musts have a correct technique when using the delivery devices. An asthma education nurse is often very helpful and educational in these circumstances. Most cases of asthma respond well to regular low dose corticosteroids and inhaled beta 2 agonists, used as needed. Beta 2 agonists have been proven to be the most effective and rapidly acting agents acting to dilate the airways immediately, for asthma treatment. Increasing use of bronchodilator therapy should alert you to review the current management of your disease, as this may indicate that you have not gained the most effective control of disease.

Side Effects Associated with Bronchodilator Treatments

Beta Agonists: The most commonly experienced side effects that patients report is a nervous or shaky feeling. This effect is more pronounced following oral, compared to inhaled routes of delivery. Other adverse effects associated with beta 2 agonists relate to stimulation of other beta receptors in the body, such as those on the heart, causing increased heart rate. Some people may also feel a bit more hyperactive and overexcited. Less common side effects include increased blood sugar levels, alteration in electrolytes in the body such as potassium and an upset stomach or difficulty sleeping.

Xanthines: Due to the fact that xanthines also have actions on other bodily systems including: the central nervous system, heart and major vessels, and kidney, common side effects patients experience include nausea and vomiting, diarrhea, headaches, increased or irregular heart rate, muscular cramps, hyperactivity and/or a nervous, jittery feeling and increased risk of seizures.

Muscarinic Receptor Antagonists: Side effects associated with these medications are minor - the most common side effects include headaches, nausea, dry throat, constipation and difficulty passing urine. If this medication affects your eyes, you may experience blurred vision for a short period of time. You should seek medical advice promptly if this occurs.

Interactions with Bronchodilator Treatments and Other Medications

Beta Agonists: If these medications are combined with other drugs that stimulate the nervous system (ephedrine, phenylephrine, pseudoephedrine), this may result in excessive stimulation and adverse effects including: shaking, jittery / nervous feelings, headache and increased heart rate. At higher doses, beta agonists can cause metabolic side effects including low potassium levels and high glucose levels. If you are on other drugs that can affect potassium levels (ie particular types of blood pressure medications) your levels should be monitored closely. If you are a diabetic, stringent blood glucose monitoring when using these medications should be employed.

Muscarinic Receptor Antagonists: If these medications are administered with other drugs which also have similar effects on the nervous system (anticholinersterases, cisapride), the risk of adverse effects is greatly increased. These combinations should be avoided - if such a combination is required, you should be monitored closely by your doctor and the dose of medication administered may need to be reduced.  

Xanthines: Due to the fact that xanthine medications can lower the seizure threshold, other drugs that have effects on the seizure likelihood should be avoided (ie some antidepressants such as selective serotonin receptor inhibitors, tricyclic antidepressants, and amantadine, baclofen etc).

Toxicity of Bronchodilator Treatments

Bronchodilators are associated with some side effects, which are related to the total dose that you are being administered. There have been concerns about the development of tolerance with long term, chronic administration of beta agonists. Taking medications orally, via the mouth have been shown to be more likely to induce tolerance than other modes of delivery. This is thought to be due to down regulation of beta 2 receptors. 

Magnesium Sulfate

Physicians have given women magnesium sulfate by IV for half a century to slow down premature labor. Recently this mineral has been explored for bronchodilation in asthmatics.

“Magnesium deficit leads to increased acetylcholine release and muscle excitability. It is known that acute temporary elevation of serum magnesium can result in bronchodilation (smooth muscle relaxation), even in patients with normal magnesium levels. Evidence also shows that magnesium acts as a competitive antagonist with calcium and reduces the neutrophilic burst associated with the inflammatory response in asthma. Regardless, the beneficial effect of magnesium is controversial because a large clinical trial has not been done, even though numerous case studies show dramatic reversal of severe bronchospasm, minimizing the need for intubation and reducing in-hospital admissions in that group of patients. Magnesium Sulfate in Prehospital Care IV magnesium sulfate can modestly improve pulmonary function in patients with asthma when combined with nebulized ß-adrenergic agents and corticosteroids. Magnesium causes bronchial smooth muscle relaxation independent of the serum magnesium level, with only minor side effects (flushing, lightheadedness). ….. The typical adult dose is 1.2 to 2 g IV given over 20 minutes. When given with a ß₂-agonist, nebulized magnesium sulfate also improved pulmonary function during acute asthma but did not reduce rate of hospitalization.

When given by IV to slow down labor, women have been known to go into pulmonary edema, and one study of asthmatics found that combining magnesium sulfate and terbutaline increased terbutaline's cardiovascular side effects (Chest, 1994, Vol. 105, pp. 701-705).  

Magnesium sulfate can decrease muscle strength –even to the point of respiratory failure due to paralysis.