Drug Agents for Respiratory Care

Editor’s note: This text-based course is an edited transcript of the webinar, Drug Agents for Respiratory Care, presented by Dr. Duane Reed, EdD, RRT, RCP.

Learning Outcomes

After this course, participants will be able to: 

• Identify short-acting and long-acting beta-agonist drugs
• Discuss the pharmacological effects of steroidal and nonsteroidal drugs
• Identify anticholinergic, surfactants, and mucus-controlling agents

Introduction

In today's course, we talk about respiratory drugs,  why we use them, and which patient populations benefit from certain drug agents. The drug categories are listed as follows:

• Short-Acting Beta Agonist (SABA)
• Long-Acting Beta Agonist (LABA)
• Corticosteroids
• Non-steroidal anti-inflammatory drugs (NSAIDS)
• Anticholinergics
• Xanthines
• Mucus-controlling drugs
• Surfactants
• Nitric Oxide (NO)
• Neuromuscular blocking agents (NMBAs)

Short-Acting Beta Agonist

Let's start by talking about Short-Acting Beta Agonist drugs (SABA). SABA’s are indicated for acute reversible airway obstruction and obstructive diseases, e.g., emphysema, chronic bronchitis. SABA’s are also called “relievers” or “rescue drugs.” They are called rescue drugs because the drug agents provide bronchodilation during an acute exacerbation of Asthma or COPD, but mainly Asthma. During an Asthma attack, the lungs are constricting, and we need to do something quickly to help alleviate bronchoconstriction. Albuterol and Levalbuterol (Xopenex) are examples of rescue drugs.

Short-Acting Beta Agonist: Onset, Peak, and Duration

Figure 1 shows the examples of SABA drugs and their onset, peak, and duration times.

Figure 1. Short-Acting Beta Agonist drug onset, peak, and duration times.

The onset is how quickly the drug will start to work. The peak is when the maximum potency of the drug is happening. The duration is how long that drug lasts, stays in the system, and causes a reaction. The onset for Albuterol and Levalbuterol is the same, about 15 minutes. Albuterol peaks at about 30 to 60 minutes, and Levalbuterol peaks at about 20 to 30 minutes. The duration is 4-12 hours for Albuterol and 5 to 8 hours for Levalbuterol. If the drug peaks at a faster rate, it will not last as long. When a drug has a quick onset and peak, the duration has to be shorter. 

Long-Acting Beta Agonist Drugs

Long-Acting Beta Agonist drugs (LABAs) are for the maintenance of bronchodilation in patients with Asthma and COPD. They are also called “maintenance” drugs or “controllers.” The two categories that you hear most often are rescue drugs and controllers. LABA’s are maintenance-type drugs to keep the patient out of the emergency room or the hospital with acute exacerbations. Figure 2 shows the examples of Long-Acting Beta Agonist drugs and device delivery.

Figure 2. Long-Acting Beta Agonist Drugs and device delivery.

Long-Acting Beta Agonist drugs are an important class of drugs that we use as respiratory therapists. Usually, LABA's are given for maintenance therapy as a dry powder inhaler (DPI) or small volume nebulizer (SVN). Remember, when you give a patient a DPI, their inspiratory flow rate must be adequate to get the powder down far enough in their lungs to take effect. You do not want the powder in the back of their throat because it will not reach the lungs in order for the drug to take effect. Keep that in mind when delivering specific types of drugs to your patients.

Long-Acting Beta Agonist Drugs: Onset and Duration

Most LABA’s have a short onset, but their duration lasts longer about 12 to 24 hours.  We know drugs have side effects. A longer duration can be a good thing for a maintenance type drug. If you can give a patient a drug that lasts longer, there is a better chance of diminishing the side effects.

Corticosteroids

Corticosteroids are given for maintenance and control therapy in chronic persistent Asthma. Corticosteroids help patients with increased inflammation in the airway and are given for chronic disease management, not for an acute situation or exacerbation. An example of an oral steroid is Prednisone. Clinical research shows during an acute Asthma attack, bronchoconstriction and inflammation are present. Your body sends different types of fighting mechanisms to what it perceives to be an injured area, but in turn, causing increased inflammation in an area where there is already inflammation occurring. It is imperative to know when you have inflammation in your airway, it means you cannot breathe as well as you should because you cannot get airflow in. Examples of aerosolized corticosteroids are as follows in Figure 3.

Figure 3. Aerosolized Corticosteroids and device delivery.

We have different brand names, and most are delivered as metered-dose inhalers (MDI). Take note many steroidal medicines have side effects. We have Beclomethasone, also called Qvar, which is a metered-dose inhaler. Aerospan is the brand name for Flunisolide and Flovent is the brand name for Fluticasone. Budesonide is Pulmicort. Mometasone is also known as Nasonex, and Ciclesonide is Alvesco. We can give Budesonide in what we call Respules, and administer it in a small volume nebulizer.  Although you cannot administer many steroids in a small volume nebulizer, Pulmicort Respules is an exception.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are indicated for maintenance and control of chronic persistent Asthma. We aim to use NSAIDs over steroids. Corticosteroids have a long list of side effects. We can use NSAIDs with steroids to reduce the dosage, but it is better to replace the steroids whenever possible. When feasible, we try to use a substitute with the same properties, helping the patient control inflammation without the various side effects of corticosteroids. When we give patients external steroids, the body will stop producing its own steroids. NSAIDs block many different types of inflammatory properties. Categories of NSAIDs are cromolyn-like agents, antileukotriene agents, and monoclonal antibodies.

Categories of NSAIDs

• Cromolyn-like agents
• Antileukotriene
• Monoclonal antibodies

Cromolyn-Like Agents

Cromolyn-like agents are called mast cell stabilizers. The mast cell contains anti-inflammatory or inflammatory agents that go to the lungs to help out what it perceives as danger. However, when the mast cells go to specific areas, it causes more inflammation. The cromolyn-like agents keep the mast cell intact by stabilizing those cells in the body. The primary cromolyn-like agent is called Cromolyn Sodium. The drug agent can eliminate some inflammation in patients with Asthma, and it can be an alternative to low-dose corticosteroid therapy. Cromolyn Sodium is administered orally or by a small volume nebulizer. For respiratory therapists, giving the drug agent using a small volume nebulizer is typical instead of administering a drug agent orally. When Cromolyn Sodium is administered orally, the drug routes through the stomach lining and lipid layers to take effect. When we administer the Cromolyn Sodium by a small volume nebulizer, the drug travels directly contacting the lungs and helps alleviate the inflammation. Most of the time, we will give these drugs in combination with steroids to reduce the overall dose of steroids. Keep in mind, the benefit of this category of drugs we are discussing, and anytime we can use the drug agents to help with inflammation, we should.

Antileukotrienes

Antileukotrienes drug agents block the release of leukotriene, which is a form of inflammation in Asthma. Leukotrienes consist of fatty acids, and when those fatty acids go to the specific area of inflammation, it creates a problem. For example, during bronchoconstriction, the body senses something and sends leukotrienes to the inflamed area to help, but this action creates further inflammation in an already aggravated area. Antileukotrienes not only protect the fatty acids but is a potent bronchodilator. We will continue to hear more about antileukotrienes as we are starting to discover the causes of inflammation in current research.

Monoclonal Antibodies

You may have heard about monoclonal antibodies when talking about COVID-19 patients. The monoclonal antibodies are administered in patients with COVID-19 to treat inflammation around the heart. Immunoglobulins are classified into five categories: IgA, IgD, IgE, IgG, and IgM. Immunoglobulin IgG mainly blocks the "G" antibodies. When the body releases the IgG antibodies, it goes to the lungs and causes inflammation. Typically, the monoclonal antibodies are used to treat severe Asthma inflammation in the lungs by controlling the IgG antibodies.

What Are Some Examples of Monoclonal Antibodies?

• Omalizumab
• Benralizumab
• Mepolizumab
• Reslizumab
• Dupilumab

There are several monoclonal antibodies available. Let's look at Mepolizumab and Dupilumab. Mepolizumab (Nucala) and Dupilumab (Dupixent) are both injections. It is given subcutaneous every two to four weeks.  Patients may receive a dose of monoclonal antibiotics every 30 days to protect them from the IgG antibodies and inflammation. As a result, patients have weaned off the use of steroids. It is important to note the monthly monoclonal antibody injections help the patients have fewer complications than steroids.

Anti-cholinergic

When given by themselves, an anti-cholinergic bronchodilator is considered a maintenance treatment for patients with both COPD and Asthma.  Atrovent, an anti-cholinergic drug, can be given to a patient with COPD because it is not categorized as a rescue drug but as a maintenance drug. Both anti-cholinergic and Beta-2 Agonist drugs can be administered together. Primarily, anti-cholinergics  are the maintenance drug of choice.

What Are Some Examples of Anti-Cholinergic Drugs?

• Ipratropium bromide – Atrovent
• Tiotropium bromide – Spiriva
• Aclidinium bromide - Pressair
• Glycopyrrolate – Robinul

Remember that anti-cholinergic drugs block the parasympathetic system, which will cause bronchodilation. That is why these drugs can be used in combination with sympathetic drugs. When administered along with a bronchodilator, you have bronchodilation on one side and constriction on the other, which we call synergy, two drugs that make one drug work better. That is why these drugs can be used in combination with sympathetic drugs like Beta-2 Agonist, e.g., Albuterol.  The MDI form is called Combivent, and when provided by a small volume nebulizer, it is known as Duoneb. It is the same drug agents provided in different forms of delivery.

Xanthines

Although sometimes questionable, Xanthines have been clinically used to treat 1) Asthma as the third line of treatment 2) COPD 3) the treatment of Apnea of Prematurity in newborns. When giving Xanthines, we have to make sure it is not a rescue drug but "adding on" to better support bronchodilation. The drugs that you are going to see most commonly are listed below. Methylxanthines is a derivative of Xanthines that consist of the following drugs used for clinical respiratory purposes:

• Theophylline
• Caffeine
• Theobromine

Theophylline

Theophylline is used to treat Asthma because of its bronchodilator effects. Although not as strong as a Beta-2 Agonist, it can be a good supplement. It also has anti-inflammatory properties. Theophylline can be used to help stimulate the respiratory drive in patients with COPD.  It is an excellent drug agent to have on hand when patients with COPD use accessory muscles for breathing, they often get tired. We can eliminate some of that accessory muscle use by using Theophylline. Theophylline can help strengthen the diaphragm, a major muscle for breathing. Theophylline comes in two forms, Theo-Dur tablets or Aminophylline drip IV. 

Caffeine

Caffeine can help stimulate the breathing of infants who have Apnea of Prematurity. When born prematurely, infants have apneic episodes, which means they stop breathing from time to time. We can give Caffeine Citrate to help stimulate an infant's breathing when an apneic episode occurs. Usually hanging on an IV bag, a Caffeine Citrate drip is provided over time, according to how many apneic episodes the baby has. 

Theobromine

Theobromine has bronchodilation effects often used in pediatrics. The research shows it seems to work better on children than adults. We tend to use it to help with their Asthma episodes, along with the other drug combinations. We give them different types of Beta Agonist drugs, along with Theobromine. We try to stay away from the steroids, but sometimes we have to give corticosteroids as well. It is a drug known to help with bronchodilation by relieving bronchoconstriction.

Toxic Levels

An important thing to remember is high levels of Theophylline can be toxic. When we give Theophylline, we have to check the serum in the blood because if it becomes elevated, past what we call a therapeutic level, the effects can be toxic. Normally, the average levels are between 10 - 20. When it starts to increase over the average level, it can cause problems. We have seen patients with high levels of Theophylline undetected in the blood given Theophylline type drugs. Adversely, high levels of Theophylline cause patients to have seizures and can lead to a critical situation for the patient. Before the doctor orders Theophylline, it is crucial they check the Aminophylline and Theophylline levels by drawing blood and checking the levels. If the levels are within the therapeutic level, we can safely administer Theophylline to help with difficulty breathing. Note when a patient cannot breathe, everything goes out the window. We need to try everything we can, but with caution, especially with the use of Theophylline.

Mucus Controlling Drugs

Let's talk about mucus-controlling drugs. We call them mucoactive drugs which are indicated for patients with thick tenacious secretions after infection control measures are complete. Patients with bacterial infections will accumulate multitudinous secretions. Although this is not the only population, note the significance of their secretions and what we need to do to control mucus production. First, we have to control what is causing the patient to produce mucus e.g., the bacteria. Second, we start the mucoactive agents to cause the mucus to thin out but not altogether remove the mucus completely. 

Mucoactive Drug Uses

Mucoactive agents are used for patients with chronic bronchitis, Cystic Fibrosis, bronchiectasis, Asthma- all of which will have increased secretions. For example, bronchiectasis is a disease that accumulates an extreme amount of secretions, so much so that it separates into three different layers. Patients with these illnesses have difficulty breathing because of the increase in airway resistance. If the quantity of secretions is high within the airway, it will block the flow of air that is trying to get in the airway, which would decrease the patient's tidal volume. Breathing will be difficult. Our goal is to try to clear some of the excess secretions for ease of breathing. The best way is to make the mucus thin enough for the patient to cough it up or suction it out. 

What Are Some Examples of Mucoactive Agents?

• Acetylcysteine 10% or 20% solution  
• Dornase Alfa
• Saline
• Mannitol

Acetylcysteine comes in 10% and 20% solutions and is delivered in a small volume nebulizer. Acetylcysteine is combined with a bronchodilator because if given by itself, it causes bronchoconstriction. Dornase alfa is utilized for patients with Cystic Fibrosis, an inherited disease. Usually, Mannitol is given to patients with head injuries but can also be applied as a mucoactive thinning agent, and the same goes for saline.

Surfactants

We use the term surface tension in respiratory because the definition of surface tension- is the pressure trying to collapse a bubble. Natural surfactants are produced in the body to reduce the surface tension in the lungs. Premature infants are often delivered before surfactant production has taken place naturally. When an infant is born premature, before 28 weeks gestation, there is not enough time for surfactant production in utero. In cases where this happens, we administer surfactant medications. Exogenous or artificial surfactants are indicated for infants with respiratory distress syndrome (RDS). When an infant is born prematurely, the job of the surfactant is to try to break the surface tension by keeping the lungs open so it is easier to ventilate. When we provide the infant with artificial surfactants, the infant can breathe in oxygen and exchange carbon dioxide, generally like a full-term.

What Are Some Examples of Surfactants?

• Beractant (Survanta)
• Calfactant (Infasurf)
• Poractant Alfa (Curosurf)

All surfactant drug agents use the "surf" suffix. It lets us know we are talking about surfactant-type medication.  Examples of surfactant medications like Beractant, Calfactant, Poractant Alfa are given via direct tracheal instillation. The patient is usually intubated and has an endotracheal tube in place during artificial surfactant administration. We can bag-mask ventilate or use the ventilator with a side port to instill the medication. We must administer the medicine directly to the lungs, including saturating all the lobes with the surfactant. Very important to remember, and we need to be careful when doing so. 

Hazards and Complications

• Airway occlusion
• Desaturation
• Bradycardia
• High arterial oxygen values
• Overventilation
• Hypocapnia
• Apnea
• Pulmonary hemorrhage

There are some hazards and complications with giving surfactants.  Think about an airway or endotracheal tube size for a neonate or preemie. It is extremely small, and we have to be careful about airway occlusion. Placing the surfactant medication into the endotracheal tube may cause occlusion of the airway, increasing airway resistance, desaturation, or bradycardic episodes. High arterial oxygen values can occur because of all the surfactant medication placed. Too much oxygen for newborns can cause blindness. We have to remember that our oxygen concentrates on the ventilator have to be reduced quickly to counteract this effect.  Hypocapnia, apnea, and pulmonary hemorrhage are other complications that we must be aware of when we instill artificial surfactants. Once we start opening up the lung, we start to ventilate more. We have to make sure that the ABGs are within acceptable limits to keep from over ventilating the infant. Surfactant medications require considerable attention.

Nitric Oxide (NO)

Nitric Oxide (NO) therapy is indicated for persistent pulmonary hypertension (PPHN) in newborns. Nitric oxide is an inhaled gas, a vasodilator. It penetrates the lower airways, reaches the lungs, and causes vasodilation of the blood vessels. Consequently, decreasing pulmonary arterial pressure and increasing oxygenation status. Additionally, vasodilation in the lungs improves perfusion and helps to correct ventilation-perfusion (VQ) mismatch in infants. In a related situation, patients with specific heart conditions are given nitro patches in the same family of NO, including Nitric and Nitroglycerin, to improve blood flow to and from the heart. Always confirm when the doctor orders NO, the situation, and the goals. Currently, there are ongoing studies on Nitric Oxide for approval on Acute Respiratory Distress Syndrome (ARDS) in adults.

How Is It Used?                                       

Various Nitric oxide delivery devices are available. There are several different systems and different manufacturers, including tankless applications. We call it inhaled Nitric Oxide (INO) therapy. Tankless devices have a built-in application, and it is easier to transport the patient to and from different procedures without worrying about changing out tanks. The device can be set to deliver the standard dosage recommended, which is 20 parts per million. 

Contraindications and Precautions

There are some contraindications and precautions with Nitric Oxide therapy. Nitric Oxide should not be administered to neonates who are known to have a right to left shunt. INO is contraindicated in infants with a right to left shunting of blood. Right to left shunting is associated with congenital heart diseases such as Hypoplastic Left Heart Syndrome or an interrupted aortic arch. INO may adversely increase the risk of embolism and clots traveling to the brain in neonates who have right to left shunting. Obtaining an echocardiogram before INO therapy is critical to document diagnosis of PPHN, shunting, and rule out congenital heart diseases.

Neuromuscular Blocking Agents (NMBAs)

Some indications for neuromuscular blocking agents (NMBAs) involve providing muscle paralysis during surgery, during endotracheal intubation, and when a patient is on mechanical ventilation. The closed head injury population can quickly become agitated with increased movements, leading to higher intracranial pressures (ICP) and complications. We administer NMBAs to assist in paralyzing muscle movements to maintain acceptable ICP pressures. Besides closed head injuries, trauma patients can also develop epileptic seizures that consume high oxygen amounts. The use of NMBAs reduces the patient's oxygen consumption during such seizures.

Types of Neuromuscular Blocking Agents

• Depolarizing
  • Succinylcholine
• Nondepolarizing
  • Vecuronium
  • Pancuronium
  • Rocuronium
  • Atracurium
  • Cisatracurium
  • Mivacurium

There are different types of neuromuscular blocking agents. NMBAs are categorized into two categories, depolarizing and nondepolarizing. Note that some NMBAs can cross the blood-brain barrier or are reversible, but others are not. There is only one depolarizing agent, Succinylcholine.  Succinylcholine crosses the blood-brain barrier. It has a shorter onset and duration, which makes it ideal for intubation. The nondepolarizing agents do not cross the blood-brain barrier and have a more prolonged onset and duration. Nondepolarizing agents are practical for long-term use and are reversible. When we use a depolarizing agent for patients in surgery or on the mechanical ventilator, we can also deliver a nondepolarizing agent for long-term needs. Then when the patient is ready to wake up, we can administer the appropriate drug agent to reverse the effects.

When Do We Use Neuromuscular Blocking Agents?

Most patients in the ICU are on nondepolarizing drugs, usually on a drip, as they may have multiple things going on. Because a neuromuscular blocking agent only paralyzes the muscles, patients can still feel pain. Therefore, we need to remember that an analgesic or sedation must also be administered along with the neuromuscular blocking agents.  When patients are ready to wean off the ventilator, they require tapering off both NMBAs and sedation medications.

Summary

Final thoughts as respiratory therapists, we go beyond just basic bronchodilator therapy. We know many other therapies are involved, and inflammation is a big part of what we treat. Furthermore, we can provide patient education on drug alternatives when we start administering steroids, especially for patients dependent on long-term steroidal use. The primary goal is to reduce long-term dependency on steroids. The drug categories discussed today provide a great "maintenance type" situation for our patients. There are commercials on television talking about several different types of respiratory drug agents. Consider this as the "new wave of the future," striving to combat inflammation as part of a patient's "breathing problems." If inflammation is controlled, there is a higher chance of keeping patients out of the hospitals. Of course, some patients will still have acute exacerbations, but once we establish the cause, we can focus on the maintenance side of these drugs. We can help reduce their hospitalizations and length of stay.

When talking to the family members about treatments and ways to help them, start mentioning the different drug agents for respiratory care. Make sure to stay abreast of the various newer drugs coming out. We may have to keep updating this type of presentation to keep up with changes in respiratory drug agents. Our knowledge base will continue to improve as new drugs are certainly continuing to be developed. We did not mention all of the categories but primarily focused on the mainstream respiratory drugs and how the lungs operate with these various drug agents. 

References

Walker, J. K., Penn, R. B., Hanania, N. A., Dickey, B. F., & Bond, R. A. (2011). New perspectives regarding β(2) -adrenoceptor ligands in the treatment of Asthma. British journal of pharmacology, 163(1), 18–28. https://doi.org/10.1111/j.1476-5381.2010.01178.x

Welhengama, C., Hall, A., & Hunter, J. M. (2021). Neuromuscular blocking drugs in the critically ill. BJA Education, 21(7), 258–263. https://doi.org/10.1016/j.bjae.2021.02.002.