This course presents you with a general overview of the principles of pharmacology and the mechanisms and effects of cardiovascular and respiratory drugs. While the focus is predominantly on disorders of the pulmonary system, the inter-relatedness of the two systems requires a review of the medications focused on heart problems. Since the respiratory system cannot be disassociated from cardiac and vascular systems, cardiovascular-respiratory pharmacology necessarily involves a relatively broad scope of drug classes.

Nurses are on the front lines in administering drugs that are specifically designed to treat the so-called pathological triad of pulmonary disease: bronchospasm, airway inflammation, and retained secretions. Their front line arsenal for treating cardio-pulmonary diseases includes bronchodilators, antimuscarinics, corticosteroids, mucokinetics, mucolytics, and decongestants. There are also a variety of other agents available for treating pulmonary ailments, including: oxygen, antibiotics, local anesthetics, respiratory stimulants, and muscle relaxants. Because of the inter-connectedness of the body systems, additional groups of drugs that may be administered to patients with respiratory diseases include: anti-infectives, CNS drugs, antiarrhythmic agents, anticoagulants, antihypertensives, and diuretics.

The course includes lengthy explanations of the uses for aerosol therapy, nebulizers, and humidifiers. Therapeutic procedures and medication functions are reviewed and you will learn about the broad categories of medications used, subgroups of medications, read articles published about those medications, and, finally, learn about some of the equipment used to deliver medications to patients. The resources drawn upon for the following material can be found in the References section at the end of the course.

Upon successful completion of this course, you will be able to:

• List the general categories of medications used to treat cardio-pulmonary disorders.
• Identify indications, contradictions, and possible side effects of four of these most commonly prescribed medications.
• Explain the functions of the various types of equipment used to deliver some of these medications
• Cite the clinical practice guidelines for selecting and using equipment to deliver medications.

Introduction

Before we begin reviewing the medications used to treat respiratory (and cardio-respiratory) problems, we believe it would be good to first present you with a brief review of the respiratory system:

a. Respiration. Respiration is the exchange of gases between the atmosphere and the cells of the body. It is a physiological process. There are two types of respiration-external and internal. External respiration is the exchange of gases between the air in the lungs and blood. Internal respiration is the exchange of gases between the blood and the individual cells of the body.

b. Breathing. Breathing is the process that moves air into and out of the lungs. It is a mechanical process. There are two types of breathing in humans--costal (thoracic) and diaphragmatic (abdominal). In costal breathing, the major structure causing the movement of the air is the rib cage. In diaphragmatic breathing, interaction between the diaphragm and the abdominal wall causes the air to move into and out of the lungs.

1-2. COMPONENTS AND SUBDIVISIONS OF THE HUMAN RESPIRATORY SYSTEM

See Figure 1-1 for an illustration of the human respiratory system.

a. Components. The components of the human respiratory system consist of air passageways and two lungs. Air moves from the outside of the body into tiny sacs in the lungs called alveoli (pronounced al-VE-oh-lie).

b. Main Subdivisions. The main subdivisions of the respiratory system may be identified by their relationship to the voice box or larynx. Thus, the main subdivisions are as follows:

Figure 1-1. The human respiratory system.

1-3. SUPRALARYNGEAL STRUCTURES

a. External Nose. The external nose is the portion projecting from the face. Primarily cartilages support it. It has a midline divider called the nasal septum, which extends from the internal nose. Paired openings (nostrils lead to paired spaces (vestibules). Guard hairs in the nostrils filter inflowing air.

Figure 1-2. Supralaryngeal structures.

b. Nasal Chambers (Internal Nose). Behind each vestibule of the external nose is a nasal chamber. The two nasal chambers together form the internal nose. These chambers too are separated by the nasal septum.

1. Mucoperiosteum. The walls of the nasal chambers are lined with a thick mucous-type membrane known as the mucoperiosteum. It has a ciliated epithelial surface and a rich blood supply, which provides warmth and moisture. At times, it may become quite swollen.
   CILIATED = Provided with cilia (hair like projections that move fluids to the rear)
2. Conchae. The lateral wall of each chamber has three scroll-like extensions into the nasal chamber, which help to increase the surface area exposed to the inflowing air. These scroll-like extensions are known as conchae.
   CONCHA =sea shell CONCHA (singular), CONCHAE (plural) (pronounced KON -kah)
3. Olfactory epithelium. The sense of smell is because of special nerve endings located in the upper areas of the nasal chambers. The epithelium containing the sensory endings is known as the olfactory epithelium.
4. Paranasal sinuses. There are air "cells" or cavities in the skull known as paranasal sinuses. The paranasal sinuses are connected with the nasal chambers and are lined with the same ciliated mucoperiosteum. Thus, these sinuses are extensions of the nasal chambers into the skull bones. For this reason, they are known as paranasal sinuses.

c. Pharynx. The pharynx (FAIR-inks) is the common posterior space for the respiratory and digestive systems.

1. Nasopharynx. That portion of the pharynx specifically related to the respiratory system is the nasopharynx. It is the portion of the pharynx above the soft palate. The two posterior openings (nares) of the nasal chambers lead into the single space of the nasopharynx. The auditory (eustachian) tubes also open into the nasopharynx. The auditory tubes connect the nasopharynx with the middle ears (to equalize the pressure between the outside and inside of the eardrum). Lying in the upper posterior wall of the nasopharynx are the pharyngeal tonsils (adenoids). The soft palate floor of the nasopharynx is a trap door that closes off the upper respiratory passageways during swallowing.
2. Oropharynx. The portion of the pharynx closely related to the digestive system is the oropharynx. It is the portion of the pharynx below the soft palate and above the upper edge of the epiglottis. (The epiglottis is the flap that prevents food from entering the larynx (discussed below) during swallowing.) (3) Laryngopharynx. That portion of the pharynx that is common to the respiratory a digestive systems is the laryngopharynx. It is the portion of the pharynx below the upper edge of the epiglottis. Thus, the digestive and respiratory systems lead into it from above, and lead off from it below.

1-4. LARYNX

The larynx, also called the Adam’s apple or voice box, connects the pharynx with the trachea. The larynx, located in the anterior neck region, has a box-like shape. See Figure 1-3 for an illustration. Since the voice box of the male becomes larger and heavier during puberty, the voice deepens. The adult male’s voice box tends to be located lower in the neck; in the female, the larynx remains higher and smaller and the voice is of a higher pitch.

Figure 1-3. The larynx.

a. Parts and Spaces. The larynx has a vestibule ("entrance hallway") that can be covered over by the epiglottis. The glottis itself is the hole between the vocal cords. Through the glottis, air passes from the vestibule into the main chamber of the larynx (below the cords) and then into the trachea. The skeleton of the larynx is made up of a series of carti1ages.

b. Muscles. The larynx serves two functions and there are two sets of muscles- -one for each function.

1. One set controls the size of the glottis. Thus, it regulates the volume of air passing through the trachea.
2. The other set controls the tension of the vocal cords. Thus, it produces vibrations of selected frequencies (variations in pitch) of the moving air to be used in the process of speaking.

1-5. INFRALARYNGEAL STRUCTURES

a. Trachea and Bronchi. The respiratory tree (Figure 1-4) is the set of tubular structures that carry the air from the larynx to the alveoli of the lungs. Looking at a person UPSIDE DOWN, the trachea is the trunk of the tree and the bronchi are the branches. These tubular parts are held open (made patent) by rings of cartilage. Their lining is ciliated to remove mucus and other materials that get into the passageway.

b. Alveoli. The alveoli (alveolus, singular) are tiny spherical (balloon-like) sacs that are connected to the larger tubes of the lungs by tiny tubes known as alveolar ducts and bronchioles. The alveoli are so small that there are millions in the adult lungs. This very small size produces a maximum surface area through which external respiration takes place. External respiration is the actual exchange of gases between the air in the alveolar spaces and the adjacent blood capillaries through their walls.

c. Lungs. A lung is an individual organ composed of tubular structures and alveoli, bound together by fibrous connective tissue (FCT). In the human, there are two lungs, right and left. Each lung is supplied by a primary or mainstem bronchus leading off from the trachea. The right lung is larger in volume than the left lung. The left lung must leave room for the heart. The right lung is divided into 3 pulmonary lobes (upper, middle and lower) and 10 bronchopulmonary segments (2 + 3 + 5). The left lung is divided into 2 pulmonary lobes upper and lower) and 8 bronchopulmonary segments (4 + 4). A pulmonary lobe is a major subdivision of a lung marked by fissures (deep folds. Each lobe is further partitioned into bronchopulmonary segments. Each lobe is supplied by a secondary or lobar bronchus. A tertiary or segmental bronchus, a branch of the lobar bronchus supplies each segment.

d. Pleural Cavities. Each serous cavity has inner and outer membranes. In the case of the lungs, the inner membrane, is known as the visceral pleura which very closely covers the surface of the lungs. The outer membrane is known as the parietal pleura, forming the outer wall of the space. The pleural spaces are the potential spaces between the inner and outer membranes. The opening between the pleural layers contains a slick fluid called pleural fluid. The pleural fluid serves as a lubricant and allows the lungs to move freely with a minimum of friction.

Figure 1-4. Infralaryngeal structures.

1-6. INTRODUCTION

a. Boyle’s law tells us that as the volume (V) of a gas-filled container increases, the pressure (P) inside decreases; as the volume (V) of a closed container decreases, the pressure (P) inside increases. When two connected spaces of air have different pressures, the air moves from the space with greater pressure to the one with lesser pressure. In regard to breathing, we can consider the air pressure around the human body to be constant. The pressure inside the lungs may be greater or less than the pressure outside the body. Thus, a greater internal pressure causes air to flow out; a greater external pressure causes air to flow in.

b. We can compare the human trunk to a hollow cylinder. This cylinder is divided into upper and lower cavities by the diaphragm. The upper is the thoracic cavity and is essentially gas-filled. The lower is the abdominopelvic cavity and is essentially water-filled.

1-7. COSTAL (THORACIC) BREATHING

a. Inhalation. Muscles attached to the thoracic cage raise the rib cage. A typical rib might be compared to a bucket handle, attached at one end to the sternum (breastbone) and at the other end to the vertebral column. The "bucket handle" is lifted by the overall movement upward and outward of the rib cage. These movements increase the thoracic diameters from right to left (transverse) and from front to back (A-P). Thus, the intrathoracic volume increases. Recalling Boyle’s law, the increase in volume leads to a decrease in pressure. The air-pressure outside the body then forces air into the lungs and inflates them.

b. Exhalation. The rib cage movements and pressure relationships are reversed for exhalation. Thus, intrathoracic volume decreases. The intrathoracic pressure increases and forces air outside the body.

1-8. DIAPHRAGMATIC (ABDOMINAL) BREATHING

The diaphragm is a thin, but strong, dome-shaped muscular membrane that separates the abdominal and thoracic cavities. The abdominal wall is elastic in nature. The abdominal cavity is filled with soft, watery tissues.

a. Inhalation. As the diaphragm contracts, the dome flattens and the diaphragm descends. This increases the depth (vertical diameter) of the thoracic cavity and thus increases its volume. This decreases air pressure within the thoracic cavity. The greater air pressure outside the body then forces air into the lungs.

b. Exhalation. As the diaphragm relaxes, the elastic abdominal wall forces the diaphragm back up by pushing the watery tissues of the abdomen against the underside of the relaxed diaphragm. The dome extends upward. The process of inhalation is thus reversed.

1-9. INTRODUCTION

Many conditions affect the respiratory system. Some of the conditions are life-threatening, while many are chronic conditions which affect thousands of patients. Many of the patients who suffer from these conditions will be standing in front of the outpatient pharmacy in order to receive prescriptions to obtain some relief.

1-10. PNEUMONIA

Pneumonia is caused by an infection of the lung. This infection is caused by either bacteria (like the pneumococcus bacterium) or viruses. In pneumonia the walls of the alveoli become inflamed and filled with fluid and the air spaces in the alveoli become filled with blood and fluid.
As you might expect, the exchange of gases in the alveoli becomes impaired. Death can result from pneumonia.

1-11. ASTHMA

Asthma, a condition usually caused by allergic reactions to substances in the environment, affects many people. The allergic reactions cause the bronchioles to spasm. Hence, the flow of air into and out of the lungs becomes impaired. For some unknown reason, the flow of air out of the lungs is more impeded than the flow of air into the lungs. Hence, the person with asthma often finds it more difficult to expire (expel the air) than to inspire. Furthermore, such labored breathing, after many years, often results in the asthma-sufferer having a barrel-shaped chest.

1-12. STATUS ASTHMATICUS

Status asthmaticus is a very sudden, continuous, and intense asthmatic attack.

1-13. EMPHYSEMA

Emphysema is a condition in which the patient has large portions of the alveolar walls destroyed. Consequently, the patient finds it necessary to breathe faster and more deeply in order to obtain the oxygen needed to live. Emphysema is often associated with smoking. Emphysema may also be referred to as Chronic Obstructive Pulmonary Disease (COPD).

1-14. PULMONARY EDEMA

Pulmonary edema is a condition in which fluid collects in the interstitial spaces of the lungs and in the alveoli. Obviously, the exchange of gases in the alveoli becomes impaired. Pulmonary edema is usually caused when the left side of the heart fails to pump efficiently; when this happens blood backs up into the pulmonary circulation and causes fluid in the lungs.

Pharmacology involves the study of drugs, and drugs are defined as chemical substances that exert a biologic effect on the recipient. Medical drugs are used for the treatment or prevention of disease, and drugs are considered useful when they can maintain, enhance or alter bodily function when a patient is cannot cope with a particular disease. Pharmacology is concerned with the following:

• the chemical and physical properties of drugs
• the physiologic effects and site of action of drugs
• how drugs exert their effects
• how the body absorbs, distributes, metabolizes, and excretes the drugs
• dosages and routes of administration of drugs
• side effects, toxicity, and contraindications

The safe administration of drugs requires awareness of the following factors:

• mode of action
• side effects
• toxicity
• range of common dosages
• rate and route of excretion
• individual differences in responses
• interaction with other drugs or food
• contraindications

For drugs to exert their expected therapeutic benefits, they need to be made available for absorption in the body’s systems. Availability depends to a large extent on the route of administration of the drug. Drugs can be administered gastrointestinally, parenterally, or topically. Topical administration includes application to the skin and directly to the lungs by inhalation.

In order for a drug to be administered via inhalation, it must first either be vaporized or placed in an aerosol suspension. This generally requires the use of special equipment. The following discussion reviews the types of equipment available for administering drugs via inhalation.

In addition to activities related to gas exchange, the respiratory system is responsible for a variety of other vital functions. One function of the upper airway to assure that inspired gases are warmed and adequately humidified. Another function involves protecting the lungs by filtering inspired gas. RCPs need to understand basic concepts of humidification and aerosol systems in order to treat patients whose airway mechanisms are compromised.

Aerosol and humidity therapy are provided to maintain normal physiologic conditions and as therapy for pathologic conditions. One of the most important, but least understood, aspects of pulmonary care is the role of humidity therapy. Many care providers and most patients do not appreciate the role of hydration in liquifying secretions and facilitating the natural flow of mucus from the lower airways.

Pulmonary patients need adequate humidification of their inspired gases and controlled fluid balance, otherwise patients can become dehydrated. Dehydration can make secretions more viscous and inhibit the mucociliary escalator activity of the airways, making secretions difficult to dislodge. If this blocks functional gas flow through the distal airways, infections, atelectasis and other respiratory problems can easily occur.

Since humidification and humidity therapy are so important to respiratory well-being, you need to take a moment and review the basic physical principles of humidity. Humidity is essentially the water vapor in a gas. This water vapor can be described in several ways, as:

1. Absolute humidity -The actual content of water vapor in a gas measured in milligrams per liter.

2. Potential humidity -The maximum amount of water vapor a gas can hold at a given temperature.

3. Relative humidity -The amount of water vapor in a gas as compared to the maximum amount possible, expressed as a percentage.

When these three are presented in equation form, their relationship becomes more clear:
Relative Humidity = Absolute Humidity/Potential Water Vapor Content x 100

When a gas or air becomes heated, it expands and more spaces are created between the molecules. The resulting warmer gases have greater capacity for “holding” more water vapor than do cooler gases. Therefore, potential humidity increases as the temperature of a gas increases. As a result, warm, humidified gas traveling through tubing tends to “rain?out” water vapor as the gas cools and has a lower water?carrying capacity. The table below illustrates the relationship of temperature and potential humidity:

Water Vapor Content of Air

One of the more important gases found in air is water vapor. The amount of water vapor in the air can vary widely day-to-day, while gases like oxygen and nitrogen are present in relatively constant amounts. In general, water in vapor form is governed by gas laws and can be treated as a gas.

All bodies of water or moist organic bodies are capable of giving off water vapor. When water enters the air as a gas, the air’s humidity increases. The measure of how much water vapor is contained in the air is identified as the humidity level, and the factors determining the humidity include:

1. The availability of water. Clearly the air over a desert has less chance of picking up water vapor than the air over a lake.
2. Temperature is also a factor since the spacing of warmer air’s molecules allows water vapor’s molecules to fit more easily. Recalling the principles of Charles’ law, the volume of a gas increases as its temperature increases. If the number of molecules of the gases increases as the temperature rises, the humidity will not increase as much.

Summarizing, if there is water available there will be a specific amount of water vapor in the air at each ambient temperature. That amount equals the air’s total capacity for water vapor at that temperature. Air that contains its total capacity for water vapor at a specific temperature is said to be 100% saturated.

Amounts of water found in air are generally measured as grams per cubic meter of air (gm/ml) or as milligrams per liter of air (mg/1). These measurements can then be converted to moles of water by dividing by the gram molecular weight of water (which is 18). The total capacity of the air for water vapor is measured in milligrams per liter, with total capacity of the air for water vapor in milligrams per liter is referred to as the air’s potential water vapor. Table 1 identifies the various values of the potential water vapor content at several different temperatures.

THE POTENTIAL WATER VAPOR IS THE MAXIMUM THE AIR CAN HOLD AT A CERTAIN TEMPERATURE.

Air’s capacity for water cannot be met if there is not enough water available, and to discover the actual amount of water vapor present in the air it is necessary to measure the absolute humidity.

Relative humidity is another important measurement, and it represents the actual amount of water vapor in the air (absolute humidity) compared to the total possible water vapor content of the air at the given ambient temperature (potential water vapor). The measurement of relative humidity is expressed as a percentage (of saturation). For example, if the air contained only 17 mg/l of water vapor at 25°C, then it would not be totally saturated (see Table 1).

Calculating the relative humidity involves dividing the absolute humidity (actual water vapor content of the air) by the potential water vapor (maximum possible water vapor content of the air), and multiplying by 100 to convert the decimal percentage:
Relative Humidity = Absolute Humidity/Potential Water Vapor Content x 100

For the example above where the air had 17 mg/l of water vapor at 25°C:
Relative Humidity = 17/23 x 100
Therefore: Relative Humidity = 73.9%

Humidity Deficit

Another factor to consider is the humidity deficit. For example, if the atmosphere’s relative humidity is less than 100%, the air of the atmosphere has what is referred to as a humidity deficit. If outside air at 20°C has 14 mg/l of water vapor, and needs to have 17.3 mg/l to be fully saturated, it is said to have a primary humidity deficit of 3.3 mg/l. To calculate the primary humidity deficit simply subtract the absolute humidity of the air from its potential water vapor at the appropriate temperature and the difference between the two is the primary humidity deficit:

Primary Humidity Deficit = Potential Water Vapor Content - Actual Water Vapor Content

The secondary humidity deficit also needs to be considered. This is the moisture deficit in the inspired air that the nose and upper airway needs to compensate for. When air is breathed into the nasal cavity and heated to body temperature, its potential water vapor rises to 44 mg/l that is the potential water vapor content of air at 37°C.

Therefore, unless the air of the atmosphere is at least 37°C and fully saturated, there exists a moisture deficit. For example, if the atmosphere’s air was 98.6°F (37°C) and the relative humidity 100%, people in such conditions would be very hot and sweaty! Luckily, inspired air is generally not that warm or humid, so most inspired air does have a secondary humidity deficit.

The secondary humidity deficit is calculated by subtracting the absolute humidity of the air from the potential water vapor content. The difference from the calculations for primary humidity deficits is that the potential water vapor content is always 44 mg/l, the potential water vapor of air at body temperature:
Secondary Humidity Deficit = 44 mg/l - Absolute Humidity.

Therefore, if inspired air’s absolute humidity is 16 mg/l at 25°C before being warmed in the nasal cavity, there is a primary humidity deficit of:
Primary Humidity Deficit = 23 mg/l - 16 mg/l = 7 mg/l

For this same absolute humidity for the atmosphere, the secondary humidity deficit is
Secondary Humidity Deficit = 44 mg/l -16 mg/l = 28 mg/l

Here are some other calculations for you to consider:

If the absolute humidity of the same inspired air at 25°C were 23 mg/l, there would be no primary humidity deficit because the potential water vapor of air at 25°C is 23 mg/l (see Table above). There would still be a secondary humidity deficit of 21 mg/l because 44 mg/l minus 23 mg/l is 21 mg/l. This illustrates that at 100% relative humidity, it is still possible that the nasal cavity’s lining will have to supply moisture to the inspired air.

• You may sometime need to calculate a primary or secondary humidity deficit when you only know the relative humidity. To perform this calculation, you first need to convert the relative humidity into absolute humidity before calculating the humidity deficit. Remember the formula for relative humidity:
  Relative Humidity = Absolute Humidity/Potential Water Vapor Content x 100
  
  
• When the temperature and relative humidity are known, you can look up the potential water vapor for the air temperature by using the Table shown above. Then substitute into the above formula the values for relative humidity and potential water vapor and calculate the absolute humidity. For example, the relative humidity at 10°C is 75% for the air in the atmosphere. Using the Table, you can see that the potential water vapor content at 10°C is 9.5 mg/l, so:
  
  Relative Humidity = Absolute Humidity/Potential Water Vapor Content x 100
  
  Absolute Humidity = 7.125 mg/l

This measurement of the absolute humidity can be used to calculate the primary and secondary humidity deficits of the same air. At 10°C, we know that the potential water vapor content is 9.5 mg/l, so the primary humidity deficit is:

Primary Humidity Deficit = Potential Water Vapor Content - Absolute Humidity
9.5 -7.125 = 2.375 mg/l

The secondary humidity deficit for the same air would be:

Secondary Humidity Deficit = 44 - Absolute Humidity
44 -7.125 = 36.875 mg/l

To summarize:

· The primary humidity deficit occurs in the atmosphere and represents the difference between what humidity there is and what there could be.

· The secondary deficit occurs in the body and represents the difference between what humidity there is and what there needs to be at body temperature (37°C).

Water Vapor Correction

Since we’ve already ascertained that water vapor acts in most ways like any other gas, air creates a partial pressure when its in a mixture of gases.

That partial pressure depends on the amount of water vapor present, which in turn depends on the temperature. However, water vapor differs from the behavior of other gases in the air since changes in the barometric pressure of the atmosphere under normal conditions do not have much impact on the partial pressure of water.

As a result, it is best to calculate the partial pressures of the other gases in the air after the partial pressure of water vapor has been determined—especially when measuring the air within the lungs. Inside the lungs, the partial pressure of water vapor is approximately 47 mm Hg. This value is relatively constant because the air entering the lungs is normally saturated and at 37°C.

By subtracting the partial pressure of the water vapor from the total atmospheric pressure, you will find what is referred to as the dry gas pressure. In the lungs:

Dry Gas Pressure = Atmospheric Pressure - 47 mmHg

At one atmosphere (760 mmHg), the dry gas pressure would be:
Dry Gas Pressure = 760 -47 = 713 mmHg

As you have seen from the previous discussion, there are a number of reasons why humidity is an important aspect of the pulmonary system, including:

• It is needed to maintain normal bronchial hygiene
• It promotes functions of the normal mucociliary escalator
• It maintains the body’s vital homeostasis
• Without humidity the cleansing activities of the cilia could not function properly, and the nearly 100 ml of mucus secreted daily would become quite thick and tenacious.
• Without humidity the actual lung parenchyma would dry up, causing a loss of normal compliance which would restrict lung movement and reduce ventilation.

If normal use of the route of humidification and recapture of water were lost, problems would most certainly present themselves. If the upper airway were bypassed or dry gases were inhaled, a series of adverse reactions could occur, including:

• Impairment of ciliary activity
• Slowing of mucus movement
• Inflammatory changes and possible necrosis of pulmonary epithelium
• Retention of thick secretions and encrustation
• Bacterial infiltration of mucosa (bronchitis)
• Atelectasis
• Pneumonia

As a result of the importance of maintaining humidity, humidity and aerosol therapy are also important, and their general goals are to:

1. Promote bronchial hygiene
2. Loosen dried and/or thick secretions
3. Promote a effective coughs to clear secretions
4. Provide adequate humidity in the presence of an artificial airway
5. Deliver adequate humidity when administering dry gases therapies
6. Delivering prescribed medications

Clinical Evaluation of the Need for Humidity and/or Aerosol Use

There are a variety of factors to be considered when deciding to add humidity to dry gas therapies, including:

• patient’s age and ability to move normal secretions
• neuromuscular status
• recent or planned surgeries
• trauma
• disease conditions

The presence of any of these may impair the patient’s ability to cough and move secretions. Another problem may occur when patients develop very thick and abundant amounts of secretions that cannot be moved with normal muscle activity—making humidity or aerosol therapy necessary.

Indications for delivery of humidified gases and aerosols

Primary indications for humidifying inspired gases include:

• Administration of medical gases
• Delivery of gas to the bypassed upper airway
• Thick secretions in non-intubated patients

Additional indications for warming inspired gases:

• Hypothermia
• Reactive airway response to cold inspired gas

Primary indications for aerosol administration:

• Delivery of medication to the airway
• Sputum inductions

Sources of Mucus

Mucus generally comes from two sources: secretion from goblet cells and bronchial (mucous) glands. The goblet cells, which are distributed throughout the epithelium of the mucosa, synthesize and secrete mucus into the airway. The mucous glands, which are in the submucosa, are the greater source of mucus. Chronic irritation or disease can cause the number and size of goblet cells and mucous glands to increase, resulting in a larger and more viscous mucous blanket.

Effects of Mucous Layer

Ciliary activity, which moves the mucus, can be adversely affected if the mucous layer is changed. Changes in the ratio of gel to sol layer will affect the flow of mucus. A higher ratio, due either to a decrease in the watery sol layer or an increase in the viscous gel layer, could make the workload of the cilia too difficult to be effective. The cilia are capable of continuing to beat even if the workload increases, but only to a certain level. If the cilia become tangled in the thick mucus or are unable to penetrate the dense layer, the transport of the mucous blanket would stop, causing secretions to become retained in the respiratory tract.

Increases in the amount of watery sol fluid would also decrease the transport of mucus. The cilia must be able to extend through the sol layer to the gel layer to transport the mucus. Transport would be impaired if the thickness of the sol layer were to eliminate ciliary contact with the gel layer.

Other factors that can impede ciliary activity and the flow of mucus include:

• tobacco smoke
• local environmental conditions
• and pathology of the airway can impede clearance due to changes in the epithelium.

Humidification Devices

The effectiveness of humidifiers' ability to adequately supply vapor to a gas depends on three factors: temperature, surface area and time.

Temperature increases cause increases in vapor pressure and potential humidity. The greater the surface area of water/gas contact and the longer time this contact takes place, the greater the number of water molecules that can enter the gas mixture. These principles are used by humidifiers to provide increased relative humidity to the gas.

Blow-By Humidifier

Figure 1. The blow-by humidifier.

The purpose of humidifiers is to deliver a gas with a maximum amount of water vapor content. These humidifiers may be heated or unheated, and the factors affecting the efficiency of humidification devices include:

• temperature
• time of exposure between gas and water
• and the surface area involved in the gas/water contact

As temperature rises, the force exerted by the water molecules increases, enabling their escape into the gas, adding to the humidity. Longer exposure of a gas to the water increases the opportunity for the water molecules to evaporate during the humidifier’s operation.

The pass-over type humidifier directs a dry gas source over a water surface area, and flowing it to the patient. Because exposure area and time of contact is limited and it is not heated, this unit is not very efficient. These units are often used in incubators and in certain ventilators, although many times the use of a heated element is added to improve this humidification system.

Bubble Diffusion Humidifier

This type of system uses conduction to introduce the gas into the water below its surface. The gas passes through the liquid in the form of bubbles of various sizes. This is more effective because it increases exposure time and contact area. These units are called diffusers. The bubble or diffuser-type humidifiers are most commonly used.

The ability to hold water vapor falls as the temperature of gas falls, with room temperature’s relative humidity falling between 30 and 50%. Since a very low water content actually reaches the patient, this type of humidification is not recommended for patients with an endotracheal tube, tracheostomy or tenacious secretions. Gas flow through these humidifiers affects humidity. The higher the flow rate of a gas, the less the exposure time to the airway. These units function best at a flow rate of 2 liters/minute and should not be run at greater than 6 liters/minute.

Jet Humidifier

This type of humidifier actually forms an aerosol, but employs baffles to break the particles into small droplets, allowing them to evaporate. The gas is humidified further before it leaves the unit. The aerosol is formed by Bernoulli’s principle. A low pressure zone at the top of the water inlet tube draws water into the jet stream and the water is then aerosolized by the flow of gas.

Bernoulli’s principle is employed as follows: Gas flows into the chamber through a restricted orifice, causing a high velocity flow which passes across a capillary tube that is immersed in water. The pressure drops around the opening of the capillary tube and water is forced up the capillary tube. The jet stream of air blows the liquid off in small particles as it reaches the top of the capillary tube.

The jet humidifier produces a high humidity output by employing Bernoulli’s principle to form an aerosol and using baffles to break up the particles.

The underwater jet humidifier utilizes the principles of two other humidifiers: the bubble and the jet humidifiers. In the underwater jet, the restricted orifice and capillary tube are both below the surface of the water. The aerosolized gas then bubbles through the water, increasing surface area and water/gas contact time, increasing efficiency.

Heated Humidifier

These humidifiers are indicated when it is necessary to deliver a humidified gas directly to the tracheobronchial tree (for example if the patient has a tracheostomy tube or an intubation tube), bypassing the natural humidification and heating system (nasal pharyngeal route). The gas must be delivered at 100% relative humidity at body temperature.

These devices (like the Cascade humidifier) incorporate a bubble pass?over type of system. Gas is moved down a tower, passes through a grid that has a thin layer of water covering it and then over the warm water before being expelled out of the unit and more humidification takes place. This humidifier can deliver 100% relative humidity at various temperatures.

These humidifiers can go well above body temperature, creating the potential for tracheal burns or possible aspiration if tubing is not drained frequently. Wide bore tubing should always be used with these humidifiers, and be sure to humidify the gas during delivery.

Aerosols

It is important to remember that an aerosol is not the same as humidity. Humidity is water in a gas in molecular form, while an aerosol is liquid or solid particles suspended in a gas. Examples of aerosol particles can be seen everywhere: as pollen, spores, dust, smoke, smog, fog, mists, and viruses.

Aerosols can be created for therapeutic uses by physically shattering or shearing matter or liquid into small particles and dispersing them into a suspension. This can be accomplished by a variety of ways, including using gas jets, spinning disks, or ultra high frequency sound.

The particle size of an aerosol depends on the device used to generate it and the substance being aerosolized. Particles of this nature, between 0.005 and 50 microns, are considered an aerosol. The smaller the particle, the greater the chance it will be deposited in the tracheobronchial tree.

Particles between 2 and 5 microns are optimal in size for depositing in the bronchi, trachea and pharynx.

Aerosol therapy is designed to increase the water content delivered to the pulmonary tree, and to deliver drugs to this area. Deposition location is of vital concern, and factors that affect aerosol deposition are aerosol particle size and particle number.

Deposition of particles is also affected by:

• Gravity - Large particles are deposited before smaller particles; and gravity affects large particles more than small particles, causing them to rain-out.
• Viscosity - The viscosity of the carrier gas plays an important role in deposition. For example, if a gas like helium, which has a low viscosity and molecular weight, is used as a carrier gas, gravity will have more of an effect upon the aerosol. Helium is very light and hence can’t carry these particles well, leading to rain-out and early deposition.
• Kinetic activity - As aerosolized particles become smaller, they begin to exhibit the properties of a gas, including the phenomenon of “Brownian movement.” This random movement of these small (below l mm) particles causes them to collide with each other and the surfaces of the surrounding structures, causing their deposition. As particle size drops below 0.1m, they become more stable with less deposition and are exhaled.

Particle inertia - Affects larger particles which are less likely to follow a course or pattern of flow that is not in a straight line. As the tracheobronchial tree bifurcates, the course of gas flow is constantly changing, causing deposition of these large particles at the bifurcation.

• Composition or nature of the aerosol particles - Some particles absorb water, become large and rain-out, while others evaporate, become smaller and are conducted further into the respiratory tree. Hypertonic solutions absorb water from the respiratory tract, become larger and rain-out sooner. Hypotonic solutions tend to lose water through evaporation and are carried deeper into the respiratory tract for deposition. Isotonic solutions (0.9% NaCl) will remain fairly stable in size until they are deposited.
  
  Heating and humidifying - As aerosols enter a warm humidified gas stream, the particle size of these aerosols win increase due to the cooling of the gas in transit to the patient. This occurs because of the warm humidified gas cooling and depositing liquid (humidity) upon the aerosol particles through condensation.
  
  
• entilatory pattern - RCPs easily control this by simple observation and instruction. For maximum deposition, the patient must be instructed to:
  1. Take a slow, deep breath.
  2. Inhale through an open mouth (not through the nose).
  3. At the end of inspiration, use an inspiratory pause, if possible, to provide maximum deposition.
  4. Follow with a slow, complete exhalation through the mouth.

In many cases, aerosols are superior in terms of efficacy and safety to the same systemically administered drugs used to treat pulmonary disorders. Aerosols deliver a high concentration of the drugs with a minimum of systemic side effects. As a result, aerosol drug delivery has a high therapeutic index; especially since they can be delivered using small, large volume, and metered dose nebulizers.

Methods of Aerosol Delivery

Aerosols are produced in respiratory therapy by utilizing devices known as nebulizers. There are a variety of nebulizers in use today, but the most common is one in which the Bernoulli principle is used through a Venturi apparatus.

As discussed earlier, the Bernoulli principle states that when gas flows through a tube, it exerts a lateral wall pressure within that tube due to its velocity. As the gas reaches a smaller diameter in the tube, the velocity is increased, which decreases lateral wall pressure. This decrease in diameter within the tube is at a structure called a jet. Just distal to the jet is a capillary tube that is immersed in a body of fluid. The decreased pressure is transmitted to the capillary tube and fluid is drawn up it. When the fluid reaches the jet, it is then atomized.

The absolute humidity that will be delivered from these devices can be increased by the use of a heater. A baffle is distal to this atomization process in the stream of gas/fluid flow. Nebulization takes place here as the liquid is impelled against the baffle. This baffle causes the larger particles to coalesce and collect in the reservoir. The smaller particles will be delivered to the patient in aerosol form. If the baffle is not used, the device is known as an atomizer. When the baffle is used, it is then called a nebulizer. In addition to the physically placed baffle, any 90° angle to gas flow can be considered a baffle. Large bore corrugated tubing should be used with baffles. This will enable the aerosol particles to be delivered to the patient.

There are several ways to deliver aerosol therapy, and the modalities available today include:
1. Aerosol mask
2. Face tent
3. Mouthpiece
4. Aerosol tent (mist tent)
5. In conjunction with IPPB

Physician orders for aerosol therapy should contain identification of:
1. Type of aerosol
2. Source gas (FIO2)
3. Fluid composition (NaCl, water, etc.)
4. Delivery modality
5. Duration of therapy
6. Frequency of therapy
7. Temperature of the aerosol

When a prescribed aerosol therapy has been completed, be sure to chart your actions and observations, making sure to include the following information:

• time of administration
• duration of therapy
• type or composition of the aerosol (NaCl)
• pulse
• respiratory rate and pattern
• breath sounds
• characteristics of sputum
• if sputum was or was not produced
• the ease of breathing
• any benefits observed
• and any other relevant observations.

The reasons for administering aerosol therapies include:

1. For bronchial hygiene
   a) Hydrate dried secretions
   b) Promote cough
   c) Restore mucous blanket
2. Humidify inspired gas
3. Deliver prescribed medications
4. Induce sputum lab culture

Aerosol delivery is accomplished in a variety of ways:

• nasal spray pump
• metered-dose inhaler (MDI)
• dry powder inhaler (DPI)
• jet nebulizer
• small volume nebulizer (SVN)
• large volume nebulizer
• small-particle aerosol generator (SPAG)
• mainstream nebulizers
• ultrasonic nebulizer (USN)
• intermittent positive pressure breathing (IPPB) devices

Spray pumps are the most common devices used for nasal aerosol administration of: antiallergics, sympathomimetics, antimuscarinics, and anti-inflammatory drugs. The spray pump generates low internal pressure, and produces large particles that are well-targeted for nasal deposition.

Metered dose inhalers (MDIs) consist of a pressurized cartridge and a mouthpiece assembly. The cartridge, which contains from 150-300 doses of medication, delivers a pre-measured amount of the drug through the mouthpiece when the MDI is inverted and depressed.

One controversial problem with MDIs involves their use of chlorofluorocarbons (CFCs) which have been identified by scientists as culprits in causing the growing hole in the earth’s ozone layer, contributing to global warming and increased ultraviolet radiation. While the manufacture and importation of other sources of CFCs, like refrigerants, have been banned in the U.S. since 1996, the FDA exempted CFCs used in “medically essential” products like MDIs. Alternatives (such as hydrofluorocarbons—HFAs) to CFCs for use in MDIs have been discovered, and the FDA has already formulated plans for facilitating a transition from CFCs to alternatives like HFAs.

However, the FDA has stipulated that CFC-medications will not be phased out until:

• acceptable treatment alternatives exist for a particular MDI or other drug product so that the patient can find a product that meets his or her medical,
• the alternatives are marketed for at least one year and are acceptable by patients, and
• the supply of alternative products is sufficient to ensure that there will be no shortages of the drug.

Successful delivery of medications with an MDI depends on the patient’s ability to coordinate the actuation of the MDI at the beginning of inspiration. Patients need to be alert, cooperative, and capable of taking a coordinated, deep breath. Patients should be instructed to:

1. Be sure to shake the MDI canister well before using.
2. Hold the MDI a few centimeters from the open mouth.
3. Holding the mouthpiece pointed downwards, actuate the MDI at the beginning of a slow, deep inspiration, with a 4-10 second breath hold. Late actuation, or at the end of the inspiration, or stopping inhaling when the cold blast of propellant hits the back of the throat will cause the medication to have only a negligible effect.
4. Exhale through pursed-lips, breathing at a normal rate for a few moments before repeating the previous steps.
5. Patients should also be instructed to rinse their mouths after taking the medication.

After instructing the patient, the RCP should ask the patient to act out the procedure, observing to see if the patient has really understood the instructions. Proper instruction and observation of the patient are crucial to the success of MDI of therapy.

The particle size of the drug released is controlled by two factors: the vapor pressure of the propellant blend, and the diameter of the actuator’s opening. Particle size is reduced as vapor pressure increases, and as diameter size of the nozzle opening decreases. The majority of the active drug delivered by an MDI is contained in the larger particles, many of which are deposited in the pharynx and swallowed.

The advantages of MDI aerosol devices include:

• They are compact and portable.
• Drug delivery is efficient.
• Treatment time is short.
  
  On the other hand, the disadvantages of using MDIs to deliver aerosolize medications include:
  
  
• They require complex hand-breathing coordination.
• Drug concentrations are pre-set.
• Canister depletion is difficult to ascertain accurately.
• A small percentage of patients may experience adverse reactions to the propellants.
• There is high oropharyngeal impaction and loss if a spacer or reservoir device is not used.
• Aspiration of foreign objects from the mouthpiece can occur.

Pollutant CFCs, which are still being used in MDIs, are released into the environment until they can be replaced by non-CFC propellant material.

Extension or reservoir devices can be used to modify the aerosol discharged from an MDI. The purposes of these spacers or extensions include:

• Allow additional time and space for more vaporization of the propellants and evaporation of initially large particles to smaller sizes.
• Slow the high velocity of particles before they reach the oropharynx.
• As holding chambers for the aerosol cloud released, reservoir devices separate the actuation of the canister from the inhalation, simplifying the coordination required for successful use.

Dry powder inhalers (DPIs) consist of a unit dose formulation of a drug in a powder form, dispensed in a small MDI-sized apparatus for administration during inspiration. Because these devices are breath-actuated, using turbulent air flow from the inspiratory effort to power the creation of an aerosol of microfine particles of drug, they don’t require the hand-breath coordination needed with MDIs.

Cromolyn sodium and albuterol are the two primary drugs available in powder form. Cromolyn sodium is dispensed in a device called the Spinhaler, which pokes holes in capsules containing the powdered drug. The albuterol formulation is dispensed in a device called the Rotahaler, which cuts the capsule in half, dropping the powdered drug into a chamber for inhalation. In both cases, a single-dose micronized powder preparation of the drug in a gelatin capsule is inserted into the device prior to inhalation.

Powder flow properties in DPIs depend on particle size distribution, with very small particles not flowing as well as the larger ones. A third drug, budesonide, is available in a pre-loaded, multi-dose (up to 200 doses) DPI unit called a Turbuhaler. The advantages of using DPI devices for drug administration include:

• They are small and portable.
• Brief preparation and administration time.
• Breath-actuation eliminates dependence on patient’s hand-breath coordination, inspiratory hold, or head-tilt needed with MDI.
• CFC propellants are not used.
• There is not the cold effect from the freon used in MDIs, eliminating the likelihood of bronchoconstriction or inhibited inspiration.
• Calculation of remaining doses is easy.

The disadvantages encountered when relying on DPIs for drug administration include:

• Limited number of drugs available for DPI delivery at this time.
• Dose inhaled is not as obvious as it is with MDIs, causing patients to distrust that they’ve received a treatment.
• Potential adverse reaction to lactose or glucose carrier substance.
• Inspiratory flowrates of 60Lpm or higher are needed with the currently available cromolyn and albuterol formulations.
• Capsules must be loaded into the devices prior to use.

Small volume nebulizers (SVNs) are gas powered (pneumatic) and are a common method of aerosol delivery to inpatients, and there are a variety of different SVNs available. Each has specific characteristics, especially in regard to output. These nebulizers fall into two subcategories: mainstream and sidestream. The mainstream nebulizer is one in which the main flow of gas passes directly through the area of nebulization. The sidestream nebulizer is one in which the nebulized particles are injected into the main flow or stream of gas as with IPPB circuits. The main difference, based upon their construction, is that the larger particles tend to rain-out with a sidestream nebulizer.

The advantage of SVN therapy is that it requires very little patient coordination or breath holding, making it ideal for very young patients. It is also indicated for patients in acute distress, or in the presence of reduced inspiratory flows and volumes. Use of SVNs allows modification of drug concentration, and facilitates the aerosolization of almost any liquid drug.

Another advantage of a SVN is that dose delivery occurs over sixty to ninety breaths, rather than in one or two inhalations. Therefore, a single ineffective breath won’t ruin the efficacy of the treatment. Disadvantages of SVNs include:

• The equipment required for use is expensive and cumbersome.
• Treatment times are lengthy compared to other aerosol devices and routes of administration.
• Contamination is possible with inadequate cleaning.
• A wet, cold spray occurs with mask delivery.
• There is a need for an external power source (electricity or compressed gas).

In a 1990 study comparing the effectiveness of MDIs, DPIs, and SVNs, it was found that approximately the same amount of drug is delivered to the lung, regardless of the type of device used, given that all three devices contain the same loading dose. The clinical response measured by the improvement in FEV1 is also similar among the three devices, although the change with the MDI was statistically significantly greater than with DPI or SVN.

The greater response with the MDI correlates with the greater amount of drug delivered by the MDI in that study. However, the study concluded, “The amount of bronchodilation obtained is a reflection of the dose of drug given, and not the method of delivery.”

Since mainstream nebulizers are normally used for continuous administration of a bland aerosol (H2O, normal saline) for airway humidification or secretion mobilization, they are not usually considered as medication delivery systems.

Also in use today is a pneumatic nebulizer that operates on the “Babbington Principle”. This is called the hydrosphere or Babbington nebulizer. In this nebulizer, a source of gas enters a hollow sphere which is covered by a thin film of water. The hollow sphere has small ports in it, where the gas escapes to the outside. These ports act as jets. When the gas moves through these ports (jets), a negative pressure is produced and the flow of water is then drawn into the flow of gas producing an aerosol. A baffle is usually used in this system also. The baffle is placed distal to the atomization process in the flow of gas/aerosol. Particle sizes in these units are usually between three and five micron.

Large-Volume Nebulizers - These units also have the capability for entraining room air to deliver a known oxygen concentration. They can deliver varying concentrations of oxygen. When using these units, you should always match or exceed the patient’s peak inspiratory flow rates. This assures delivery of oxygen and nebulized particles. These units produce particle sizes between two and ten microns and may be heated to improve output.

Centrifugal Room Nebulizers - This nebulizer works on the principle of a rotating disk that spins on a hollow tube. This action draws water up the hollow tube that acts as a center shaft. Once the water reaches the rotating disk (which is spinning at a rapid rate), it is thrown outward by centrifugal force through comb-like structures that break up the water and produce an aerosol.

Although these are in fact nebulizers, they are used as room humidifiers. The aerosol particles are expelled into the room. Since they are very small particles, they evaporate to become humidity. Humidification is more effective if the door to the room is left closed.

Small-particle aerosol generator (SPAG) - This is a highly specialized jet-type aerosol generator designed to for administering ribavirin (Virazole), the antiviral recommended for treating high risk infants and children with respiratory syncytial virus infections.

Ultrasonic nebulizers - Ultrasonic nebulizers (USN) have been in use and production since the mid 1960s and have gained high popularity. Ultrasonic nebulizers work on the principle that high frequency sound waves can break up water into aerosol particles. This form of nebulizer is powered by electricity and uses the piezoelectric principle. This principle is described as the ability of a substance to change shape when a charge is applied to it.

An ultrasonic nebulizer contains a transducer that has piezoelectric qualities. When an electrical charge is applied, it emits vibrations that are transmitted through a volume of water above the transducer to the water surface, where it produces an aerosol. The frequency of these sound waves is between 1.35 and 1.65 megacycles, depending on the model and brand of the unit.

Their frequency determines the particle size of the aerosol. The transducers that transmit this frequency are of two types. One type is the flat transducer, which creates straight, unfocused sound waves that can be used with various water levels. The other type is a curved transducer, which needs a constant water level above it because its sound waves are focused at a point slightly above the water surface. if the water level falls below this point, the unit loses its ability to nebulize.

As stated, the frequency of an ultrasonic nebulizer determines the particle size of the aerosol. In ultrasonic nebulizers, the particle size falls in the range of .5 to 3 microns. The amplitude or strength of these sound waves determines the output of the nebulizer, which falls in the range of 0 to 3 ml/minute and 0 to 6 ml/minute. Ultrasonic nebulizers also incorporate a fan unit to move the aerosol to the patient. This fan action also helps cool the unit. The gas flow generated by this fan falls in the range of between 21 and 35 liters/minute. This flow of air also depends on the brand and model of the unit.

The transducer of an ultrasonic nebulizer is often found in the coupling chamber, which is filled with water. This water acts to cool the transducer and allows the transfer of sound waves needed for the nebulizer, which takes place in a nebulizer chamber. The nebulizer chamber is found just above the coupling chamber. A thin plastic diaphragm that also allows sound waves to pass usually separates these two chambers.

Ultrasonic nebulizers are useful in the treatment of thick secretions that are difficult to expectorate, and they can help to stimulate a cough. The therapy can be delivered through a mouthpiece or facemask. Therapy can be given with sterile water, saline or a mixture of the two.

Although IPPB has been used to deliver aerosolized drugs from a SVN, the consensus of clinical findings is that IPPB delivery of aerosolized medication is no more clinically effective than simple, spontaneous, unassisted inhalation from SVNs. If the patient is able to breathe spontaneously without machine support, the use of IPPB for delivery of aerosolized is not supported for general clinical or at-home use, and should be reserved for patients who are not capable of taking deep, coordinated breaths.

Aerosol generation and delivery to the lung is a complex and dynamic topic, with clinicians and researchers finding out more about its dynamics every day. The aerosol route of drug administration has become a preference for those treating pulmonary disease for a variety of reasons. The advantages of aerosol delivery of drugs include:

• Aerosol doses are smaller than those for systemic treatments.
• Onset of drug action is rapid.
• Drug delivery is directly targeted to the respiratory system.
• Systemic side effects are fewer and less severe than with oral or parenteral therapy
• Inhaled drug therapy is painless and relatively convenient.

As with nearly everything that has advantages, aerosol delivery of drugs also has its disadvantages, including:

• Special equipment is often needed for its administration.
• Patients generally must be capable of taking deep, coordinated breaths.
• There are a number of variables affecting the dose of aerosol drug delivered to the airways.
• Difficulties in dose estimation and dose reproducibility.
• Difficulty in coordinating hand action and breathing with metered dose inhalers.
• Lack of physician, nurse, and therapist knowledge of device use and administration protocols.
• Lack of technical information on aerosol producing devices.
• Systemic absorption also occurs through oropharyngeal deposition.
• The potential for tracheobronchial irritation, bronchospasm, contamination, and infection of the airway.

The common hazards of aerosol therapy are:

Airway obstruction - Dehydrated secretions in the patient’s airways may absorb water delivered via aerosol and swell up large enough to obstruct airways. To avoid this, watch the patient very closely and let him progress with therapy at a reasonable rate. You may want to have suction apparatus on hand.

Bronchospasms - It is common for aerosol particles to cause this condition (especially among asthmatics) and it is more prevalent when administering a cold aerosol as compared to a heated one. If a very large amount of coughing occurs, stop therapy and give the patient a rest. If this persists in farther therapy, stop treatment and notify the physician.

Fluid overload - This can occur when administering continuous aerosol therapy. It can happen quite frequently when treating infants or patients in congestive heart failure, renal failure or patients who are very old andimmobile. In the infant, because of the smaller body size and possible underdeveloped fluid control mechanism, a quantity of water that an adult can easily handle will cause fluid overload. In a patient with congestive heart failure, any addition of fluid to the vascular system will put an increased strain on the heart. In a patient with renal failure who is probably already in fluid overload, it is easily seen that you will not want to increase the fluid volume. In older patients, the fluid control mechanisms may be impaired due to age.

Procedures

The following are sample instructions for procedures to be followed related to aerosol applications:

Procedure for Aerosol Medication Delivery

The following procedure is provided for use when delivering medications by means of an aerosol generator:

A. Check Order. Verify the physician’s order as follows:

Compare the requisition with the physicians order to ensure that no discrepancies exist

1. Review the order to ensure that the following are prescribed:

• FIO2
• Medication to be used
• Frequency of therapy
• Duration of therapy
• If any part of the order is unfamiliar, question its accuracy.

B. Review Chart. Use the following procedure to review the patient’s chart: On the patient’s chart, identify all pertinent data in the following areas:

• History and physical
• Admitting diagnosis
• Progress notes
• Blood gas analysis
• Chest x?rays

2. Based on the patient data, identify the following:

• Conditions that indicate the need for aerosol medication delivery
• Potential hazards of aerosol medication delivery for the patient

C. Maintain Asepsis. While performing the remainder of this procedure, you are expected to maintain aseptic conditions.
     This includes following universal precautions and washing your hands:

• Before obtaining equipment
• Following performance of step K. Conclude Procedure
• Anytime during the procedure that contamination is suspected

D. Obtain Equipment Collect the following equipment and supplies:

• Flowmeter or air compressor
• Miniature nebulizer
• Supply tubing
• Prescribed medication
• Stethoscope

E. Assemble Equipment. Prepare the equipment for use as follows:

1. . Connect the supply tubing to the nebulizer.
2. Attach the other end of the supply tubing to the flowmeter.
3. Insert the prescribed medication into the nebulizer.

F. Test Equipment. Test the aerosol medication delivery equipment as follows:

1. Connect the flowmeter to the correct gas source.
2. Turn on the flowmeter.
3. If a fine mist is absent, tighten all connections and adjust the jets, if applicable.
4. If a fine mist is still absent:
   a. Label the nebulizer as defective and replace it
   b. Reassemble and retest the new equipment

G. Confirm Patient. Ensure that the procedure is performed with the correct patient as follows:

1. Match the information on the order with the following:
   · Room number
   · Name on the door or bed
   · Name on the wristband
2. Greet the patient by name (in a questioning manner if unknown).
3. Resolve any discrepancies in the patient identification information by conferring with the nursing staff.

H. Inform Patient: Interact with the patient as follows:

1. Introduce yourself by name and department (if not already acquainted).
2. Tell the patient what procedure is to be performed.
3. Explain the procedure by describing:

• Why it is to be performed
• How it will be performed
• What the patient is expected to do
• What you will be doing
• How frequently it will be performed

I. Implement Procedure. Perform the following tasks:

1. Position the patient in an upright position (45 to 90° angle).
2. Administer the aerosol medication as follows:
   a. Turn on the flow meter.
   b. Attach the aerosol medication delivery device to the patient
   c. Ensure that the delivery device fits comfortably.
3. Coach the patient to breathe in the following manner:
   · Diaphragmatically
   · Through the mouth
   · Slowly and deeply
   · Pause at end?inspiration, maintaining an I:E ratio of at least 1:2

J. Monitor Patient. Determine the patient’s response to therapy as follows:

1. Determine the pulse rate. (Count for at least one minute.)
2. Determine the respiratory rate. (Count for at least one minute.)
3. Observe respiration to identify any abnormalities in the breathing pattern.
4. Auscultate the patient’s chest
5. Note any abnormalities in the patient’s appearance or behavior.

K. Conclude Procedure. Complete the following tasks:

1. Place the patient in a comfortable position.
2. Assure that the call bell and bedside table are within the patient’s reach.
3. Ask if the patient has any needs.
4. Answer any questions as effectively as possible.
5. Unplug and cover all equipment and move it away from the patient’s bed (or remove it from the room).

L. Record Results. Document the therapy as follows:

1. Record the following data on the patient’s chart:
   · Aerosol medication administered
   · Pulse rate
   · Respiratory rate
   · Volume, color, and consistency of sputum
   · Abnormal patient characteristics
   · Therapy-related patient complaints
2. Sign the patient’s chart (first initial and full last name).

M. Report Observations. Report the following information:

1. Report any significant adverse changes in the patient’s condition to the nurse or physician whenever observed.
2. Following the procedure, inform the appropriate personnel of:
   · Patient requests
   · Patient complaints
   · Unexpressed patient needs
3. Following the procedure, report to the nurse or physician:
   · Any non?critical adverse reactions to the therapy
   · Other pertinent observations of the patients condition

Procedure for Administering Metered Dose Inhaler

The following procedure is provided for use when delivering medications by means of a metered dose inhaler:

A. Check Order. Verify the physician’s order as follows:

1. Compare the requisition with the physician’s order to ensure that no discrepancies exist.
2. Review the order to ensure that the following are prescribed:
   · Medication to be used
   · Frequency of therapy
   · Duration of therapy
   · Any special devices or chambers required

B. Review Chart. Use the following procedure to review the patient’s chart:

On the patient’s chart, identify all pertinent data in the following areas:

• History and physical
• Admitting diagnosis
• Progress notes
• Blood gas analysis
• Chest x-rays
• Based on the patient data, identify the following:
  · Conditions that indicate the need for metered dose inhaler delivery
  · Potential hazards of aerosol medication delivery for the patient

C. Maintain Asepsis. While performing the remainder of this procedure, you are expected to maintain aseptic.
    This includes the use of universal precautions and handwashing. Hands should be washed:

• Before obtaining equipment
• Following performance of Step J. Conclude Procedure
• Anytime during the procedure that contamination is suspected.

D. Obtain Equipment. Collect the following equipment and supplies:

• Metered Dose Inhaler (as prescribed)
• Any special devices or chambers (as applicable)
• Stethoscope

E. Assemble Equipment. Prepare the equipment for use as follows:

1. Shake the inhaler to mix the medications.
2. Remove the cap and attach the mouthpiece.
3. If a chamber is ordered, attach the device to the mouthpiece.

F. Confirm Patient. Ensure that the procedure is performed on the correct patient as follows:

1. Match the information on the order with the following:
   · Room number
   · Name on the door or bed
   · Name on the wristband
2. Greet the patient by name (in a questioning manner if unknown).
3. Resolve any discrepancies in the patient identification information by conferring with the nursing staff.

G. Inform Patient. Interact with the patient as follows:

1. Introduce yourself by name and department (if not already acquainted).
2. Tell the patient what procedure is to be performed.
3. Explain the procedure by describing:
   · Why it is to be performed
   · How it will be performed
   · What the patient is expected to do
   · What you will be doing
   · How frequently it will be performed

H. Implement Procedure. Perform the following tasks:

1. Position the patient in an upright position (45 to 90° angle).
2. Instruct the patient as follows:
   a) Grasp the MDI medication chamber between the thumb and first two fingers with the thumb on the bottom of the chamber.
   b) Hold the mouthpiece of the medication chamber (or additional chamber device if ordered) in front of the mouth
       with the lips around the mouthpiece but not closed on.
   c) If the patient has difficulty holding the device without closing his lips, instruct him to rest the mouthpiece on the lower lip for balance.
   d) Exhale completely. Begin to inhale deeply through the mouth and immediately compress the medication chamber between
       the thumb and fingers to release the medication.
   e) Following complete inhalation, hold his/her breath for 5 to 10 seconds.
   f) If an additional chamber was used, inhale from the device again, without compressing the medication chamber, to
      ensure complete aerosol delivery.
   g) Repeat the process until the prescribed duration is accomplished.

I. Monitor Patient. Determine the patient’s response to the therapy as follows:

1. Determine the pulse rate. (Count for at least one minute).
2. Determine the respiratory rate. (Count for at least one minute).
3. Observe respiration to identify any abnormalities in the breathing pattern.
4. Auscultate the patient’s chest
5. Note any abnormalities in the patient’s appearance or behavior.

J. Conclude Procedure. Complete the following tasks:

• Place the patient in a comfortable position.
• Assure that the call bell and bedside table are within the patient’s reach.
• Ask if the patient has any needs.
• Answer any questions as effectively as possible.

K. Record Results. Record the following data on the laboratory data form and on the patient’s chart as required:

• Patient name Room number
• Aerosol medication delivered
• Pulse rate
• Respiratory rate
• Breath sounds
• Volume, color and consistence of sputum
• Any adverse patient reactions
• Therapy-related patient complaints

L. Report Observations. Report the following information:

1. Report any significant adverse changes in the patient’s condition to the nurse or physician.
2. Following the procedure, inform the appropriate personnel of:
   · Patient requests
   · Patient complaints
   · Unexpressed patient needs
3. Following the procedure, report to the nurse or physician:
   · Any non-critical adverse reactions to the therapy
   · Other pertinent observations of the patient’s condition

1-15. INTRODUCTION

Drugs affecting the respiratory system have been in use for years. In the 20th century, for example, various members of the morphine family (that is, heroin) were used in the treatment of coughs. In the 21st Century, people are using both legend and over-the-counter cough preparations. At certain times of the year you will see many prescriptions for cough medicines and expectorants. You have probably seen such increases when winter arrives. This section of the course will discuss some of the respiratory systems medications commonly seen in the pharmacy.

Medications Used in Respiratory Pharmacology

The goal of respiratory pharmacology is to prevent or relieve the pathologic triad discussed earlier: bronchospasm, airway inflammation or mucosal edema, and retained secretions. The medicating agents used to relieve these symptoms can be referred to as the "treatment triad." The pathologic triad and treatments include:

Pathologic Condition Treatment

Bronchoconstriction      Bronchodilator (e.g., albuterol)

Airway edema              Decongestant (e.g., racemic epinephrine)

Retained secretions       Hydration or mucolytics

The actions of the various categories of pharmacologic agents used to relieve the pathologic triad can be briefly summarized as:

• Bronchodilators increase airway patency by relaxing the bronchial muscle spasm triggered by disease or irritation.
• Decongestants cause contraction of the muscle fibers of the arterioles and small arteries, triggering a reduction of blood flow to the affected area and lowering of hydrostatic pressure that permits fluid to move into the tissues.
• Mucokinetics facilitate loosening and mobilization of secretions.

Throughout this part of the course we will present information regarding individual drugs. Some will contain more information than others. Regarding some of the medications, we will include the full text of what can be found in drug reference books such as the Physicians Desk Reference or other texts which go into respiratory medications in great. For the purposes of this CEU, will not do so for every drug mentioned as to do so would turn this into a textbook rather than what it is: a continuing education unit.

There are a wide variety of patient circumstances that can necessitate the modification of recommended dosage or frequency of medications administered to pulmonary patients. Following administration, most drugs go through several steps in a well-defined sequence before being excreted from the body, including:

1. Absorption from the site of administration
2. Distribution via the circulatory system
3. Metabolism
4. Excretion from the body

Metabolism, also known as biotransformation, is the step in which a drug circulating in the bloodstream is transformed from its original active form to a less active form. While other organs participate to a limited degree in the metabolism process, the liver is the principal site of drug metabolism. Drugs absorbed through the mucous membrane of the stomach or intestines, enter the bloodstream via the portal vein. Before this vein empties into the general circulation system, it passes through the liver where the drugs carried by the vein are exposed immediately to metabolism by liver enzymes.

Because the liver plays such a key role in the metabolism of most drugs, a decreased rate of drug metabolism can occur in patients with liver diseases or hepatitis. Drug dosages for these patients need to be adjusted in order to avoid toxicity, and to compensate for the prolonged pharmacologic action of un-metabolized drug in the blood stream.

The kidney is the principal organ involved in the excretion of drugs from the body. Poor renal function can significantly prolong the effects of some drugs, and altered pH levels can inactivate some drugs, such as bronchodilators. Since mechanical ventilation can affect kidney function by decreasing perfusion pressure, drug dosages may need to be modified for patients on ventilation.

Also, since many patients are being treated with more than one drug at a time, drug interaction and synergism needs to be taken into account when setting dosages and administration frequencies. All of these factors contribute to making the task of prescribing proper dosage of medications for respiratory patients a more complex undertaking.

Drug interactions

Types of drug interactions

There may be two outcomes of drug interaction. Antagonism occurs when the action of one drug opposes that of another, while synergism occurs when the effects of coadministration of drugs is additive. When the sum of two drugs is more than a simple additive effect, this is known as "potentiation." Not all drug interactions are harmful. For example, the ISIS-2 study showed that aspirin and streptokinase each improve outcome in myocardial infarction, and that the combination of both these drugs has an additive therapeutic effect.1

Drug interactions may be divided into three main types

Pharmaceutical interactions

This is probably the least important of the types of interactions. It is the interaction of drugs on a chemical, not a pharmacological, level. An example is the formation of a complex between thiopentone and suxamethonium, which cannot therefore be mixed in the same syringe. These types of interactions are best avoided by giving drugs as bolus injections where appropriate, avoiding the mixing of drugs before administration except when this is known to be safe and making up infusions immediately before use.

Pharmacodynamic interactions

This is the reduction or enhancement of the effect of one drug by another without altering its concentration at its site of action. These are usually predictable from the knowledge of the pharmacological mechanism of action of the drugs, and usually occur through competition at receptor sites or through an action on similar physiological systems. An example of this type of interaction is that between loop diuretics and digoxin. Loop diuretics lower plasma potassium and this reduces competition between the glycoside and potassium for the sodium potassium pump in the heart muscle. The consequent increased glycoside binding enhances the risk of arrhythmias.

Pharmacokinetic interactions

This is the alteration of drug concentration reaching its target site by a second drug. The four determinants of drug pharmacokinetics may each be affected by this coadministration: absorption, distribution, metabolism, and excretion. These types of interaction are not easily predicted and the severity of interaction, unlike the pharmacodynamic variety, often differs markedly between patients.

• Absorption may be affected from the gut either because two drugs form an insoluble complex (seen sometimes with antacids and prednisolone) or because one drug alters gut motility, as seen with drugs such as loperamide or metoclopramide, and affects the time available for drug absorption to occur. In the skin, reduced absorption (and hence redistribution or metabolism) of lignocaine after subcutaneous injection is usefully achieved by combining this with the vasoconstrictor adrenaline. This prolongs the anesthetic action of lignocaine.
  
  
• Distribution is commonly a factor in those drugs that are extensively protein bound in the plasma, where they may be displaced from their binding sites by a second drug. This is rarely important pharmacologically, because although the free drug accounts for its pharmacological action, it is this same fraction which is available for redistribution and metabolism, which usually restores free levels. Thus most serious interactions are seen when displacement from plasma proteins occurs in addition to other effects such as inhibition of drug metabolism. An example of this is sodium valproate, which not only displaces phenytoin from plasma proteins but also reduces the rate at which it is metabolized.
  
  
• Metabolism of a drug is most commonly altered by enzyme inducers such as phenytoin combined with another drug--for example, the contraceptive pill. The pill is metabolized more frequently, and the resultant reduced plasma levels may result in pregnancy. Enzyme inhibitors also exist. The most common drugs in this category are those with an action which includes inhibition of isoenzymes of cytochrome --for example, cimetidine and erythromycin.
  
  
• Elimination becomes a factor in those drugs sharing common transporter mechanisms in the kidney. An example of this is the lithium accumulation seen in patients treated with concomitant diuretics.

Identifying possible drug interactions

Drug interactions may manifest as a lack of effect of a newly introduced drug treatment, or more seriously as a clinical deterioration. It should always be considered in people who are severely ill, in whom interactions may be difficult to identify, and in the elderly. Both these groups are likely to be taking several medications simultaneously. Patients with renal or hepatic impairment are also more likely to suffer the effects of interactions, as metabolism and excretion will be impaired. Others at risk include those taking drugs long term where the precise plasma level is important--for example, people with epilepsy.

With so many drugs available to prescribers, it is not possible to learn all the different combinations and interactions. An understanding of the above principles should allow a reasoned approach to the problem. In general terms, certain drugs are more likely to be involved in interactions. These include drugs with a small therapeutic index (a small change in drug concentration resulting in a substantial change in therapeutic effect). Drugs that are known to be enzyme inducers or inhibitors or those with a saturable metabolism should also be used with caution.

Finally, there are several drugs that, although used for treating the same disease, are capable of causing serious drug interactions when used together. These include digoxin with thiazide or loop diuretics, theophylline with ß adrenoceptor agonists (both combinations may cause cardiac arrythmias), phenytoin with sodium valproate (phenytoin toxicity), and verapamil with ß adrenoceptor antagonists (bradycardia).

Bronchodilators

Most drug effects are mediated through the agency of a receptor, which is special protein molecule on the cell membrane that is specifically designed to interact with natural body chemicals, and it also interacts with drugs.

There are many types of receptors throughout the body. For example, adrengic receptors are part of the sympathetic nervous system and are activated by the natural neurotransmitters epinephrine, norepinephrine, and dopamine, or by drugs. There are three types of adrenergic receptors (alpha, beta1, and beta2). Cholinergic receptors are part of the parasympathetic nervous system, and are activated by the natural neurotransmitter acetylcholine.

The G protein-linked receptors mediate both bronchodilation and bronchoconstriction in the airways, in response to endogenous stimulation by neurotransmitters epinephrine and acetylcholine. These same airway responses can also be elicited by adrenergic bronchodilator drugs, or blocked by acetylcholine blocking (anticholinergic) agents.

Bronchodilators relax the smooth muscle that surrounds the bronchi, thereby increasing airflow. This dilation of the bronchi is due either to stimulation of beta2 receptors in the smooth muscle of the bronchi, the release of epinephrine which itself stimulates beta2 receptors, or to inhibition of acetylcholine at cholinergic receptor sites in the smooth muscle.

Drugs, which produce bronchodilation via the parasympathetic pathway, do so by blocking the action of acetylcholine at the parasympathetic synapse. Remember that sympathetic stimulation elicits a bronchodilation effect, while the parasympathetic system offers counter balancing by eliciting a bronchoconstricting effect. Therefore, a drug that can block the parasympathetic system's action will increase airway diameter by allowing bronchodilation to occur.

Drugs, which block the actions of the parasympathetic system, are called parasympatholytics because of their inhibitory action. Because they are competitively blocking the action of acetylcholine, they are also called anticholinergics. As the nerve impulse arrives at the synapse, the head of the presynaptic neuron releases acetylcholine into the synaptic cleft. The acetylcholine then diffuses to the receptor sits located on the surface of the postsynaptic neuron, where they bind and elicit an impulse in that neuron. All anticholinergics exert their action by competitively binding to those receptor sites on the postsynaptic neuron.

Because the receptors are already bound, acetylcholine cannot bind, and no neuro-impulse is transmitted. The target areas for bronchodilation with anticholinergics seem to emphasize the larger airways, while beta agonists seem to emphasize the lower airways. The effects of co-administered sympathomimetics and parasympatholytics are additive.

In general, parasympatholytic drugs have pulmonary indications consisting of the treatment of cholinergic-mediated bronchospasm. This has been suggested as particularly useful in the treatment of chronic bronchitis, although parasympatholytics may be used with other chronic obstructive diseases. These drugs are typically not used for acute obstructive disease.

Atropine was the first drug to be used as an anticholinergic bronchodilator. It elicits a fairly good bronchodilatory effect; unfortunately, it also has fairly significant side effects. Systemic actions of atropine include decreased gastric motility, dryness of mouth, thirst, dryness of eyes, increased heart rate, palpitations, pupillary dilation, urinary retention, and blurring of vision. These effects are certainly dose related. Other parasympatholytic drugs have much fewer side effects relative to atropine. It should be mentioned that a common misconception regarding atropine and other parasympatholytic drugs is their presumed effect on drying pulmonary secretions. The dryness of mouth that occurs with atropine administration results because the salivary glands are innervated with the parasympathetic pathway. (Remember the SLUD effects of stimulation of the parasympathetic system... Salivation, Lacrimation, Urination, Defecation) The mucous secreting glands and cells of the lower respiratory tract are not affected by administration of parasympatholytics, and therefore administration of this kind of drug does not produce significant dryness of pulmonary secretions.

Contraindications for parasympatholytics are relative, and include hypersensitivity, glaucoma, prostatic hypertrophy, and tachycardia.Specific parasympatholytic drugs include:

1. Atropine
   1. None
   2. Actions
       1. Onset: approximately 15 minutes
       2. Peak: 1-2 hours
       3. Duration: 3-6 hours (dose-related)
   3. Dosage and Dosage form available in injectable ampules, 1 mg/ml (typically a vial containing 1 ml of that concentration) Nebulize between 1.0-2.5mg (typically 1.0 mg) diluted in 3.0ml saline. May repeat dose every 4-6 hours
   
   
2. Glycopyrrolate
   1. Trade Names: Robinul
   2. Actions
       1. Onset: within 30 minutes
       2. Peak: 1-2 hours
       3. Duration: 6-8 hours
   3. Dosage and Dosage form: available in injectable form only, not FDA-approved for use as inhaled drug. Solution is supplied in a concentration of 0.2 mg/ml. Aerosol administration is suggested with a dose of 1 mg given three or four times a day. This drug has the same action as atropine, but fewer adverse side effects.
   
   
3. Ipratropium Bromide
   1. Trade Names: Atrovent
   2. Actions
       1. Onset: 15 minutes
       2. Peak: 1-2 hours
       3. Duration: 4-6 hours
   3. Dosage and Dosage form: Available as a solution for inhalation, 0.5 mg in a pre-diluted unit dose. Also available as an MDI, for administration of 2 puffs taken four times a day.
   4. Note: This drug is related to atropine, but is chemically different enough that some very desirable characteristics are produced. First, the drug is not broken down very quickly, and so its effect is relatively long lasting. Second, it has essentially no systemic side effects, so it does not increase heart rate significantly, or cause oral dryness, or any of the other side effects common to atropine. Third, it has really no known toxic levels because the drug is not absorbed well systemically, so the drug is very safe. One last characteristic worth noting about ipratropium bromide is that there seems to be no real added benefit to additional dose once the four times daily dose has been met. Patients with persistent bronchoconstriction will receive no added benefit from further doses past the QID regimen.
   

Drugs are thought to produce their effects either by acting directly at some specific receptor site, or by acting diffusely at many tissues. Those acting diffusely are called saturation-dependent or non-receptor drugs, and include alcohol, hypnotics, anesthetics, and mucus-diluting agents such as water or saline. However, the majority of drugs act at specific receptor sites.

A receptor is a specific protein-related molecule embedded within and protruding out from cell membranes, where reversible bonds can be formed with specific drugs. When a drug binds to the receptor, a chemical change occurs which is transmitted to the inside of the cell. This changes the biochemistry within the cell.

Receptor-drug interactions have been described as a lock and key mechanism. Receptors (the lock) are very specific as to what drugs (the keys) that will bond there. The shape, size, and polarity (electric charge) of the drug molecule have to reasonably match the receptor's specifications, or no reaction and thus no drug effect will occur. Affinity is the tendency a drug has to combine with a receptor. If a drug has affinity and produces an effect, it is called an agonist. A partial agonist is a drug, which has affinity but cannot produce the total effect. In contrast, an antagonist is a drug that has affinity for a receptor but produces no effect. An antagonist is capable of blocking any effect that an agonist would produce, if the antagonist gets to the receptor and binds first. This might be like inserting a toothpick into a lock. The lock cannot open, but neither can the key be inserted into the lock when the toothpick is in there. An antagonist can be competitive (it forms a reversible bond with the receptor) or it can be noncompetitive (the bond formed is irreversible).

Specificity of the part of a drug is very important. A receptor will not respond to simply any molecule that happens by; only specific chemicals will react and bond with the receptor. This characteristic allows drugs to be designed to target one specific organ system with one specific receptor site and one specific biophysiologic effect. The challenge is to create medications that are in fact very specific for their intended receptor sites. An example of this is that the first bronchodilators were very non-specific to the receptor sites in he airways; consequently, there were many systemic side effects of the drugs used as they interacted with receptor sites distributed in other organ systems, particularly the cardiovascular system. Today's bronchodilators have been chemically designed to have more specificity, so that the desired pulmonary effect remains, but there are significantly fewer cardiovascular side effects.

The nervous and endocrine systems are the body's internal communication pathways. The nervous system is specifically capable of rapid response and specific control, whereas the endocrine system is slower in its response and less precise in its effects. Both systems help regulate the body internally, a process referred to as homeostasis. Both systems are similar pharmacologically in that drugs can interact with them both at receptor sites and thereby modify functions at selected tissue locations.

The Nervous System:

1. Can be grouped into two general categories according to location of structures:
   1. Central Nervous System (CNS) consists of the brain and the spinal chord and related structures.
   2. The Peripheral Nervous System consists of all nerve pathways outside the CNS.
   
   
2. Can also be grouped into two general categories according to conscious control:
   1. The somatic system
       1. Under conscious control
       2. Typically innervates and controls skeletal muscle
   2. The autonomic nervous system,
       1. Not under conscious control
       2. Typically innervates cardiac and the various pulmonary and GI smooth muscles, sweat glands, and certain endocrine glands
       3. Name comes from the fact that it is the pathway for the automatic control of these organs
       4. Autonomic system maintains homeostasis
       5. Autonomic system itself is divided into two functional subdivisions:
           1. Sympathetic system
               1. Fibers arise in the thoracic and lumbar area of the spinal chord
               2. Once leaving the spinal chord, the fibers travel a rather short uninterrupted distance until they reach a ganglion
                   (simply a neurological relay point). Ganglia are typically near the spinal chord.
                    1. The ratio of sympathetic preganglionic and postganglionic fibers is roughly 1:15, which suggests that a single preganglionic                      impulse can result in many outgoing impulses. As a result, sympathetic stimulation typically results in a diffuse response                      throughout the body.
                          1. The post-ganglionic neurotransmitter chemical is mostly norepinephrine, but may also be epinephrine.
            2. Parasympathetic
               1. Fibers arise in the cervical and sacral areas of the spinal chord
               2. Once leaving the spinal chord, the fibers travel uninterrupted for relatively long distances. Their ganglia are typically
                   located near the effector organs.
                   1. The ratio of parasympathetic preganglionic and postganglionic fibers is roughly 1:2, which results in a very local and
                       specific response.
                       1. The post-ganglionic neurotransmitter is acetylcholine.
               3. Balance between the sympathetic and parasympathetic and the fact that the pathways typically oppose each other in their
                   effects result in the body's ability to control the various organ and tissue systems. Each exerts a constant and steady
                   antagonistic force on the other, much like pulling on the two ends of a rope. The balance of the two systems is called the tone.                 The effects of stimulation of the parasympathetic and sympathetic systems very from organ to organ. Stimulation of the                 sympathetic system cause bronchial muscle dilation, increased heart rate and contractility, increased peripheral vasomotor tone.                 Stimulation of the parasympathetic system produces bronchial constriction and decreased heart rate and contractility, as well as                 decreased vasomotor tone. In addition, parasympathetic stimulation causes increased activity in the SLUD organs, or Salivation,                 Lacrimation, Urination, and Defecation.

A Note About Synapses

The synapse is the connection between one neuro fiber and the next, such as occurs at the ganglia. When a nerve impulse arrives on the incoming axon, a chemical transmitter is released into a cleft between the axon of the incoming fiber and the axon of the outgoing fiber or effector organ. Once the synaptic neurotransmitter is released, enzymes in the cleft work quickly to break down the transmitter so that the effect of the impulse transmission will be temporary. Also, some neurotransmitter chemical is reabsorbed back into the incoming axon.

At the synapse, the parasympathetic system's neurotransmitter acetylcholine is released into the synaptic cleft and carries the nerve impulse to the outgoing nerve fiber. Because of this, the parasympathetic system is often referred to as the cholinergic system. Acetylcholine is broken down into he synaptic cleft and deactivated by acetylcholinesterase.

The sympathetic system transmits its nerve impulses across the synaptic cleft using norepinephrine (nor-adrenaline). Because of this, the sympathetic system is often called the adrenergic system. In the cleft, the norepinephrine may be removed via a combination of several mechanisms.

4. The norepinephrine can be reabsorbed back into the incoming axon
5. It can be deactivated by the enzyme, catechol-o-methyl transferase (COMT)
6. It can be deactivated by monamine oxidase (MAO) enzyme

A Final Note About Receptors

The receptors of the sympathetic system can be divided into four major categories:

• Beta1 receptors are located mainly in the cardiac muscle, and stimulation of them increases cardiac rate and contractility.
• Beta2 receptors are located mainly in the bronchial smooth muscle, and stimulation cause smooth muscle relaxation.
• Alpha1 receptors are located mainly in the peripheral arterioles and stimulation causes contraction of the smooth muscle in those vessels with resultant increase systemic vascular resistance (SVR).
• Alpha2 receptors less important than the other three but are located in the pre-synaptic sympathetic nerves and in the CNS, and stimulation can decrease the norepinephrine released at the synapse, as well as decrease sympathetic nervous outflow from the CNS.

This discussion covers the classification of drugs known as glucocorticoids, or steroids.

Glucocorticoids are a subtype of the general classification of corticosteroids. These substances are produced in vivo by the adrenal cortex.

Recall that the hypothalamus is located on the inferior surface of the brain, just posterior to the nasal cavity. As part of the brain, it receives incoming sensory impulses and coordinates these afferent signals with chemical information arriving continually through the blood supply. In addition, the hypothalamus is capable of producing its own chemical messengers and releasing them into the blood stream. Glands such as the hypothalamus lack secretory ducts, and are referred to as endocrine glands.

Hormones, the products of such glands, are regulatory substances released into the blood supply and carried to target areas. Hormones have the ability to alter a preexisting reaction, usually by enhancing it in some way. Most hormones are composed of proteins, or modified amino acids. But a few possess a complex ring structure and are referred to as steroid hormones. The word "steroid" means sterol-like, and a sterol is a compound with a complex alcohol ring. Cholesterol is one such alcohol-ringed compound. Other compounds sharing this characteristic include testosterone, progesterone, and the adrenal corticosteroids.

Within the hypothalamus, distinct groupings of cells synthesize specific hormones. The anterior portion of the hypothalamus controls the glandular portion of the pituitary gland (the anterior pituitary). When physiological stressors occur, such as infection, trauma, emotional stress, exercise, surgery, or thermal changes, the hypothalamus secretes a hormone called corticotropin releasing factor, or CRF.

This hormone travels the short distance to the anterior pituitary via specialized blood channels, and stimulates the production and release of corticotropin, or adrenocorticotropic hormone (ACTH). ACTH travels via the blood stream to the adrenal glands, and stimulates the adrenal cortex to synthesize and release corticosteroid hormones. These corticosteroids travel throughout the body to accomplish two purposes: restore homeostasis by minimizing the effects of the original stressor, and inhibit the hypothalamus from producing more CRF. If the physiological stress persists, the suppression of the hypothalamus is incomplete, and another round of hormonal release is initiated.

When corticosteroids are administered therapeutically, they mimic the action of native corticosteroids. In addition, they have the ability to influence the production of native corticosteroids via suppression of the hypothalamus with resultant suppression of the adrenal cortex.
The adrenal glands are interesting little fellows. They are small highly vascularized glands located on the anterior aspect of both kidneys. Within a single gland, two distinct endocrine glands are found. They share a blood supply but little else. Their embryonic origins, cell populations, hormone chemical types, physiologic controls, and functions differ significantly. They are as separate as two glands can be, yet they appear grossly as one organ, approximately 5 cm long, 3 cm wide, and only 1 cm thick. The outer portion, or adrenal cortex, is a relatively thin layer over the catecholamine-producing adrenal medulla. The adrenal cortex possesses three distinct cell populations each located in a separate layer of the cortex, and each responsible for the synthesis of a different class of corticosteroid hormone.

The steroid hormones synthesized in the three layers of the adrenal cortex can be described in functional terms. One group regulates plasma electrolytes, another is involved in the maintenance of blood glucose levels, and a third promotes protein synthesis. The relatively complex chemical structure of the steroid base-molecule is common to all three of the adrenocortical hormones.

The differences in them result from the differences in the location and type of substituted chemical groups attached on the steroid base. The slight structural differences in the chemical structure of these complex molecules account for the observed differences in activity of the hormones. However, the differences are better viewed as differences in potency: there is overlapping of physiological effects among the corticosteroids; the chemical structure of each, however, makes each more potent for a given set of effects versus the others.

The ability of one class of corticosteroid to influence body functions usually regulated by another is the cause of many of the side effects seen with steroid drug therapy. The recognized side effects are simply the exaggeration of body functions normally controlled by the adrenocortical hormones. The overlapping effects of various steroid compounds are due to their close chemical similarity. For example, steroid hormones that have gained notability for their potent anabolic effects on the muscular system also produce unwanted side effects, including salt and water retention. This occurs because the structure of the anabolic steroids is similar to that of the steroids that promote electrolyte and fluid shifts.

The middle layer of the adrenal cortex produces hormones that are especially potent to increase blood glucose levels, and as such, is referred to as glucocorticoids. The two naturally occurring steroids of this class are cortisone and cortisol. These substances increase blood glucose levels by converting fats and proteins to glucose, when the body is deprived of glucose, or perhaps when a severe stress depletes blood glucose. Overall, the mechanism diverts resources from dispensable tissues such as muscle and adipose, and converts these resources for use by indispensable tissues such as brain and heart.

Glucocorticoids are also potent anti-inflammatory and immunosuppressive agents, for several reasons:

1. inflammatory substances such as collagen and mucoproteins that are associated with the inflammatory reaction in tissue are used as non-carbohydrate sources of glucose.
2. glucocorticoids suppress the activities of common connective tissue cells called fibroblasts, which normally respond to tissue trauma by producing collagen.
3. proteins in lymphoid tissue are another non-carbohydrate source of blood glucose, the metabolism of which is mediated by glucocorticoids. As a result, antibody formulation, which normally occurs in lymphoid tissue, is suppressed. Circulating antibody concentrations are decreased. In addition, glucocorticoids suppress plasma immunoglobulins, the material from which antibodies are made. With decreased antibody levels, the severity of inflammatory reactions decreases.
4. glucocorticoids inhibit the synthesis and release of histamine from target cells.
5. glucocorticoids decrease the release of arachidonic acid; consequently, the serum levels of leukotrienes and prostaglandins decrease.
6. glucocorticoids act on smooth muscle cells by increasing the number of beta-2 adrenergic receptors, and increasing the affinity these receptors have for beta agonists. The result of this is improved efficacy of beta agonist therapy.

Because glucocorticoids are systemically active, the side effects they have when administered systemically can be very diverse, and stem from the mimicking of normal activities of the native hormones, as well as repression of the adrenal cortex via the previously mentioned feedback loop. Some specific side effects along these lines include:

• Endocrine gland repression. Administration of exogenous steroids when circulating systemically, inhibit the hypothalamus' output of CRF. The decreased CRF levels fail to stimulate the anterior pituitary to produce ACTH. Decreased levels of ACTH fail to stimulate the adrenal cortex, and blood levels of endogenous steroids decrease. This suppression of the feedback loop by exogenous corticosteroids results in physiologic dependency. The body becomes dependent on exogenous corticosteroids while the levels of native hormones gradually decrease. The hypothalamus, anterior pituitary, and adrenal cortex enter a physiological dormancy as a result of exogenously administered corticosteroids, and will only slowly emerge from their suppressed states when the exogenous corticosteroids are cautiously withdrawn.
• Cushingoid effects. Cushing’s disease is a tumor of the anterior pituitary, which causes hypersecretion of ACTH. The result is an increase in endogenous corticosteroids, and classic body morphology, including central obesity, exophthalmus, dowager's hump (a fatty deposit between the shoulder blades resulting in the appearance of a 'buffalo hump'), edema, hypertension, and masculinization of females. Administration of exogenous glucocorticosteroids over the long run can cause these symptoms to appear as well, a condition referred to as "Cushing's syndrome" or "Cushingism."
• Withdrawal and Addisonian crisis. Addison's disease is a condition of pathological suppression of the adrenal cortex, leading to hyposecretion of the corticosteroids. Symptoms include diuresis, fluid loss, hypotension, hyponatremia, hyperkalemia, hypoglycemia, weakness, and weight loss. Sudden withdrawal of exogenous steroid therapy that has been given for an extended period can result in systemic drops in serum corticosteroid levels, with resultant production of symptoms similar to Addison's disease. The production of these symptoms from the sudden withdrawal of steroid therapy is referred to as 'Addison's Syndrome.'

One further note about the effects of systemic steroids: The secretion and balance of corticosteroids follows a normal ebb and tide over the course of a day. Levels of cortisol typically peak in the morning to help meet the stress of starting the day, and then decrease in the evening to prepare for sleep. The normal fluctuation of cortisol is the basis of the circadian rhythm, or diurnal variation.

If there is no major change to upset this pattern, diurnal variation quietly functions to provide the body with the optimal levels of the hormones required to respond to various physiologic stressors. Interruptions in this normal biological pattern can occur with interruptions in normal day night patterns, or possibly with administration of exogenous corticosteroids. The effect of exogenous steroid therapy, or shift work, or jet lag, all can affect the body's circadian rhythm of corticosteroid hormones. Administration of systemic steroid therapy often follows an alternate-day regimen, to help minimize the effects of the exogenous steroid on circadian rhythm and hypothalamic CRF production. In addition, systemic steroid therapy that is administered in "boluses" such as with p.o. administration should be done in the morning.

Indications for Glucocorticoids:

In general, indications include an inflammatory process such as atopic processes, asthma, chronic bronchitis, rheumatoid arthritis, bursitis, and soft-tissue or joint injury. In addition, these drugs are useful in conjunction with tissue transplantation because of their reduction of the rejection phenomenon. Finally, these drugs may be used as replacement hormones in patients with adrenal insufficiency.

Contraindications for Glucocorticoids:

These drugs, via their ability to cause fluid retention, can worsen preexisting conditions of heart disease or hypertension. Fluid retention may also elevate intraocular pressure and aggravate glaucoma. Glucocorticoids are relatively contraindicated in conjunction with serious infections, because of their ability to decrease serum antibody concentrations. Because of the ability to elevate serum glucose levels, glucocorticoids can overload the glucose-processing ability in people with diabetic conditions.

Systemic Glucocorticoids:

The major differences in the various glucocorticoids are the duration of action, their potency, and their relative mineral corticoid effects. Potency is expressed as anti-inflammatory action relative to Cortisol (the potency number is h0w many times more potent the drug is versus Cortisol)

Short-Acting Glucocorticoids (8 - 12 hours)

Intermediate-Acting Glucocorticoids (12 - 36 hours)

Long-Acting Glucocorticoids (36 - 72 hours)

INHALED GLUCOCORTICOID THERAPY

In striking contrast to the cushingism and adrenal suppression seen with systemic administration, nonsystemic steroid drugs have virtually no systemic side effects unless high doses are given. At their therapeutic doses, nonsystemic steroids produce a local anti-inflammatory effect without significant systemic absorption.

The local effect is similar to the systemic actions; however, the action of the nonsystemic drug is limited to the site of administration. These drugs typically are in various forms of inhalers. Some are dry powder inhalers (DPI) which use no chlorofluorocarbon (CFC) propellants, some are metered does inhalers (MDI) which do have CFC propellants, and some are sprays that are intended for nasal action alone, to treat seasonal rhinitis or nasal polyps.

These drugs have come to the forefront in the arsenal of medications to combat reactive airway disease. As recently as 12 years ago, these were add-on drugs to include in treatment regimens for relatively severe, difficult-to-manage asthmatics; however, within the last 7 years or so, there has been a greater understanding about the significant role inflammation has in asthma, and these drugs have become the first-line medications in the treatment of moderate to severe asthma. Much research has been done to develop stronger, more potent anti-inflammatory action in new drugs; as a result, there are many new-generation drugs available.

Adverse side effects unique to inhaled steroids include thrush, or oral candida albicans infection. Rinsing the mouth and gargling following administration can avoid this.

It should be reiterated that any inhaled agent has the ability to cause cough and bronchospasm. Nasal preparations may cause sneezing, nasal irritation, or bleeding.

Because of the wide variety of doses seen with inhaled steroids, the specific doses will not be addressed here. Check the package insert or Physicians Desk Reference, but be aware that higher doses than listed are relatively common. Specific drugs include:

Steroids comprise five general groups of complex organic compounds which are produced in the adrenal cortex. The group that has clinical relevance to respiratory therapy is the glucocorticoids. Cortisol and glucocorticoids regulate the metabolism of carbohydrates, fats, and proteins to generally increase levels of glucose for energy to be used by the body. That is why cortisol and its analogues are called glucocorticoids.

One of the major therapeutic effects seen with analogues of natural adrenal cortical hormone hydrocortisone is an antiinflammatory action. Glucocorticoid analogs are used for their antiinflammatory effects in treating asthma, which is basically a disease in which there is chronic inflammation of the airway wall that causes airflow limitation and hyperresponsiveness to a variety of stimuli.

Steroids can be administered orally, intravenously (IV), or aerosolized for respiratory symptoms. The IV drug of choice is usually hydrocortisone or methylprednisolone. Oral drug of choice is prednisone or prednisolone. Aerosolized corticosteroid preparations that have antiinflammatory effectiveness in the treatment of asthma include: hydrocortisone, cortisone, prednisone, prednisolone, and methylprednisolone.

In treating respiratory diseases, steroids are administered orally for more significant exacerbations of bronchospasms, and by IV for serious bronchospasm. However, the potential side effects of systemic administration of corticosteroid treatments are well recognized, and include:

• HPA suppression
• immunosuppression
• increased glucose levels
• fluid retention
• hypertension
• increased white blood cell count
• peptic ulcer
• osteoporosis
• psychiatric reactions
• growth retardation
• myopathy of skeletal muscle
• cataract formation
• dermatologic changes

The quantity, severity, and frequency with which these complicating side effects appear when systemic steroid treatments are used have provided the motivation for transferring patients to aerosolized, inhaled steroids whenever possible. The introduction of synthetic analogues of hydrocortisone, which have a high topical antiinflammatory activity, have paved the way for effectively using aerosolized steroids with little systemic side effects. These drugs include: beclomethasone, triamcinolone, flunisolide, budesonide, and fluticasone.

While the switch to inhaled aerosol steroids has reduced the number of side effects previously seen with systemic steroid therapy, there remain some local and system side effects that need to be considered by caregivers. The following table illustrates the potential hazards and side effects associated with using inhaled aerosol corticosteroids:

1 Following transfer from systemic corticosteroid therapy.

Aerosol corticosteroid therapy is currently considered clinically indicated for:

• control of asthma
• treatment of related steroid-responsive bronchospastic states not controlled by other therapies
• control of seasonal allergic or non-allergic rhinitis

The increased emphasis on viewing asthma as primarily a disease of inflammation leading to bronchial hyperresponsiveness has shifted the indicated use of inhaled aerosol steroids from second or third line to front line, primary therapy. The NIH's 1997 Guidelines for Diagnosis and Management of Asthma now identify aerosolized corticosteroids as long-term control therapy rather than as quick-relief for acute, severe asthmatic episodes.

The late-phase response of allergic induced bronchospasm can be mitigated or prevented by early application of inhaled steroids. In general, steroids do not replace bronchodilators, but should be used to supplement them.

Corticosteroid Medications

Dexamethasone (Decadron) is one of the first successfully aerosolized agents (available since 1976) for inhalation, and it has an antiinflammatory potency of 30 times that of hydrocortisone. However, because it does not potentiate the beta2 receptors and the systemic side effects associated with it, the use of aerosolized dexamethasone has declined in favor of newer medications. It is available as a nasal spray (Turbinaire) and MDI (Respihaler). Each activation of the MDI delivers approximately 0.1 mg. Adult dose is 3 puffs TID or QID, up to a maximum of 12 per day. Pediatric dose is 2 puffs TID or QID, up to 8 per day. Each MDI delivers about 170 puffs.

Beclomethasone dipropionate (Vanceril, Beclovent) was the second aerosolized corticosteroid made available in this country, and is indicated for controlling intrinsic, extrinsic, and mixed asthma in patients over six years of age who require steroid therapy. The drug's success as an aerosol in reducing or replacing the use of systemic steroids is due to its high topical to systemic activity ratio (approximately 500 times that of dexamethasone). Beclomethasone has also been reported to minimize symptoms of perennial rhinitis in patients susceptible to antigens such as pollen.

An aerosol dose of 400 mcg of beclomethasone is approximately equivalent to 5-10 mg of oral prednisone. Adult dose is 0.5 to 1 mg QID. For the Vanceril MDI, one to four puffs are given 3?4 times a day. Each puff delivers about 42 mcg. The maximum daily adult dose is 840 mcg, with the pediatric dosage being about half of this. Asthmatic symptoms decrease in about 80% of patients concurrent with an improvement in pulmonary function. This occurs without the systemic side effects of oral steroids, although Candidiasis has been reported in some cases.

Betamethasone is a synthetic corticosteroid indicated for severe inflammation, immunosuppression, or adrenocortical insufficiency. Its duration of action is similar to dexamethasone, and has about 75% of the potency of beclomethasone. Daily dosage is 4 applications of 200 mcg each.

Triamcinolone Acetonide (Azmacort) an aerosol that is also topically active, and was available as Kenalog and Aristocort prior to its release as an aerosol. Available in an MDI preparation with a built-in spacer device, inhalations doses of about 100mcg, four times daily allow most steroid-dependent asthmatics to stop taking oral steroids. Aerosolized triamcinolone can cause hoarseness, voice weakness, and oropharyngeal candidiasis; however, rinsing the mouth and gargling after use generally prevents these side effects.

Flunisolide (AeroBid), another topically active MDI-packaged aerosol, is similar to triamcinolone in potency, but is longer acting. Like beclomethasone, it shows a peak plasma level after inhalation between 2 and 60 minutes, indicating good absorption from the lungs. Because it is more potent than many steroids, its recommended dosage is reduced: two inhalations (250 mcg each) twice daily for adults, with half of this recommended for pediatric patients.

Fluticasone propionate (Flowvent, Flonase) is a further analogue of previous agents with high topical potency, synthesized in order to avoid systemic side effects. It is part of androstane analogues which has a very weak HPA inhibitory activity, but high antiinflammatory effect. Available as a nasal spray and in MDI form in three different strengths, recommended adult dosage is 44-220 mcg BID. Fluticasone
propionate is contraindicated in patients with acute status asthmaticus, respiratory tract infections, or tuberculosis.

Budesonide is a topically active inhaled corticosteroid less potent than fluticasone, but greater than beclomethasone. After inhalation with a spacer device, peak plasma concentrations occur between 15-45 minutes with a half-life of 2 hours, and there appears to be minimal metabolism in the lung (about 70% of inhaled dose reaches the circulation). The recommended adult dosage is one puff (200 mcg) BID. Half this dose is used for children using a 50 mcg MDI. Budesonide may be given up to 3 puffs (600 mcg) BID, and is available as a nasal aerosol for treating allergic rhinitis.

Hydrocortisone (variety of trade names including Hydrocortone, Acticort, and Cetacort) is a steroid that can be administered orally, parenterally, and only rarely by aerosol. Its plasma concentrations of 100?150 mcg/ml are generally high enough to diminish the symptoms of status asthmaticus. The adult daily dose can range from 300 to 2000 mg.

Prednisone (Deltasone) is an oral steroid in tablet form that has an anti?inflammatory potency 3?4 times that of hydrocortisone. Its onset of action is somewhat delayed because it becomes active only after its been converted to prednisolone in the liver. As an aerosol, it is completely ineffective. Indications include severe inflammation or immunosuppression, nephrosis, or acute exacerbations of multiple sclerosis. Adult dosage is PO 1.5-2.5 BID-QID, followed by once daily or QOD, with maintenance dosage up to 250 mg daily.

Prednisolone (numerous trade names include Prelone, Predicort, Key-Pred) is an intermediate acting synthetic steroid that is available by injection, orally, and is rarely aerosolized. Anti?inflammatory potency is 3?4 times that of hydrocortisone but it takes longer to reach its peak effect. The half?life is 2 to 4 hours and pharmacological effects last up to 36 hours. Usual adult dose is PO 2.5-15 mg BID-QID; IM 2-30 mg Q 12 hours; IV 1-30 mg daily..

Methylprednisolone (Duralone, Medralone, Depopred, et al) has 4-5 times the anti?inflammatory potency of prednisolone, and is used frequently because it has little effect on electrolyte balance. Available orally, but is usually administered intravenously. Methylprednisolone is indicated for severe shock, status asthmaticus, ARDS, and aspiration pneumonia. Onset of action is rapid, half?life is 78?188 minutes, and pharmacological effects remain for up to 36 hours. Dosage varies depending upon symptoms.

Asthma is essentially an inflammatory disorder of the airways, in which allergic stimuli often trigger IgE-mediated mast cell release of mediators of inflammation. Airway reactivity can be triggered by such nonspecific stimuli as cold air or dust. Allergic inflammation of the airway is a product of an immune response, and the T-lymphocyte plays a central role in attracting mast cells and eosinophils, which in turn release mediators that attract other cells and damage epithelial cells.

The clinical result of asthma is a chronic persistent inflammation of the airway, coupled with occasional acute episodes of wheezing and airway obstruction caused by bronchoconstriction, mucosal swelling and mucus secretion. There are drugs available to inhibit the mediators of inflammation, including: cromolyn sodium, nedocromil sodium, zafirlukast, and zileuton. These agents, sometimes referred to as mediator modifiers, are prophylactic and are intended to assist the management of chronic asthma, not to relieve acute airway obstruction or provide bronchodilation in an acute asthma attack. Patients who show an improvement in bronchospastic symptoms with steroids may benefit from mediator modifier

Cromolyn sodium (Disodium Cromoglycate) is considered an antiasthmatic, antiallergic, and mast cell stabilizer. Cromolyn is available as a dry powder inhaler, a nebulizer solution, and an MDI. It does not block cholinergic, muscarinic receptors, and has no intrinsic bronchodilating capability. Pretreatment with inhaled cromolyn sodium results in inhibition of mast cell degranulation, thereby blocking release of the chemical mediators of inflammation. While the dosage varies at the discretion of the physician, the usual adult dose of cromolyn is 20 mg TID or QID.

Nedocromil sodium (Tilade) is another prophylactic drug used in the management of mild to moderate asthma. It exerts its antiinflammatory and antiasthmatic effect by inhibiting the activation and activity of multiple inflammatory cells, including mast cells, eosinophils, airway epithelial cells, and sensory neurons. Available as an MDI with 1.75 mg per actuation, the recommended dosage for maintenance therapy in asthma is two inhalations 4 times a day.

Zafirlukast (Accolate) is a relatively new (approved for use in U.S. in 1996) prophylactic agent that acts on a portion of the inflammatory process as a leukotriene receptor antagonist, preventing the inflammatory response of airway contractility, vascular permeability, and mucus secretion caused by certain leukotrienes.

While its been in use a relatively short period of time, Zafirlukast gives evidence of being effective in preventing bronchoconstriction and other asthmatic airway responses, against LTD4-induced constriction, allergen, exercise, and cold air challenge. Side effects have included headache, respiratory infection, nausea, diarrhea, generalized and abdominal pain.

Zileuton (Zyflo) also new (approved in 1997), inhibits the 5-lipoxygenase enzyme, which would otherwise catalyze the formation of leukotrienes from arachidonic acid. It is indicated for the prophylaxis and chronic treatment of asthma in patients over 12 years of age, and has been effective in attenuating the asthma response to allergen challenge, cold air, and aspirin challenges. It is available in a 600 mg tablet form, with dosage being recommended at one tablet 4 times daily.

There are at least four classes of drugs which provide antiinflammatory activity within the arachidonic acid cascade, and which are being investigated for possible use in assisting the treatment of asthma (some only have code names at this time):

1. Cysteinyl LT antagonists
   Zafirlukast, ICI-204, 219 (Accolate)
   Pobilukast, SKF 104353-Q
   Pranlukast ONO-1078
   Verlukast MK-679
   
   
2. 5-lipoxygenase inhibitors
   Zileuton, A-64077 (Zyflo)
   Z-02128
   
   
3. FLAP binding inhibitors
   M-886
   MK-0591
   BAY x1005
   
   
4. LTB4 antagonists
   ONO-4057
   U-75,302

Inhibitors of 5?lipoxygenase either inhibit the enzyme directly or bind to a membrane protein called FLAP. FLAP then combines with 5?lipoxygenase to inhibit leukotriene synthesis. Zileuton is an agent that directly inhibits 5?lipoxygenase. While there are still questions regarding the usefulness of blocking the synthesis or activity of a single family of mediators such as leukotrienes, there has been a high efficacy in clinical trials of these drugs that supports the thesis that these may prove useful in the future.

Prostaglandins

Prostaglandins are synthesized in all tissues, and the three that are of substantial interest in respiratory therapy are PGE1, PGE2, AND PGF2A. The first two because they cause relaxation of bronchial smooth muscle, and the latter because it causes contraction of bronchial muscle. Prostaglandins, unlike adrenergic or anticholinergic drugs, act directly on smooth muscle.

Prostaglandins are used for vasodilation of the pulmonary vascular bed in patent ductus arteriosus (PDA). Increased pulmonary vascular resistance in PDA helps maintain a shunt through the patent ductus, and lowered resistance allows more blood to flow through the pulmonary system and less through the ductus. It is important to release the prostaglandin via a line located distal to the ductus, otherwise the ductus becomes dilated and the problem is worsened.

Anticholinergic bronchodilators

Anticholinergics or parasympatholytic bronchodilators, which are also often referred to as antimuscarinics because they act at the muscarinic receptors of the parasympathetic nervous system, achieve bronchodilation through a different pathway in the autonomic nervous system. As a result, anticholinergics can be used either alone or in combination with beta adrenergics.

Because they tend to decrease secretion production, drying of the airways can be a problem if significant doses are administered. Additional side?effects can include: drying of the mouth and skin, blurred vision, and an increase in speech, swallowing, and micturition problems. Among these drugs, the most common include:

Atropine sulfate which has traditionally been the model antimuscarinic bronchodilator agent used in the treatment of airway disease. It has an additive effect to the Beta-adrenergic agonists when given together. However, the development and increased use of adrenergic drugs has tended to gradually displace atropine as a bronchodilator.

Atropine is available as a nebulized solution administered via injection or aerosol (Dey-Dose). Because it is a tertiary ammonium compound, atropine is readily absorbed by aerosol, and side effects are seen in the dosages required for effective bronchodilation. Duration and incidence of side effects are therefore dose dependent. Normal inhaled dose for atropine is around 0.025 mg/kg for adults (2.5 mg per 24 hours maximum), with onset in 15 minutes, peak at .5-1.0 hour, and duration 3-4 hours. Atropine is also available in tablets and elixirs.

Ipratropium Bromide (Atrovent) is approved specifically for the maintenance treatment of airflow obstruction in COPD. It is considered a first-line medication for COPD patients, particularly those with chronic bronchitis. It is currently available in two formulations for bronchodilator use: an MDI with 18 mcg per puff, and a nebulizer solution of 0.02% concentration in a 2.5 ml vial, providing a 500 mcg dose per treatment. Usual adult dose is 2 puffs QID via MDI (12 puffs per 24 hours maximum).

The side-effects of antimuscarinics are minimal or absent in most patients using ipratropium, and systemic absorption via the GI tract and mucosal surface is also minimal. It has an additive effect to the Beta-adrenergic agonists and, provides better bronchodilation for many COPD patients. It should be delivered prior to Beta agonists in order to achieve the best results.

Some other antimuscarinics include:

Glycopyrrolate, a derivative of atropine, which is usually administered parenterally, is used as an alternative to atropine because it has fewer ocular or central nervous system side effects. The injectable solution has been nebulized into a 1 mg dose for bronchodilation.

Oxitropium bromide is a derivative of scopolamine that has been investigated as an aerosolized anticholinergic bronchodilator in patients with obstructive airway disease. An MDI-delivered dose of 200 mcg provides a peak effect on FEV1 within 1-2 hours, with a duration of 6-8 hours. Normal dosage is 2 puffs BID or TID, and systemic anticholinergic effects are rare. Side effects include local irritation of the throat and nose, dry mouth, nausea, wheeze, cough, and a tightness in the chest in a few patients.
Tiotropium bromide is still an investigational, long-acting antimuscarinic drug that may offer an attractive and safe alternative for maintenance treatment of COPE, and protection for nocturnal asthma.

Vasoactives encompass a general group of chemicals that some of which can cause vasodilation to respond to hypertension, and others of which cause vasoconstriction to respond to hypotension. Also worth briefly noting along with this discussion is the importance of diuretics for treating hypertension. While not vasoactive, they still have an important role to play in correcting high blood pressure.

Before discussing vasoconstrictors, it would be appropriate to review shock, or hypotension, and its various forms and causes.

Hypovolemic shock is the result of the loss of intravascular volume. This loss of volume may be real, as with hemorrhage, or it can be an effective volume loss, such as occurs with post-traumatic systemic vasodilation. The result is the same: a decrease in cardiac preload and a consequent drop in both cardiac output and oxygen delivery to the tissues. Problems in contractility generally do not accompany hypovolemic shock, unless there is preexisting cardiac disease or if the blood volume falls to such critically low levels that coronary circulation is impaired.

The body's response to hypovolemic shock is to compensate by
1) shifting fluid from the interstitial space to the intravascular space;
2) reducing urinary output by increasing the reabsorption of sodium in the kidneys, and
3) increasing antidiuretic hormone (ADH) which prevents the loss of solute-free water by the kidneys. In addition, cardiac compensatory mechanisms act to re-establish cardiac output by increasing the heart rate.

The treatment of hypovolemic shock is composed of two concurrent strategies: First, the effective and rapid control of any volume loss, for example by controlling hemorrhage; and second, replenishment and maintenance of the volume lost and the restoration of normal cardiovascular mechanisms through the appropriate selection of replacement fluids and the use of pharmacologic agents that support blood pressure and maintain the delivery of oxygen.

Cardiogenic shock is hypotension that results from an inability of the heart to pump away the blood volume returned to it. The approach to the management of cardiogenic shock depends on whether the patient has pulmonary edema, which is usually assessed by an evaluation of chest x-ray and a measurement of pulmonary capillary wedge pressure (PCWP). Recall that PCWP measures left ventricular end-diastolic pressure (LVEDP) and reflects the preload on the left heart. In cardiogenic shock, if the PCWP is less than 18 mm Hg (normal) cardiogenic pulmonary edema is unlikely. In this case, fluid loading is attempted while the PCWP is monitored to judge the degree of ventricular compliance. If the presence of pulmonary edema is documented by a PCWP of greater than 18 mm Hg, diuretics, vasodilators, and inotropic agents may be used. In addition, antiarrhythmic agents, circulatory assist devices, and cardiac surgery may be indicated.

Septic shock results from an infective agent in the blood, which causes changes in the systemic microvasculature. A high cardiac output, a normal pulmonary vascular resistance, and a systemic vascular resistance that is low characterize septic shock. Microvascular changes shunt blood from arterial to venous systems bypassing tissues; as a result, the oxygen saturation of mixed venous blood is typically high.

As in hypovolemic shock, the restoration of intravascular fluid volume is indicated unless cardiac problems or fluid overload complicate the situation. Indices of particular value are the serum lactate, oxygen uptake (VO2) and oxygen delivery (DO2). If preload correction does not result in an improvement in the delivery of oxygen, inotropic agents and afterload reduction must be considered.

The appropriate identification of the underlying septic conditions is necessary for the control of septic shock, with appropriate selection of antimicrobial therapy. However, the origin of a septic condition may not be identified.

Pharmacologic Agents for Preload Correction. A high preload indicates that the heart is not pumping away the blood volume that is returned to it; in such cases, an inotropic agent should be considered, depending on the mechanism for increasing the preload. Some instances of atrial fibrillation or flutter can increase preload secondary to the loss of the "atrial kick" and an agent such as antiarrhythmics or digitalis preparations should be considered.

A low preload in the face of a low systemic blood pressure suggests shock, and volume replacement therapy should be instituted. This discussion will not address the rationale for the various choices for fluid replacement therapy; however, the following are the major categories of volume replacement therapy:

AFTERLOAD REDUCTION AGENTS: VASODILATORS

Since the 1970s, vasodilators have been shown to be improving hemodynamics through afterload reduction in patients with heart failure, mitral or aortic valvular disease, or cardiogenic shock. Therapy for cardiogenic shock begins typically with optimization of preload. 50 ml fluid challenges with normal saline are used in succession, while monitoring the PCWP. When PCWP is below 18 mm Hg, additional fluid challenges are given until either the blood pressure stabilizes, or the PCWP rises above 18 mm Hg. When that occurs, and provided the MAP is not less than 50 mm Hg, vasodilator therapy is begun to decrease afterload. Refractory situations may call for inotropic agents, mechanical assist devices, or cardiac surgery.

Vasodilators may be classified according to their predominant site of action:

Arterial Vasodilators

Hydralazine induces a relaxation of arteriolar smooth muscle by a mechanism that is not yet clear. By its effect on arteriolar resistance, hydralazine increases cardiac output and stroke volume through reduction of afterload. The drug may be given orally, but the preferred method is intravenously provided the patient is in an intensive care unit. The side effects are headache, nausea, vomiting, cardiac and GI complaints. Administration of Hydralazine over a period of at least several months may induce a collagen-vascular syndrome suggestive of systemic lupus erythematosus; the syndrome usually subsides after the drug is withdrawn, but may persist for long periods.

Minoxidil is another vasodilator used for decreasing afterload by relaxation of systemic arteriolar smooth muscle. The preparation is only available in p.o. form. A side note is that chronic use of minoxidil was noted to slow or reverse male pattern baldness, and a topical preparation was developed: Rogaine.

Venous Vasodilators

Nitrates have been used extensively for more than a century for the treatment of anginal symptoms. Nitrates activate guanylate cyclase and thereby increase guanosine monophosphate (c-GMP) in vascular smooth muscle. Nitrates are believed to exert their smooth muscle relaxing effect by forming nitrous oxide (NO), which is thought to be related to the body's own vascular relaxing factor, endothelium-derived relaxing factor, or EDRF.

In a healthy patient, one without heart disease, the sublingual application of nitroglycerin decreases cardiac output. The arterial dilation of the face and neck, which may accompany the use of this drug, produces a characteristic flushing and headache.

However, in a patient suffering from angina, the relief of coronary insufficiency by nitroglycerine may result from a reduction in both preload and afterload and a resultant decrease in the myocardial oxygen requirement, and also from coronary dilation in the case of coronary spasm (Prinzmetal Angina). In acute cardiac failure, the reduction of preload and afterload increases cardiac output.

Nitroglycerin is far less effective in patients with chronic cardiac failure. In the critical care setting, nitrates are administered IV in the interests of quick administration and rapid discontinuation. The principle side effects are headache and cardiac insufficiency in the case of rapid withdrawal.

Arterial & Venous Vasodilators

Nitroprusside is an extremely powerful drug that, given intravenously via infusion, treats hypertensive emergencies and is also useful for the treatment of severe refractory heart failure. This drug reduces both preload and afterload, as it dilates both venous and arteriolar vessels. Its effect begins very rapidly and disappears within minutes after the infusion is stopped. By titrating the intravenous drip, blood pressure may be maintained at normotensive levels. Administration of excessive amounts of the drug may lead to hypotension, and its prolonged use leads to an accumulation of cyanide, the drug's metabolite. Toxicity usually occurs two to three days following initiation of administration, so that substitution to other vasodilator drugs should be accomplished before that time.

Captopril is the first agent in a series of antihypertensive agents that work by inhibiting the renin-angiotensin system. Other agents in this category include enalapril and lisinopril.

Renin is an enzyme that is stored in the juxtaglomerular cells within the kidneys. When renin is released into the circulation, it transforms angiotensinogen to angiotensin I. Then, angiotensin I is transformed into angiotensin II by the action of angiotensin converting enzyme (ACE), which is located in the membranes of the endothelial cells that line the pulmonary vasculature. Angiotensin II is a potent vasopressor that increases afterload; it also stimulates release of aldosterone to promote sodium retention. When electrolytes are retained, so is fluid, and as a result, intravascular volume increases also.

In a patient with severe heart failure, captopril improves cardiac function by both a reduction in afterload and a reduction in preload. As such, these agents are useful for the treatment of heart failure that is refractory to diuretic and other conventional therapies. The drug is increasingly becoming a first-line drug for the treatment of CHF.

Captopril is an oral agent that is generally tolerated well. Side effects include an intractable cough, hypotension, and some blood disorders.

AFTERLOAD AUGMENTATION AGENTS: VASOPRESSORS

The goal of vasopressor and inotropic agents is to both ensure the perfusion of vital organs by enhancing cardiac output and ensuring a more appropriate distribution of blood flow. Like inotropes, the principle agents used as vasopressors are catecholamines, exerting their action via alpha-adrenergic receptors in the arteriolar smooth muscle. All have similar toxicities, namely, induction of tachyarrhythmias, myocardial ischemia and angina, and even possibly myocardial infarction and severe hypertension. All these catecholamines require the correction of any fluid deficits or pH abnormalities (particularly acidic pH) for proper function.

Epinephrine

This drug is an endogenously produced hormone whose primary source is the adrenal gland, and it appears to be a hormone that is important to the homeostasis of the body's hemodynamic equilibrium. It is potent for both alpha and beta receptors, but because of its very potent alpha effects it is a strong vasoconstrictor that causes a rise in both systolic and diastolic systemic pressures. Cardiac output is increased as a result of increases in both stroke volume and heart rate. Its use in shock, particularly that associated with myocardial disease, is somewhat limited because of its potential to cause ventricular arrhythmias. It is also commonly used for the treatment of anaphylaxis and status asthmaticus.

Norepinephrine

Norepinephrine (Levarterenol, Levophed) is also an endogenous catecholamine from the adrenal gland, but the more important role of this chemical is that of neurotransmitter for the sympathetic nervous system. As with epinephrin, Norepinephrine exerts stimulation strongly on alpha and less strongly on beta-receptors; however, its action is, in general, less potent than epinephrine. Intravenous administration of norepinephrine results in an increase in both systolic and diastolic systemic blood pressure, with a resultant increase in mean arterial pressure (MAP). Systemic vascular resistance is increased with the use of this drug, and in particular, the blood flow to the kidneys is reduced. Heart rate tends to stay normal because of vagal reflexes, and cardiac output is increased generally because of an increase in stroke volume alone. This drug has such vasoconstrictive properties that it should be only administered via a central line, lest tissue damage should occur at a peripheral administration site.

As discussed earlier adrenergic bronchodilators are the most widely used of all medications in respiratory therapy. The name adrenergic comes from their ability to act like adrenaline on the beta sites and cause smooth muscle relaxation.

At the effector site, the bronchial smooth muscle cell, the stimulation of the beta site results in the stimulation of adenyl cyclase, which in turn catalyzes the formation cyclic 3',5' adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The presence of cAMP causes the smooth muscle to relax, leading to bronchodilation. cAMP is inactivated by the enzyme phosphodiesterase into AMP, losing the bronchodilatory effect. Stimulation of the bronchial smooth muscle beta site, whether by sympathetic system or by sympathomimetic drug, increases the level of 3'5' AMP, and results in dilation.

The bronchodilating action of the adrenergic drugs is primarily caused by stimulation of beta2 receptors located on bronchial smooth muscle. In addition, some adrenergic bronchodilators can stimulate alpha and beta1 receptors. The clinical effects of these stimulations include:

• Alpha-receptor stimulation causes vasoconstriction and a vasopressor effect; in the upper airway (nasal passages) this can provide decongestion.
• Beta1 receptor stimulation causes increased myocardial conductivity, increased heart rate, and increased contractile force.
• Beta2 receptor stimulation can cause:
  relaxation of bronchial smooth muscle
  inhibition of inflammatory mediator release
  stimulation of mucociliary clearance

The general indication for the use of adrenergic bronchodilators is relaxation of airway smooth muscle to reverse or improve airflow obstruction. They are used clinically to reverse bronchoconstriction seen with asthma, acute and chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, and other obstructive airway diseases.

The sympathomimetic bronchodilators are all either catecholamines or derivatives of catecholamines. Catecholamines, or sympathomimetic amines, mimic the actions of epinephrine fairly precisely, causing tachycardia, elevated blood pressure, smooth muscle relaxation of bronchioles and skeletal muscle blood vessels, glycogenolysis, skeletal muscle tremor, and central nervous system stimulation.

Complications

The effects of bronchodilators, including the side effects, occur as a result of the aerosolized medications being absorbed into the circulation. The most common complications experienced in relation using adrenergic bronchodilators include:

While all patients using adrenergic bronchodilators will experience one or more of these side effects, some will be more sensitive to the adverse effects than others. Careful monitoring is essential when treating respiratory patients with adrenergic bronchodilators, and should include:

• assessment of pulse and respiratory rate before, during and after treatment
• auscultation of lungs before and after treatment
• observation for systemic symptoms of side effects such as tremor, sweating, or fatigue

Treatments should be suspended or terminated should serious side effects occur.

1-16. ANTITUSSIVE AGENTS

a. Background. Antitussives are agents that relieve or prevent coughing. These agents, in general, act on the central nervous system to depress the cough reflex center in the medulla of the brain. Antitussives are used to reduce respiratory irritation. Such reduction of respiratory irritation results in the patient’s being able to rest better at night because he is not kept awake by his coughing.

b. Antitussive Agents.

1. Codeine. Codeine is considered to be the most useful narcotic antitussive agent. Codeine aids in relieving the pain (that is, producing analgesia) associated with a hacking cough. The main side effects associated with codeine include drowsiness, nausea, vomiting, and constipation. When a preparation containing codeine is dispensed to a patient that patient should be told that the product may cause drowsiness, and that he should not drink alcohol while taking the medication. Codeine is a Note R drug alone and cannot be refilled. It is a Note Q item when it is found in combination products (for example: Robitussin A-C Syrup). The usual oral dosage of codeine alone is 15 milligrams (1/4 grain) every 4 to 6 hours as needed for cough. The dosage can be increased but should not exceed 120 milligrams in 24 hours because of its central nervous system (CNS) depressant effects.
2. Benzonatate (Tessalon®). Benzonatate is a nonnarcotic antitussive that produces its effect through a CNS depressant effect similar to codeine. Furthermore, it produces a local anesthetic effect on the stretch receptors in the lower respiratory tract, which control coughing. Benzonatate is usually given in 100 milligram doses--three to six times daily. This drug has few side effects except that it will numb the mouth, tongue, and pharynx if the capsules are chewed (this is because of its topical anesthetic effect). Benzonatate is available in the form of 100 milligram capsules.
3. Dextromethorphan, DM (Pertussin CS®). Dextromethorphan is another non-narcotic antitussive. It is found alone or in combination--usually with expectorants. The most common side effect associated with this drug is gastrointestinal (G.I.) upset. Dextromethorphan is a non-legend drug, which may be written as a prescription drug or as a hand-out item depending on the local policy of your hospital. The usual oral dosage of this drug is 10 to 30 milligrams, every four to eight hours. Do not exceed 120mg in 24 hours. There are many products on the market, which contain dextromethorphan in combination. Examples of such products include Robitussin-DM® and Baytussin-DM®.

1-17. EXPECTORANT AGENTS

a. Background. Expectorants are agents, which facilitate the removal of secretions of the bronchopulmonary mucous membrane. Most of the expectorants discussed below act reflexively by irritating the gastric mucosa. This, in turn, stimulates secretions in the respiratory tract. Expectorants are used to remove bronchial secretions which are purulent (containing pus), viscid (thick), or excessive. The loosened material is then moved toward the pharynx through ciliary motion and coughing.

b. Expectorant Agents.

1. Guaifenesin (Robitussin®, Baytussin®). Guaifenesin is the most commonly used expectorant today. This nonlegend drug has the side effect of gastrointestinal (G.I.) upset. Guaifenesin may be found alone as a syrup (100 milligrams per 5 milliliters), tablet 600 mg (Humibid® L.A.), or in many combination products such as Robitussin-DM®.
2. Saturated Solution of Potassium Iodide. Saturated Solution of Potassium Iodide (SSKI) is an expectorant administered as 300 milligrams (10 drops) in a glass of water or fruit juice every three or four times daily. SSKI has a very unpleasant taste. Overdoses of this product may lead to a condition known as iodism that produces an acne-type rash, fever, and rhinitis or runny nose. Patient compliance with this product may be low because of its unpleasant taste. Consequently, when the medication is dispensed you should tell the patient to place the required amount of SSKI in fruit juice in order to mask its taste. This drug is available in a saturated solution of 1 gram per milliliter in 30 milliliter containers.
3. Elixir of Terpin Hydrate. Elixir of Terpin Hydrate (ETH) is an expectorant, which works directly on the bronchial secretory cells in the lower respiratory tract to facilitate the removal of bronchial secretions. It is usually given in doses, which range from 85 to 170 milligrams (1 or 2 teaspoonsful) 3 or 4 times daily. The side effects of this drug are related to its alcohol content (42 percent or 84 proof). If enough ETH is consumed it will produce significant CNS depression. Even with the high alcohol content, ETH is an Over the Counter (OTC) product. It is available as a syrup (85 milligrams per 5 milliliters) in 120 milliliter containers.
   NOTE: Terpin Hydrate is no longer approved for use as an expectorant; it is used mainly as a vehicle for cough mixtures.

1-18. ANTITUSSIVE-EXPECTORANT COMBINATION PRODUCTS

The antitussive-expectorant combinations are used for a hyperactive nonproductive cough. The side effects of these drugs, or course, will be dependent on the antitussive-expectorant combination used. Some typical combination products used by the military are Robitussin-DM®, Robitussin® A-C Syrup, and Novahistine® Expectorant Liquid.

1-19. MUCOLYTICS

a. Background. Mucolytics are respiratory drugs that dissolve mucous in the respiratory tract. They are used by inhalation in an attempt to reduce the viscosity (thickness) of respiratory tract fluid. The loosened material can then be moved toward the pharynx more easily by ciliary motion and coughing. Like the expectorants, the mucolytics are used in the treatment of respiratory disorders in which the secretions are purulent (contain pus), viscid, or excessive. Consequently, the mucolytics represent an alternative to the oral use of expectorants.

b. Mucolytic Agents.

1. Acetylcysteine (Mucomyst®). This is a mucolytic given by inhalation or nebulization. Nebulization is treatment by spray. Two to twenty milliliters of a 10 percent drug solution or 1 to 10 milliliters of a 20 percent Mucomyst® solution is nebulized into a face mask or mouth piece every two to six hours daily. Acetylcysteine has an unpleasant (like rotten eggs) smell. Side effects associated with this agent include nausea and vomiting and broncho-spasms with higher concentrations (with the 20 percent solution). This medication is only dispensed for inpatient use--usually to the respiratory therapy clinic or to the nursing station. The sterile solution should be covered, refrigerated, and used within 96 hours after the vial is opened. It is available in 10 percent and 20 percent solutions in containers of 4, 10, or 30 milliliters.
2. Sodium Chloride Solution U.S.P. (0.9 percent sodium chloride solution). This agent is used alone or in combination with other mucolytic agents. Sodium chloride solution increases the respiratory fluid volume by osmosis, which tends to decrease the viscosity of the respiratory fluid. It is also administered by inhalation in a nebulized form as a dense mist in a tent or delivered through a face mask or mouth piece. The main side effect seen with sodium chloride solution occurs after prolonged inhalation. This will cause localized irritation of the bronchial mucosa. Sodium chloride solution for this purpose is for inpatient use by respiratory therapy personnel or by nursing personnel. Concentrated Sodium Chloride (23.4%) is used by respiratory therapy to induce sputum production (sputum induction procedure).

This class of drugs encompasses those agents that improve the overall effectiveness of the mucociliary system of the pulmonary tree. To get an understanding of this system let’s do an anatomy and physiology review.

The mucous blanket of the normal lung consists of a highly viscous mucopolysaccharide 'gel' layer, which floats on top of a low-viscosity serous 'sol' layer. The interesting nature of the gel layer is that, although it is mostly comprised of water, it is relatively impervious to, and insoluble in water. In addition to the mucopolysaccharides, it has proteins, lipids, and carbohydrates. All these components have varying degrees of water-insolubility.

A balance between the goblet cells and the mucous glands in the airways produces the secretions in normal lungs. The goblet cells are primarily responsible for producing the gel layer, whereas the bronchial mucous glands produce most of the watery sol layer. The goblet cells are under local control, increasing their production mainly in response to local irritation from, for example, noxious gasses (such as cigarette smoke) or infective agents.

The mucous glands can respond locally, but they are mainly under central control through vagal nerve stimulation. Therefore, drugs that act locally, through topical cholinergic stimulation, or systemically, though agents that evoke a vagal response can affect the bronchial glands. Oral expectorants such as glyceryl guaiacolate or the iodides (found in common over-the-counter expectorants) act by evoking a vagal response by irritating the lining of the stomach.

Within the sol layer, tiny fibers called cilia beat at a rate of approximately 60 times per second. There are nearly 6000 cilia on each epithelial cell lining the airways, each approximately 4-6 microns long. The cilia beat together in a pattern that looks much the same as when a breeze creates waves in a field of grain. Chemical and physical agents, being increased by adrenergic drugs and methylxanthines, also affect ciliary activity. In contrast, ciliary activity is decreased by dehydration, cigarette smoke, ozone, alcohol, and anticholinergics such as atropine. Ipratropium Bromide (Atrovent) does not appear to affect mucociliary beat frequency (MCBF)

Therefore, normal secretion clearance depends on correct composition of the sol and gel layers, as well as optimum functioning of the ciliary system. Mucokinetic therapy aims to maintain or improve functioning of the mucociliary mechanism, thereby promoting effecting secretion mobilization and clearance.

Mucokinetic drugs fall into one of five categories: diluting or hydrating agents, wetting agents, mucolytics, proteolytics, and ciliary stimulants.
One of the major clearing and defense mechanisms of the airway- conducting zone of the lung is referred to as the mucociliary system. Mucokinetics is primarily concerned with the movement of mucus in the respiratory tract, and the overall effectiveness of the mucociliary system.

The effectiveness of the system depends largely on the interactions between the cilia and the mucus blanket, whose composition represents a delicate balance between the secretions of the goblet cells and bronchial glands. Failure of this system results in mechanical obstruction of the airway with thickened, adhesive secretions. A significant slowing of mucus transport is associated with the abnormal mucociliary function seen in bronchitis, asthma, and cystic fibrosis. Mucokinetic therapy is designed to maintain or improve functioning of the mucociliary mechanism, thereby promoting clearance of respiratory tract secretions and reducing the potential for infection.

Mucokinetic/mucolytic agents achieve their effect through a variety of ways, including:

• acting directly upon the chemical constituents of mucus to decrease mucus viscosity or tenacity
• diluting the mucus resulting in disadherence from the airway
• making the ciliary action more effective by replenishing or increasing the watery sol layer of mucus
• directly stimulating the cilia
• stimulating the bronchial glands to produce secretions that are less viscous
• a combination of several of these actions

DILUTING or HYDRATING AGENTS

Of all the agents used to modify the character of pulmonary secretions, none is more important than water. Water can be aerosolized or vaporized, but THERE IS NO SUBSTITUTE FOR ADEQUATE SYSTEMIC HYDRATION. Any patient for whom secretions present potential problems should be assessed for their systemic hydration. Two good rules of thumb for normal adults are approximately 100 cc of water per hour, or approximately 1.4-1.6 cc/kg/hr. Water is one of the few agents we can use that has no side effects unless taken in extremely large quantities. Wherever there are no fluid restrictions, systemic water should be used first, and generously for patients having difficulty mobilizing bronchial secretions.

Water is one of the most important and safest agents used to modify the character of respiratory tract secretions. Consumption of adequate amounts of water is crucial for optimal functioning of the respiratory system, and is even more important for a patient who has difficulty mobilizing bronchial secretions. Water can also be vaporized or aerosolized for delivery to patients whose upper airway has been bypassed by intubation. However, caution should be taken to avoid either over- or under-hydration if normal mucus is to be achieved. This is especially true for patients on fluid restriction or with congestive heart failure.

Aerosolized water is at best only marginally effective for enhancing mucociliary clearance. Remember that pulmonary secretions are largely made of water, but are relatively water-insoluble. Water applied systemically allows secretions to be made more thinly in the first place; however, topical water does little more than coat the secretions. The next time you have a really good, raging chest cold with lots of thick, nasty junk to be coughed out, try a little experiment. Get a clear glass and fill it with water. Get a spoon and then cough up a nice sizable bit of gook from your lungs. Spit the creature into the water and stir. What you should notice is that the little critter does not dissolve, it merely swims around. That is because the secretions aren't water soluble, and are not thinned to any great degree by adding topical water.

Water may be aerosolized in various forms. Sterile water is sometimes used, but is a bit irritating to the airways because of its hypotonism. Normal saline (0.9% NaCl) is also frequently used, and is less irritating; however, as the aerosol is inhaled the water droplets may evaporate to a certain extent and as this occurs, the actual salinity of the particles will increase, because the water decreases but the salt stays. For this reason, half-normal saline (0.45% NaCl) is sometimes used. Hypertonic saline (1% to 15% NaCl) is used for sputum inductions.

Saline (NaCl) is commonly nebulized for diluting the mucus and enhancing clearance, and small amounts (1-3 cc) of normal saline (0.9% NaCl) are used to dilute other medications for aerosolization. Like water, saline is absorbed into the sol layer to disadhere mucus from the airway. Many clinicians prefer to use half-normal saline (0.45% NaCl) for mucosal hydration, especially with ultrasonic nebulization, because the evaporation of water from droplets of this solution results in a solute concentration like that of normal saline.

Hypertonic saline solutions (1?15% NaCl) are the agents of choice for sputum inductions, because its elevated osmolarity can result in increased movement of fluid into the bronchorrhea. These solutions are obviously contraindicated for sodium-restricted patients.
The increased salinity is thought to possibly promote bronchorrhea through increasing the osmolarity of the mucous blanket. Also, the hypertonism is irritating to the airway, and may promote coughing. Care should be taken in regard to frequent or repeated use of hypertonic saline in sodium-restricted patients. In practice, the use of hypertonic saline is also only marginally effective at best in creating a productive cough with expectoration.

Propylene Glycol, which is both a solvent and hygroscopic agent, is used to stabilize aerosol droplets from bronchodilators and to inhibit the potential for bacterial growth. It is safe in low concentrations, creating a soothing effect on the respiratory mucosa. In concentrations greater than 5%, it is often used to induce sputum.

Oral Expectorants

This class of drugs is mimokinetic through promoting dilution of mucus indirectly. Examples of this class include potassium iodide; commonly referred to as SSKI (saturated solution of potassium iodide), and currently the most frequently used expectorant, guaifenesin (glyceryl guaiacolate). In addition, this class of drugs includes some common home remedies such as spices, garlic, or onion. All these agents work by irritating the lining of the stomach, thereby stimulating the afferent fibers of the vagus nerve. Impulses sent to the CNS elicit an efferent vagal response, stimulating bronchial glands to increase secretion.

WETTING AGENTS

These are chemical substances designed to lower the surface tension of respiratory tract fluids.

Some agents represent true detergents, interacting with the mucus to produce emulsification of the hydrophobic bonds between water and the mucopolysaccharide molecules. In concept, these agents should disperse the mucus into smaller particles, thereby improving water penetration and facilitating transport and removal. This, however, has not been shown. Currently, there are no true detergents on the market; two detergents have been offered on the market in the past, Alevaire and Tergemist. Both these preparations were withdrawn from the market due to unproved efficacy.

Ethyl Alcohol (ETOH) is a wetting agent that has been used to destabilize the alveolar plasma exudates occurring in cardiogenic pulmonary edema. It acts to destabilize the froth observed in the alveoli and bronchioles in cardiogenic pulmonary edema. Normally, 5-15 mL of 30-50% ETOH is vaporized by positive pressure. Temporary irritation of the airway mucosa is the only side effect experienced in this treatment.

Ethyl alcohol acts by destabilizing the alveolar plasma exudates in acute cardiogenic pulmonary edema. The characteristic thin, watery exudate that fills the alveoli and bronchioles in cardiogenic pulmonary edema contains a significant amount of surfactant from the pulmonary alveoli. Because of this, it tends to foam, and does not easily mobilize upward through the tracheobronchial tree. The stable bubbles that are formed can obstruct ventilation, decreasing gas exchange.

Introduction of ethyl alcohol probably destabilizes these bubbles by changing the properties of the lecithin component of the surfactant, and increases surface tension, thereby allowing the bubbles to burst. Normally, 5 - 15 cc of 30% - 50% ethyl alcohol is nebulized. The only side effect is airway irritation. We used to have a small bottle of Smirnoff's vodka in the equipment we took on aeromedical transport years ago. The vodka has the appropriate alcohol content and can be used without dilution.

MUCOLYTICS

The high viscosity of sputum in certain respiratory diseases is largely due to the mucoproteins found in pulmonary secretions. One of the early substances studied was L-cysteine, a naturally occurring amino acid. The results of L-cysteine were very favorable in terms of its ability to break the proteinaceous bonds within sputum; however, it had substantial irritating properties. These irritating properties were minimized by chemically altering the acid into an acetyl form. The resultant N-acetylcysteine is the generic name of Mucomyst. Within the protein molecules of sputum, there are two chains of proteins held together with a disulfide bond; that is, both chains have a sulfur atom such that the two sulfur atoms bind together. Mucomyst breaks up the chain by replacing the sulfurs with weaker bonds between sulfhydryl molecules.

Mucomyst is available in a 10% and a 20% solution; the 10% is just as effective as the 20% solution, while the latter exhibits stronger tendencies toward irritation and bronchospasm. Therefore, it is common to nebulize 3-5 cc of the 10% solution, or dilute the 20% solution to make a 10% solution. It is most common (and very advisable) to co-administer a beta agonist bronchodilator with Mucomyst to minimize bronchospastic side effects, although the Mucomyst package insert specifically states that this is unnecessary.

The only other significant recognized side effect is patient complaint of the unpleasant rotten-egg odor characteristic of the drug. One unpublished study suggested that Mucomyst might cause eye tissue breakdown. In this study, Mucomyst was nebulized, with the mist directed at a cow eye sitting in a Petri dish. After several hours, there was visible tissue breakdown on the eye. For this reason, it is advisable that Mucomyst should not be nebulized into infant oxygen hoods or isolettes.

Mucomyst is fairly well-recognized and commonly used for its potential for thinning sputum; however, some studies suggest that while it has been shown effective with in vitro testing, it has not shown any benefit in patients and is of insignificant clinical value. A second drug has been widely used to thin secretions, but is not commonly used anymore because of the popularity of Mucomyst. I personally feel that nebulization of Sodium Bicarbonate should be considered when choosing a mucolytic agent. The large mucoid molecular chains in sputum tend to break as the pH of their environment rises, and local bronchial alkalinity can reach a pH of 8.3 without untoward irritation or tissue damage. Nebulizing 3-5 cc of pediatric strength (4.2%).

Sodium Bicarbonate has been fairly useful in thinning secretions, and has not shown the airway irritation and bronchospastic characteristics common to Mucomyst. Patients tolerate the nebulization well because of its lack of bad taste, bad odor, or airway irritation. Patients requiring long-term treatment of thick secretions can prepare a solution of sodium bicarbonate at home by mixing a teaspoon of baking soda in a cup of sterile water.

Mucolytics

True mucolytics are drugs intended to control mucus and bronchial secretions. The two primary agent approved for administration as aerosols to treat abnormal pulmonary secretions are acetylcysteine and dornase alfa. Both act to disrupt the disulfide bond in mucus and break down DNA materials in airway secretions.

Acetylcysteine (Mucomyst) is an aerosolized medication indicated for treatment of the thick, purulent, viscous mucus secretions that can occur in COPD, especially chronic bronchitis, tuberculosis, cystic fibrosis, and acute tracheobronchitis. It is also administered orally as an antidote to reduce hepatic injury with overdoses of acetaminophen, and is designated as an orphan drug.

Aerosol doses of Mucomyst are available in either 10 or 20% solutions, and normal dosage with 20% solution is 3-5 ml TID or QID, and 6-10 ml TID or QID with the 10% solution. The most serious potential side effect is bronchospasm, especially with hyperreactive airways seen in asthmatics, so using bronchodilators mixed with acetylcysteine or administer previously by MDI or nebulizer is recommended. Other potential side effects include stomatitis, nausea, and rhinorrhea.

Dornase Alfa (Pulmozyme) is an orphan drug that was produced by recombinant DNA techniques, and is indicated for the treatment and management of the viscid respiratory secretions seen in patients with cystic fibrosis (CF). In CF patients, Pulmozyme helps reduce the frequency of respiratory infections requiring parenteral antibiotics, and generally improves their overall pulmonary function.

Pulmozyme available as a single use ampule, with 2.5 mg drug in 2.5 ml of clear solution. Recommended dosage is 2.5 mg daily, delivered by nebulizers specifically approved for this use. Few side effects have been observed, including voice alteration, pharyngitis, laryngitis, rash, chest pain, and conjunctivitis.

Sodium bicarbonate (NaHCO3) helps break up large mucoid molecular chains because of its alkalinity. Some patients benefit from occasional aerosolized 2% sodium bicarbonate, which is a readily available solution for home use by simply putting a teaspoonful of the soda in a cup of sterile water. However, with the availability of more potent mucolytics like acetylcysteine, it is rarely used.

In addition to these most commonly used mucus-controlling agents, other muco-active agents that have been or are now being explored include:

Beta-adrenergic agonists can aid in mucokinesis, possibly by increasing the beat frequency of cilia. Active transport of the chloride ion into the airway lumen, augmented with a resulting water flux, may produce a less viscous, thinner mucus and enhance ciliary movement.

S-Carboxy methylcysteine (Mycodone), an oral mucokinetic investigated in Britain, decreases sputum viscosity in vitro, but is not considered effective for mucolysis when administered orally. It is chemically related to garlic, a common home remedy mucokinetic, and other home remedies for mucokinesis including chicken soup, horseradish, pepper, and mustard.