RESPIRATORY PHARMACOLOGY

Transcription

1 by Kevin T. Martin BVE, RRT, RCP RC Educational Consulting Services, Inc Van Buren Blvd, Suite B, Riverside, CA (800) 441-LUNG / (877) 367-NURS

2 BEHAVIORAL OBJECTIVES UPON COMPLETION OF THE READING MATERIAL, THE PRACTITIONER WILL BE ABLE TO: 1. Identify the mechanism of action for common respiratory medications. 2. List the factors affecting aerosol deposition within the respiratory tract. 3. Discuss the advantages and disadvantages of aerosolized medications. 4. Identify complications and side effects of common respiratory medications. 5. Describe methods of aerosol delivery. 6. Summarize the action of specific medication in various drug categories. 7. Identify medications used for ARDS. 8. Discuss medication used in the treatment of smoking cessation therapy. 9. Perform common medication calculation. 10. Discuss the use of specific pharmacological agents used to treat asthma. COPYRIGHT November, 1987 By RC Educational Consulting Services, Inc. COPYRIGHT April, 2000 By RC Educational Consulting Services, Inc. (#TX ) AUTHORED By Kevin T. Martin, BVE, RRT, RCP REVISED 1990, 1993, 1995, 1997 By Kevin T. Martin, BVE, RRT, RCP REVISED 2002, 2005 By Michael R. Carr, BA, RRT, RCP REVISED (2009) By Susan Jett Lawson, RCP,RRT-NPS ALL RIGHTS RESERVED This course is for reference and education only. Every effort is made to ensure that the clinical principles, procedures and practices are based on current knowledge and state of the art information from acknowledged authorities, texts and journals. This information is not intended as a substitution for a diagnosis or treatment given in consultation with a qualified health care professional. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 2

3 TABLE OF CONTENTS INTRODUCTION...6 ADVANTAGES, DISADVANTAGES AND HAZARDS OF AEROSOL THERAPY...6 AEROSOL DELIVERY DEVICES...6 AEROSOL CONSIDERATIONS...7 METHODS OF AEROSOL DELIVERY...8 INHALER / DEVICE TYPES...9 INSTRUCTION IN THE USE OF pmdi s...16 PRESSURE METERED DOSE INHALER (pmdi s)...16 DRY POWDER INHALER...17 SMALL VOLUME NEBULIZER...18 WHICH METHOD IS BEST?...18 LARGE-VOLUME NEBULIZERS (LVN)...18 GENERAL MEDICATION INFORMATION...19 BRONCHODILATORS...20 BETA ADRENERGIC AGONISTS...21 COMPLICATIONS...23 ALPHA RECEPTORS...24 BETA ADRENERGIC MEDICATIONS...24 THERAPEUTIC RECOMMENDATION...27 DOSING AND ADMINISTRATION...27 DOSAGES AND STRENGTHS...27 LEUKOTRIENE INHIBITORS (NONSTEROIDAL ANTIASTHMA DRUGS)...29 This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 3

4 HIGH-DOSE BRONCHODILATORS...30 THEOPHYLLINE...31 ANTIMUSCARINICS...32 TIOTROPIUM BROMIDE (SPIRIVA )...33 COMBINATION THERAPY: β ADRENERGIC and ANTICHOLENGERIC...35 CORTICOSTEROIDS...35 CORTICOSTEROID MEDICATIONS...37 COMBINATION THERAPY: β ADRENERGIC and CORTICOSTEROID...39 BETA BLOCKERS AND ASTHMA...40 MEDIATOR MODIFIERS...41 PROSTAGLANDINS...43 MUCOKINETICS AND MUCOLYTICS...43 MUCOKINETIC AND MUCOLYTIC MEDICATIONS...44 EXPECTORANTS AND COUGH SUPPRESSANTS...46 ANTI-INFECTIVES...48 ANTIBIOTICS...48 ANTIBIOTIC MEDICATIONS...49 ANTIFUNGAL DRUGS...52 ANTITUBERCULOSIS DRUG...52 PENTAMIDINE...52 VIRAZOLE...53 SURFACTANTS...54 DRUGS FOR ARDS...56 This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 4

5 SMOKING CESSATION THERAPY DRUGS...59 MISCELLANEOUS...59 DRUG DOSAGE CALCULATIONS...61 PRACTICE PROBLEMS...63 CLINICAL PRACTICE EXERCISE...64 SUMMARY...65 PRACTICE EXERCISE DISCUSSION...67 SUGGESTED READING AND REFERENCES...68 APPENDIX A...72 APPENDIX B...86 This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 5

6 INTRODUCTION Respiratory pharmacology primarily deals with agents used to treat the pathological triad of pulmonary disease. The pathological triad consists of: bronchospasm, airway inflammation, and retained secretions. Agents used to treat these conditions consist of bronchodilators, antimuscarinics, corticosteroids, mucokinetics, mucolytics, and decongestants, among others. Additional agents used in the treatment of pulmonary disease are oxygen, antibiotics, local anesthetics, respiratory stimulants, and muscle relaxers. All of these, with the exception of oxygen, are discussed in this paper. Particular emphasis is placed on medications delivered in an aerosol form. Before we discuss specific medications, a brief review of aerosol therapy will be provided. ADVANTAGES, DISADVANTAGES AND HAZARDS OF AEROSOL THERAPY The aerosol route is preferred for pulmonary disease for several reasons. First, a lower dose of the medicine can by used. Secondly, the direct delivery of the medicine to the site of action has its rewards. Lastly, aerosol medication delivery provides topical administration for a rapid therapeutic effect. This form of delivery helps provide a faster response with the use of the short-acting Beta agonists. The beta 2 agonistic drugs (bronchodilators) often begin their actions within a few seconds. Eighty per cent of their effects are reached within 5 minutes and their peak effect occurs within 1-2 hours. In addition, aerosol administration minimizes systemic absorption so side-effects are minimal. As a final point, the airway is a readily available route of medication delivery when other routes are inaccessible. Included in the disadvantages of aerosol therapy is that special equipment may be necessary. Another is that the patient (in most instances) must be capable of taking a coordinated, deep breath. Another is that actual delivery of the drug is erratic when aerosolized. This makes both underdosage and overdosage common. Generally, only a small proportion of the drug is actually retained in the lung, usually 5-10%. This is a major disadvantage necessitating aerosol doses that are ten times what the patient actually receives. Most is simply wasted or exhaled. Systemic absorption also can occur through oropharyngeal deposition. This can result in unwanted side-effects. Finally, hazards of aerosol therapy consist of: tracheobronchial irritation, bronchospasm, contamination, drug reconcentration and infection of the airway. Aerosol delivery devices Metered Dose Inhalers (MDI) Advantages: quick, less expensive, compact, portable, no auxiliary power needed, available in multidose formulation, difficult to contaminate, can be used with an extender device in an intubated patient. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 6

7 Disadvantages: technique-dependent, incorrect use, difficult to deliver large doses, oropharyngeal deposition, limited medications available in this formulation. Nebulizers Advantages: aerosolize large volumes; deliver medications not available in MDI s, use of oxygen as the delivery gas, use in a ventilator circuit, ease of administration, no propellants. Disadvantages: inefficiency of dose delivery, higher doses needed, cost, lack of portability, preparation and cleaning, risk of contamination. Breath-Activated Devices Advantages: useful with patients unwilling to carry a spacer/holding chamber for their shortacting Beta agonist, and for those unable to use an MDI effectively. Disadvantages: cold Freon effect on inhalation, requires different inhalation technique than that used with their anti-inflammatory medication, need for enough inspiratory flow to activate the mechanism during an asthma attack. Spacers/Holding Chambers Advantages: easy to use for all ages, improved drug delivery to the airways, decrease oropharyngeal deposition (potential decrease in local and systemic side effects). Disadvantages: size, cost, prescription required, lack of consistent drug delivery. Dry Powder Inhalers (DPI) Advantages: ease of use, convenient, absence of chloroflurocarbons. Disadvantages: limited drugs available in this formulation, high inspiratory flows needed to adequately deliver the drug, only single dose formulation available, decreased usefulness in acute exacerbations AEROSOL CONSIDERATIONS An aerosol consists of particulate matter suspended in a gas. As such, it is inherently unstable and has a tendency to rain out due to gravity. Extremely small particles may remain suspended in a gas due to Brownian motion of gas molecules, but are a small proportion of the total gas. Most aerosol particles are large enough to be affected by gravity. In addition to gravity, thermal and electrical forces affect aerosol particles. In the lungs, these are of little to no significance. The solute concentration of aerosol particles also affects its eventual deposition within the respiratory tract. Particles increase or decrease in size as they travel through the respiratory tract by gaining or losing water. Isotonic particles remain relatively stable in size. Hypertonic particles grow in size due to absorption of H 2 O. This causes hypertonic aerosols to be deposited in the upper airways. Hypotonic particles do the opposite. They give up water and decrease in size. This allows deeper penetration into the lung and deposition in the lower airways. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 7

8 Anatomical baffles tremendously influence the site of deposition for any given particle. This makes it extremely important that a patient be instructed to breathe through their mouth for an aerosol treatment. Particles greater than 5 microns are deposited in the oropharynx and large airways. Particles less than 5 microns are deposited deeper within the lung and are called respirable particles. The majority of respiratory aerosol particles should be in this range for most medications. Submicronic particles (less than 0.5 microns) may be deposited in the alveolar region or simply exhaled. Deposition of these submicronic particles is enhanced by a breath-holding phase. The nose filters up to 95% of all aerosol particles passing through it. Depending upon what type of medication is being provided, a specific particle size may be necessary. If the medication being aerosolized is intended for the airways, a particle size of 2 to 5 microns is optimal. If the medication is intended for the parenchyma, 0.8 to 3 microns is optimal. Nebulizers produce particles over a wide range of sizes but, depending upon the device, most fall within a specific range. Particle sizes produced are described by a bell-shaped distribution curves with the majority falling in the respirable range. The appropriate nebulizer should be selected for the type of medication being given. Bronchodilators should be in the range of 0.3 to 3 microns for maximum effectiveness. SITE OF DEPOSITION IDEAL PARTICLE SIZE MOUTH, NOSE, UPPER AIRWAY microns AIRWAYS 2 to 5 microns PARENCHYMA 0.5 to 2 microns METHODS OF AEROSOL DELIVERY Aerosol delivery is accomplished one of five ways: According to the AARC Clinical Practice Guidelines, the device selected for administration of pharmacologically active aerosol to the lower airway should produce particles with an Mass Median Aerodynamic Diameter (MMAD) of 2 to 5µ. These devices include pmdi's, pmdi's with accessory devices (e.g., spacers), DPI s, SVN s, LVN s, and (ultrasonic nebulizers USN s). This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 8

9 INHALERS AND DEVICES Types Advantages Disadvantages AEROSOL MDI MDI WITH a) AEROCHAMBER Convenient size for portability Canisters contain many doses ( puffs) Available for relief and preventive use Easily used by most patients Low inspiratory flow required (20-25 L/min) Choice of open or closed mouth method Can be used by most individuals with suitable added device Some are now breathactuated Some now have dosecounters Easy to coordinate spraying when inhaling Choice of one or more breath Flow signal warning Increases drug delivery for those with poor inhaler technique Reduces hoarseness and oral thrush from inhaled steroids Fits most MDI s Available with mouthpiece or mask Mask size vary for infants / children / adults Breath coordination can be a problem for some May be difficult to use for those with restricted hand / arm movement Some disadvantages with closed mouth method vs. open mouth method Examples: Proventil HFA (albuterol sulfate inhalation aerosol) Ventolin HFA (albuterol sulfate inhalation aerosol) Ivax's albuterol sulfate HFA (albuterol sulfate inhalation aerosol) Flovent HFA (fluticasone propionate HFA inhalation aerosol) Atrovent HFA (ipratropium bromide HFA inhalation aerosol) Xopenex (levalbuterol sulfate HFA inhalation aerosol) Must be replaced periodically because of wear and tear Can be costly unless covered by insurance plan The device is bulky Some patients troubled by a lack of spray sensation when using aerosol drugs This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 9

10 b) VENTAHALER c) ACE (AEROSOL CLOUD ENHANCER) Size smaller than some spacers Clear chamber allows assessment of valve opening by care giver Reusable Consider models of VHCs without electrostatic charge Eliminates coordination problems Increases drug delivery for those with poor inhaler technique Reduces the possibility of oral thrush and hoarseness from inhaled steroids Long-lasting, clear chamber Lower cost compared to other spacers Eliminates coordination problems Increases drug delivery for those with poor inhaler technique Prevents hoarseness and oral thrush from inhaled steroids Flow signal warning Can be adapted for use with intubated / ventilated / resuscitation bag / incentive spirometer and portable MDI therapy Reasonable cost Replaceable mouthpiece and flow signal Long lasting, clear chamber with universal adapter No flow signal Cannot be used with all MDI s Large size may decrease compliance Interchanging canisters may cause misuse when more than one type of MDI is used This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 10

11 d) HALER AID Used by those with good MDI technique with some restricted finger or hand movement Eliminates need to change device Can also be used with an Aerochamber or Ventahaler Low cost Cannot be used with ACE spacer Cannot be used with all MDI s e.g. Intal, Tilade, Atrovent, Flovent, or Serevent * All spacer devices decrease oropharyngeal drug deposition. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 11

12 Dry Powder Inhalers a) TURBUHALER All Dry Powder Inhalers Are Propellant Free Easy to use Convenient size Little or no taste of medication Relief and preventive medication available Breath coordination not needed Multiple dose capacity Whistle adapter to assess adequate inspiratory flow available Also available, trainer usage device to assess inspiratory flow rate (30-60 L/min) Grip attachment for arthritic or restricted finger movement to load dose All Powdered Inhalers Require Deep Forceful Inspiration Some patients mistakenly interchange covers of Bricanyl and Pulmicort turbuhalers causing misuse No definite guide as to when inhaler is completely empty Some patients hearing the dessicant mistakenly think they still have medication and continue to use it when empty Exhaling into the device can affect the delivery of medication Some patients are doubtful that they are getting their dose (don t feel or taste anything) Not suitable for all ages (required flow rate) Unless held upright when loading the Turbuhaler, the correct dose may not be delivered Examples: Pulmicort Turbohaler (budesonide inhalation powder) Foradil Aerolizer (formoterol fumarate inhalation powder) Spiriva Handihaler (tiotropium bromide inhalation powder) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 12

13 b) DISKHALER c) ROTAHALER Disks are available for relief and preventive medications Convenient size and design Easy to use by most individuals Breath coordination not needed Multiple dose Small convenient size Can be used by most individuals Breath coordination not needed Rotacaps available for relief and preventive use Only 4-8 doses per disk (limited) May require more than one inspiration per dose Not suitable for all ages Requires forceful inspiration ( L/min) Disks cost more than MDI equivalent Loading disks can be cumbersome Examples Serevent Diskus (salmeterol xinafoate powder for inhalation) ADVAIR Diskus (salmeterol xinafoate / fluticasone propionate powder for inhalation) Each dose must be loaded Requires carrying extra supply of Rotacaps Difficult for those with restricted finger or hand movement to load the Rotahaler Not suitable for all ages (inspiration flow L/min) Rotacaps cost more than MDI equivalent May require more than one inspiration per dose Rotacaps can be affected by humidity This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 13

14 d) SPINHALER SOLUTIONS NEBULIZER/COMPRESSOR Can be used by most individuals Convenient size Available for non-steroidal medication Can be used at home, school, clinics or hospital in emergency Can also be used for maintenance therapy at home Available in electric or battery powered Some costs may be covered by government and/or private insurance plans Can be used with mask or mouthpiece Each dose must be loaded Requires carrying extra supply of Spincaps Parts can be misplaced easily Difficult for those with restricted finger or hand movements or tremors Not suitable for all ages Requires forceful inspiration ( L/min) Can be expensive without assistance Over reliance on relief medication can delay appropriate treatment Treatment takes longer to administer Eyes may be affected by nebulized medications escaping poor fitting masks (inhaled steroids or Atrovent) The need for regular daily use may cause some patients to become home bound Neglect to change or clean mask / tubing set-up may increase the risk of chest infection Example: QVAR (beclomethasone dipropionate inhalation aerosol) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 14

15 Method of checking the fullness of a metered dose inhaler Full 200 puffs ¾ Full approx. 150 puffs remaining ½ Full approx. 100 puffs remaining ¼ Full approx. 50 puffs remaining Empty Water This illustration is a simple way of educating the patient on how to determine the quantity of aerosol contained in their MDI. Keeping track of the number of puffs that are performed can be difficult for the young and elderly patient. Although this practice continues it is no longer recommended by the manufactures. Interpretation is difficult and the performance of the device may be affected. Patients should note the start date of the medication, the number of doses to be taken each day, the number of doses to be taken in the canister and from this information calculate the discard date. Place this date on the canister where it can be seen. MDI are pressurized (pmdi) gas cylinders that deliver a set amount of the drug with each activation or puff. Alert, cooperative patients who are capable of taking a coordinated, deep breath are the primarily user s of pmdi s. They are designed for self-administration so the patient must be carefully instructed in its use. Many hospitals have converted SVN patients to the pmdi in an effort to decrease costs with no loss in effectiveness. Studies have documented equivalent patient outcome for pmdi s vs. SVN s 20. In 1989 the Montreal Protocol was adopted into United States legislation. The purpose of the international treaty is to eliminate the use of substances that contribute to the destruction of the stratospheric ozone layer, including products that contain chlorofluorocarbons (CFCs). As of December, 2008, no meter dose inhalers will be allowed to contain CFCs. Please see Appendix B for the FDA Public Health Advisory regarding the transition from CFC propelled Albuterol inhalers to HFA propelled Albuterol inhalers. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 15

16 Instruction in the use of the pmdi s After instruction, the patient must be observed for proper technique in using the device. Proper instruction and observation of the patient are crucial to the success of this form of therapy. Instructions should include: 1. Warm the pmdi to hand or body temperature by rubbing it vigorously between the palms of your hand. 2. Assemble the apparatus, making sure there are no objects or coins in the device that could be aspirated or obstruct outflow. 3. Shake the container several times to mix the contents. 4. Hold the head erect. 5. Place the holding chamber in your mouth (or place mask over nose and mouth), and breathe through the mouth. 6. Hold the container approximately 1-2 inches from the mouth with the mouthpiece pointed downwards. 7. Breathe out normally. 8. Open mouth wide. 9. Begin to inhale slowly and deeply. 10. Squeeze the cartridge of the inhaler. 11. Continue to inhale deeply. 12. Hold the breath for 5-10 seconds. 13. Exhale through pursed-lips. 14. Breathe normally for 20 t0 30 seconds before another inhalation from the MDI. 15. Rinse mouth out without swallowing the water. Pressurized Metered Dose Inhaler (pmdi) Most of the drug from a pmdi is contained in the larger particles. Many of these are deposited in the pharynx and swallowed. It is estimated that an average of only 10% of the actual medication that leaves the pmdi enters the lower respiratory tract. The initial speed of pmdi This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 16

17 particles approach 100 km/hr. These particles crash in the back of the throat. The use of a spacer, cone, or holding chamber/reservoir bag, will nearly doubles particle deposition in the airways. Spacers and chambers slow the particle down so there is less impaction in the throat. Slowing particles also allow for evaporation to occur. This, in turn, decreases diameter of the larger particles bringing them into a respirable range. Slowing the velocity of the particles and preventing pharyngeal impaction also eliminates the need for perfect timing of inspiration. Spacers are useful for children and patients who cannot coordinate the pmdi without the spacer. Although pmdi s can be effective, patient instruction and proper use are paramount to optimal delivery. MDI with Spacer Attached Metered-Dose Inhaler Holding Chamber DRY POWDER INHALER DPI s are an alternate method for delivering various medications, such as bronchodilators and antiallergic medications. DPI s are similar to MDI s except the medication is powder instead of liquid. The powdered medication is contained in capsules that are inserted in the device. When activated, the device pokes holes into or cuts the capsule releasing the powder. The spinhaler device pokes holes in the drug capsule. The rotahaler device cuts the capsule in half and drops the powder in a chamber for inhalation. DPI s are breath-actuated, so there is no need to This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 17

18 coordinate actuation and inspiration. Unlike the MDI, a rapid inhalation (> 30 lpm) is necessary to deposit the drug in the lungs. Most DPI s are designed for a single dose at a time. Multi-dose DPI s (called turbohalers ) are now available in the United States. They contain up to 200 doses. Very few drugs are available as DPI s. Examples of drugs available in the dry powder formulation are cromolyn sodium (Intal), albuterol (Ventolin rotacaps), beclomethasone, budesonide and Serevent. SMALL VOLUME NEBULIZER Small volume nebulizers are a common method of aerosol delivery to inpatients. Like the MDI and DPI, proper instruction and observation of the patient are crucial to its success. If the patient is self-administering treatments, proper instruction is even more critical. A small proportion of the drug is placed within the SVN and diluted with 2-3 cc of normal saline (single unit-doses are available for most respiratory medications). The patient is instructed to take slow, deep breaths from the device through their mouth. This is done for minutes or until all the medication is gone. (Some physicians may order a specific number of breaths to be taken). Particular care should be taken to avoid hyperventilation with this form of therapy. Several reports have described significant variability in performance and efficiency of SVN nebulizers, including leakage of solution 18, 19. Two thirds to three fourths of the medication is lost on expiration alone. The use of an expiratory reservoir tube or a nebulizer that nebulizes on inspiration only captures much of this medication. Additional medication coalesces on the walls of the nebulizer and is lost. This can be prevented by occasionally tapping the nebulizer. Dosage for SVN treatments are approximately 10 times those of pmdi s because of the large amount that is wasted. WHICH METHOD IS BEST? The most important characteristic of nebulizer performance is the devices mass median aerodynamic diameter (MMAD). The droplet size should be 2-5 µm for airway deposition and 1-2 µm for parenchymal deposition. Studies show pmdi s, DPI s and SVN s are relatively equal in effectiveness if there is proper training and correct use 20. pmdi s and DPI s have better deposition per total output. They deposit about % of the drug in the lungs compared to 12.4% from an SVN. When the proper technique is used, pmdi s with a spacer have the best deposition with 13.0%. 20 Additional factors that effect nebulizer performance include nebulization time, cost, ease of use, and requirements for cleaning and sterilization. LARGE-VOLUME NEBULIZERS (LVN) The fourth method, mainstream nebulizers, is not generally thought of as medication treatment devices. As a general rule, they are used for continuous administration of a bland aerosol (H 2 O, normal saline) for airway humidification or secretion mobilization. If the patient is receiving intermittent treatments for secretion mobilization, they are instructed to take slow, deep breaths This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 18

19 through their mouth for the duration of the treatment. A fifth method of choice for aggressive care of patients with airway inflammation (asthma) may include frequent or continuous delivery of aerosolized bronchodilators. Vortran s HEART nebulizer (standard or mini-unit) is an example of an LVN designed to deliver continuous therapy. It has a 240 ml solution reservoir and generates particles between 2.2 and 3.2 µm MMAD. Rarely, bronchodilator medications will be continuously nebulized for a patient in persistent asthma. In ending, a method that wasn t mentioned earlier, IPPB delivery is reserved for the patient who is not capable of taking deep, coordinated breaths. SVN s and pmdi s are preferred over IPPB because the patient takes the deep breath on their own. A spontaneous deep breath produces a laminar flow pattern. Such a flow pattern provides a more even deposition of the aerosol and minimizes oropharyngeal deposition. One also avoids the side-effects of positive pressure by using a pmdi or SVN. However, one should remember that the patient must be able to take a deep breath to use pmdi s and SVN s. If the patient is unable to do this, IPPB remains the only effective choice for aerosol delivery. However, the effectiveness of IPPB therapy is directly related to the efficiency and knowledge of the practitioner providing the therapy. GENERAL MEDICATION INFORMATION Many conditions exist that require modification of the recommended dosage or frequency of a given medication. The first of these is the liver function of the patient. Impaired liver function necessitates a decrease in dosage or frequency to avoid toxicity. The liver is responsible for the breakdown of many drugs. Therefore, any alteration of liver function may prolong the half-life of the delivered drug. (Half-life of a drug is the time it takes the body to decrease a given concentration of the drug to half its initial level). Obese patients may require an increase in the dosage since the additional tissue may absorb much of the drug. Emaciated patients may require the opposite. Many drugs are altered by ph changes. For example, bronchodilators are inactivated in an alkaline environment. Renal function is another factor to consider. The kidneys are responsible for the excretion of many substances so renal impairment leads to an accumulation of the medication. Mechanical ventilation also affects kidney function by decreasing perfusion pressure. Dosage may therefore have to be decreased in the presence of kidney disease or mechanical ventilation. A final consideration is related medications the patient is receiving. These may have an additive, synergistic, or antagonistic effect. All medications being administered should be reviewed prior to the institution of a new one into the therapeutic regimen. The discussion of the actual agents used for pulmonary disease will begin with the bronchodilators. This course should be considered an overview of the common medications used for lung disease. For additional or more complete information, the reader is referred to the Physician s Desk Reference, the package insert of the medication, or other standard texts on pharmacology. The most common drug used in the treatment of lung disease, oxygen, is not This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 19

20 discussed in this course. NOTE: All dosages provided, unless otherwise specified, are for the adult population. Pediatric and neonatal dosage mixture may be identical to the adult, but due to hospital delivery procedure, the actual dose delivered is less. For example, the procedure for an aerosol bronchodilator treatment may be to give the drug full strength but only give 5 breaths for babies or children. Another institution may have a procedure where the procedure is only given for 3-5 minutes instead of minutes. In both cases, the actual amount of drug is considerably less for the pediatric or neonatal patient than for the adult. Drugs used to treat or prevent bronchospasm include the beta-adrenergic agonists, antimuscarinics, theophylline, corticosteroids, anticholinergics, and mediator modifiers. Mucokinetic/mucolytic agents, anti-infectives, respiratory stimulants, surfactants, muscle relaxants, sedatives and topical anesthetics used follow these specific procedures, such as, bronchoscopies. Some experimental drugs for special situations also are discussed. BRONCHODILATORS The bronchi, like other organs of the body, is innervated by the autonomic nervous system (ANS). The two components of that system, the sympathetic (SNS) and parasympathetic (PNS) nervous systems, compete with one another to maintain normal smooth muscle tone. The action of the SNS stimulation causes bronchodilation and PNS stimulation bronchoconstriction. SNS stimulation causes bronchodilation through increased production of cyclic adenosine monophosphate (camp). This is achieved by stimulation and release of the enzyme adenylate cyclase. Cyclic AMP is converted to non-cyclic AMP by phosphodiesterase. The PNS pathway is very similar to the SNS pathway but has the opposite effect on smooth muscle. Guanylate cyclase is produced, converting guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cgmp). This leads to bronchoconstriction. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 20

21 SNS PNS Beta receptor Cholinergic receptor Adenylate cyclase Guanylate cyclase ATP GTP Cyclic AMP Cyclic GTP Phosphodiesterase RELAXATION CONSTRICTION Based upon the above, one can see that bronchodilation is accomplished one of three ways. The first is through SNS stimulation and increased production of camp. Beta-adrenergic agonists work via this mechanism. The second is to decrease the destruction of camp through inhibition of phosphodiesterase. The third is to decrease the bronchoconstricting influence of the PNS. Antimuscarinics (anticholinergics) accomplish this by decreasing production of cgmp. BETA ADRENERGIC AGONISTS These are the most common and important of the bronchodilators. They achieve their action by reacting with receptor proteins embedded in the cell membrane. This, in turn, enhances the coupling of the receptor to adenylate cyclase. Adenylate cyclase then converts ATP to camp causing certain protein enzymes to obtain a tissue response. In the bronchi, the response is smooth muscle relaxation. There are 2 subtypes of beta adrenergic receptors in the SNS known as beta 1 (β 1 ) and beta 2 (β 2 ), respectively. β 1 receptors predominate in the heart and adipose tissue. The β 2 receptors predominate in the lung, blood vessels, skeletal muscles and liver. The stimulation of β 1 receptors result in lipolysis, an increase in heart rate and force of contraction. β 2 stimulation results in bronchial, vascular, and uterine smooth muscle relaxation, skeletal muscle tremor, glycogenolysis, decreased serum potassium, and inhibition of mediator release. Most organs contain both types of β receptors with one of the two predominating. In the past, it was difficult to give a β adrenergic agonist that had specificity for one subtype and not the other. Consequently, the effects of giving such a drug were widespread. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 21

22 BRONCHOSPASM BRONCHODILATION Airway lumen camp Beta adrenergic agonists increase levels of camp. This produces smooth muscle relaxation and bronchodilation. Catecholamines (older agents, such as epinephrine, isoproterenol, and isoetharine) were the traditional β adrenergic drug of choice. However, catecholamines are rapidly degraded through the enzyme catechol-o-methyl-transferase (COMT). This gives them a relatively short duration of action. If given orally, catecholamines also undergo sulfate conjugation and monoamine oxidation (MAO) in the intestinal mucosa and liver. This makes them almost completely inactive. By altering the catechol ring structure these events are prevented or minimized, allowing longer duration of action, 4-6 hours. Changes to the benzene ring of catecholamines turn them into noncatecholamine bronchodilators. These are resorcinol and saligenin compounds. Metaproterenol (orciprenaline) and terbutaline are examples of the former and albuterol (salbutamol) is an example of the latter. Metaproterenol and terbutaline are catecholamines that lacked β 2 specificity. This is the reason for cardiac effects, especially tachycardia and increased blood pressure. Because of their strong α1-activity and vasoconstricting effect, epinephrine and synthetic racemic epinephrine are used to reduce swelling in the nose, larynx, and to control bleeding during bronchoscopic biopsy. Recent compounds (metaproterenol, terbutaline, albuterol, and pirbuterol) have been altered to give them a longer duration of action, and have replaced the shorter acting catecholamines as the drugs of choice. Their specificity for the β 2 receptor also has been improved to minimize unwanted side effects. As a result, they are much more effective than the original catecholamines when given orally. Because their duration of action is approximately 4 to 6 hours, these drugs are more suited to maintenance therapy than catecholamines and could be taken on an every four hours schedule. Specificity for the β 2 receptor or duration of action, and sometimes both, are improved with the newer medications. In March of 1999, levalbuterol was approved for general clinical use in the United States as a single-isomer β 2 -selective agonist, Xopenex. Growing evidence described the S-isomer of albuterol has the source of some serious side effects when that medication was administered. Levalbuterol is the pure R-isomer of racemic albuterol. This medication is discussed at length This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 22

23 later in the course. The order of potency for bronchodilators in use in the United States is: isoproterenol, fenoterol, albuterol, terbutaline, isoetharine, bitolterol and metaproterenol. Recommended dose of these via MDI are bioequivalent in potency with the exception of fenoterol. COMPLICATIONS T here are numerous side-effects to the β adrenergic agonists. The first is an increase in heart rate and force of contraction. This is substantial with some compounds and should be closely monitored. The increase is a result of both direct myocardial action (β 1 stimulation) and an indirect bata receptor reflex response to peripheral vasodilation (β 2 stimulation). In most cases, an increase in heart rate of 20 or more with the administration of the medication warrants its termination. A second side effect is skeletal muscle tremor. Tremors are a result of muscle cell β 2 stimulation. Tremors also can be a result of hyperventilation (causing an increase in ph and an excitation of the central nervous system) during the treatment. Careful attention should be paid to minute volume and proper patient coaching to prevent hyperventilation. Continuous stimulation by a β adrenergic agonist can lead to a third problem known as tachyphylaxis. This is a loss of drug responsiveness. Tachyphylaxis is a result of β receptors becoming internalized leading to a loss of their functional number. Tachyphylaxis also results from phosphorylation of the receptor. This causes a loss of affinity for the medication. Put simply the receptor becomes tolerant, so larger doses are necessary to achieve the same result. There is considerable debate on whether tachyphylaxis actually occurs with the β agonists. Many believe a lack of drug responsiveness simply means the disease has worsened or small airways have become obstructed and the drug isn t being delivered. However, drug responsiveness returns if corticosteroids are administered. Drug responsiveness returns within one hour of IV corticosteroids. Concurrent use of steroids may actually prevent tachyphylaxis from developing Many also recommend using β agonists for symptomatic relief rather than continuous use to prevent tolerance. Should tachyphylaxis develop, drug responsiveness returns if the β agonist is discontinued for a few days to weeks. β adrenergic agonists also may worsen hypoxia by disrupting V/Q ratios in the lung. β 2 stimulation of pulmonary blood vessels results in vasodilation. Vasodilation may be greater than bronchodilation. If this is significant, V/Q ratios decrease and lower PaO 2. This explains the rare patient whose PaO 2 decreases with bronchodilator treatment. People with hyperactive airways may be sensitive to sulfite preservatives, which are found in many bronchodilators. These sulfite agents can provoke bronchospasms. They convert to sulfur dioxide in saliva, which is known to cause bronchoconstriction in asthmatics. The popular medication Alupent contains sulfites, for example. Clinicians should check the medications they administer for sulfites and monitor patients reactions. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 23

24 ALPHA RECEPTORS Athird receptor of the sympathetic nervous system, the alpha (α) receptor, needs to be mentioned. Vasoconstriction, slight bronchoconstriction, and a slight decrease in heart rate result with stimulation of α receptors. Of these, the predominant response is vasoconstriction. This can be valuable in decreasing airway edema and inflammation. Airway lumen is increased with a decrease in edema or inflammation. This is not bronchodilation, but the results may be the same. Hence, α stimulants are discussed in this section on bronchodilators, but they are actually decongestants. BETA ADRENERGIC MEDICATIONS T here are three classes of β adrenergic medications; catecholamines, resorcinols, and saligenins. The catecholamines consist of epinephrine, isoproterenol, isoetharine, rimiterol, and hexoprenaline. (The latter two are not available in the United States). Bitolterol is converted to its active catecholamine structure in the body so it probably belongs in this class also. Modifications to the primary catechol nucleus resulted in the resorcinols and saligenins. The resorcinols are metaproterenol, terbutaline, and fenoterol. The saligenins consist of albuterol, pirbuterol, and carbuterol. The resorcinols and saligenins are not readily degraded by the enzyme catechol-methyl transerase (COMT), so they have a longer duration of action than the catecholamines. They are also more β 2 specific so cardiac problems are minimal. EPINEPHRINE (Adrenaline, Primatene ) is the original β 2 stimulant. It is administered subcutaneously, intramuscularly, intravenously, aerosolized, or instilled directly into the airway. It is a strong β 1 stimulant and is often used for this reason during emergency situations to increase heart rate and circulation. Epinephrine is also used in combating allergic/anaphylactic reactions. Alpha stimulation is high for epinephrine, making it valuable during bronchoscopies. Small areas of hemorrhage from specimens or suctioning are controlled by direct instillation of epinephrine at the site. For acute asthma attacks, epinephrine is administered parenterally. It is rarely aerosolized due to its strong β 1 action. Epinephrine is short-acting (one-half to two hours) so much longer acting aerosols have replaced it. If aerosolized, the 1% (1:100) aqueous solution is used. Two puffs from an MDI Q4 hours or 0.5 cc in 2-3 cc of normal saline (NS) Q4 hours from SVN or IPPB are safe dosages. During a cardiac arrest, epinephrine is instilled directly into an artificial airway should another route be unavailable. RACEMIC EPINEPHRINE (MicroNefrin ) is less potent than epinephrine and has fewer side effects. It also is a short-acting medication. The primary use for racemic epinephrine is for its α stimulation properties. It is used for vasoconstriction and decongestion of the upper airway. Specific indications for its use are laryngeal edema, laryngotracheobronchitis, croup, and for post-extubation glottic edema. The usual aerosol dose is 0.25 cc to 0.5 cc 2.25% in 2-3 cc NS Q4 hours. For patients less than 2 years old, use 0.1 to 0.25 cc. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 24

25 EPHEDRINE (Tedral, Marax, Primatene, Quadrinal ) is one of the few β adrenergic agonists effective when given orally. It is considered long-acting (four to six hours) and slightly less potent than epinephrine. It is a noncatecholamine and weak bronchodilator. Tablets are the usual method of administration. The tablets also contain theophylline. Ephedrine is a potent CNS stimulant so a tranquilizer is often added. Because of its alpha-receptor stimulation it is used more as a decongestant in cold medications than as a bronchodilator. 20 In some states ephedrine is a component of over the counter cold medications because of it s decongestion capabilities. Tachyphylaxis readily develops with ephedrine, along with excessive CNS stimulation, which may result in insomnia. Dosage varies depending upon the patient s condition. Proprietary preparations contain between mg of ephedrine with mg of theophylline. ISOPROTERENOL (Isuprel, Mistometer ) is a very strong beta 1 and 2 stimulant. It is a very effective bronchodilator, but also a potent beta 1 stimulant. Therefore, heart rate must be closely monitored. Because of the probability of tachycardia, isoproterenol is rarely used for bronchodilation today. Depending upon the manufacturer, concentrations range from 0.25% to 1% isoproterenol. Consequently, dosage varies from 0.25 cc to 1 cc diluted in 2-3 cc of NS Q4 hours. The normal adult dose is 0.5 cc of the 1:200 solution and the normal pediatric dose is 0.25 cc of the same solution. When aerosolized, it is one of the shortest-acting bronchodilators. Aqueous solutions of 1:100 and 1:200 concentrations are available for aerosol use. The latter is recommended. Should an MDI be used, 2 to 4 puffs Q4 hours are sufficient. METAPROTERENOL (Metaprel, Alupent ) is a derivative of isoproterenol having a longer duration of action (4 to 6 hours). It is less likely to cause tachycardia and is effective when given orally or aerosolized. The usual aerosol dose is 0.2 to 0.3 cc of the 5% solution in 2-3 cc NS Q4 hours. ISOETHARINE (Bronkosol, Bronkometer ) has a strong β 2 effect with minimal β 1 stimulation. Both effects are less than that of isoproterenol. Isoetharine is administered orally or by MDI, SVN, IPPB. Duration of action is 2 to 4 hours. The usual aerosol dose of 0.5 cc of the 1% solution in 2-3 cc NS Q4 hours may be increased to 1 cc for severe bronchospasm. TERBUTALINE (Bricanyl, Brethine, Brethaire ) is claimed to have a very specific β 2 effect with minimal β 1 stimulation. It is comparable to metaproterenol but may be more β 2 specific. It has a longer duration of action. Oral and subcutaneous administration is more common than aerosolization for terbutaline. Dosage depends upon the ordering physician. ALBUTEROL/SALBUTAMOL (Proventil, Ventolin, Airet ) is similar to terbutaline, but claims to have a slightly better bronchodilation effect. Albuterol is effective when given orally, IV, or aerosolized. It is a long-acting bronchodilator. Onset of action is within 15 minutes, peak effect is in minutes, and effects last up to 6 hours. Aerosolization appears to have the fewest side effects. The usual aerosol dose is 0.5 cc of the 0.5% solution. This dose provides This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 25

26 approximately 2.5 mg and is given Q4 hours. One MDI puff delivers.18 mg and each tablet contains 4 mg. Each of these doses is bioequivalent. The tablets release 2 mg of albuterol from their outer coat rapidly. The other 2 mg is released from the core later. CARBUTEROL is similar to albuterol, but is less potent and only lasts 4 hours. PROCATEROL (Pro-Air ) is available in Canada. It has a higher potency and longer duration of action (8 hours) than albuterol. Its onset is within 5 minutes and peaks within minutes. PIRBUTEROL (Maxair ) is effective when aerosolized or given orally. It is available as an MDI and is a long-acting bronchodilator. Duration of action is approximately 5 hours. Onset of action is within 5 minutes and peak effects are reached in minutes. Recommended dose is 2 puffs (0.4 mg) every 4-6 hours. Twice the recommended dose has been safely given. FENOTEROL has been used in Europe for some time. Fenoterol appears to have a very long duration of action (8 hours) with minimal β 1 effects. Bronchodilation properties are proportional to isoproterenol. It is administered orally or via inhalation. It should be noted that the MDI of fenoterol does not deliver a bioequivalent dose compared to other MDI s. Fenoterol MDI s deliver a higher comparative dose of medication than do other MDI s. Adverse effects of fenoterol are greater than those of albuterol or terbutaline. It also has been associated with an increase in morbidity and mortality. BITOLTEROL (Tornalate ) is similar to fenoterol in duration of action with fewer side effects. The mean duration of action is 6-7 hours and its onset is 3-4 minutes. Dosage to relieve bronchospasm in patients more than 12 years old is 2-3 puffs every 6 hours. To prevent bronchospasm 2 puffs every 8 hours is recommended. Maximum dosage should not exceed 3 puffs every 6 hours or 2 puffs every 4 hours. Activation of the MDI delivers about 0.37 mg of bitolterol. SALMETEROL XINAFOATE (Serevent ) is used for maintenance and prevention of bronchospasm. The release of salmeterol offered the first long-acting adrenergic bronchodilator in the United States. It is not used for acute symptoms because its onset is longer than 20 minutes, with a peak effect occurring by 3 to 5 hours. Salmeterol is indicated for long-term, twice daily (q 12 hrs.) administration. It is supplied as an MDI. Dosage is 2 puffs (42mcg) in the morning and evening. Patients are to take two puffs minutes before exercise protects against exercise-induced bronchospasm in many patients. It is approximately 10 times more potent than albuterol and lasts 2-3 times as long (> 12 hours). Salmeterol is useful for stable asthmatics and nocturnal asthma. FORMOTEROL is similar to salmeterol but has a very rapid onset of action. In 2001, formoterol was approved for general clinical use in the United States and represents a second long-acting, β 2 -specific agent. Onset is within one minute. About 12 mcg of formoterol is bioequivalent to 50 mcg of salmeterol. It is very potent and lasts approximately 12 hours. Toxicity may develop if this drug is used like the other shorter acting rescue medications. A single-isomer racemic mixture of formoterol is under investigation. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 26

27 Perforomist Inhalation Solution (formoterol fumarate) has recently been approved by the FDA for long-term, twice-daily maintenance treatment of bronchoconstriction for emphysema and chronic bronchitis (COPD). XOPENEX (levalbuterol) is a relatively selective β 2 -adrenergic receptor agonist that was FDA approved on March 25, Levalbuterol is indicated for the treatment or prevention of bronchospasm in adults and adolescents 12 years of age and older with reversible obstructive airway disease. Therapeutic Recommendation: Levalbuterol is the pure R-isomer of racemic albuterol. The R-isomer is known to be responsible for the bronchodilator effects of the racemic mixture. Levalbuterol is a more potent bronchodilator than the racemic mixture when administered at the same dose. However, at equipotent doses of levalbuterol and racemic albuterol, studies have not demonstrated a significant difference in efficacy and safety. As the dose of levalbuterol is increased from 0.63 mg to 1.25 mg, there is an increased likelihood for adverse reactions. Since levalbuterol is more expensive when compared to racemic albuterol but not superior in efficacy, it should only be used for patients experiencing unacceptable adverse effects while on racemic albuterol treatment. Dosing and Administration: Levalbuterol is supplied in 3 ml, unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free solution in two different strengths of levalbuterol (0.63 mg, 1.25 mg). Unlike albuterol, levalbuterol does not require dilution before administration. The recommended starting dose for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization. Patients who do not respond adequately to a dose of 0.63 mg may increase to 1.25 mg of levalbuterol three times a day. Patients receiving this higher dose of levalbuterol should be monitored closely for adverse systemic effects. Increasing the dose or frequency of the following medications beyond these guidelines is not recommended by the manufacturer. DOSAGES AND STRENGTHS USED FOR VARIOUS METHODS OF ADMINISTERING β-adrenergic BRONCHODILATORS Drug Brand Name Administration Method Strength Dosage Epinephrine Adrenalin Nebulizer 1:100 (1%) ml qid Racemic epinephrine MicroNefrin Vaponefrin AsthmaNefrin Nebulizer 2.25% ml qid Isoproterenol Isuprel Nebulizer 1:200 (0.5%) ml qid This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 27

28 Isuprel Mistometer MDI 131 µg/puff 1-2 puffs qid Isoetharine Bronkosol Bronkometer Nebulizer MDI 1% 340 µg/spray ml qid 1-2 puffs qid Metaproterenol Alupent Metaprel Nebulizer MDI (Alupent discontinued as of ) Tablets Syrup 5% 0.65 mg/puff 10, 20 mg 10 mg/5 ml 0.3 ml tid, qid 2-3 puffs q4h 20 mg tid, qid 10 mg tid, qid Terbutaline Brethaire Brethine Bricanyl MDI Injection Tablets 0.2 mg/puff 1 mg/ml 2.5, 5 mg 2 puffs q4-6h 0.25 mg SC 2.5 or 5 mg tid Albuterol Proventil Ventolin Proventil HFA Ventolin HFA Ivax's HFA Nebulizer MDI DPI Tablets Extendedrelease tablet Syrup 0.5% 90 µg/puff 200 µg/caps 2 or 4 mg, 4 mg, 8 mg 2 mg/5 ml 2 puff tid, qid 2 puffs tid, qid 1 caps, q4-6h 2 or 4 mg tid, qid q12h 2 or 4 mg tid,qid Levalbuterol Xopenex SVN Inhalation Solution, 0.31 mg, Inhalation Solution, 0.63 mg, Inhalation Solution, 0.63 mg 0.31 mg and 0.63 mg/3 ml tid or 1.25 mg/3 ml tid Bitolterol (colterol) Tornalate MDI 0.37 mg/puff 2 puffs q8h Pirbuterol Maxair MDI 0.2 mg/puff 2 puffs q4-6h Salmeterol Serevent MDI 25 µg/puff 2 puffs q12h Formoterol Foradil Perforomist DPI Nebulizer 12 µg capsule 12 µg/inhalation bid This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 28

29 LEUKOTRIENE INHIBITORS (NONSTEROIDAL ANTIASTHMA DRUGS) Leukotrienes are among the molecules released in response to various asthma triggers. These molecules are formed by the action of 5-lipoxygenase on arachidonic acid and are produced by mast cells, eosinophils and alveolar macrophages. Leukotrienes are responsible, in part, for increased mucus production, bronchoconstriction and eosinophil infiltration observed in asthma. Two different types of leukotriene inhibitors are now available: 1) leukotriene receptor antagonists (LTRAs), i.e., zafirlukast (Accolate ) and montelukast (Singulair ); and 2) leukotriene synthesis inhibitors, 5-lipoxygenase inhibitors (5LO-I), i.e.; zileuton (Zyflo ). These drugs partially block both the early and late-phase response to allergen exposure and blunt exercise-induced asthma. In patients with aspirin-induced asthma, administration of a leukotriene synthesis inhibitor appears to block all of the effects of aspirin exposure. Leukotriene inhibitors also produce an acute effect (within 2 hours) on airway tone resulting in bronchodilation. The complex role of leukotrienes in asthma, and the availability of highly effective leukotriene inhibitors, offer expanded treatment options to the widely accepted model of asthma as a condition with an inflammatory and a bronchoconstrictive component that should be managed by inhaled corticosteroids and bronchodilators. Recent evidence suggests in some individuals leukotrienes play an important role as mediators of tissue edema, mucus secretion, smooth muscle proliferation, and bronchoconstriction. 39 However, as with all available anti-asthma treatments, anti-leukotrienes do not cure asthma. Anti-leukotrienes must be used in a balanced program of asthma pharmacotherapy. In 1998 Canada licensed two members of a new class of drugs for asthma, leukotriene inhibitors, zafirlukast (Accolate ), montelukast (Singulair ) and zileuton (Zyflo). As they have an effect on neutrophil mediated inflammation, they may be of benefit in bronchiectasis. Leukotriene inhibitors in Asthma: Cause statistically significant effects on measures of airway obstruction and symptoms as compared to placebo in short-term trials. - Average clinical effects are small and would unlikely be detectable by individual patients. - Effects are detectable on the first day and do not change appreciably over 6 to 13 weeks. Cause average clinical benefits that are less than low-dose inhaled glucocorticoids. Cause few adverse effects in short-term use, but long-term risks are unknown. Are not appropriate for treatment of acute asthma exacerbations. May be useful as add-on or an alternative to inhaled glucocorticoids in problematic patients with inadequate response or intolerance, respectively. Inhibits asthma reactions induced by exercise, cold air, allergens, and aspirin Require long-term RCTs compared to standard therapy before their role in management This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 29

30 can be established The second edition of the NIH Asthma Guidelines, published in 1997, suggests the use of leukotriene modifiers as long-term controller drugs, rather than relievers in patients 12 years or older with mild persistent asthma, perhaps as an alternative to low-dose inhaled corticosteroids or antiasthmatic drugs, such as nedocromil. 27 Summary of Comparative Features of the Three Currently Available Anti-leukotriene Agents 44 Zileuton Zafirlukast Montelukast Brand Zyflo Accolate Singular Action 5-LO inhibitor CysLT1 receptor block CysLT1 receptor block Age range > 12 year > 12 years > 2 years Dose 600 mg tab, qid Adult: 20 mg tab, bid children 5-11 yr: 10 mg tab, bid Administration Can be taken with food 1 hr before or 2 hr after meal Drug Interaction Yes (theophylline, Yes (theophylline, warfarin, propranolol) warfarin, aspirin) Side effects Headache, dyspepsia, Headache, infection, (common) unspecified pain, liver nausea, possible liver enzyme elevation Contraindications Active liver disease or elevated liver enzyme levels, hypersensitivity to components enzyme changes Hypersensitivity to components Adult: 10 mg tab, q evening 6-14 years: 5 mg tab, q evening 2-5 years: 4 mg tab, q evening mo: 4 mg oral granules q evening Taken with or without food No Headache, influenza, abdominal pain Hypersensitivity to components HIGH-DOSE BRONCHODILATORS The standard doses for the above bronchodilators were not created for the patient with severe bronchospasm or in persistent asthma. These patients require an increase in both dosage and frequency of aerosol medications. The greater the degree of constriction, the greater the amount of bronchodilator needed. The greater the degree of constriction, the faster the bronchodilator is degraded so more frequent administration also is necessary. Fortunately, the safety of the newer compounds makes this possible. For moderate-to-severe chronic asthma, maintenance doses of 2.5 to 8 times the conventional This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 30

31 dose can be safely provided. For acute severe asthma, many combinations of dosage and frequency have been utilized. They share in common careful monitoring and evaluation of the patient to determine an optimal dosage regimen A sample optimal dose procedure requires providing the patient a conventional dose of 2 puffs from an MDI with a spacer. Peak flow and breath sounds are evaluated before and after this dose. Two more puffs are provided after 1-2 minutes. PF and breath sounds are then reevaluated. This is repeated until the patient shows no improvement or an adverse reaction, such as; increased heart rate or tremors develop. A ceiling dose of 20 puffs is generally used as a maximum limit. After the optimal dose is determined, optimal frequency needs to be determined. Conventional frequency of aerosol bronchodilators is 3-4 hours. This can be reduced to 1-2 hours for severe asthma. Initially, treatments may even be as often as every 20 minutes. Continuous nebulizer therapy (CNT) has even been used in some patients. It is considered safer than intravenous betaadrenergic agonists for persistent asthma. Another option is the Circulaire aerosol drug delivery system (Westmed Inc., Tucson, AZ). This is a high-efficiency SVN with an attached reservoir bag. The efficiency of this nebulizer and reservoir bag gives more stable therapeutic particle sizes. Treatment time is decreased to several minutes and the medication can be delivered full strength (w/o diluent). Frequency can be every 20 minutes initially and then every 1-hour until symptoms are relieved. Patients with artificial airways also benefit from a higher than normal conventional dose. Intubated and mechanically ventilated patients receive considerably less medication than nonintubated patients. In fact, only about 3% of the medication makes it out of the end of an endotracheal tube. Therefore, it is wise to at least double the conventional MDI dose for an intubated patient. If the MDI is being used inline with a ventilator circuit, one needs even more. Six inline MDI puffs are equal to one puff on a nonintubated patient. The use of a holding chamber or spacer also increases aerosol delivery on intubated patients. If an SVN is being used inline with a ventilator circuit, one also needs to increase aerosol delivery. A patient with severe exacerbation of asthma may receive up to six treatments in 1 hour, or a nebulizer dosage of 15 mg of albuterol in 1 hour 27. This can be done several ways. A larger fill volume of 4-5 ml should be used instead of the usual 2-3 ml. Higher flows of 8-10 lpm also are recommended. (One should note that higher external flows may make ventilator triggering difficult, particularly during pressure ventilation modes). Lastly, one should bypass or turn off the ventilator humidifier during the treatment. Dry gas will deliver approximately twice as much aerosol to the patient. THEOPHYLLINE T heophylline (Aerolate, Slo-bid, Theo-dur, Tedral, Marax, Primatene, Respbid, Theolair ) is commonly used for the relief and prevention of bronchospasm. Traditionally, it has been thought to achieve bronchodilation by inhibition of the enzyme This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 31

32 phosphodiesterase. This is doubtful because effective plasma levels in the body have not been shown to inhibit phosphodiesterase. It s also believed that there may be competitive antagonism of adenosine receptors. Theophylline is one of the oldest medicinal agents used in the treatment of respiratory disorders. It was the mainstay of asthma therapy throughout the 1970 s but fell out of favor with the discovery of the role of airway inflammation in asthma and the development of inhaled corticosteroids. The recent discovery of theophylline s anti-inflammatory effects, along with its low cost and long duration of action, has revived interest in the compound. However, many clinicians consider theophylline a difficult drug to manage, which has tempered its use. 45 In addition to bronchodilation, theophylline improves contractility of a normal or fatigued diaphragm. This generally increases minute volume. Theophylline also stimulates the phrenic nerve. This makes it useful in reducing the severity of both sleep and neonatal apnea. Ventricular output and rate are increased from direct stimulation of the heart and/or vasodilation of vascular beds. Tachycardia is therefore a potential complication. Theophylline belongs to a group of vegetable organic compounds known as xanthines that include caffeine and theobromide. These have been replaced in medicine with other compounds. Theophylline is given orally, as in ephedrine tablets. It also is provided parenterally or in suppository form. Dosage is titrated to achieve a serum level between 5-15 mcg/ml. If possible, serum levels should be kept between 8-10 mcg/ml leaving a cushion of toxicity. Plasma levels above 15 mcg/ml provide persistent side-effects in many patients. Side-effects include: nausea, diaphoresis, anorexia, tremors, palpitations, tachycardia, headache, and nervousness. These caffeine-like side-effects usually disappear with continued use. Some children on theophylline have been observed to have learning and behavioral problems. Many variables affect the half-life of theophylline. Dosage therefore varies considerably, depending upon their presence. Variables necessitating an increase in the usual dose are: cigarette or marijuana smoking, smog, high caffeine intake, barbiturate use, or high protein diets. Variables necessitating a decrease in the dosage are: liver congestion or disease, marked obesity, congestive heart failure, severe hypoxemia, fever, pneumonia or other acute illnesses in the ICU, use of cimetidine, propranolol, erythromycin, allopurinol, or oral contraceptives. ANTIMUSCARINICS Antimuscarinics (often called anticholinergics) compete for receptor sites with acetylcholine in bronchial smooth muscle. This blocks the PNS from causing bronchoconstriction by decreasing levels of cgmp. Antimuscarinics can decrease secretion production so drying of the airways is a potential problem. The fluid volume of secretions also may be decreased causing an increase in their viscosity. This is usually not a significant problem unless excessive doses are given. Additional side-effects include: drying of the mouth and skin, blurred vision, and an increase in speech, swallowing, and micturition problems. Atropine has traditionally been the anticholinergic used for bronchodilation. It has an additive effect to the β adrenergic agonists when given together. Atropine is absorbed by both the GI tract and mucosal surfaces. The inhaled dose for atropine is around mg/kg for This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 32

33 adults (2.5 mg per 24 hours maximum). Atropine is available in many tablets and elixirs, such as, astrohist plus, Donnatal, and Lomotil. A derivative of atropine, IPRATROPIUM BROMIDE, (Atrovent ) is far more common in pulmonary medicine. The side effects of antimuscarinics are minimal or absent in most patients with the use of ipratropium. Systemic absorption via the GI tract and mucosal surface is also minimal. Ipratropium is recommended for use with COPD patients having a bronchospastic component to their disease. It has an additive effect to the β adrenergic agonists and, by itself, provides better bronchodilation for many COPD patients. It should be delivered prior to a β agonist for the best results. Ipratropium is often a first-line medication for COPD patients, particularly for those with chronic bronchitis. Usual adult dose is 2 puffs QID via MDI (12 puffs per 24 hours maximum). Each puff delivers approximately 18 mcg. Each MDI provides 200 puffs. Patients should be instructed that for maximum effectiveness the medication should be used consistently, not intermittently. If accidentally sprayed into the eye, prolonged pupil dilation and blurred vision may result 14, 20, 29. Glycopyrrolate (Robinul) is a quaternary anticholinergic compound. These agents are used to inhibit the muscarinic actions of acetylcholine at multiple sites. Glycopyrrolate is used specifically to inhibit salivation and excessive secretions of the respiratory tract. It is also used to counter the muscarinic effects of neostigmine and pyridostimine during reversal of neuromuscular blockade 20,27. Adverse reactions include tachycardia, ventricular fibrillation, and palpitations. Centrally it can cause drowsiness, headache, and ataxia. The other side effects are also related to its anticholinergic nature. Glycopyrrolate is contraindicated in tachycardia, paralytic ileus, and myasthenia gravis. Glycopyrrolate is not recommended for use in children under 12 years of age. The dose for controlling secretions in children is mcg/kg/dose 3 to 4 times daily. The IM and IV dose is 4-10 mcg/kg/dose every 3 to 4 hours. Ipratropium bromide nasal spray (0.03% or 0.06%) is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, or to any of the other ingredients. Antimuscarinics also provide some protection from airway irritants, such as, gases, cold and dry air, and smoke. They are not as effective against histamine, prostaglandins, leukotrienes, or serotonin. They do not inhibit mediator release and are not particularly effective against antigeninduced bronchospasm. Tiotropium Bromide (Spiriva ) Tiotropium is a new medication for those with severe asthma and COPD. It is similar in action to Atrovent (ipratropium bromide) and classified as an anticholinergic medication with extended action up to 36 hours. Like Atrovent, tiotropium works from an opposite direction to provide bronchodilation than do Rescue Medications such as albuterol. Tiotropium acts on the parasympathetic nervous system as opposed to the sympathetic. Anticholinergics inhibit muscarinic or M receptors. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 33

34 Tiotropium specifically targets M 3 and to a lesser extent M 1 receptors. These two receptors are important in bronchoconstriction and mucus production especially the M 3 receptor. Many COPD patients, as well as severe asthmatics, have a reduced effectiveness with beta 2 agonists such as albuterol. Being able to stimulate some bronchodilatation through blocking the actions of the M 1 and M 3 receptors allows for better symptom control. Medications such as Combivent already take advantage for this by combining albuterol and ipratropium. A drawback to ipratropium is its shorter length of action, though longer than albuterol. Ipratropium also inhibits the M 2 receptor, which may increase acetylcholine release and stimulate bronchoconstriction. A possible benefit from using tiotropium is an apparent reduction in side effects over ipratropium. This is probably due to its reduced action on the M 2 receptor. Some of the common side effects of ipratropium are nervousness, dizziness, headache, nausea, upset stomach, dry mouth, throat irritation, and cough. Another important advantage of tiotropium over ipratropium is length of action. One study saw a three day length of action. General consensus for length of action is around 36 hours, making tiotropium an excellent candidate for a daily long acting medication. Daily medications are seen as an effective way of increasing compliance among patients in taking their medications. Tiotropium is not currently available in a number of countries including the U.S. It is in clinical phase IIIb/IV, so hopefully it won t be long before this medication is available. In clinical trials with Spiriva HandiHaler, (tiotropium bromide inhalation powder) the most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, increased heart rate, blurred vision, glaucoma, urinary difficulty, and urinary retention. SPIRIVA is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, including ipratropium or to any component of this product. SPIRIVA is intended as a once-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm, i.e., rescue therapy. Immediate hypersensitivity reactions, including angioedema, may occur after administration of SPIRIVA. If such a reaction occurs, therapy with SPIRIVA should be stopped at once and alternative treatments should be considered. Inhaled medicines, including SPIRIVA, may cause paradoxical bronchospasm. If this occurs, treatment with SPIRIVA should be stopped and other treatments considered. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 34

35 Combination Therapy: β adrenergic and Anticholinergic IPRATROPIUM BROMIDE and ALBUTEROL (Combivent) Ipratropium bromide and albuterol is a combination MDI product, with the usual doses of each agent released from the valve (21 mcg of ipratropium, 100 mcg of albuterol base as 120 mcg of albuterol sulfate). The combination therapy has been shown to be more effective in stable COPD than other agents alone. 20 DuoNeb TM (3.0 mg albuterol sulfate and 0.5 mg ipratropium bromide per 3 ml) Inhalation Solution. DuoNeb is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator. CORTICOSTEROIDS Corticosteroids are very useful when the common bronchodilators appear less than effective. In the past, they were used primarily for asthmatics that didn t respond well to β adrenergic agonists or methylxanthines. Presently, they are considered a first-line medication for asthma. Corticosteroids are primarily anti-inflammatory, but they also facilitate airway smooth muscle relaxation through an SNS pathway. Some potentiation of the β 2 drugs also can occur. Steroids have many effects on the body. They promote vasoconstriction in areas of inflammation and decrease capillary permeability. This decreases edema fluid. In the airways, a decrease in edema fluid decreases airway wall thickness. This results in an increase in lumen size and decrease in airway resistance. Steroids stabilize cell membranes resulting in a decrease in synthesis, storage, and release of histamine. This is very helpful in preventing allergic bronchospasm. Corticosteroids increase blood sugar significantly, due to the formation of glucose from body protein. Another complication is that calcium is removed from bone during steroid use. This may lead to osteoporosis with chronic use. Steroids cause an increase in fat production that is characteristically deposited in the subcutaneous tissues of the head and trunk. This alters the facial contour, giving the patient a moon-faced appearance (cushinoid effects). Steroids inactivate circulating antibodies that normally protect the body via the allergic reaction. Steroids also decrease the formation of fibrous tissue that is part of the repair process. Impairment of the normal immunologic response from steroid use can therefore lower the patient s resistance to infection. Steroids also cause fluid and electrolyte imbalances and elevate blood pressure. In cases of shock where the cardiovascular system no longer responds to sympathomimetics, steroids aid vasopressors in their action. With prolonged use, steroids lead to adrenal insufficiency. Patients have to be weaned slowly to allow the adrenals to begin proper functioning again. Most of the above complications are a result of long-term steroid use. Short-term therapy, even with high doses, is relatively safe. Many of the complications of long-term use are minimized by This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 35

36 alternate-day dosage regimens or delivering the steroid as an aerosol. Aerosolization diminishes systemic absorption and should be considered for patients who show an improvement with systemic steroids 20, 27. Steroids are administered orally, 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 steroids are beclomethasone dipropionate, flunisolide, triamcinolone acetonide, or, more recently, fluticasone. Fortunately, a fungal infection of the oropharynx is the only major side-effect of aerosolized steroids. Having the patient rinse their mouth out after use can prevent even this. (Also instruct the patient to spit out, rather than swallow, the rinse water). For patients on a BID regimen, instruct the patient to take their medications before brushing their teeth in the morning and evening. This ensures rinsing and is easy to remember. It may take 4 to 6 hours to get a noticeable improvement in asthmatic symptoms after instituting steroids. One must therefore be patient when giving steroids for persistent asthma. In most cases, steroids are given as a prophylactic against bronchospasm and used to maintain normal airway tone. For patients who are self-administering the drug it is extremely important they be instructed in regular, daily use for maximum benefit from the medication. Steroids achieve their effects primarily through regulation of protein synthesis. The steroid hormone is initially taken up by the target cell and bound to specific cytoplasmic receptor proteins. This steroid-receptor complex is then transported to the nucleus of the cell. There it binds to a specific acceptor site on the DNA molecule. Messenger RNA is then formed from the DNA. The messenger RNA is transported to the cytoplasm where it causes new protein synthesis along the ribosomes. The new protein then gives a cellular response to the steroid (anti-inflammatory action, decreased permeability, etc.). Because of the potential side effects of steroids (decreased resistance to infection, adrenal insufficiency, electrolyte imbalances, metabolic alkalosis, osteoporosis, cushinoid effects, etc.) alternate-day dosage regimens are recommended for oral steroids However, the inhaled route is preferable since side effects are minimal with this route. Aerosolized steroid doses can safely be increased 300% without significant side effects in adults for a crisis. There is insignificant adrenal suppression at doses 2-3 times normal in adults. Several agents have been investigated as steroid-sparing agents for those on high-dose oral steroids. Methotrexate has both anti-inflammatory and steroid-sparing properties. Doses of mg/wk may permit a reduction in steroid dosage up to 50%. Severe side effects are possible, so close monitoring is necessary. Injected gold salts, troleandomycin, hydroxychloroquine, and ketotifen have also been studied. Patients who are receiving steroids should be given supplemental calcium. Blood pressure and blood glucose levels should be checked periodically. A TB test should be done and isoniazid therapy instituted if positive. In addition, an ophthalmological exam should be done for possible cataracts and glaucoma. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 36

37 CORTICOSTEROID MEDICATIONS HYDROCORTISONE is a steroid administered parenterally and rarely aerosolized. Plasma concentrations of mcg/ml are usually sufficient to decrease the symptoms of persistent asthma. The adult daily dose can range from 300 to 2000 mg. It is available in tablets under the name of Hydrocortone and several others. Hydrocortisone is a common ingredient in anti-inflammatory creams and lotions. PREDNISONE is a popular oral steroid. It is available in Deltasone tablets. It has an antiinflammatory potency 3-4 times that of hydrocortisone. The liver converts prednisolone to become active prednisone. This can delay its onset of action. It is virtually ineffective when aerosolized. The usual oral dose is 5-80 mg/day. PREDNISOLONE is a synthetic steroid that is rarely aerosolized. Anti-inflammatory potency is 3-4 times that of hydrocortisone but it takes longer to reach its peak effect. Route of administration is oral or parenteral. The injectable solution is available as Hydeltrasol, the liquid solution as Pediapred. The half-life is 2 to 4 hours and pharmacological effects last up to 36 hours. Usual adult dose is 5-80 mg/day. METHYLPREDNISOLONE has four to five times the anti-inflammatory potency of prednisolone. It has little effect on electrolyte balance so it is often used. It may be given orally, but is usually administered intravenously. Methylprednisolone is used for severe shock, persistent asthma, ARDS, and aspiration pneumonia. Onset of action is rapid, half-life is minutes, and pharmacological effects last up to 36 hours. Dosage varies depending upon symptoms. DEXAMETHASONE (Decadron ) is similar to prednisolone but lasts slightly longer (48 hours). It has thirty times the anti-inflammatory potency of hydrocortisone. It may be administered orally or aerosolized via MDI. Unfortunately, it doesn t potentiate the beta 2 drugs like methylprednisolone or hydrocortisone so it is not very popular. Dexamethasone can cause adrenal suppression. It is available as an 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. TRIAMCINOLONE (Kenalog, Azmacort ) is a synthetic steroid having an anti-inflammatory potency similar to methylprednisolone. It can cause sodium and water diuresis. Oral dose is 4-48 mg/day depending upon symptoms. The half-life is 3 hours and pharmacological effects last up to 48 hours. Prolonged use can cause skeletal muscle weakness and possible mental depression. The usual aerosol dose is 0.1 to 0.2 mg QID, up to a maximum of 1.2 mg per day. Aerosolization can cause hoarseness, voice weakness, and oropharyngeal candidiasis. Gargling and rinsing the mouth after use prevents these problems. Triamcinolone is available as an MDI (Azmacort ). Each puff provides 100 mcg and there are approximately 240 puffs in the MDI. Usual dose is 2 puffs TID or QID, up to a maximum of 16 per day for adults and 12 per day for This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 37

38 children. A preparation for nasal inflammation and administration is known as Nasacort. BECLOMETHASONE DIPROPIONATE, (Beclovent, Vanceril ) when delivered topically as an aerosol, has an anti-inflammatory potency several hundred times that of hydrocortisone. 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. Pediatric dosage is half of this. Each MDI provides about 200 puffs. The major side-effect is a fungal infection of the oropharynx. Gargling and rinsing the mouth after use prevents this as with other steriods. It is virtually ineffective when given orally. Nasal preparations are available as Beconase and Vancenase for rhinitis. BETAMETHASONE has 75% of the potency of beclomethasone. Its duration of action is similar to dexamethasone. It is most effective as an aerosol but is not used for lung inflammation. Daily dosage of 800 mcg should be divided over 4 doses. FLUNISOLIDE (Aerobid ) is an MDI that delivers 250 mcg per activation. It is several hundred times more potent than hydrocortisone. The usual adult dose is 2 puffs BID, but a maximum of 4 puffs BID (2 mg per day) can be given. Pediatric dose is half of this. The MDI provides about 100 puffs. Nasalide is a nasal preparation of flunsolide. BUDESONIDE is an inhaled corticosteroid with high topical potency and relatively low systemic activity. Standard adult dose 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. A nasal aerosol is available for allergic rhinitis. FLUTICASONE (Flovent ) is available in three MDI s delivering 44 mcg, 110 mcg, or 220 mcg. The recommended starting dose for patients receiving bronchodilators alone is 88 mcg twice daily. The highest recommended dose is 440 mcg daily. For those already taking inhaled steroids, starting dose is mcg twice daily and highest dose is 440 mcg daily. For those taking oral steroids, starting dose and highest recommended dose is 880 mcg twice daily. Candidates for high-dose inhaled corticosteroids (approximately double the conventional dose) are those who continue to have symptoms of wheezing, cough, and dyspnea despite standard-dose steroid and bronchodilator therapy. For these patients, increase beclomethasone and triamcinolone dose to 3-4 puffs QID. For flunisolide, increase the dose to 2 puffs TID or QID. Monitor patient symptoms and flow rates to assess the effectiveness of the dosage regimen. If the patient remains symptomatic, increase the dosage by one puff up to a maximum of 5-6 puffs QID. As the patient improves, decrease the dosage to the lowest amount required to keep the patient asymptomatic. Side-effects of high-dose inhaled steroids are less than those of oral steroids. It may be possible to decrease or discontinue systemic steroids by increasing the standard aerosol dose. Systemic steroids can then be reserved for periods of infection, trauma, or surgery. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 38

39 ALVESCO (ciclesonide), manufactured by Nycomed, comes in and HFA, MDI form and was approved for the treatment of asthma in January of It is specifically indicated for the maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients 12 years and older. It is supplied as either an 80 mcg or 160 mcg dose. In patients over 12 years of age who previously received bronchodilators alone, the recommended starting dose is 80 mcg twice daily with the highest recommended dose of 160 mcg twice daily. In patients over 12 years who previously received inhaled corticosteroids, the recommended starting dose is 80 mcg twice daily with a maximum recommended dose of 320 mcg twice daily. Patients over 12 years who received oral corticosteroids are recommended a starting dose of 320 mcg twice daily with that dose also being the highest recommended daily dose. ASMANEX TWISTHALER (mometasone furoate) is a DPI manufactured by Schering Corporation, and was approved by the FDA in March of 2005, and is recommended for the maintenance treatment of asthma in patients 12 years of age and older, but does have recommended dosing information for children ages This approval by the FDA of Asmanex for use in asthmatic children came in February, It comes in two strengths, 220 mcg and 110 mcg. As most inhaled corticosteroids, Asmanex is contraindicated in patients with status asthmaticus and hypersensitivity. Combination Therapy: β adrenergic and Corticosteroid ADVAIR DISKUS (salmeterol xinafoate/fluticasone propionate inhalation powder), combines an inhaled corticosteroid and a long-acting inhaled bronchodilator to simultaneously treat both of the underlying causes of asthma symptoms: inflammation (swelling and irritation of the lungs airways) and bronchoconstriction (tightening of the smooth muscle surrounding the airways). Advair Diskus combines two leading asthma controller medications Serevent (salmeterol xinafoate), a long-acting inhaled bronchodilator, and Flovent (fluticasone propionate), an inhaled corticosteroid, in a single asthma medication. It is intended for the maintenance treatment of asthma as prophylactic therapy in patients 12 years and older where combination therapy is appropriate. SYMBICORT is available in MDI. This contains the two medicines budesonide and formoterol in the same single inhaler. It is used to treat asthma. The reason for putting the two medicines together in one single inhaler is that they work on different aspects of asthma: Budesonide is a type of medicine called a glucocorticosteroid, which treats the chronic, underlying part of asthma. This is the inflammation - the quiet part of asthma that you cannot hear, see, or feel. When it is left untreated, inflammation can worsen. The lungs can become more inflamed and asthma symptoms and attacks can increase. Formoterol is a fast and long-acting bronchodilator. Bronchodilators are medicines that open up the bronchial tubes (air passages) of the lungs. They are used to treat the This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 39

40 symptoms of bronchial asthma, chronic bronchitis, emphysema, and other lung diseases. They relieve cough, wheezing, shortness of breath, and troubled breathing by allowing an increased flow of air through the bronchial tubes. Used together, budesonide and formoterol provide better control of asthma, decreasing the number of asthma attacks. Symbicort provides both medications in the same single inhaler, so that treatment is more convenient for the patient. September 18, M Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has granted approval for QVAR (beclomethasone dipropionate HFA) as an inhalation aerosol for the treatment of asthma. QVAR, a unique aerosol metered dose inhaler (MDI) which contains beclomethasone dipropionate (BDP) in a solution, is the first inhaler designed to deliver smaller-particle-sized medication to the large, intermediate and small airways. New QVAR is indicated for the preventive management of asthma for people over the age of 12 and contains the safe and effective corticosteroid, beclomethasone dipropionate. Both the large and small airways in the lungs play an important role in asthma, but current inhalers fail to deliver medication to the smallest airways. This new drug represents a potential breakthrough for patients with asthma, said Sally Wenzel, M.D., a leading Pulmonologist from the National Jewish Medical and Research Center in Denver, Colorado. The efficacy of inhaled corticosteroids for the treatment of asthma is well established, both nationally and internationally, with treatment guidelines recommending their use as first-line therapy. (30-36) Corticosteroids, such as QVAR, for the treatment of asthma are usually administered by inhalation through a metered dose inhaler. With QVAR, approximately 50 percent of the drug is administered to the lungs. Clinical trials have shown QVAR to be effective to conventional BDP at a lower dose. At recommended doses, QVAR was not associated with any clinically relevant systemic side effects in adults. (38) (30, 31, 37, 38) QVAR is the first CFC-free metered dose inhaler containing a corticosteroid. QVAR is a formulation of the anti-inflammatory drug BDP, which uses the ozone friendly propellant hydrofluoroalkane (HFA). Common side effects associated with the use of QVAR and placebo in clinical trials include, but are not limited to, headache (12 percent and 9 percent, respectively) and pharyngitis (8 percent and 4 percent, respectively). QVAR is not a bronchodilator and is not indicated for rapid relief of bronchospasm. Caution: Adrenal insufficiency may occur when transferring patients from systemic steroids Beta Blockers and Asthma The conflicting effects of various medications used can complicate the treatment of heart This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 40

41 problems and asthma. A common type of heart medication is a beta-blocker such as atenolol, metoprolol, or propranolol. Unlike bronchodilators used by asthmatics, which are beta stimulants, beta blockers block the actions of the sympathetic nervous system. There are two very important innervation sites in the sympathetic nervous system, Beta1 and Beta2. Stimulating Beta-2 sites causes bronchodilation, which helps reverse the wheezing during an asthma attack. Asthma medications such as albuterol, metaproteranol, and terbutaline are designed to have strong affinity to the Beta2 receptors, but they also have some Beta1 effects. Stimulation of the Beta1 receptor cause many of the familiar side effects associated with rescue inhalers such as increased heart rate, tremors, and nervousness. Beta Blockers are meant to treat heart related problems. To name just a few: high blood pressure (hypertension), atrial fibrillation, angina, myocardial infarction, and ventricular arrhythmias. Beta Blockers are also used in the treatment of glaucoma, migraine, and tremor. The problems arise when an asthmatic also has heart problems or one of the other ailments treated by beta-blockers. For example, one of the side effects of beta-blockers is bronchospasm and wheezing. But there are ways to get around these medication conflicts - there are some alternatives. For asthma problems, there s Atrovent, AKA ipratropium bromide. Atrovent works by blocking the parasympathetic nervous system instead of stimulating the sympathetic. The parasympathetic system serves as a balancing force to the sympathetic. One of the alternatives to beta-blockers is calcium channel blockers such as diltiazem (Cardizem, Dilacor) and nifedipine (Procardia, Adalat). Calcium channel blockers work by interfering with the movement of calcium in and out of the muscle cells in the heart. This helps slow the heart rate, relax heart muscles, opening cardiac blood vessels and increasing the supply of oxygen to the heart. For patients with cardiac and asthma problems, coordination of efforts between physicians is extremely important. Asthma specialists and cardiologist must consult each other on the best course of action in dealing with the health problems. The patient should not be burdened with the responsibility of coordinating health care professionals. MEDIATOR MODIFIERS Patients who show an improvement in bronchospastic symptoms with steroids may benefit from mediator modifiers, such as, CROMOLYN SODIUM (Intal, Aerine ) or NEDOCROMIL SODIUM (Tilade ). These are prophylactic drugs only. They are never used to treat active bronchospasm. In fact, the powder form of cromolyn may worsen bronchospasm. Their action is to prevent bronchospasm caused by sensitization of airway mast cells and their release of inflammatory mediators. Cromolyn is administered as an aerosolized This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 41

42 powder through special devices. It is also available as a liquid for aerosolization. If cromolyn or nedocromil are inhaled prior to degranulation of mast cells, the release of histamine and other mediators is prevented. Therefore, bronchospasm does not take place from an inhaled allergen. Cromolyn also may act on cholinergic and irritant receptors directly. This also provides some protection from non-allergic bronchospasm. The value of cromolyn and nedocromil is that they decrease the frequency and severity of asthmatic attacks if used regularly. It is also possible to decrease the amount of steroids with regular use. Dosage varies and is at the discretion of the physician. The usual adult dose of cromolyn is 20 mg TID or QID. KETOTIFEN has both antihistaminic and antiallergic properties similar to cromolyn sodium. It is available as a capsule, tablet, or syrup. It takes about one month to see therapeutic effects from ketotifen. Benefits gradually increase over a six-month period. It is well-tolerated in adults and children. The standard dose is l mg twice daily but can be increased to 2 mg twice daily if necessary. In recent years, a new approach to control and treat asthma has been introduced. What has been described as SRS-A in the past is actually a mixture of arachidonic acid metabolites called leukotrienes. Asthmatics produce more leukotrienes than normal. Cysteinyl leukotrienes (LTD 4, LTE 4, LTF 4 ) cause bronchospasm, increase capillary permeability, and stimulate mucus secretion. Several medications have been studied to block leukotriene receptor sites or inhibit its synthesis. Two approaches are used: competitive antagonists at the receptor site or inhibition of 5 lipoxygenase to decrease synthesis. Competitive antagonists studied have been zafirlukast, verkulast, tomelukast, MK-571, and ICI (Zafirlukast has been commercially released under the name Accolate ). The most potent antagonist appears to be ICI As these antagonists prove their efficacy and safety they will be given names instead of numbers and released. 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. MK-571 is a FLAP binding agent. Thromboxanes, like leukotrienes, are arachadonic acid derivatives that cause bronchospasm. BAY-U305 is an experimental antagonist. OKY-0046 (ozagrel) is an inhibitor of thromboxane. These may prove useful in the future. Additional medications studied attempt to interfere with platelet activating factor, lymphocytederived cytokines, or camp breakdown. Platelet-activating factor causes marked bronchospasm and is prominent in the allergic/inflammatory response. Inhibition of lymphocyte-derived cytokines, such as interleukin 4 and 5, limit the allergic/inflammatory response. Phosphodiesterase type IV catalyzes camp breakdown. Interference with this enzyme allows a longer camp duration of action. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 42

43 PROSTAGLANDINS Prostaglandins are the final agents to be mentioned in relation to bronchodilation. They have been investigated as bronchodilators but are not currently available for clinical use. Some prostaglandins cause bronchodilation and some do the reverse. PGE 1 and PGE 2 have shown bronchodilation properties comparable to the beta 2 adrenergic drugs. These compounds may be available as bronchodilators in the future. 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. Lowering the 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 or the ductus will be dilated and the problem worsened. MUCOKINETICS AND MUCOLYTICS Mucokinetic/mucolytic agents achieve their effect through one of several mechanisms. They may act directly upon the chemical constituents of mucus to decrease mucus viscosity or tenacity. They may dilute the mucus resulting in disadherence from the airway. The watery sol layer of mucus may be replenished or increased by some agents. This makes ciliary action more effective. The cilia themselves also may be directly stimulated. Lastly, serous bronchial glands can be stimulated to produce secretions that are less viscous. Some medications have several of the above actions. A brief review of the mucociliary escalator system is provided below to further illustrate these actions. Within airway walls are goblet cells and serous-producing bronchial glands. The goblet cells produce a very sticky gel-like secretion. The bronchial glands produce a watery serous-type of secretion. This watery secretion becomes the sol layer of mucus. The sol layer of mucus rests directly atop the airway cells and bathes the cilia. The gel layer of mucus rests atop the sol layer. The function of the gel layer is to trap foreign particles in the airway for transport out of the lungs. The cilia form a dense brush like network lining the airways. There are approximately 200 cilia per cell. Most of their movement takes place within the watery sol layer. Through their whip-like motion, they propel items trapped in the gel layer out of the lungs. There is a fast forward motion with a flick at the peak of their forward movement. The flick at the peak extends the tips into the gel layer producing a wave in the gel layer. This propels particles out of the airway. Should the sol layer be depleted, the gel layer increased, or ciliary action be impaired, secretion and particle removal are inhibited. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 43

44 MUCOCILIARY ESCALATOR Gel Layer Cilia Sol Layer Goblet Cell Ciliated Epithelium Bronchial Gland MUCOKINETIC AND MUCOLYTIC MEDICATIONS WATER is the safest and most common agent used to mobilize secretions. It may be provided orally or aerosolized as a bland aerosol. (However, neither has been conclusively shown to affect sputum characteristics however). Most often, water is aerosolized to a patient whose upper airway has been bypassed by intubation. For those who are not intubated, high humidity tents, face tents, or aerosol masks provide water. Water may be provided continuously or on an intermittent basis, depending upon the severity of the problem. (For those who are intubated it is continuous). Caution is advised for patients in congestive heart failure or on fluid restriction, too much water could lead to fluid overload. Sensitive patients may find aerosolized water irritating, particularly if an ultrasonic nebulizer is used. Saline solutions are recommended in ultrasonic nebulizers. SALINE solutions are commonly delivered. Normal saline (0.9% NaCl) is used in small amounts (1-3 cc) to dilute other medications for aerosolization. One to three cc also may be instilled directly into the airway for lavage and suctioning purposes. Larger amounts may be nebulized for secretion dilution. It, like water, is absorbed into the sol layer to disadhere mucus from the airway. Half-normal (0.45% NaCl) saline is also used, particularly in ultrasonic nebulizers. Half-normal saline particles are believed to evaporate slightly as they travel through the respiratory tract. Upon deposition, they may be very close to normal saline in actual composition. Hypertonic solutions (1-15% NaCl) are used for sputum inductions. This solution is very irritating to the airways and stimulates the cough reflex. The high salinity has a bronchorrhea effect causing dilution of the mucus. There is also a direct effect on mucoprotein and DNA complexes that causes a reduction in mucus viscosity. Caution should be used in sodium-restricted patients. No more than 10 ml/day of hypertonic saline should be given. SODIUM BICARBONATE (NaHCO 3 ) may be aerosolized or instilled directly into the airway. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 44

45 Its alkalinity decreases the adherence of mucus to the airway. The salt in NaHCO 3 disrupts mucoprotein and DNA complexes like hypertonic solutions. Some bronchorrhea is also produced. NaHCO 3 has an additive effect when given with acetylcysteine. NaHCO 3 may break down some bronchodilators so they should not be administered simultaneously. N-ACETYLCYSTEINE (Mucomyst ) is a mucolytic that achieves its effect by rupturing the disulfide bonds of mucus. This makes secretions less viscous. Mucomyst irritates the airways producing a bronchorrhea. This irritation also may lead to bronchospasm. Mucomyst should therefore be administered with a bronchodilator for most patients. Upon opening, it should be used within 3-4 days because it rapidly degrades. It should be kept refrigerated when not in use. Nausea, gagging, and vomiting may be produced from the foul odor and taste. Route of administration is oral, IV, or aerosolization. Aerosolization is the most popular method in the United States. Mucomyst is available in 10% and 20% solutions. The usual aerosol dose is 1-2 cc of the 10% solution. Aerosol dose of the 20% solution is half that of the 10% solution (0.5-1 cc). These are the usual doses, however much more can be given. Up to 3-5 cc of the 20% solution and up to 6-10 cc of the 10% solution can be aerosolized. One to two cc of either solution may be instilled directly into the airway every hour. One should keep in mind the danger of bronchospasm with larger doses and direct instillation. N-acetylcysteine (NAC) increases glutathione levels which makes it useful for acetaminophen overdoses. Glutathione inactivates acetaminophen metabolites that cause kidney and liver damage. (Preliminary studies show ARDS also improves with NAC due to increased glutathione). Via the oral or IV route, doses as high as 3 gm/day for 3 days have been given for overdoses. Via aerosolization, 1-10 cc of the 20% solution or 2-20 cc of the 10% solution every 2-6 hours has been given. BROMHEXINE (Bisolvon ) is used in Europe for mucokinesis. It increases bronchial gland secretion and has a slight mucolytic effect. The resulting mucus is less viscous and easier to expectorate. S-CARBOXYMETHYLCYSTEINE (Mucodyne ) is an oral mucokinetic that acts directly on the bronchial glands. The glands are believed to be stimulated to produce a secretion with an increased amount of sialomucins. Such secretions have a decrease in viscosity. It is chemically related to garlic, a common home mucokinetic. Other common home remedies for mucokinesis include chicken soup, horseradish, pepper, and mustard. These cause a bronchorrhea, possibly through vagal stimulation. Several enzymes have been used in the past for mucokinesis/mucolysis. They are rarely used today because they are costly, toxic, and very irritating. There also are hypersensitivity problems and severe bronchospasm is not uncommon. The specific indication for their use is purulent secretions. PANCREATIC DORNASE (Dornavac ) was the most common one administered. Formal approval by the FDA of pancreatic dornase was withdrawn in This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 45

46 DORNASE ALFA (Pulmozyme ) is a genetically engineered enzyme created to specifically cleave DNA. Purulent secretions contain significant amounts of extracellular DNA as a result of degenerating leukocytes. When this DNA is hydrolyzed, the mucus becomes more fluid. The specific indication for Pulmozyme is cystic fibrosis, however, some chronic bronchitics also may benefit from its use. Dosage is 2.5 mg aerosolized once or twice daily. Pulmozyme is supplied in single-use ampules, which should not be mixed with other drugs or diluted 27. Cystic fibrosis (CF) is an incurable inherited disease, affecting mainly the lungs and the digestive system. In the lungs, where the effects of the disease are most devastating, CF causes increasingly severe respiratory problems. In the digestive tract CF often results in extreme difficulty in digesting adequate nutrients from food. Pulmozyme is a recombinant human deoxyribonuclease I (rhdnase/dornase alfa). It is an inhaled medication that reduces CF-related morbidity, including the risk of respiratory tract infectious exacerbations requiring treatment with parenteral antibiotics, improves pulmonary function and improves quality of life. BETA ADRENERGIC AGONISTS also aid in mucokinesis. They appear to increase the beat frequency of cilia. This may be due to direct stimulation or as a result of a change in the character of the respiratory tract secretions. Active transport of the chloride ion into the airway lumen may be augmented with a resulting water flux. This may produce less viscous, thinner mucus and enhance ciliary movement. ETHYL ALCOHOL (ETOH) has been used specifically for acute fulminating pulmonary edema. Its surface-active properties cause the frothy bubbles characteristic of this condition to pop. The resulting liquid occupies less alveolar space so gas exchange is improved. Suctioning also becomes more effective. ETOH may be aerosolized or instilled directly into the airway. Three to five cc may be given at a time. EXPECTORANTS AND COUGH SUPPRESSANTS Expectorants and cough suppressants work centrally or peripherally. Central drugs increase the cough threshold in the medullary cough center. Peripheral drugs inhibit the cough at the mucosa, usually by coating supraglottic receptors with thick syrup. Expectorants depend on the gastropulmonary mucokinetic vagal reflex. Stimulation of the gastric mucosa increases mucus secretion from the bronchial glands. Further stimulation of the gastric mucosa results in vomiting which is an unfortunate side-effect of excessive expectorant. SUPER SATURATED POTASSIUM IODIDE (SSKI) is an orally administered expectorant that achieves its action through stimulation of the vagus nerve. This, in turn, stimulates the submucosal bronchial glands to produce more serous fluid. The result is bronchorrhea. SSKI also stimulates natural proteolytic enzymes for a direct mucolytic effect. Ciliary action also may be stimulated. Nausea and vomiting occur with excessive dosage. Five to ten drops in a glass of water given 3-4 times a day may be given. (This translates to 0.3 to 0.6 cc or mg 3-4 times a day). Children can receive half of this dosage. Patients can develop acne or rashes and This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 46

47 long-term use may disrupt thyroid function. SSKI should not be given to those with thyroid disease. Pima is a black raspberry flavored syrup containing potassium iodide containing 325 mg in 5cc. GUAIFENESIN (Triaminic, Robitussin, Novahistine, Guaifed, Anatuss ) is a popular expectorant in proprietary cough medicines. (Guaifenesin is also known as glycerol guaiacolate or glyceryl quaiacolate). It is believed to increase bronchial gland secretion through direct vagal stimulation. In large amounts, it causes vomiting and cerebral depression. For children 6-12 years old, mg every 4 hours with a maximum of 2400 mg in 24 hours may be given. For children 2-6 years old, half of this may be given. For younger children, half again ( mg every 4 hours) may be given. IODINATED GLYCEROL (Organidin ) is available as a tablet, solution, or elixir. The adult dose of the 5% solution is 20 drops in a liquid QID. The 30 mg tablet dose is 2 tablets QID. The 1.2% elixir dose is 1 teaspoon QID. Pediatric dose is one half the adult dose. CODEINE is a popular cough suppressant. It is less addictive and its respiratory depressant activity is about 1/4 that of morphine. It is also less likely to cause bronchospasm or constipation. (Morphine, codeine, and other narcotics release histamine causing bronchospasm). Dosage is mg every 4-6 hours, not to exceed 120 mg in 24 hours. For children 6-12 years old dosage is mg every 4-6 hours. DEXTROMETHORPHAN is also common because it has no analgesic, respiratory depression, or addictive properties. It is used in more than 60 different medications under more than 20 brand names. Cough suppression is comparable to codeine. Dosage is mg every 4-8 hours up to a maximum of 120 mg in 24 hours. For children 6-12 years old, dosage is 5-10 mg every 4 hours. For children 2-6 years old, dosage is mg every 4-8 hours. DIPHENHYDRAMINE is an antihistamine with antitussive properties. It can cause sedation and anticholinergic effects. Diphenhydramine is found is several over-the-counter medications, such as Benylin. Dosage is 25 mg every 4 hours up to a maximum of 150 mg in 24 hours. Pediatric dosage is one-half the adult dose. Other central-acting cough suppressants consist of hydrocodone, hydromorphone, methadone, and caramiphen. Hydrocodone is a derivative of opium so it is addictive and can cause respiratory depression. It is more potent than codeine. Hydromorphone is a derivative of morphone. It is available in combination with quaifenesin in Dilaudid. Methadone is very addictive and rarely used for cough suppression. Its main indication is for intractable cough caused by inoperable lung cancer. Caramiphen is available in combination with phenylpropanolamine (a decongestant) in Tuss-Ornade. BENZONATATE works peripherally to block the cough. TESSALON is also a peripherallyacting prescription product. It prevents both the cough and gag reflex. CAMPHOR and MENTHOL decrease the cough when applied to the chest or inhaled. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 47

48 ANTI-INFECTIVES Several types of anti-infectives will be discussed. Antibiotics are the first discussed, followed by antifungal and antituberculosis medications. Pentamidine and Virazole are then discussed. ANTIBIOTICS Antibiotics bind to certain cell constituents, such as, enzymes, ribosomes, or nucleic acids. In so doing, they inhibit bacterial cell-wall synthesis or function, inhibit protein synthesis, interfere with nucleic acid metabolism, or interfere with intermediary metabolism. Antibiotics are generally provided systemically, but several (carbenicillin, gentamicin and streptomycin) have been aerosolized for localized infections (lung abscess and bronchiectasis). Tobramycin has been used for chronic infections in cystic fibrosis. Parenteral medications are often ineffective in lung infections because the presence of edema, fibrosis, or thick exudates limit diffusion of the drug into the lung. Administering the drug topically may then be of benefit but is an uncommon option. Aerosolized antibiotics also may be useful when infections appear resistant to systemic therapy. Aerosolized antibiotics should be considered a supplement to systemic therapy, not a replacement. They are probably most useful for stubborn gram negative infections. Results on aerosolized antibiotics have been mixed; some patients have responded dramatically, while others not at all. However, resistant strains also may develop from such therapy. If the nebulizer does not deliver uniform particles of the proper size, there is uneven distribution of the medication. Organisms in central airways may be killed but organisms in smaller airways may receive a sublethal dose. This quickly leads to resistance of the organism. Nebulizers producing particles around 1 micron in diameter are recommended. There are several disadvantages to aerosolized antibiotics. The first is that bronchospasm is very common. Secondly, DNA inactivates some antibiotics and enzymes found in mucus. Third, doses for this route of administration have not been clearly established. Fourth, resistant microorganisms are created, as mentioned above. A final disadvantage is that expensive equipment may be needed and considerable staff time required for administration. Despite the above, aerosolized antibiotics may be considered for children with cystic fibrosis, fungal infections (pulmonary coccidioidomycosis, endobronchial histoplasmosis) and when systemic therapy appears ineffective or toxicity has been reached. The common pulmonary pathogens consist of: staphylococcus aureus, streptococcus pneumoniae, klebsiella pneumoniae, hemophilus influenzae, escherichia coli, proteus mirabilis, and pseudomonas aeruginosa. The first two are gram positive cocci. The remainder are gram negative bacilli. The mycobacterium tuberculosis is also relatively common. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 48

49 ANTIBIOTIC MEDICATIONS PENICILLINS are probably the most important of the bactericidal antibiotics. They are used for pneumococcal pneumonias, nonhospital-acquired aspiration pneumonia, and lung abscesses. Penicillin G is the agent of choice for streptococcus pneumoniae, streptococcus pyogenes, and nonpenicillinase-producing staphylococcus aureus. Intramuscular or intravenous delivery is the preferred routes of administration for acute and serious pulmonary infections. Aerosolization is not recommended. A number of bacteria have become resistant to penicillin by the production of the enzyme penicillinase. Penicillinase hydrolyzes a portion of the penicillin molecule. A subgroup of the penicillins was therefore created that is resistant to penicillinase. They include: cloxacillin, dicloxacillin, methicillin, nafcillin, and oxacillin. These drugs are not a substitute for penicillin G when it has been proven effective. They are specifically for penicillinaseproducing bacteria, such as staphylococcus aureus. Broad-spectrum semisynthetic penicillin derivatives are given for gram negative microorganisms. These include: ampicillin, amoxicillin, carbenicillin, piperacillin and ticarcillin. Ampicillin is used for pneumococcal pneumonia, bronchitis, and bacterial exacerbations of COPD, streptococcus pneumoniae, and hemophilus influenzae. Amoxicillin is used for the same and is closely related to ampicillin. Both may be given orally but amoxicillin achieves an effective plasma concentration lasting twice as long as ampicillin. Carbenicillin is effective against pseudomonas, proteus, and other gram negative bacteria. It is not as effective as ampicillin against gram positive organisms. Carbenicillin should be used with another antibiotic to prevent development of resistant strains. It may be administered in a 1-3 gram aerosol dose. Ticarcillin is similar but has greater anti-pseudomonas activity. Piperacillin is the most potent, carbenicillin the least potent. These are often given in combination with an aminoglycoside for pseudomonas because they are synergistic. Problems with the penicillins consist mainly of hypersensitivity reactions. Rashes, fever, and anaphylactic shock can occur. High doses can cause cerebral irritation and gastrointestinal upset (nausea, vomiting and diarrhea). CEPHALOSPORINS are similar to penicillin but are resistant to penicillinase. They are active against gram negative and gram positive bacteria. Cephalosporins are effective against staphylococcal, streptococcal, and klebsiella pneumonias, along with proteus mirabilis and escherichia coli. They are not effective against pseudomonas or bacteroides fragilis. Their major use in pulmonary disease is concurrent use with gentamicin for undiagnosed sepsis and for cephalosporin-sensitive gram negative organisms. Cephalosporins are also useful for patients who are allergic to penicillin with staphylococcal infections. (Caution is advised because patients also may be allergic to cephalosporin). The important cephalosporins are cephalothin, cephaloridine, cefazolin, cephapirin, cephalexin, and cephradine. Cephalosporins achieve their action through interference with bacterial cell-wall synthesis. Problems associated with their use consist of hypersensitivity reactions, skin rashes, fever, This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 49

50 urticaria, anaphylaxis, and pain at the injection site, phlebitis, and renal toxicity. Aerosolization is not recommended. Cephalosporins are seldom the first drug of choice but are the most prescribed group of antibiotics in the United States. They are also the most expensive. Cephalosporins are often used for severe hospital-acquired bacterial pneumonia. AMINOGLYCOSIDES inhibit the synthesis of protein. They are useful for undiagnosed sepsis, organisms specifically sensitive to the aminoglycosides, and for preventing resistant strains of pseudomonas. The important aminoglycosides for respiratory problems are gentamicin, amikacin, kanamycin, tobramycin, and streptomycin. Gentamicin is used for staphylococcus aureus, escherichia coli, hemophilus influenzae, diplococcus pneumoniae, pseudomonas, klebsiella, enterobacter, serratia, proteus, and neisseria. Amikacin and kanamycin are similar to gentamicin but kanamycin is effective against fewer organisms. Kanamycin is particularly ineffective against pseudomonas and streptococcus. Tobramycin is very effective against pseudomonas and is the least toxic of the amino-glycosides. Tobramycin can be mixed with albuterol and stored for up to 7 days if kept refrigerated. The albuterol prevents the bronchospasm common to antibiotics and pre-mixing eases administration for both the RCP and the home therapy patient. Only one treatment is required to deliver both medications instead of two treatments with pre-mixing. Forty mg of tobramycin is mixed with 2.5 mg of albuterol and NS added to a final volume of 3.5 ml per treatment. Streptomycin is effective against gram negative and acid-fast organisms, such as, tuberculosis bacilli. Aminoglycosides are administered parenterally. Gentamicin has been aerosolized and instilled directly into the airway. Aerosol dose is approximately mg. Streptomycin has also been aerosolized in a dose of approximately mg. Problems associated with the aminoglycosides are serious renal injury, ototoxicity, headache, vertigo, nausea, vomiting and hypersensitivity reactions. TETRACYCLINES inhibit phosphorylation and protein synthesis. They are effective against streptococcus pneumoniae, hemophilus influenzae, and mycoplasma pneumoniae. Tetracyclines are used as a prophylactic and for acute exacerbations of chronic bronchitis. Milk and milk products interfere with their absorption from the gastrointestinal tract. Problems consist of hypersensitivity reactions, nausea, vomiting, diarrhea, hepatic damage and discoloration of teeth in children. Many common respiratory pathogens have become resistant to tetracyclines. They are still useful for atypical pneumonias. SULFONAMIDES are bacteriostatic against gram positive and gram negative organisms except pseudomonas. They interfere with formation of folic acid. Sulfonamides are usually given orally to manage hemophilus, diplococcus, and klebsiella infection. Problems associated with their use are hypersensitivity reactions, fever, urticaria, nausea, vomiting, dizziness, headache, irritability, mental depression and renal damage. An additional problem is that sulfonamides convert hemoglobin to sulfhemoglobin. This interferes with oxygen carrying capacity. Septra and Bactrim are two commonly prescribed sulfonamides. POLYMYXIN B is effective against gram negative organisms, particularly pseudomonas. It This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 50

51 disturbs osmotic properties of the cell membrane in its action. It can be aerosolized for both pseudomonas and gram negative bacteria colonizing the airway. Polymyxin B is usually given intramuscularly. Renal damage is the major problem with its use. Polymyxin B may result in severe bronchospasm with aerosol administration. It can also cause a neuromuscular blockade leading to respiratory paralysis. ERYTHROMYCIN is effective against gram positive organisms including pneumococcus, mycoplasma pneumoniae, chlamydia psittici, beta hemolytic streptococcus and some hemophilus influenzae. Erythromycin also has been used for Legionnaires disease and for those allergic to penicillin. Its action is to inhibit protein synthesis. Erythromycin is a wide spectrum antibiotic that is useful for patients allergic to penicillin. Route of administration is oral, IM, or IV. It is relatively nontoxic, but can cause nausea, vomiting, diarrhea, phlebitis and pain on injection. Erythromycin is primarily used for community-acquired pneumonia. It is one of the safest antibiotics. CLINDAMYCIN is effective against some staphylococcus aureus, diplococcus, bacteroides and other gram positive organisms. Specific pulmonary indications for its use are aspiration pneumonias, empyema, and lung abscess. Problems associated with its use are diarrhea and skin rashes. TRIMETHOPRIM is a synthetic, broad-spectrum antibiotic. It is useful for pneumococcus and hemophilus influenzae infections. The action of trimethoprim is to interfere with bacterial amino acid synthesis. Trimethoprim is often combined with a sulfanomide (sulphameth-oxazole) in a preparation called co-trimoxazole. Co-trimoxazole is the drug of choice for pneumocystis carinii pneumonia. GI disturbances and rash are possible adverse effects. Trimethoprim is generally used as a second-line drug for acute, purulent exacerbations of chronic bronchitis after amoxicillin has failed. AEROSOLIZED ANTIBIOTICS MEDICATION ORGANISMS DOSAGE Amikacin gram negative uncertain Carbenicillin pseudomonas mg Gentamicin gram negative mg Kanamycin gram negative mg Polymyxin gram negative 5-50 mg Streptomycin gram negative mg Tobramycin gram negative mg This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 51

52 ANTIFUNGAL DRUGS AMPHOTERICIN B is the drug of choice for aspergillosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, North American blastomycosis, and sporotrichosis. It is thought to act by combining with sterols. Amphotericin B is administered intravenously. Amphotericin B is very toxic. It is only used for severe mycotic infections. Many complications are associated with its use, including chills, fever, nausea, vomiting, diarrhea, headache, pain at the injection site, renal damage, anemia, liver damage and cardiac problems. These are minimized by a gradual increase in dosage and slow infusion rates. Amphotericin B must be reconstituted before use and protected from light. ANTITUBERCULOSIS DRUG The most important antituberculosis drugs are ISONIAZID, STREPTOMYCIN, ETHAMBUTOL, RIFAMPIN, and PYRAZINAMIDE. These primarily inhibit the growth of the mycobacterium tuberculosis, but can be bactericidal with proper dosage. Usually 2 or more of the above agents are given simultaneously for 6-9 months. Isoniazid is the most effective. It is believed to act as an antimetabolite in the bacilli. This inhibits most enzyme systems in the organism. Side-effects are directly related to dosage, duration of treatment, and increasing patient age. Complications include: mouth dryness, visual problems, headache, insomnia, constipation, anemia, orthostatic hypotension, skin rashes, seizures, peripheral neuritis and hepatitis. Vitamin B6 (pyridoxine) can decrease the neurotoxic effects. Resistant strains develop rapidly when any of the above are given by themselves. Multidrug combinations are the normal mode of therapy for treatment of TB infection. (Rifamate is a capsule containing 300 mg rifampin and 150 mg isoniazid). Despite this, the emergence of multidrug resistant tuberculosis organisms has become a significant problem in recent years. Second-line antituberculosis drugs consist of: capreomycin, kanamycin, ethionamide, paraaminosalicylic acid, and cycloserine. PENTAMIDINE PENTAMIDINE ISOETHIONATE is an antiprotozoal drug of interest to the respiratory care practitioner. Pentamidine is used for treatment and prophylaxis of pneumocystis carinii pneumonia. Pneumocystis pneumonia is a common complication of the autoimmune deficiency syndrome (AIDS). Co-trimoxazole is the first drug of choice for pneumocystis pneumonia since it has fewer side effects than pentamidine. However, if cotrimoxazole appears ineffective or toxicity is reached, pentamidine is be used. Pentamidine is often aerosolized to minimize its adverse effects. If there is a response to pentamidine, respiratory function may improve within hours. Improvement generally takes between 2-8 days for most patients. Improvement in the chest X-ray may take a week or longer, particularly with an AIDS patient. The exact mechanism of action for pentamidine is not fully understood. Several mechanisms may be involved and the role of each may vary, depending upon which protozoon is involved. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 52

53 (Additional organisms sensitive to pentamidine include: Leishmania donovani, tropica, and aethiopica, Trypanosoma, and possibly Babesiosis, among others). In vitro, pentamidine has been shown to inhibit protein and nucleic acid polyamine and phospholipid synthesis. It also may inhibit phosphorylation. Folic acid antagonism may also play a role in its effect. Numerous adverse effects have occurred with pentamidine. These include death from severe hypotension, arrhythmias, and hypoglycemia. Additional complications include: diabetes mellitus, hyperglycemia, nephrotoxicity, phlebitis, nausea, vomiting, diarrhea and pain at the injection site. Pentamidine is available as a powder that must be reconstituted with sterile H 2 O or 5% dextrose to a concentration of mg/ml for use. Do not mix the solution with any other drug. It is usually injected, but has been aerosolized. (Aerosol solutions are under the brand name of Nebupent and Pentam ). The adult and pediatric dose for pneumocystis carinii is 4 mg/kg once daily for 14 days. A pediatric dose of 150 mg/m 2 once daily for 5 days followed with 100 mg/m 2 once daily for the remainder of therapy also is used. One may need longer than 14 days of therapy for AIDS patients. Dosage may have to be decreased if there is renal impairment. Pentamidine is often used prophylactically for the AIDS patient to avoid pneumocystis pneumonia. Aerosol treatments of 300 mg in 6 ml of sterile distilled water given every 4 weeks decreases the incidence of pneumocystis pneumonia in patients with AIDS. (The half-life of pentamidine in the lung is about one month). Pretreatment with a bronchodilator is required to prevent bronchospasm and cough. A nebulizer that provides particles of 1 to 3 microns is needed for aerosol pentamidine. Complete nebulization of the drug is very important because the drug becomes concentrated during the second half of the treatment. Special equipment and other precautions are needed to scavenge any excess aerosol to prevent the practitioner from inhaling the mist. High-efficiency filters should be placed inline on the expiratory limb to capture excess aerosol. A high-quality synthetic-fiber mask with a good fit is needed for the practitioner. Treatments also should be provided in a negative-pressure room. Ventilation of the room should provide at least six air changes per hour. As an alternative, containment areas, booths, or exhaust hoods can be used. The greatest danger of inhaling aerosol pentamidine exists when the patient coughs or removes the mouthpiece from their mouth while nebulization continues. Proper instruction of the patient on controlling aerosol particles when coughing, i.e., cough into a tissue, minimizes the former. Automatic shut-off devices or Y-valve setups that allow nebulization on inspiration only minimize the latter. VIRAZOLE V IRAZOLE (Ribavirin ) has been shown to have inhibitory activity, in vitro, against respiratory syncytial virus (RSV), influenza virus, and herpes simplex virus. It is currently used in hospitalized neonates, infants, and small children with severe lower respiratory tract infections due to RSV. 20 Ribavirin is not used for mild infections. Virazole comes as a powder that must be mixed with sterile H 2 O for use. Precipitation of the This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 53

54 drug is common. In ventilated patients, precipitation in the tubing causes an increase in the peak inspiratory pressure and PEEP. Virazole is sequestered in red blood cells for weeks after dosing. Rash and conjunctivitis have been reported with its use. In adult COPD and asthma patients, pulmonary function significantly deteriorates after administration of Virazole. It should not be used during pregnancy. Ribavirin is supplied as 6 grams per 100 ml vial. Sterile H 2 O is injected into the vial to achieve a concentration of 20 mg/ml (final total volume for administration is 300 ml). The mixture is good for 24 hours and then must be discarded. Virazole must be administered through a special nebulizing device known as a small particle aerosol generator (SPAG). The aerosol is delivered into an O 2 hood, tent, or ventilator circuit. 20 Treatment is usually for hours per day for 3-7 days. 20 Virazole should only be used for documented RSV. The package insert should be consulted for more complete information. All the precautions discussed above under pentamidine for protecting the practitioner apply to Virazole also. A double-hood aerosol containment system for health care worker protection has been developed specifically for Virazole administration. SURFACTANTS Surfactant replacement has worked well for infant respiratory distress syndrome (RDS) for many years. It has been less successful in adults because the causes of RDS are different for adults. In adults, surfactant deficiency and RDS are secondary abnormalities rather than primary abnormalities. In adults, there are both quantitative and qualitative surfactant abnormalities. There is a decrease in the quantity of surfactant and the surfactant present is coagulated by protein-rich exudate from capillary leakage. The latter is not present in infant RDS. Increasing the quantity of surfactant is all that is needed in RDS. This is not sufficient in ARDS. Natural surfactant is composed of phospholipids, neutral lipids, and surfactant-related proteins (apoproteins). Approximately 85% of surfactant is phospholipids. Of this amount, approximately fifty to sixty per cent is dipalmitylphosphatidylcholine (DPPC). (DPPC is commonly known as lecithin). In ARDS, the composition as well as the quantity of surfactant, is disrupted. Therefore, simple replacement is insufficient. In addition, replacement surfactant simply coagulates in ARDS. The composition of replacement surfactants varies. Some are derived from natural animal sources, others are purely artificial. Those from animal sources contain DPPC and surfactantrelated proteins. Surfactant preparation from natural sources are Survanta (bovine), Surfactant TA (bovine), Curosurf (porcine), Infasurf (bovine) and Alveofact (bovine). The latter are very important. One, SP-A is associated with secretion, recycling, and spreading of surfactant. Others (SP-B and SP-C) facilitate spreading and mixing of surfactant. Purely artificial surfactants contain DPPC and artificial spreading agents. They are less effective. Those derived from animal sources appear more physiologically active, but the presence of This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 54

55 animal proteins also triggers immune (allergic) responses in adults. Infants have a poorly developed immune system so this is not a significant problem in infants. Adults also require days of treatment and repeated dosing, thereby increasing the possibility of toxicity. There is little experience with surfactant replacement in ARDS. It has been instilled or aerosolized. Direct instillation causes a transient decrease in oxygenation until the fluid is absorbed. Several small studies have aerosolized surfactant for up to 5 days. These have shown a trend towards decreased mortality, improved compliance, decreased shunt, decreased FIO 2, and decreased A-a gradient. If these results are confirmed in larger studies, aerosolized surfactant for ARDS may be possible in the future. Results with replacement surfactant in ARDS have been less than those seen with infant RDS. However, there are numerous problems with the studies to date. The dosages used (based on weight) have been considerably less than those used on infants. There are also questions regarding delivery method, timing, and the specific disease process involved. For example, sepsis-induced ARDS responds poorly to surfactant replacement. In 1998 Infasurf and Curosurf were approved for use in the United States. Colfosceril palmitate (Exosurf) and Surfactant TA (Survanta) were approved in In Europe, artificial lung expanding compound (ALEC or Pulmactant) is used. Natural human surfactant is derived from amniotic fluid. Natural animal surfactants are Alveofact, calf lung surfactant extract (CLSE or Infasurf) Curosurf, and Survanta, ALEC and Exosurf are synthetic surfactants. 20 A generic procedure* for surfactant instillation on infants is provided below. See manufacturer s instructions regarding reconstitution and preparation of the medication. 1. Place the infant in a midline position and suction thoroughly. 2. Inject 1/2 of the dose ordered over 1-2 minutes or mechanical breaths. 3. Turn the infant to the right approximately 45 degrees and hold for seconds. 4. Return to the midline position and inject remainder of dose. 5. Turn 45 degrees to the left and hold for seconds. 6. Monitor patient closely for 30 minutes after treatment. 7. Readjust ventilator parameters as necessary. * The procedure varies depending upon the brand of surfactant used. Some brands are given in quarter-doses and position the infant differently than the above. When quarter-doses are given, a dose is given to each quadrant of the lung. Position the infant in trendelenberg on their right side for a quarter-dose and then repeat on the left side. Then position the infant in a semi-fowlers position and give quarter doses to each side. (A dose is injected into each corner of the lung). This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 55

56 Consult the manufacturer s recommendations for additional information. A special ET tube adapter with a luer-lock sideport is necessary so the infant can remain ventilated during treatment. Indications for surfactant replacement are pulmonary immaturity, infants who have RDS, or infants who are at risk of developing RDS. It can be used prophylactically on high-risk infants or as a rescue treatment for those already with RDS. There is little experience with surfactant replacement in ARDS. Anecdotal reports and small preliminary studies are favorable. Several studies have aerosolized Exosurf for 12 or 24 hours a day up to 5 days. These have shown a trend towards decreased mortality, improved compliance, decreased shunt, decreased FIO 2, and decreased A-a gradient. If the results are confirmed in larger studies, aerosolized surfactant may be possible in the future. DRUGS FOR ARDS Medications have been tried in ARDS to block organ injury and improve oxygenation. There are two strategies for the use of drugs for ARDS: 20 improve/correct lung function and prevent/correct lung and systemic inflammation. Drugs for the former consist of almitrine, nitric oxide, surfactant replacement, and prostaglandin E 1. Drugs for the latter consist of antioxidants, anticytokines, antiendotoxins, corticosteroids, and monoclonal antibodies. Most of these are considered experimental. At the present time, medications do not play a prominent role in treatment of ARDS. ALMITRINE improves PaO 2 and decreases PaCO 2 in COPD patients through decreasing V/Q mismatch. In ARDS, almitrine has been effective in redistributing blood flow from areas of shunt to normal areas. It gives a similar increase in PaO 2 to 10 cm H 2 O PEEP without the side effects of positive pressure. NITRIC OXIDE (NO) is a potent pulmonary vasodilator when inhaled. It has relatively no effect on the systemic circulation because it is inactivated by hemoglobin. (NO combines with hemoglobin to form methemoglobin, a potential problem with its use). Inhaled NO selectively improves perfusion of ventilated areas. This selective improvement in V/Q relationships improves oxygenation in ARDS. Nitric oxide significantly decreases pulmonary artery pressure, decreases shunting and improves PaO 2. However, NO can be lethal, being a toxic component of air pollution. It can result in pulmonary edema and unacceptable levels of methemoglobin. Not all patients respond to NO and it is impossible to predict which patients will respond. (Patients with a mean PAP greater than 30 mm Hg were more likely to respond in one study) It is interesting to note that the body synthesizes NO in nearly every cell. Some of its functions are smooth muscle relaxation, neurotransmission, bacteriostasis, tumor-cell lysis, and platelet inhibition. Effective doses of inhaled NO are less than 20 parts per million (ppm). Several studies have reported effective doses at less than 5 ppm. At doses less than 20 ppm, NO is considered relatively free of toxicity. PROSTAGLANDIN E 1 decreases systemic and pulmonary vascular resistance, decreases blood pressure, increases stroke volume, increases cardiac output, and increases heart rate. It may be This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 56

57 useful to decrease pulmonary hypertension and improve cardiac function, but doesn t appear to enhance survival in ARDS. SURFACTANT REPLACEMENT has been discussed in the previous section. ANTIOXIDANTS also may be of use in ARDS. N-acetylcysteine has improved lung function, O 2 delivery, and cardiac output in one study. A larger study showed no improvement in oxygenation, but an improvement in compliance. There was no difference in survival with the use of N-acetylcysteine. CYTOKINES, such as interleukins, play a major role in causing the systemic effects associated with the sepsis syndrome. Clinical trials of ANTICYTOKINES have been conducted. Studies of interleukin-1 receptor antagonist showed a minor but statistically insignificant improvement in mortality. ANTIENDOTOXINS ay prove useful, particularly in gram negative sepsis. Endotoxins produced by gram negative bacteria cause severe disturbances. Several antibodies against endotoxins have been studied. HA-1A showed an improvement in mortality in patients with gram-negative bacteremia. CORTICOSTEROIDS have been recommended in the past for ARDS, but are less popular now. The current emphasis is on the damaging potential of WBC s. However, if steroids interfere with WBC s, patients run the risk of increased infection. Steroids may be useful in minimizing fibrosis formation in the latter stages of ARDS. They are recommended if the patient is hypotensive from adrenal insufficiency. They also may be useful in aspiration, fat embolism, and chemical injuries to the airway. Monoclonal antibodies are being studied to inhibit WBC-adhesion molecules, particularly those of the neutrophil. Neutrophils adhere to tissue and create a microenvironment for the release of proteases and O 2 radicals in the area. These destroy or damage the adjacent tissue. Antiproteases and antioxidants delivered systemically cannot penetrate this microenvironment so they are ineffective in preventing lung injury. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 57

58 NEUTROPHIL ADHESION Proteases Toxic O 2 Metabolites Neutrophils slowly roll along the capillary wall at the site of trauma until they adhere to the surface. Once attached, a microenvironment is created for the release of tissue-damaging substances, such as, proteases and toxic O 2 metabolites. Two types of molecules on the neutrophil are associated with adhesion: selectins and integrins. Selectins react with carbohydrates on a tissue cell to cause the neutrophil to roll along the vascular wall. (They select the site). Integrins then react with molecules on the wall causing the neutrophil to adhere. (They cause integration of the neutrophil and tissue cell). Once this occurs, a microenvironment is created and damage begins. Animal studies using monoclonal antibodies against selectins and integrins are promising. A pilot study of ibuprofen showed a decrease in the incidence and development of ARDS, increased rate of reversal, and improved survival. Some soluble protective agents against lung damage are tocopherol, ascorbate, and beta-carotene. These help protect cell membranes and other cellular elements from oxidant injury. Their value in ARDS is unconfirmed. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 58

59 SMOKING CESSATION THERAPY DRUGS Ten percent of cigarette smokers per year try to quit. At the end of one year, only about 20% of these 10% have been successful at quitting smoking. Cigarettes create both a psychological and physiological dependence. Both need to be treated with behavioral and pharmacological therapies for maximum success. For the latter, there are nicotine and nonnicotine replacements. They are most effective when combined with appropriate behavior modification therapy. Nicotine replacements come in the form of gum, patches, nasal spray, and inhalers. Nicotine polacrilex gum has been used the longest. Nicotine patches are available in 16 and 24 hour forms. The 16 hour patch was created to prevent excess nicotine release during sleep. The patches are available in 21 mg, 14 mg, and 7 mg doses for weaning. Nicotine nasal spray and inhalers are uncommon at this time (1997). Nonnicotine replacements consist of CLONIDINE and BUSPIRONE. The primary use for clonidine is for hypertension, but it also relieves withdrawal symptoms from nicotine and the opiates. It is available as tablets or patches in doses of 0.1 to 0.3 mg/day. Buspirone is an antianxiety drug from the benzodiazepine family. Early trials of buspirone for nicotine withdrawal are encouraging. Lobeline is a nicotine-related alkaloid with some, but limited, activity at nicotinic receptors 40 and is found in several over-the-counter smoking cessation aids. Both older studies 41 and two more recent studies 42,43 have failed to find that lobeline increases quit rates. MISCELLANEOUS DOXAPRAM is a respiratory stimulant used for post-operative depression and alveolar hypoventilation syndromes. It stimulates peripheral chemoreceptors and brainstem respiratory centers. Dosage is 1-3 mg/min by IV, up to a maximum of 600 mg. Doxapram can cause arrhythmias and hypertension by stimulating the release of epinephrine from the adrenals. It also can result in excessive CNS stimulation. PROGESTERONE is also a respiratory stimulant. It is used for Pickwickian syndrome. Progesterone is administered sublingually for outpatients. Inpatients are given a bolus of 100 mg/day IM. Progesterone takes 2-3 weeks for maximum effects to develop. NALOXONE is used to reverse ventilatory depression as a result of opiate administration (morphine, methadone, heroin). It is also effective in diazepam, propoxyphene, and ethanol overdoses. A bolus of mg is given, but some patients may require 0.1 mg/kg. Naloxone is short-acting so continuous infusion may be necessary. Muscle relaxants and sedatives are used to improve the balance between gas exchange and the rate of metabolism. Muscle relaxants (paralyzers) must be used in combination with adequate sedation. If not, patients become extremely frightened and possibly psychotic. Indications for their use are: shivering after bypass surgery, difficult intubations, and temporary control of the This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 59

60 ventilator patient. PANCURONIUM (Pavulon ) is probably the most common paralyzer used. Intermittent bolus administration is recommended. If tachycardia develops from its use, VERCURONIUM should be substituted. Vercuronium can be given as a continuous infusion. ATRACURONIUM also can be used, but is shorter-acting and can cause histamine release. Agitation causes catecholamine release, can produce auto-peep in ventilator patients, and causes an imbalance between O 2 delivery and O 2 consumption. Sedatives prevent these adverse conditions from occurring. HALOPERIDOL (Haldol ) is the preferred sedative because of its lack of ventilatory depression or hypotension. It can cause cardiovascular depression if hypovolemia is present or if given with propranolol. A 3-5 mg bolus is given IV and if there is no response in minutes the dose is doubled. Another option if there is no response is to add a BENZODIAZEPINE (Valium, Ativan, Versed ). These can cause ventilatory depression, however. They also can result in rapid sedation and they accumulate in the body over time. MORPHINE SULFATE (MS) is used for vasodilation, CNS sedation, and has a mild inotrophic effect in patients with pulmonary edema. If the patient is not hypotensive, 5-10 mg of MS is given slowly via IV over several minutes. MS lowers pulmonary capillary pressure resulting in less leakage. Patient anxiety is also relieved. Ventilatory depression is possible but is rarely a problem. Problems associated with MS are rapidly reversed with naloxone. One should avoid the use of MS as a sedative for asthmatic patients. MS (and other narcotics) cause histamine release and worsen asthma symptoms. Both oral and aerosolized MS have been used to increase exercise tolerance in the COPD patient. MS may reduce perceptions of dyspnea by acting directly on lung afferent nerves. This increases exercise capacity. An oral dose of 0.8 mg/kg or aerosol dose of 5 ml of a 1 mg/ml MS solution improve exercise endurance in these patients. PROPYLENE GLYCOL is a physiologically inert substance found in many aerosol preparations. It is used as a solvent and stabilizing agent. It is hygroscopic and used to minimize the shrinkage of aerosol particles as they travel through the respiratory tract. Pulmonary hypertension is defined as a mean pulmonary artery pressure >25 mm Hg at rest or >30 mm Hg with exercise. Most cases of pulmonary hypertension are secondary, meaning they are a result of another process. For example, hypoxia causes pulmonary vasoconstriction and therefore hypertension. Treatment for these causes of hypertension consists of fixing the primary problem, rather than treating the hypertension. Primary pulmonary hypertension is not a result of another problem. It is treated with a vasodilator or anticoagulants. Primary pulmonary hypertension (PPH) usually develops in the third or fourth decade of life. Without treatment, most die within 2-3 years. PPH is a result of pulmonary capillary lumen cellular proliferation, thrombi, or fibrosis. WARFARIN and HEPARIN have been used for anticoagulation and to prevent further thrombi. Vasodilators are effective for some patients, but not all. However, those who respond initially have a favorable response over the long term. EPOPROSTENOL (formerly prostacycline) is given to test the patients response. If favorable, continue its use. The alternative is heart-lung or single lung transplantation. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 60

61 Alpha 1 proteinase inhibitor (α 1 -AT) deficiency is a hereditary disorder associated with emphysema. α 1 -AT protects the lung from trypsin and other proteolytic enzymes released by neutrophils and macrophages. Without it, lung tissue is destroyed by a normal immune response. PROLASTIN is an α 1 -AT inhibitor. It is still considered experimental. Dosage is 60 mg/kg IV once per week. Another study aerosolized 100 mg every 12 hours for a week. Replacement gene therapy is another future possibility for those with a deficiency. The final drugs to be discussed are those used in bronchoscopies. EPINEPHRINE has previously been mentioned. Epinephrine is instilled directly through the scope to sites of hemorrhage. Its potent vasoconstricting properties arrest the bleeding. The remaining drugs used during the procedure are for topical anesthesia of the airway. The most common are LIDOCAINE, PONTOCAINE, and TETRACAINE. These may be aerosolized or instilled directly into the respiratory tract via the scope. Lidocaine is the most common and has very few complications associated with its use. Usual dose of the 4% solution is 1-5 cc ( mg). Pontocaine is less common but relatively safe. Tetracaine has the highest incidence of complications and is rarely used. Both the upper and lower airway are anesthetized for the procedure so the danger of aspiration post-bronchoscopy is high. The patient should remain NPO for several hours after the procedure and closely monitored. Complications are rare unless excessive doses are given. DRUG DOSAGE CALCULATIONS Solving drug calculation problems can be easy if you remember a few key points. 1. One milliliter (1 ml) or 1 cubic centimeter (1 cc) of water = 1 gram (g) of mass. 2. Most drug doses are listed in milligrams instead of grams. Convert grams to milligrams by moving the decimal point three places to the right (the same as multiplying by 1000). For example 0.5 g equals 500 mg 3. Know how to interconvert fractions, decimal fractions, and percentages. For example: 1:100 = 1/100 = 0.01 = 1%. One common way to solve any drug dosage calculation is by creating a proportional problem. The drug concentration must be converted into a fractional form. The proportional problem can then be set up to solve for the unknown. For example: a. How much active ingredient would be in 0.5 ml of Bronkosol? A 1% (1:100) drug concentration means that there is 1 part of active ingredient in 100 parts of solution, or 1 ml or 1 g of active ingredient in 100 ml or 100 g of solution. This can be set up in the following proportion: 1 ml active ingredient = unknown active ingredient 100 ml total solution 0.5 ml solution This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 61

62 1 ml = x ml 100 ml = 0.5 ml (cross multiply) 100x = 0.5 ml x = ml = g = 5 mg of active ingredient b. How much active ingredient would be in 0.25 ml of Alupent? (Alupent is 5.0% active ingredient.) A 5.0% drug concentration means that there are 5 parts of active ingredient in 100 parts of the solution, or 5 ml or 5 g of active ingredient in 100 ml or 100 g of the solution. This can be set up in the following proportion. 5 ml active ingredient = unknown active ingredient 100 ml total solution 0.25 ml solution (cross multiply) 100x = 1.25 ml (Divide both sides of the equation by 100) x = ml = g = 12.5 mg of active ingredient The next example deals with calculating the volume of medication needed to deliver a desired amount of active ingredient. With these types it is necessary to convert to consistent units, usually converting grams to milligrams. 4. How much 0.5% Proventil would be needed to give a patient 2.5 mg of active ingredient by SVN? A 0.5% (1:200) drug concentration means that there is 1 part of active ingredient in 200 parts of the solution, or 1 ml or 1 g of active ingredient in 200 ml or 200 g of the solution. This converts to 1000 mg/200 ml. Set up the following proportion: 1000 mg active ingredient = 2.5 mg (Cross multiply) 200 ml total solution xml solution 1000 x = 500 ml (Divide both sides by 1000) x = 0.5 ml of Proventil should be given This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 62

63 PRACTICE PROBLEMS 1. Dr. Carr wants you to give his patient, Mr. Michael Martin, a continuous bronchodilator treatment with 1:200 strength albuterol. Dr. Carr wants the duration of the treatment to last 4 hours. How much albuterol and how much diluent are needed if the output of the nebulizer is 25 ml/hr.? Answer: 12 ml of 0.5% albuterol with 88 ml of normal saline 2. How much active ingredient would be in 0.6 ml of 2.25% racemic epinephrine (Vaponefrin)? A. 26,700 mg B mg C g D mg Answer: D 13.5 mg 3. A unit dose of albuterol sulfate contains 3.0 ml of a 0.083% solution. If eight unit doses are used in a large volume nebulizer treatment, what is the total amount of active ingredient in the nebulizer? A. 2.5 mg B. 5 mg C. 10 mg D. 20 mg E. 40 mg Answer: D 20 mg 4. The physician orders 0.5 ml of a unit dose of Brethine (terbutaline sulfate) with saline for a pediatric patient. If the 1 ml unit dose ampule comes in a 0.1% solution, how many mg of this drug are used? A mg B. 0.1 mg C. 0.5 mg D. 1.0 mg E. 2 mg Answer: C 0.5 mg This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 63

64 CLINICAL PRACTICE EXERCISE The following practice exercise is discussed at the end of the course. Answers are based on the text material. There may be other equally correct choices based upon personal preference or experience. 1. The patient is a 67-year-old male with known COPD admitted for possible pneumonia. He has a three-day history of productive cough of a small amount of thick, yellow mucus. His normal daily sputum production is a moderate amount of thick, white mucus. Bilateral crackles and rhonchi are auscultated. Heart rate is 100, blood pressure is 130/90, temperature is 101 o F, oximetry is 87%, and respiratory rate is 24. He is complaining of dyspnea and his respirations appear labored. Based upon this information, what types of respiratory medications might be beneficial and why? 2. You are asked to recommend specific medications for treatment. What are your suggestions and why? 3. Several hours later, patient temperature remains at 101 o F. Gram stain reveals moderate amounts of gram negative bacteria. Oximetry is 91% on 4 lpm nasal cannula. Heart rate is 105, respiratory rate is 16. Copious amounts of thick, yellow mucus produced following an aerosol treatment of albuterol and mucomyst. There is a slight decrease in bilateral crackles and rhonchi after the treatment. Trials of albuterol vs ipratropium reveal peak flow before albuterol is 90 lpm and after is 100, before ipratropium is 85 lpm and after is 105 lpm. Evaluate this information and make suggestions. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 64

65 4. Several days later, the patient is stable but not improving. Sputum culture has revealed pseudomonas as the probable causative agent. Sputum production is moderate amounts of thick, green mucus. Breath sounds are slight crackles bilaterally at the bases. Chest X-ray shows persistent right and left lower lobe infiltrates. Oximetry is 90% on 4 lpm nasal cannula. What do you suggest? SUMMARY Respiratory pharmacology consists of medications used to treat the pathological triad of bronchospasm, airway inflammation, and retained secretions. Drugs used for these are bronchodilators, decongestants, corticosteroids, and mucokinetic/mucolytic agents. There are several routes of administration with the aerosol route being the most often used by the RCP. Some of the advantages of aerosol therapy are: rapid therapeutic effect, a small total dose may be given, and topical administration minimizes systemic side-effects. The disadvantages of aerosol therapy consist of: underdosage, overdosage, very little medication actually deposited in the lung, airway irritation, and systemic absorption through oropharyngeal deposition. Excluding mainstream nebulization of large volumes of H 2 O, there are 4 methods of aerosol medication delivery. They are: metered-dose inhaler (MDI), dry powder inhaler (DPI), small volume nebulizer (SVN), and IPPB. The patient must be able to take a deep coordinated breath for the first three. IPPB is reserved for the patient who cannot spontaneously hyperinflate their lungs. Many conditions require modification of the recommended dose. Conditions such as liver dysfunction, kidney dysfunction, mechanical ventilation, emaciation, obesity, very young or very old patients require appropriate adjustment of dosage. Bronchodilation is most often achieved through SNS stimulation. SNS stimulation results in conversion of ATP to camp through activation of the enzyme adenylate cyclase. This leads to airway smooth muscle relaxation. β adrenergic agonists increase the production of camp through the above mechanism. The enzyme phosphodiesterase inactivates camp thereby removing its bronchodilating influence. Theophylline may work by inhibiting phosphodiesterase but this is unproven. Another mechanism to achieve bronchodilation is to block PNS stimulation of the airway. PNS stimulation leads to bronchoconstriction. Antimuscarinics are used to block PNS stimulation thereby resulting in bronchodilation. Complications of the β adrenergic agonists include tachycardia, skeletal muscle tremor and tachyphylaxis. Tachycardia is a result of excessive β 1 stimulation. A worsening of V/Q relationships is also possible with these drugs. β 2 stimulation can result in both bronchodilation and vasodilation. If the circulatory response exceeds the airway response, hypoxia may ensue. Complications of theophylline include tachycardia and tremors. It also can cause nausea and headache. Therapeutic levels should be maintained between mcg/ml. Decongestants and corticosteroids are not bronchodilators but their effects can lead to an This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 65

66 increase in lumen size. Decongestants, through stimulation of α receptors, cause vasoconstriction and decrease fluid in the airway. The resulting decrease in airway wall thickness and fluid in the lumen have the same effect as a bronchodilator. Corticosteroids can have the same result through their anti-inflammatory properties. They also help prevent episodes of bronchospasm through inhibition of the allergic response to irritants. Chronic or excessive steroid use can result in adrenal insufficiency, cushinoid effects and decreased resistance to infection and osteoporosis. Acute complications include fluid and electrolyte imbalances. If steroids prove successful, cromolyn sodium may be of benefit to the patient. It is a prophylactic drug only, preventing bronchospasm through inhibition of mast cell degranulation. Mucokinetic/mucolytic drugs aid secretion removal by one or more of several mechanisms. They dilute mucus, replenish the sol layer, stimulate bronchial glands, stimulate cilia, or chemically destroy components found in mucus. The safest and most common mucokinetic is water. Normal saline solutions also are very common, particularly for lavage purposes. A common mucolytic is N-acetylcysteine. Its action is to rupture disulfide bonds of mucus making it less tenacious and viscous. Bronchospasm is a possible complication of its use. Complications of the mucokinetic/mucolytic agents are overhydration, bronchospasm and tissue irritation. Antibiotics are rarely aerosolized. Several (carbenicillin, streptomycin, gentamicin) have been aerosolized with mixed results. Antibiotic lavage solutions are administered during a bronchoscopy for severe infections. Cystic fibrosis is a condition that may benefit from this. The penicillins and aminoglycosides are common antibiotics. Complications of various antibiotics include: hypersensitivity reactions, nausea, vomiting, diarrhea, inner ear problems, renal problems, and rarely, a blockade of the phrenic nerve. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 66

67 PRACTICE EXERCISE DISCUSSION 1. Diagnosis, temperature, and sputum indicate possible infection so antibiotics will be necessary. Consistency of mucus, productive cough, and bilateral crackles indicate mucokinetics will be useful. Complaint of dyspnea, labored breathing, % saturation, and COPD diagnosis indicate oxygen is necessary. A bronchodilator is indicated if the patient s COPD has a bronchospastic component. 2. Recommend a broad-spectrum antibiotic be started until culture results become available. Possible choices for acute exacerbations of COPD are ampicillin, amoxicillin, carbenicillin, piperacillin, and ticarcillin. Recommend pushing fluids for systemic hydration to dilute mucus. Aerosolized mucomyst for mucolysis may also be useful. Recommend an evaluation of patient s response to inhaled albuterol and ipratropium to relieve rhonchi. Recommend oxygen at 2 lpm to increase % saturation and relieve dyspnea. 3. Gram stain information indicates initial choice of above antibiotics is correct. Systemic hydration and mucomyst appear effective in mobilizing secretions. The patient demonstrates minimal bronchodilation response to both albuterol and ipratropium. Oxygenation improved on 4 lpm nasal cannula. Suggest continue current meds including inhaled albuterol and ipratropium. 4. Stability of patient indicates current antibiotic effective in preventing further deterioration but patient has not improved. Suggest adding an aminoglycoside, such as, tobramycin for the pseudomonas. Continue other medications. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 67

68 SUGGESTED READING AND REFERENCES 1. AARC Clinical Practice Guideline, Selection of a Device for Delivery of Aerosol to the Lung Parenchyma, RESPIRATORY CARE, July 1996, Vol. 41, #7, pp Scanlan C, Spearman C, Sheldon R., EGAN S FUNDAMENTALS OF RESPIRATORY THERAPY, 6th ed., 1995, Mosby-Yearbook, Ind., pp Witek T, Schachter E., PHARMACOLOGY AND THERAPEUTICS IN RESPIRATORY CARE, 1994, W.B. Saunders Co., pp 31-51, , , 167, , , Hess D. et al, Use of Inhaled Nitric Oxide in Patients with ARDS, RESPIRATORY CARE, May 1996, Vol.41, #5, pp Haas C, Weg, J, Exogenous Surfactant Therapy, RESPIRATORY CARE, May 1996, Vol. 41, #5, pp Jenne, J., DRUG THERAPY OF ASTHMA: PARTS 1 & 2, Pulmonary Clinical Updates, Vol. 1, Lessons 5 & 6, 1985, Continuing Professional Education Center Inc. 7. Fallat R, Kandal K., Aerosol Exhaust: Escape of Aerosolized Medication into the Patient and Caregiver s Environment, RESPIRATORY CARE, September 1991, Vol.36, #9, pp Waskin H., Toxicology of Antimicrobial Aerosols: A Review of Aerosolized Ribavirin and Pentamidine, RESPIRATORY CARE, September 1991, Vol. 36, #9, pp Svedmyr N., Clinical Advantages of the Aerosol Route of Drug Administration, RESPIRATORY CARE, September 1991, Vol. 36, #9, pp Dolovich M., Clinical Aspects of Aerosol Physics, RESPIRATORY CARE, September 1991, Vol. 36, #9, pp Marino P., THE ICU BOOK, 1991, Lea and Febiger, pp Tashkin, D., Dosing Strategies for Bronchodilator Aerosol Delivery, RESPIRATORY CARE, Sept 91, Vol 36, #9, pp McFadden, E., When to use High-Dose Inhaled Steroids, THE JOURNAL OF RESPIRATORY DISEASES, Nov. 91, Vol 12, #11, pp Howder C., Antimuscarinic and Beta Two-Adrenoceptor Bronchodilators in Obstructive Airways Disease, RESPIRATORY CARE, Dec 93, Vol 38, #12, pp This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 68

69 15. Gooch M., Stability of Albuterol and Tobramycin when Mixed for Aerosol Administration, RESPIRATORY CARE, Dec. 91, Vol 36, #12, pp Young I, Daviskas E, Keena V., Effect of Low Dose Nebulized Morphine on Exercise Endurance in Patients with Chronic Lung Disease, THORAX, 1989, Vol 44, pp Egan s Fundamentals Of Respiratory Care, Seventh Edition, Alvine GF et al: Disposable jet nebulizers: How reliable are they? Chest 101:316, Hollie mc et al: Extreme Variability in Aerosol output of the Devilbiss 646 Jet Nebulizers, Chest 100:1339, Rau JL, Respiratory Care Pharmacology 5 th ed., 1998 Mosby-Year Book pp. 138, , Holgate ST, Baldwin CJ, Tattersfield AE: β-adrenergic Agonist Resistance in Normal Human Airways, Lancet ii: 375, Plummer AL: The Development of Drug Tolerance to Beta2 Adrenergic Agents, Chest 73 (Suppl): 949, Svedmyr N: Action of Corticosteriods on Beta-Adrengic Receptors: Clinical Aspects, AMERICAN REVIEW OF RESPIRATORY DISEASE 141:531, Papo MC, Frank J, Thompson AE: A prospective, Randomized Study of Continuous Versus intermittent Nebulized Albuterol for Severe Persistant asthma in Children. CRITICAL CARE MEDICINE 1993: 21; Moler FW, Johnson CE, Van Leansen C, etal. Continuous Versus Intermittent Nebulized Terbutaline: Plasma Levels and Effects. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 1995: 151: Lin RY, Smith AJ, Hergenroeder. High Serum Albuterol Levels and Tachycardia in Adult Asthmatics Treated with High-Dose Continuously Aerosolized Albuterol. Chest. 1993: 103: Fink JB, Hunt GE, Clinical Practice in Respiratory Care, Lippincott 1999, pp NAEPP- Expert Panel II: Guidelines for the Diagnosis and Management of Asthma, Bethesda, Md, 1997, National Institutes of Health. 30. Busse WW, et al. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. 1999: 104: This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 69

70 31. Demedts M, et al. Switch to non-cfc inhaled corticosteroids: a comparative efficacy study of HFA-BDP and CFC-BDP metered-dose inhalers. INTERNATIONAL JOURNAL OF CLINICAL PRACTICE. 1999: 53: Goldin JG, et al. Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 1999: 104:S258-S Leach CL, et al. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. EUROPEAN RESPIRATORY JOURNAL. 1998: 12: Hamid Q, et al. Respiratory pathophysiologic responses. Inflammation of small airways in asthma. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 1997: 100: Martin RJ. Small airway and alveolar tissue changes in nocturnal asthma. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 1998: 157:S188- S Macklem PT. The physiology of small airways. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 1998: 157:S181-S Matthys H, et al. Efficacy of chlorofluorocarbon-free beclomethasone dipropionate 400 mcg day-1 delivered as an extrafine aerosol in adults with moderate asthma. RESPIRATORY MEDICINE 1998: 92 (suppl A): Gross G, et al. Hydrofluoroalkane-134a beclomethasone dipropionate, 400 mcg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 mcg, for the treatment of moderate asthma. CHEST. 1999: 115: Smith LJ. Leukotrienes in asthma. The potential therapeutic role of antileukotriene agents. ARCHIVES OF INTERNAL MEDICINE. 1996: 156: Damaj MI, Patrick GS, Creasey KR, Martin BR. Pharmacology of lobeline, a nicotinic AChR ligand. THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1997: 282: Davison GC, Rosen RC. Lobeline and reduction of cigarette smoking. PSYCHOLOGICAL REPORT 1972: 31: Glover ED, Leischow SJ, Rennard SI, Glover PN, et al. A smoking cessation trial with lobeline sulfate: a pilot study. AMERICAN JOURNAL OF HEALTH BEHAVIOR 1998: 22: Covey LS, Glassman AH, Stetner F. Naltrexone effects on short-term and long-term smoking cessation. JOURNAL OF ADDITIVE DISEASES 1999: 18: This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 70

71 44. Wilkins, R.L, et al. Egan s Fundamentals of Respiratory Care, Eighth Edition, Mosby, Hess, D. R., MacIntyre, N. R., Respiratory Care-Principles & Practice, W.B. Saunders Company Chang, D. W., Respiratory Care Calculations Second Edition, Delmar Publishers, United States Environmental Protection Agency; United States Food and Drug Administration; Boehringer Ingelheim Pharmaceuticals via AARC 50. Asmus, M. et al, In Vitro Performance Characteristics of Valved Holding Chamber and Spacer Devices With a Fluticasone Metered-Dose Inhaler; Pharmacotherapy 24(2): , Pharmacotherapy Publications. 51. Colice, G. new Drugs for Asthma Respiratory Care; Vol. 53, No. 6, June, Hess, D. Aerosol Delivery Devices in the Treatment of Asthma Respir Care; Vol. 53, No. 6 June, Myers, T. Guidelines for Asthma Management; A Review and Comparison of 5 Current Guidelines Respiratory Care; Vol. 53, No. 6, June, This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 71

72 APPENDIX A (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 72

73 Acute Exacerbations Of Asthma In Adults* Emergency Department Management Initial assessment History (Hx) Physical examination (PE): ausculation, use of accessory muscles, heart rate Peak flow determination (PEFR) or spirometry (FEV 1 ) Arterial blood gas (ABG) if patient in extrermis Respiratory arrest Intubation and mechanical ventilation Nebulized or parenteral beta 2 -agonist bronchodilators Initial treatment Inhaled beta 2 -agonist bronchodilator x 3 doses over minutes. (If PEFR >90% baseline** after first dose, additional doses not necessary.) Alternative: Subcutaneous beta 2 -agonist x 3 doses over minutes Supplemental oxygen: - For hypoxemic patients - For all patients if oximeter not available: Consider systemic steroids for those not responding immediately to bronchodilator and for those already taking regular oral corticosteroids Continue assessment Hx, PEFR, PE - In selected patients: ABG, complete blood count, chest x-ray, theophylline concentration, serum potassium Good response Hx and PE: No wheezing or shortness of breath PEFR or FEV 1 : > 70% baseline ** Incomplete response Hx and PE: Mild wheezing or shortness of breath persists PEFR or FEV 1 : >40% but <70% Poor response Hx and PE: Marked or diffuse wheezes or shortness of breath persists PEFR or FEV 1 : < 40% Respiratory failure Hx and PE: Extreme distress, impaired consciousness, severe wheezes or silent chest PEFR or FEV 1 : <25% and PCO 2 > 40mmHg Discharge Continue medication after discharge, consider corticosteroids Close medical follow-up Patient education Continue treatment Hourly inhaled beta 2 -agonist Begin systemic corticosteroids in most instances Consider subcutaneous epinephrine Continue treatment Hourly inhaled beta 2 -agonist Begin systemic corticosteroids Consider subcutaneous epinephrine Evaluate for hospital admission Admit to Intensive Care Unit Begin systemic corticosteroids Frequent inhaled beta 2 agonists Possible intubation and mechanical ventilation Continue assessment At least hourly: Hx, PE and PEFR or FEV 1 Within 4 hours of initiating treatment Decision regarding disposition Good response Incomplete response Poor response Discharge home Continued treatment at home - consider systemic corticosteroids Close medical follow-up Patient education Individualized decision regarding hospitalization Based on: Severity of symptoms Severity of airflow obstruction Past history of severe asthma Prolonged symptoms before visit Multiple medication use/steroid use at time of exacerbation Access to medical care and medications Adequacy of home conditions Presence of psychiatric illness Admit to hospital See Chart (Hospital Management) Discharge home Continued treatment at home, including a course of systemic corticosteroids Close medical follow-up Patient education Admit to hospital See Chart (Hospital Management) *Therapies are often available in a physician s office. However most acutely severe exacerbations of asthma require a complete course of therapy in an Emergency Department. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 73

74 Acute Exacerbations Of Asthma In Adults Hospital Management Initial Assessment Detailed medical history (Hx) Special attention for: Complete physical examination (PE) - past history of respiratory failure Expiratory flow measurements: PEFR or FEV 1 - elderly Chest radiograph - pregnant Arterial blood gas/oximetry - complicating medical conditions - history of steroid-induced complications (e.g., psychosis) Treatment Inhaled beta 2 -agonist up to every 1 2 hours Systemic corticosteroids; e.g., intravenous methylprednisolone mg every 6 8 hours Intravenous aminophylline or oral theophylline Supplemental oxygen (if hypoxemic) Continued Assessments Hx, PE, PEFR or FEV 1 (measured at least twice daily; before and after bronchodilator desirable) Intensive Care Unit PCO 2 > 40mmHg with severe airflow obstruction Deterioration despite maximal therapy ICU Treatment Nebulized beta 2 agonists every minutes; may supplement with subcutaneous epinephrine Intravenous corticosteroids Intravenous aminophylline Oxygen supplementation Intubation and mechanical ventilation for hypercapnic respiratory failure Transfer ICU Improved Suggested goals prior to discharge: Hx and PE: Minimal or no wheezing; < 1 awakening at night with mild symptoms; good activity tolerance PEFR or FEV 1 : > 70% of baseline** Not Improved Deterioration despite maximal therapy Preparation For Discharge Inhaled beta 2 -agonist no more than every 3 4 hours Oral corticosteroids; role of inhaled corticosteroids discussed in text Oral theophylline Adequate oxygen saturation breathing room air Provide patient education, especially: - medication use - PEFR measurement at home - need for follow-up and chronic care (contact with physician within 7 10 days of discharge recommended Home with patient education, medications and follow-up plan **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 74

75 Acute Exacerbations Of Asthma In Adults Home Management Assess Severity Measure PEFR, cough, breathlessness, use of accessory muscles, wheeze, chest tightness Inhaled beta 2 -agonist 2 4 puffs every 20 minutes up to 1 hour if needed Good response Mild wheeze, cough, breathlessness or chest tightness Symptoms occur with activity, but not at rest Can climb 1 flight of stairs without stopping to rest PEFR > 70 90% baseline** Incomplete Response Marked wheeze, breathlessness, or chest tightness; repetitive cough Symptoms occur while at rest and may interfere with daily activity Cannot climb 1 flight of stairs without stopping to rest PEFR 50 70% of baseline** Poor Response Severe wheeze or breathlessness; speech fragmented by rapid breathing Severe symptoms at rest Unable to walk 100 feet without stopping to rest PEFR <50% of baseline** Continue treatments every 3-4 hours for hours as needed Continue routine medications Contact physician if symptoms recur Good Response PEFR > 70 90% and sustained over 4 hours Continue Assessment Contact Physician For Follow-up Instructions Inhaled or nebulized beta 2 -agonist every hour Begin or increase dose of oral corticosteroids Contact health care provider if not improving within 2 6 hours Continue Assessment Incomplete Response PEFR > 50% and < 70% baseline** or symptoms and PEFR deteriorate Contact Physician Or Go To Emergency Department Contact health provider If little response to initial dose of inhaled beta 2 -agonist: 4 6 puffs beta 2 agonist every 10 minutes up to 2 times or 1 dose nebulized solution Begin or increase dose of corticosteroids Seek further medical care if - No significant improvement after 30 minutes or - Severe symptoms persist and PEFR remains <50% of baseline** or - If continue to require inhaled beta 2 -agonist every 1 3 hours for more than 6 12 hours (PEFR <70% or deteriorating symptoms persist) Go To Emergency Department **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 75

76 Management Of Asthma In Adults Chronic Mild Asthma Clinical Characteristics Assessment Of Lung Function (FEV 1 Or PEFR) Therapy* Outcome Intermittent, brief (< 1 hour) wheeze/cough/dyspnea up to 2 times weekly Asymptomatic between exacerbations Brief (< ½ hour) wheeze/ cough/dyspnea with activity Infrequent (< 2 times a month) nocturnal cough/wheeze Asymptomatic > 80% baseline** Symptomatic Varies 20% or more Pretreat prn 1 2 puffs beta 2 -agonist and/or cromolyn for exposure to exercise, allergen, or other stimuli Inhaled beta 2 -agonist (2 puffs, repeated every 3 4 hours prn for the duration of the episode) Prevent symptoms Symptoms controlled Normal lung function Reduced PEFR variability Normal activity level No or incomplete response: See Charts (Acute Exacerbations Of Asthma In Adults) If medication required daily: See Chart (Chronic Moderate Asthma) * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 76

77 Management Of Asthma In Adults Chronic Moderate Asthma Clinical Characteristics Assessment Of Lung Function (FEV 1 Or PEFR) Therapy* Outcome Symptoms > 1 2 times weekly Exacerbations affect sleep and activity level Exacerbations may last several days Occasional emergency care 60 80% baseline** Varies 20 30% when symptomatic Inhaled beta 2 -agonist prn to tid/qid*** and Anti-Inflammatory agents Inhaled corticosteroids (2 4 puffs bid) or Cromolyn (2 puffs qid) If symptoms persist Additional therapy Increase inhaled corticosteroids and/or Sustained release theophylline and/or Oral beta 2 -agonist Alternative Inhaled beta 2 -agonist prn to tid/qid** and Sustained release theophylline If symptoms persist Symptoms controlled Pulmonary function values optimal for patient Reduced PEFR variability Normal activity level Rarely awakened at night Infrequent exacerbations Reduced frequency of prn inhaled beta 2 -agonist Increasingly frequent symptoms Varies more than 30% during worst exacerbations Oral corticosteroids Short course of oral prednisone or equivalent followed by inhaled corticosteroids Symptoms reduced Peak flow values stabilized Get specialist consultation See chart (Chronic Severe Asthma In Adults Get assessment by specialist No or intermittent response * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. *** If exceed 3 4 doses a day, consider additional therapy other than inhaled beta 2 agonist. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 77

78 Management Of Asthma In Adults Chronic Severe Asthma Clinical Characteristics Assessment Of Lung Function (FEV 1 Or PEFR) Therapy* Outcome Continuous symptoms Limited activity level Frequent exacerbations Frequent nocturnal symptoms Occasional hospitalization and emergency treatment < 60% baseline** Highly variable: 20 30% changes with routine medicine Varies more than 50% during worst exacerbations Inhaled beta 2 -agonist prn-qid*** and Anti-inflammatory agents - Inhaled corticosteroid 2 6 puffs bid-qid with or without - Cromolyn 2 puffs qid with or without (especially for nocturnal symptoms) Oral sustained released theophylline and/or Oral beta 2 -agonist with Episodic extra beta 2 -agonist (2 4 puffs MDI or nebulized treatment) for exacerbations Improved pulmonary function Reduced peak flow variability Almost normal activity Infrequent awakening at night Reduced frequency of exacerbations Reduced frequency of P.M. inhaled beta 2 -agonist Reduced need for corticosteroid burst Reduced need for Emergency Department treatment and Oral corticosteroids Burst for active symptoms (40 mg a day, single or divided dose, for 1 week, then tapered for 1 week) Consider Daily or alternate day use (single dose A.M.) Note: Individuals with severe asthma should be evaluated by an asthma specialist * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. *** If exceed 3 4 doses a day, consider additional therapy other than inhaled beta 2 agonist. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 78

79 Chart 1: Management Of Asthma During Pregnancy Chronic Mild Asthma Clinical Characteristics Assessment Of Maternal Lung Function (FEV 1 or PEFR) Therapy* Outcome Intermittent, brief (< 1 hour) wheeze/cough/dyspnea up to 2 times weekly Asymptomatic between exacerbations Brief (< ½ hour) wheeze/ cough/dyspnea with activity Infrequent (< 2 times a month) nocturnal cough/wheeze Asymptomatic > 80% baseline** Symptomatic Varies 20% or more Pretreat prn 1 2 puffs beta 2 -agonist and/or cromolyn for exposure to exercise, allergen or other stimuli Inhaled beta 2 -agonist (2 puffs, repeated every 3 4 hours prn for the duration of the episode) Prevent symptoms Symptoms controlled Normal lung function Reduces PEFR variability Normal activity level Assessment Of Fetus (Second & Third Trimester But Before Labor) Sonography weeks if clinical dating unreliable Measure fundal height at each visit Inquire about fetal activity Consider kick counts No or incomplete response: See Charts 4-6 (Acute Exacerbations Of Asthma During Pregnancy) If medication required daily: See Chart 2 (Chronic Moderate Asthma) If poor growth or decreased fetal activity Electronic/sonographic fetal monitoring If abnormal Review status of mother s asthma Urgent fetal evaluation Obstetric/perinatal evaluation useful Birth of a healthy baby * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 79

80 Chart 2: Management Of Asthma During Pregnancy Chronic Moderate Asthma Clinical Characteristics Assessment Of Maternal Lung Function (FEV 1 or PEFR) Therapy* Outcome Symptoms > 1-2 times weekly Exacerbations affect sleep or activity level Exacerbations may last several days Occasional emergency care 60 80% baseline** (may be normal when asymptomatic Varies 20 30% when symptomatic Assessment Of Fetus (Second & Third Trimester But Before Labor) Anti-inflammatory agents Cromolyn (2 puffs qid) or Inhaled corticosteroids (2 4 puffs bid, µg/day) and Inhaled beta 2 -agonist prn to tid/qid*** If symptoms persist Symptoms controlled Pulmonary function values optimal for patient Reduced PEFR variability Normal activity level Rarely awakened at night Sonography for dating and growth evaluation Measure fundal height at each visit Daily kick counts Consider serial antepartum fetal assessment beginning at 32 weeks Additional therapy Increase inhaled corticosteroids and/or Sustained release theophylline and/or Oral beta 2 -agonist Infrequent exacerbations Reduced frequency of prn inhaled beta 2 -agonist If poor growth or decreased fetal activity Electronic/sonographic fetal monitoring Review status of mother s asthma Urgent fetal evaluation Obstetric/perinatal consultation useful Birth of a healthy baby Increasingly frequent symptoms If abnormal Varies more than 30% during worst exacerbations Oral corticosteroids Short course of oral prednisone followed by inhaled corticosteroids Symptoms reduced Peak flow values stabilized Get specialist consultation See Chart 3: Chronic Severe Asthma Get assessment by specialist No or intermittent response * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. *** If exceed 3 4 doses a day, consider additional therapy other than inhaled beta 2 agonist. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 80

81 Chart 3: Management Of Asthma During Pregnancy Chronic Severe Asthma Clinical Characteristics Assessment Of Maternal Lung Function (FEV 1 or PEFR) Therapy* Outcome Continuous symptoms Limited activity level Frequent exacerbations Frequent nocturnal symptoms Occasional hospitalization and emergency treatment < 60% baseline** Highly variable: 20 30% changes with routine medicine Varies more than 50% during worst exacerbations Assessment Of Fetus (Second & Third Trimester But Before Labor) Sonograms for dating and growth evaluation Measure fundal height at each visit Daily kick counts Consider serial antepartum fetal assessment beginning at 32 weeks Perinatal consultation useful If Poor Growth Or Decreased Fetal Activity Electronic/sonographic fetal monitoring Anti-inflammatory agents - Inhaled corticosteroid 4 6 puffs bid or 2 5 puffs qid ( µg/day) with or without - Cromolyn 2 puffs qid with or without (especially for nocturnal symptoms) Oral sustained-released theophylline and/or Oral beta 2 -agonist and Inhaled beta 2 -agonist prn-qid*** with Episodic extra beta 2 -agonist (2 4 puffs MDI or nebulized treatment) for exacerbations and Oral corticosteroids Burst for active symptoms (40 mg a day, single or divided dose for 1 week, then tapered for 1 week) Consider Daily or alternate day use (single dose A.M.) Improved pulmonary function Reduced peak flow variability Almost normal activity Infrequent awakening at night Reduced frequency of exacerbations Reduced frequency of prn inhaled beta 2 -agonist Reduced need for corticosteroid burst Reduced need for emergency department treatment If Abnormal Review status of mother s asthma Birth of a healthy baby Urgent fetal evaluation Perinatal consultation useful Note: Individuals with severe asthma should be evaluated by an asthma specialist * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. *** If exceed 3 4 doses a day, consider additional therapy other than inhaled beta 2 agonist. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 81

82 Chart 4: Acute Exacerbations Of Asthma During Pregnancy Home Management Assess severity Measure PEFR, cough, breathlessness, use of accessory muscles, wheeze, chest tightness, presence of fetal activity Inhaled beta 2 -agonist 2 4 puffs every 20 minutes up to 1 hour if needed Good response Mild wheeze, cough, breathlessness or chest tightness Symptoms occur with activity, but not at rest Can climb 1 flight of stairs without stopping to rest PEFR > 70 90% baseline** Appropriate fetal activity Continue treatments every 3 4 hours for 6 12 hours as needed Continue routine medications Contact physician if symptoms recur Good response PEFR > 70 90% and sustained over 4 hours Incomplete response Marked wheeze, breathlessness, or chest tightness; repetitive cough Symptoms occur while at rest and may interfere with daily activity Cannot climb 1 flight of stairs without stopping to rest PEFR 50 70% of baseline** Decreased fetal activity Contact physician or Go to emergency department Poor response Severe wheeze or breathlessness; speech fragmented by rapid breathing Severe symptoms at rest Unable to walk 100 feet without stopping to rest PEFR < 50% of baseline** Decreased fetal activity Go to emergency department Continue assessment Contact physician if good response is not sustained over 4 hours or symptoms recur Contact physician for follow-up instructions **PEFR % baseline refers to the norm for the individual, established by the clinician. This may be % of standardized norms or % patient s personal best. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 82

83 Chart 5: Management Of Asthma During Labor Assessment at Admission Medical history Physical examination Expiratory flow measurement (PEFR or FEV 1 ) Careful fetal monitoring (consider electronic fetal monitoring for at least 20 minutes admission test) Well controlled asthma (PEFR/FEV 1 >80% baseline, no/minimal symptoms) Continue routine asthma medications Administer hydrocortisone every 8 hours until postpartum if systemic steroids were taken within 4 weeks If labor is induced, avoid 15 methyl prostaglandin F 2 alpha Analgesia - Avoid morphine and meperidine - Consider fentanyl - Consider lumbar epidural Continue assessment PEFR/FEV 1 every 12 hours or, if symptoms develop Continued intermittent fetal monitoring -Intensive fetal monitoring recommended if admission test indicates abnormality or other risk factors present - If abnormal, urgent fetal evaluation with perinatal consultation Exacerbation of asthma (PEFR/FEV 1 < 80% baseline. Symptoms: wheeze, cough, breathlessness, or chest tightness) Anesthesia consultation useful Treatment* Inhaled beta 2 -agonist IV corticosteroids Hydrocortisone (100 mg every 8 hours) if systemic taken within 4 weeks Oxygen to maintain O 2 saturation > 95% Analgesia - Consider fentanyl - Consider epidural analgesia Continue assessment PEFR/FEV 1 Oxygen saturation Intensive fetal monitoring (consider either continuous electronic fetal monitoring or intermittent auscultation) - If abnormal, urgent fetal evaluation with perinatal consultation Continue treatment for asthma and for labor Continue treatment for asthma Continue efforts for vaginal delivery *See Charts: Acute Exacerbations Of Asthma and Management Of Asthma During Pregnancy (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 83

84 Chart 6: Management Of Asthma During Delivery Assessment at Admission Medical history Physical examination Expiratory flow measurement (PEFR or FEV 1 ) Oxygen saturation (oximeter or arterial blood gas) Careful fetal monitoring Well controlled mild, moderate, or severe asthma (PEFR/FEV 1 > 80% baseline, no/minimal symptoms) Continue routine inhaled asthma medications Transfer routine oral asthma medications to IV route Administer hydrocortisone (100 mg every 8 hours until postpartum) if systemic steroids were taken within 4 weeks Analgesia - Avoid morphine and meperidine - Consider fentanyl - Consider lumbar epidural with diluted concentrations of local anesthetic and narcotics Anesthesia, if necessary - Pre-anesthetic atropine and glycopyrrolate - Low concentrations of halogenated anesthetics Exacerbation of asthma (PEFR/FEV 1 < 80% baseline Symptoms: wheeze, cough, breathlessness, or chest tightness) Treat exacerbation* Inhaled beta 2 -agonist IV corticosteroids Hydrocortisone (100 mg every 8 hours until postpartum) if systemic steroids were taken within 4 weeks Oxygen to maintain O 2 saturation > 95% Continue efforts for vaginal delivery Notify anesthesia consultant and pediatrician Analgesia - Consider fentanyl - Consider epidural analgesia Anesthetic, if necessary - Pre-anesthetic atropine and glycopyrrolate - Low concentrations of hologenated anesthetic Respiratory failure (PEFR/FEV 1 < 25% and CO 2 > 35 mm Hg) Symptoms: extreme distress, confusion Continue assessment PEFR/FEV 1 Oxygen saturation Intensive fetal monitoring (consider either continuous electronic fetal monitoring or intermittent auscultation) Perform vaginal delivery, if possible Notify anesthesia consultant and pediatrician Initiate mechanical ventilation Perform vaginal delivery, if possible Emergency cesarean section, if necessary *See charts: Acute Exacerbations Of Asthma Emergency Department Management; and Management Of Asthma During Pregnancy (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 84

85 Exercise-Induced Asthma Clinical Characteristics Assessment Of Lung Function (PF or FEV 1 ) Therapy* Outcome Cough, chest congestion or constriction, wheeze, or dyspnea upon exercise Limited endurance during exercise <15% with exercise challenge Premedicate Beta 2- agonist or cromolyn 2 puffs immediately preexercise Repeat prn after 2 hours if exercise continues Controlled symptoms Exercise Tolerance for activity of choice If experience symptoms with exercise Treatment for symptom relief Beta 2 -agonist 2 puffs Future exercise pretreatment Beta 2 -agonist or cromolyn 4 puffs or Beta 2 -agonist 2 puffs and cromolyn 2 puffs No or incomplete control of symptoms Refer to specialist * All therapy must include patient education about prevention (including environmental control where appropriate) as well as control of symptoms. (Source: National Asthma Education Program. Expert Panel Report. Office of Prevention, Education, and Control; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, MD) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 85

86 APPENDIX B FDA Public Health Advisory National Transition from Chlorofluorocarbon (CFC) Propelled Albuterol Inhalers to Hydrofluroalkane (HFA) Propelled Albuterol Inhalers FDA is alerting patients, caregivers, and healthcare professionals of important information about albuterol inhalers. As part of a multi-year phase out, chlorofluorocarbon (CFC) propelled albuterol inhalers will not be available after December 31, Healthcare professionals should transition patients to the hydrofluoralkane (HFA) propelled albuterol inhalers now. Albuterol inhalers are used to treat bronchospasm (wheezing) in patients with obstructive airways disease, such as asthma and chronic obstructive pulmonary disease (COPD). The propellants (spray), CFC and HFA, push the albuterol into the lungs when a patient inhales. Currently there are three approved HFA propelled albuterol inhalers: Proair HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, and Ventolin HFA Inhalation Aerosol. In addition, an HFA propelled inhaler containing levalbuterol, a medicine similar to albuterol, is available as Xopenex HFA Inhalation Aerosol. Each of the above four HFA propelled inhalers is a safe and effective replacement for CFC propelled albuterol inhalers. The manufacturers of HFA inhalers have increased production so that there is adequate supply of these products available now. HFA propelled albuterol inhalers may taste and feel different than the CFC propelled albuterol inhalers. Notably, the force of the spray of an HFA propelled inhaler may feel softer than that of a CFC propelled inhaler. It is important to prime and clean the HFA propelled inhalers to prevent blockage in the inhaler device that will prevent the medicine from reaching the lungs. Each HFA propelled inhaler has different priming, cleaning, and drying instructions. Therefore, it is important to read and understand the instructions that come with each of the HFA propelled albuterol inhalers before using. The national transition from CFC propelled to HFA propelled albuterol inhalers is due to an international environmental treaty called the Montreal Protocol on Substances that Deplete the Ozone Layer. Under this treaty, the United States has agreed to phase out production and importation of Ozone Depleting Substances (ODS) including CFCs. Several CFC propelled inhalers containing other medicines have already been phased out. Over the next several years, other CFC propelled inhalers will be phased out. You can find more information at This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 86

87 POST TEST DIRECTIONS: IF COURSE WAS MAILED TO YOU, CIRCLE THE MOST CORRECT ANSWERS ON THE ANSWER SHEET PROVIDED AND RETURN TO: RCECS, VAN BUREN BLVD, SUITE B, RIVERSIDE, CA OR FAX TO: (951) IF YOU ELECTED ONLINE DELIVERY, COMPLETE THE TEST ONLINE PLEASE DO NOT MAIL OR FAX BACK. 1. The mechanism of action for N-acetylcysteine is: a. stimulation of submucosal bronchial glands. b. rupture of mucus disulfide bonds. c. rupture of mucus DNA. d. conversion of ATP to camp. e. direct smooth muscle relaxation. 2. β adrenergic agonists stimulate an increase in: a. sialomucins. b. histamine. c. mast cell degranulation. d. adenylate cyclase. e. goblet cell secretion. 3. Adenylate cyclase is responsible for: a. converting GTP to cyclic GMP. b. dilution of mucus. c. converting ATP to cyclic AMP. d. increased serous secretion. e. c and d. 4. A disadvantage of a breath-activated device is that cooled freon is used. a. True b. False 5. Spiriva may cause paradoxical bronchospasms in some patients. a. True b. False This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 87

88 6. Tiotropium s action can last up to hrs. a. 36 hrs. b. 24 hrs. c. 12 hrs d. 8 hrs. e. 6 hrs. 7. Potential side effects of steroids is/are: 8. Salmeterol is a: a. decreased resistance to infection. b. adrenal insufficiency. c. electrolyte imbalances. d. osteoporosis. e. all of the above. a. bronchodilator. b. corticosteroid. c. mucolytic. d. mediator modifier. e. antibiotic. 9. Xopenex is just a different brand name for albuterol. a. True b. False 10. Bitolterol is indicated for: a. mucolysis. b. decrease mediator release. c. bronchospasm. d. airway infection. e. scavenging O 2 radicals. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 88

89 11. Fluticasone is a: a. bronchodilator. b. corticosteroid. c. mucolytic.. d. mediator modifier. e. a & d. 12. Salmeterol is recommended for: a. persistent asthma. b. pneumonia. c. short-term bronchospastic relief. d. stable or nocturnal asthma. e. a & c. 13. To improve aerosol deposition from an MDI one should: a. instruct the patient to take short, rapid breaths. b. instruct the patient to inhale slowly and deeply. c. add a spacer. d. exhale forcibly. e. b & c. 14. What is an indication for high-dose bronchodilators? a. pneumonia. b. ARDS. c. pulmonary edema. d. pulmonary hypertension. e. persistent asthma. 15. When are high-dose inhaled corticosteroids indicated? a. when standard doses are ineffective. b. pneumonia. c. severe bronchospasm. d. mild bronchospasm. e. a & c. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 89

90 16. Of the following medication, which is considered a rescue medication? a. Zileuton b. Zafirlukast c. Montelukast d. Tiotropium e. Levalbuterol 17. Theophylline is one of the oldest medicinal agents used in the treatment used in of respiratory disorders. a. True b. False 18. Reduction of leukotrienes is useful in: a. asthma. b. pneumoconiosis. c. pneumonia. d. ARDS. e. none of the above. 19. The following medications: atenolol, metoprolol, or propranolol should not be used with: a. Adrenergic bronchodilators b. Anticholinergics bronchodilators c. Leukotriene modifiers d. Prostaglandin bronchodilators e. Mucolytics 20. Antimuscarinics are useful for: a. bronchodilation. b. increasing PNS stimulation. c. decreasing PNS stimulation. d. a & b. e. a & c. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 90

91 21. Each ampule of Brethine (terbutaline sulfate) contains 1 ml of a 0.1% solution. What is the total dosage if two ampules (2 ml) are used? a. 1 mg b. 2 mg c. 3 mg d. 4 mg e. 5 mg 22. A 10 ml bottle of 5% metaproterenol is used to prepare a dosage of 20 mg of this bronchodilator. How much of this solution should be used? a. 0.2 ml b. 0.3 ml c. 0.4 ml d. 0.5 ml e. 0.6 ml 23. A stock bottle of albuterol sulfate has a concentration of 1:200 (0.5%). How many mg of active ingredient are present in a HEART (High-output extended aerosol respiratory therapy) treatment if 4 ml of this bronchodilator are used? a. 5 mg b. 10 mg c. 15 mg d. 20 mg e. 40 mg 24. You are working the night shift when a 17-year-old patient with persistent asthma is admitted through the emergency room. The intern on call asks for your recommendation on what medication to give first to treat the patient. You would recommend: a. Salmeterol (Serevent) by aerosol b. Terbutaline sulfate (Bricanyl) tablets c. Albuterol (Proventil) by aerosol d. Intravenous theophylline ethylenediamine (Aminophylline) This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 91

92 25. You are working with a 10-year-old cystic fibrosis patient with a pulmonary infection and thick secretions. What would be your best recommendation to help him cough out the secretions? a. 0.9% (normal) saline solution b. Acetylcysteine (Mucomyst) should be instilled into his lungs c. Dornase alpha (Pulmozyme) d. 10% (hypertonic) saline solution 26. The Montreal Protocol is a treaty designed to: 1. Eliminate substances that deplete the ozone layer 2. Eliminate HFAs from pmdis 3. Eliminate CFCs from pmdis 4. Prevent bronchospasm a. 1, 2 & 3 b. 1 & 3 c. 1 & 2 d. 2, 3 & Which of the following medications are available in DPI form? 1. Albuterol 2. Pulmicort 3. Foradil 4. Spiriva a. 1, 2 & 3 b. 2, 3 & 4 c. 3, 4 & 1 d. All of the above 28. Which of the following inhaled medications are recommended for maintenance treatment of asthma? 1. Beclomethasone dipropionate 2. Ciclesonide 3. Bromhexine 4. Mometasone a. 1, 2 & 3 b. 2, 3 & 4 c. 1, 2 & 4 d. All of the above This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 92

93 29. Disadvantages of aerosol administration of antibiotics include: 1. There is a high prevalence of bronchospasm during administration of inhaled antibiotics 2. DNA inactivates some antibiotics and enzymes found in mucus 3. Dosage of antibiotics via inhalation has not been clearly established 4. Frequent administration of the same antibiotic via inhalation can create resistant microorganisms a. 1, 2 & 3 b. 2, 3 & 4 c. 1, 3 & 4 d. All of the above 30. A spacer is recommended for use with bronchodilator pmdi s because: 1. Spacers improve drug delivery to the airways 2. Spacers help prevent oropharyngeal deposition 3. Spacers help prevent systemic side effects 4. Spacers are easier for the patient to hold a. 1, 2 & 3 b. 2, 3 & 4 c. 1, 2 & 4 d. 1, 3 & 4 KM: Test Version G This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 93

94 ANSWER SHEET NAME STATE LIC # ADDRESS AARC# (if applic.) DIRECTIONS: (REFER TO THE TEXT IF NECESSARY PASSING SCORE FOR CE CREDIT IS 70%). IF COURSE WAS MAILED TO YOU, CIRCLE THE MOST CORRECT ANSWERS AND RETURN TO: RCECS, VAN BUREN BLVD, SUITE B, RIVERSIDE, CA OR FAX TO: (951) IF YOU ELECTED ONLINE DELIVERY, COMPLETE THE TEST ONLINE PLEASE DO NOT MAIL OR FAX BACK. 1. a b c d e 16. a b c d e 2. a b c d e 17. a b 3. a b c d e 18. a b c d e 4. a b 19. a b c d e 5. a b 20. a b c d e 6. a b c d e 21. a b c d e 7. a b c d e 22. a b c d e 8. a b c d e 23. a b c d e 9. a b 24. a b c d 10. a b c d e 25. a b c d 11. a b c d e 26. a b c d 12. a b c d e 27. a b c d 13. a b c d e 28. a b c d 14. a b c d e 29. a b c d 15. a b c d e 30. a b c d KM: Test Version G This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 94

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