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