June 19, 2005
Changes in Inhaler Devices for Asthma And COPD
Asthma and chronic obstructive pulmonary disease (COPD) involve chronic inflammation and constriction of the bronchioles. Optimal therapy for many patients requires control of both pathologic mechanisms through the use of inhaled bronchodilators and corticosteroids. Bronchodilator and corticosteroid inhalers eject a fine mist of medication which works directly on the bronchiole mucosa and smooth muscle when used properly. These inhaled medications are intended to exert localized, sitespecific therapeutic effects on the bronchioles (Skrepnek & Skrepnek, 2004).
Bronchiole smooth muscle is innervated by both sympathetic (beta- 2 adrenergic) and parasympathetic (cholinergic) autonomie nerves, which exert opposite effects on the airways. Stimulation of beta-2 adrenergic nerve fibers causes relaxation of bronchiole smooth muscle, leading to bronchodilation. Conversely, stimulation of the parasympathetic or cholinergic nerve fibers causes contraction of bronchiole smooth muscle, leading to bronchoconstriction (McPhee, Lingappa, Ganong, & Lange, 2000). Bronchospasm, a major component of asthma and COPD, limits airflow and can be relieved by bronchodilator inhaler medication. To exert bronchodilation, medications work by stimulating beta-2 adrenergic nerve receptors or blocking the cholinergic nerve receptors in bronchiole smooth muscle. Bronchodilator inhalers, therefore, are either beta-2 adrenergic agonists or anti-cholinergic medications (Skrepnek & Skrepnek, 2004).Differences between the pathologic mechanisms of asthma and COPD dictate the implementation of distinctively different treatment methods. Asthma is primarily a chronic inflammatory disease involving episodes of reversible bronchoconstriction. Because inflammation is the main pathologic mechanism, anti- inflammatory agents (specifically inhaled corticosteroids) are first-line therapy in asthma. To prevent and counteract reversible episodes of bronchospasm, beta-2 adrenergic inhalers directly dilate the bronchioles. In contrast, bronchoconstriction in COPD is progressive, largely cholinergic mediated, and only partially reversible. Because bronchoconstriction is a major pathologic mechanism in COPD, bronchodilators (specifically anticholinergic inhalers) are first-line pharmacologic therapy (Doherty, 2004).
Therapeutic effects of inhalers are exhibited mainly by improving the patient's pulmonary function test parameters: FEVl, PEFR, and PIF. FEVl is the forced expiratory volume in the first second of exhalation. PIF is the peak inspiratory now, and the PEFR indicates peak expiratory flow rate. Inhaled bronchodilator and corticosteroid medications directly ease the patient's bronchiole resistance to air flow by widening the diameter of the airways and diminishing inflammation, thus increasing FEVl, PIF, and PEFR (Skrepnek & Skrepnek, 2004).
Mechanisms of "Rescue" vs. "Maintenance" Inhalers
Inhalers also are categorized as containing short-acting or long- acting medications. Short-acting bronchodilators are used as rescue medications for immediate relief of acute bronchospasm in asthma or COPD. These beta-2 adrenergic agonists exert a rapid bronchodilator effect and have a short duration. Long-acting beta-2 adrenergic bronchodilators are used as maintenance medications taken daily on a scheduled basis to prevent acute bronchospastic events. Long-acting adrenergic bronchodilators act within hours and have a prolonged duration of therapeutic effect (see Table 1) (Skrepnek & Skrepnek, 2004).
Anticholinergic bronchodilator inhalers, also used as maintenance therapy, are first-line medications in managing COPD (National Institutes of Health/National Heart, Lung, and Blood Institute/ World Health Organization [NIH/NHLBI/ WHO] Workshop Report, 2003). These inhalers block cholinergic stimulation of the bronchioles, thereby inhibiting bronchoconstriction. Anticholinergic inhalers are used on a scheduled, daily basis for preventing bronchoconstriction, not for acute episodes of bronchospasm (see Table 1).
Inhaled corticosteroids are long-acting maintenance medications taken daily for asthma. They have not been shown consistently to improve airway resistance in COPD, and their use is controversial in this disease group (Calverly & Barnes, 2000; Highland, Strange, & Heffner, 2003). They are to be taken on a scheduled, daily basis, not for acute bronchospasm. Corticosteroids are often found in combination with long-acting beta-2 adrenergic bronchodilators in inhaler devices (see Table 1).
Current Types of Rescue and Maintenance Inhalers Available
A common therapeutic regimen for a patient with persistent asthma or COPD consists of scheduled daily use of maintenance inhaler medications with rescue inhaler use as needed. In persistent asthma, this regimen consists of a daily inhaled long-acting bronchodilator and corticosteroid, with a short-acting bronchodilator (rescue) inhaler used as needed for acute bronchospastic episodes. Another combination maintenance inhaler consists of an anticholinergic medication and a short-acting beta-2 adrenergic agonist. These have proven beneficial in COPD due to the synergistic effect of anticholinergic inhibition of bronchoconstriction and the beta-2 adrenergic agonist stimulation of bronchodilation (American Thoracic Society, 1995; National Asthma Education and Prevention Program, 1997, 2003; NIH/NHLBI/WHO Workshop Report, 2003) (see Table 1).
Cromolyn, a unique anti-inflammatory medication, is used for long- term management and prevention of acute bronchospastic episodes. Cromolyn stabilizes bronchiole mast cells and inhibits release of inflammatory mediators. Used as maintenance treatment, cromolyn can inhibit bronchospasm incited by exercise, aspirin, cold air, sulfur dioxide, toluene diisocyanate, and environmental pollutants. It also should be used shortly before anticipated exposure to bronchospasm- inciting factors such as exercise (Randolph, 2000) (see Table 1).
Both persistent asthma and COPD are chronic inflammatory conditions with potential for acute bronchospastic episodes. The overall therapeutic goal is to avert acute bronchospastic attacks with the use of daily maintenance inhaler medications. Preventing acute bronchospastic episodes is crucial because research has shown that each acute attack leads to detrimental long-term remodeling of the airways (Chetta et al., 1997; Elias, Zhu, Chupp, & Homer, 1999).
In summary, inhaler pulmonary medications may be categorized as follows:
Rescue inhaler treatment
* Short-acting beta-2 adrenergic bronchodilators
Maintenance inhaler treatment
* Long-acting beta-2 adrenergic bronchodilators
* Anticholinergic bronchodilators
* Corticosteroid inhalers
Combination inhaler treatment
* Corticosteroid plus short-acting beta-2 adrenergic bronchodilator
* Anticholinergic bronchodilator plus short-acting beta-2 adrenergic bronchodilator
Cromolyn inhaler treatment
Environmental Need for a Change in Inhaler Devices
In the past, chlorofluorocarbons (CFCs) were the primary substances used as propellants in aerosols. Since 1978, the use of CFCemitting products in the United States has been curtailed sharply because they were deteriorating the ozone layer (the earth's protective screen against the harmful rays of the sun). Because CFCs were the propellants used in pulmonary inhalers, they were considered "essential-use" CFCs and exempt from a government- mandated ban under the Clean Air Act (Food & Drug Administration [FDA], 1997). The Clean Air Act allowed the pharmaceutical industry to develop alternative non-CFC propellant inhalers and introduce these gradually to the public by 2005 (FDA, 1997). This transition to non-CFC aerosol delivery systems is apparent in new pulmonary inhaler devices such as hydro-fluoroalkane-pressurized metered dose inhalers (HFA p MDIs) and dry powder inhalers (DPIs).
Current Types of Inhaler Devices
Pressurized metered-dose inhalers (pMDIs) use a chemical propellant to eject aerosolized medication. Chlorofluorocarbons (CFCs), chemical propellants used in the past, are now being phased out. Hydrofluoroalkanes (HFAs) are the new environmentally friendly chemical propellants replacing CFCs in pMDIs. Patients should be advised that the new HFA inhaler may have a different taste and inhalation sensation than CFC-propelled inhalers. However, HFA propellants deliver medication via inhalers in the same way as CFCs.
Pressurized MDIs are either squeeze-and-breathe inhalers or breath-activated inhalers. Squeezeand-breathe pMDIs are pressurized canisters with measured doses of medication activated by squeezing the top of the canister releasing a fine microcrystalline suspension of medication. Patients must use the proper inhalation method to obtain the optimal benefit of pMDIs. First, the canister should be shaken 3 to 4 times. The patient then needs to exhale fully. Next, the patient should place the lips around the mouthpiece, inhale slowly through the mouth, and simultaneously squeeze the canister top. The canister should be removed from the mouth and the medication should be held in the lungs for approximately 10 seconds before the patient exhales. After 30 seconds, this method can be repeated if additional inhalations are advised (Medical Economics, 2005).
The other type of pMDI is a breath-activated inhaler which automatically releases medication when the patient inhales. An HFA propellant mechanism, activated by inhalation, triggers the pressurizedmetered dose inhaler to release medication. The patient does not have to coordinate squeezing of the canister with inhalation. As with all breath-activated inhaler devices, the release of medication is influenced significantly by the patient's strength of inspiration (3M Pharmaceuticals, 2000; Medical Economics, 2005).
DPIs are all breath-activated and do not use a chemical propellant to eject medication. Each device contains medication in the form of powder which is dispersed into particles by inspiration. DPIs require the patient to place the lips around a mouthpiece and inhale rapidly. Examples of DPI devices are the Serevent Diskus and Advair Diskus. These diskhalers consist of a series of foil pouches on a disk. The patient loads the diskhaler with a medication disk of numbered foil pouches. Activation of the device punctures a pouch to release powder into the disk, and the drug is inhaled through a mouthpiece. The patient places the mouthpiece between the teeth and lips. After each inhalation, the patient slides the next powder pouch into place for the next dose (Asthma Society of Canada, 2004; GlaxoSmithKline, 2004a, 2004b).
The Pulmicort Turbuhaler is another DPI device which requires loading of medication in the form of a pellet. When the body of the turbuhaler is rotated, a prescribed amount of drug is ground off the pellet. The ground pellet powder is then inhaled through a fluted aperture on the top of the device. The patient must inhale forcefully with lips on the device mouthpiece (AstraZeneca, 2002).
The Spiriva Handihaler is a DPI device which includes a spherical covered plastic chamber and foil blister card of Spiriva capsules. Each capsule contains the dry powder medication, which the patient loads into the device. The patient then presses a button to pierce the capsule, and inhales deeply and slowly until all the capsule powder is inhaled (Medical Economics, 2005).
Rescue Inhalers: Short-Acting Beta-2 Adrenergic Bronchodilator Inhalers
Albuterol. Short-acting bronchodilators are indicated for acute bronchospasm when immediate rescue medication is necessary. A prototypical, short-acting bronchodilator is albuterol (also called salbutamol), a selective beta-2 adrenergic agonist which relaxes bronchiole smooth muscle. The albuterol inhaler (Ventolin HFA) is a pressurized MDI. The recommended dose is two inhalations every 4 to 6 hours in patients 4 years of age and older. The peak effect is reached within an average of 5 to 7 minutes and remains in the bloodstream for 4 to 6 hours (Medical Economics, 2005).
Metaproterenol (Alupent Inhalation Aerosol) is another selective beta-2 adrenergic agonist bronchodilator. This inhaler is supplied as 75 mg metaproterenol contained in a 100-inhalation canister, or as 150 mg of metaproterenol in a 200-inhalation canister. The recommended dose is 2 to 3 inhalations every 3 to 4 hours for patients over age 12 (Medical Economics, 2005).
Pirbuterol (Maxair Autohaler) is a short-acting selective beta-2 adrenergic agonist. This is a breathactivated inhaler which delivers medication automatically with inspiration and does not require the patient to coordinate inhalation with squeezing of the canister. Each 14 g canister contains 400 inhalations. After inhalation, bronchodilation occurs within 5 minutes, with maximum improvement in 1 to 2 hours and duration of effect for 5 hours. As with all breath- activated devices, the autohaler device is dependent on the strength of the patient's inhalation force. Most patients are advised to take 1 to 2 inhalations every 4 to 6 hours as needed during episodes of acute bronchospasm (3M Pharmaceuticals, 2000; Medical Economics, 2005).
Maintenance Inhalers: Long-Acting Adrenergic Bronchodilator Inhalers
Salmeterol is a long-acting selective beta-2 adrenergic bronchodilator supplied as a DPI. This delivery system contains a double foil blister strip of 50 meg of powdered salmeterol in 12.5 mg of lactose. Salmeterol is available alone as the Serevent Diskus and Serevent Inhalation Aerosol, and in combination with flucatisone in the Advair Diskus. This is a long-acting medication; a 50 meg dose of salmeterol produces maximal bronchodilation within 2 hours and a continual therapeutic effect for 12 hours. The recommended dosage is two inhalations twice daily (once in the morning and evening) for patients age 4 and older. Salmeterol is used for maintenance therapy in persistent asthma and COPD, not as a rescue medication for acute bronchospasm. It is also used for prevention of exercise-induced asthma (GlaxoSmithKline, 2004a, 2004b; Medical Economics, 2005).
Formoterol (Foradil Aerolizer) is another long-acting selective beta-2 adrenergic bronchodilator supplied as a DPI. The DPI requires insertion of one formoterol capsule with each use. Each capsule contains 12 meg of formoterol; the patient inhales the contents of each capsule with activation of the aerolizer device. For adults and children older than 5 years of age, the recommended dosage is inhalation of the 12 meg capsule contents once every 12 hours, not to exceed 24 meg total daily (Medical Economics, 2005).
Maintenance Inhalers: Anticholinergic Bronchodilators in COPD
Ipratropium (Atrovent Inhalation Aerosol), a CFC-propelled pMDI, is indicated for maintenance treatment of bronchospasm associated with COPD. After inhalation, peak therapeutic effects occur in 1 to 2 hours and persist for a period of 3 to 4 hours. The recommended dose is two inhalations 4 times a day. Patients may take additional inhalations if required; however, total number of inhalations should not exceed 12 in 24 hours (Medical Economics, 2005).
Tiotropium inhalation powder (Spiriva Handihaler) is an anticholinergic bronchodilator used once daily for maintenance treatment of COPD. Once daily usage of this long-acting bronchodilator reaches peak effect in 3 hours and exerts therapeutic effects for 24 hours. Maximum improvement in FEVl and FVC occurs after the drug reaches a pharmacodynamic steady state at approximately 1 week. This medication is not to be used for acute episodes of bronchospasm. The handihaler is a DPI device which requires insertion of a Spiriva capsule (18 meg of tiotropium blended with lactose) (Boehringer Ingelheim Pharmaceuticals, 2004; Medical Economics, 2005).
Maintenance Inhalers: Corticosteroids
Flucatisone (Flovent Inhalation Aerosol), available as an HFA or CFC-propelled device, is a long-acting inhaled corticosteroid available in several dose strengths (44 meg, 110 meg, and 220 meg). After inhalation, flucatisone exerts initial effects within 24 hours; maximum benefit occurs after 1 to 2 weeks of treatment. Corticosteroids offer a cumulative therapeutic effect over several weeks in asthma and for some patients with COPD. For patients who do not experience adequate effects within 2 weeks of starting treatment, dosage increases may provide additional improvement. As with all corticosteroids, it is desirable to use the lowest effective dosage to reduce possibility of side effects. Flucatisone pMDIs are not recommended for children under 12 years of age (Medical Economics, 2005). Flucatisone was available as a DPI device (Flovent Rotadisk) manufactured by Glaxo SmithKline. Due to low product utilization, this product was discontinued (Lippincott, Williams, & Wilkins, 2004).
Budesonide (Pulmicort Turbuhaler) is a corticosteroid supplied for DPI. This DPI provides approximately 200 meg of budesonide per inhalation. The Pulmicort Turbuhaler contains 200 inhalation doses with an indicator which appears when 20 doses remain. The patient should discard the turbuhaler when empty because these devices are not reusable (Astra Zeneca, 2002).
Flunisolide (Aerobid Inhaler System) is a corticosteroid supplied as a CFC-propelled pMDI. Each activation of the inhaler delivers 250 meg of flunisolide, and each canister contains 100 inhalations. A mentholated form of the inhaled corticosteroid is available as the Aerobid-M Inhaler. The recommended dose is two inhalations twice daily (morning and evening) as maintenance treatment in asthma (Medical Economics, 2005).
Beclamethasone (Qvar Inhalation Aerosol) is a corticosteroid available in doses of 40 meg and 80 meg and supplied as an HFA propellant inhaler device. The recommended dose is one to two inhalations as directed by the physician for persistent asthma in patients over 5 years of age. Maximum therapeutic benefit of this corticosteroid requires 3 to 4 weeks of use. The dose of this medication should be titrated to the lowest effective dosage which provides adequate control of asthma. Patients are often started on this inhaler as they are being weaned from oral corticosteroids (Medical Economics, 2005).
Triamcinolone (Azmacort Inhalation Aerosol) is a corticosteroid available in dosages of 200 meg and 400 meg, and supplied as a CFC propellant pMDI. The recommended adult dosage is two inhalations of 200 meg 3 to 4 times a day or four inhalations of 400 meg twice a day. Maximum daily intake should not exceed 1,600 meg ( Medical Economics, 2005).
Mometasone is a corticosteroid undergoing clinical trials as a DPI which can be administered once daily. Each inhalation delivers 400 meg of mometasone. A recent study found comparable efficacy of flucatisone 125 meg administered via pMDI twice a day and mometasone 400 meg DPI once daily in patients with persistent asthma (Wardlaw et al., 2004).
Combination Inhalers: Corticosteroid with LongActing Beta-2 Adrenergic Agonist
The Advair Diskus contains a combination of flucatisone and salmeterol, which are two distinct classes of medications. Flucatisone is a corticosteroid and salmeterol is a selective long- acting beta-2 adrenergic receptor agonist. This DPI is available as Advair Diskus 100/50, Advair 250/50, and Advair 500/50, which represent the flucatisone dose (100 meg, 250 meg, or 500 mcg)/ salmeterol dose (50 meg) per inhalation. The recommen\ded starting dose is Advair 100/50 twice daily (morning and evening) approximately 12 hours apart. Following administration of Advair Diskus, peak plasma concentrations of flucatisone were achieved in 1 to 2 hours and those of salmeterol were achieved in 5 minutes (Medical Economics, 2005). Advair Diskus is indicated for longterm, twice daily, maintenance treatment of airway obstruction in asthma and COPD. This inhaler is not indicated for relief of acute bronchospasm. An inhaled shortacting beta-2 adrenergic agonist (for example, albuterol) should be used to relieve acute shortness of breath due to bronchospasm. Use of Advair more than twice daily is not recommended because excessive beta adrenergic stimulation can occur with high doses of salmeterol. Improvement in bronchospasm and inflammation following inhaled administration can occur within 30 minutes of treatment, although maximum benefit may not be achieved for 1 week or longer. Patients who do not respond adequately to the starting dosage after 2 weeks of therapy may require a higher strength of Advair (Medical Economics, 2005).
A recent study compared the combination of flucatisone 100 mcg/ salmeterol 50 meg delivered via diskus with flucatisone 100 meg and salmeterol 50 meg alone in patients with persistent asthma. The combination flucatisone/salmeterol diskus was more effective in improving morning and evening PEFR than the individual agents used alone. Additionally, patients who used the combination diskus required less rescue albuterol (Murray et al., 2004).
Combination Maintenance Inhaler: Anticholinergics with Short- Acting Beta-2 Adrenergic Agonists
Combiuent Inhalation Aerosol is a combination of ipratropium (a long-acting, anticholinergic, bronchoconstrictor antagonist) and albuterol (a beta-2 adrenergic bronchodilator). This is available as a CFC propellant pMDI containing 200 inhalations of 21 meg of ipratropium and 120 mg of albuterol. Primarily indicated for COPD, the aerosol causes peak improvement in FEV1 occurring within 1 hour; therapeutic effects endure for 4 to 5 hours. Studies show that this combination therapy is more effective than either ipratropium or albuterol administered alone (Chrischilles, Gilden, Kubisiak, Rubenstein, & Shah, 2002; Rodrigo & Rodrigo, 2000). The recommended dose for adults is two inhalations 4 times daily, not to exceed 12 inhalations in 24 hours (Medical Economics, 2005).
Cromolyn inhaler. The Intal Inhaler contains cromolyn, a unique anti-inflammatory agent, in a CFC propellant pMDI. Cromolyn inhibits antigen-stimulated mast cell release of inflammatory mediators. Cromolyn is used most often to prevent exercise-induced bronchospasm and should be used on a daily, long-term basis. Peak therapeutic effects are seen after several weeks of daily scheduled use. Intal should be used shortly before exposure to the precipitating antigen or factor, as well as on a daily basis. The Intal inhaler provides 112 inhalations from the 8.1 g canister and 200 inhalations from the 14.2 g canister. Each inhalation dispenses 800 meg of cromolyn, with recommended dosage schedule of two inhalations 4 times a day for adults and children at least 5 years of age. Within 10 to 15 minutes before anticipated exposure to bronchospasm-inducing factors, the patient should take two inhalations of cromolyn (Medical Economics, 2005; Randolph, 2000).
Nursing Implications of Pulmonary Inhaler Treatment
Precautions with use of CFC propellant inhalers. CFC propellants are being phased out in all aerosol devices to protect the environment. However, some inhaler medications are still supplied using these substances. These pressurized canisters should never be punctured, used, or stored near open flames, or in heat greater than 120 F (Medical Economics, 2005).
Precautions with use of (HFA) propellant inhalers. HFA (hydrofluoroalkane) propellants, safe for the environment, do not have any pharmacologie activity except at extremely high dosages. At doses of 300 to 1,300 times the maximum human exposure, tremor, dyspnea, salivation, and ataxia were the adverse effects observed in laboratory animals. HFAs do not accumulate in the bloodstream and are eliminated rapidly (Medical Economics, 2005). These are similar findings with CFC propellants. These pressurized canisters should never be punctured, or used or stored near open flames, or in heat greater than 120 F. Prior to initial use, four priming actuations are necessary; if the canister is not activated for 2 weeks or more, priming is necessary before use. Cleaning of the device once a week is recommended. These canisters should never be immersed in water; hence, the "float test" to check for canister emptiness, as with CFC devices, is contraindicated in HFA devices (Medical Economics, 2005).
Precautions with use of dry powder inhalers. Some dry powder inhalers use lactose as an ingredient in the medication mixture. Patients allergic to lactose or milk products should not use this type of inhaler due to the potential for hypersensitivity reactions. Specific powder formulations and capsules should only be used with their corresponding specific inhaler devices. Inhaler devices are not interchangeable (Medical Economics, 2005).
Adverse Effects of Beta-2 Adrenergic Agonist Inhalers
Paradoxical bronchospasm. All beta-2 adrenergic agonist inhalers can stimulate immediate airway hyperactivity which leads to acute bronchospasm. This side effect requires discontinuation of inhaler therapy immediately (Medical Economics, 2005).
Possible cardiovascular side effects. Whether they are short- acting or long-acting, beta-2 adrenergic agonists can have cardiovascular side effects. Histologically, beta-2 adrenergic receptors are located primarily within bronchiole smooth muscle; beta-1 adrenergic receptors are located within the cardiovascular system. Stimulation of beta-2 adrenergic receptors in the bronchioles leads to relaxation of the bronchiole smooth muscle, initiating therapeutic bronchodilation in asthma and COPD. However, a population of beta-2 adrenergic receptors in the heart also can be stimulated by these medications. Studies have shown that beta-2 adrenergic agonists can increase systolic blood pressure, heart rate, and cardiac contractility, thus increasing oxygen consumption by the myocardium (Guhan et al., 2000; Rossinen, Partanen, Stenius- Aarniala, & Nieminen, 1998). The patient can experience tachycardia, palpitations, and elevated blood pressure. Additionally, ECG changes such as flattening of the T wave, prolongation of the QT interval, and ST segment depression have been reported (Medical Economics, 2005). Health care providers therefore must be cautious with use of beta-2 adrenergics in patients with coronary insufficiency, dysrhythmias, heart failure, and hypertension.
Patients often suffer COPD, asthma, and cardiovascular conditions concurrently, and require treatment with both bronchodilator and cardiovascular medications. Limited research compares long-acting beta-2 adrenergic inhalers and their cardiovascular side effects. In a comparison study of formoterol and salmeterol (Guhan et al, 2000), investigators found that both medications caused an early dose- dependent increase in heart rate and glucose concentrations, and a fall in diastolic blood pressure and plasma potassium concentration. Formoterol caused an early increase in systolic blood pressure and a more rapid onset than salmeterol, whereas salmeterol had more prolonged activity.
In hypertensive patients with asthma or susceptibility to bronchospasm, beta-adrenergic blockers may be contraindicated. To reduce blood pressure, beta blocker antihypertensive drugs are intended to inhibit specific, cardioselective, beta-1 adrenergic receptors in the heart and vascular walls. However, some concomitant blockade of beta-2 adrenergic receptors can occur, resulting in bronchospasm in susceptible individuals (Medical Economics, 2005).
Metabolic side effects. Beta-2 adrenergic receptors are located in the smooth muscle of the bronchioles, blood vessels, genitourinary tract, uterus, gastrointestinal tract, liver, skeletal muscle, and pancreas. Consequently, beta-2 adrenergic stimulants can cause side effects involving these organs. In the liver, beta-2 adrenergic agonists stimulate glycogenolysis and gluconeogenesis (McPhee et al., 2000). The hepatic effect can cause hyperglycemia, which is significant in diabetic patients. Also, beta-2 adrenergic stimulation of skeletal muscle can cause tremors in some patients. Beta 2-adrenergic drugs should be used with caution in patients with coronary insufficiency, dysrhythmias, hypertension, hyperthyroidism, seizure disorders, diabetes, or susceptibility to hypokalemia (Medical Economics, 2005).
Drug-drug interactions and other effects. Patients should not take other sympathomimetic drugs, monoamine oxidase (MAO) inhibitors, or tricyclic antidepressants while taking beta-2 adrenergic agonists. Digitalis levels need careful monitoring because adrenergic agonists can cause elevation of digitalis blood levels. Beta-2 adrenergic agonists should be used cautiously in pregnant and nursing women. No adequate, well-controlled studies assure safety in these populations. These medications are safe for children 4 years of age and older. Patients should not use more inhalations than as directed by their physician. Some persons experience oropharyngeal irritation from the inhaled aerosol. Patients can rinse their mouths out with water after completion of inhalations to prevent oropharyngeal irritation (Medical Economics, 2005).
Adverse Effects of Anticholinergic Inhalers
Although inhaler medications are absorbed minimally into the bloodstream, some potential exists for systemic effects. Anticholinergic drugs can cause parasympathetic blockade of the heart, ocular ciliary muscle, gastrointestinal wall muscles, and bladder muscle (McPhee et al., 2000). Caution should be used wi\th administration of these inhaled drugs in patients with narrow angle glaucoma, prostate enlargement, or bladder neck obstruction. Patients should be warned not to spray these medications into the eyes because precipitation of glaucoma can occur. Mydriasis, eye pain, blurred vision, tachycardia, palpitations, nervousness, urinary retention, and constipation are reported side effects. No studies document use of these drugs in pregnant or nursing women. Safety of these drugs in children under age 12 has not been established. These drugs are safe when used in conjunction with beta- 2 adrenergic agonists and corticosteroid inhalers (Medical Economics, 2005).
Adverse Effects of Corticosteroid Inhalers
Inhaled corticosteroids may be used in patients with asthma and COPD being weaned off oral corticosteroids. After withdrawal of oral corticosteroids, a number of months is required for full recovery of hypothalalmic-pituitary-adrenal axis function. Patients being weaned from oral corticosteroids should be assessed for signs of adrenal insufficiency, or hypotension, fatigue, depression, lassitude, weakness, joint pain, myalgias, nausea, and vomiting, particularly during times of stress or postoperatively. Persons who have been on long-term oral corticosteroids may be immunosuppressed and susceptible to infections such as chicken pox and measles. Because corticosteroids can cause immunosuppression, inhaled corticosteroids should be used with caution in patients with tuberculosis, systemic fungal infections, bacterial, viral, or parasitic infections, or ocular herpes simplex. Inhaled corticosteroids also increase risk of osteoporosis, cataracts, and adrenal suppression in adults (Clark & Lipworth, 1997; Patel, 2004; Wilson, Clark, Devlin, McFarlane, & Lipworth, 1998). Due to the wide number of possible adverse effects, the lowest dosage of inhaled corticosteroids which provide control for asthma or COPD is recommended (Medical Economics, 2005).
A reduction in growth velocity has been observed in those taking long-term oral corticosteroids, and has been under investigation in children and adolescents who use inhaled steroids. Some studies have found suppression of adrenal function and inhibited growth and bone development in children who use high doses of inhaled corticosteroids. Suppression of growth in children on high doses of inhaled corticosteroids has been detected but appears temporary and not associated with reduced adult height (Alien, 2004; Clark, Clark, & Lipworth, 1996; Goldberg et al., 2002). A recent 3-year study of inhaled budesonide use in children revealed no effect on adrenal function (Bacharier et al., 2004). Although there are disparities in research findings, most investigators agree that the benefits of inhaled corticosteroids in children outweigh the risks of poorly controlled asthma. No adequate studies in pregnant or nursing women are available.
Candida albicans infection of the oropharynx ("thrush") has been experienced by some long-term users of inhaled corticosteroids. Rinsing out the mouth after inhaler use may prevent these infections. Inhaled corticosteroid therapy should be interrupted temporarily to administer antifungal medications to eliminate Candida infection (Medical Economics, 2005).
Drug-drug interactions. Flucatisone is metabolized in the liver by the cytochrome p 450 enzyme system. Ritonavir, a protease inhibitor used in treatment of HIV infection, is a potent inhibitor of this hepatic cytochrome system. The concomitant use of ritonavir and flucatisone resulted in elevated blood levels of flucatisone. This also occurred with another hepatic cytochrome inhibitor, ketoconazole. Therefore, ritonavir and ketoconazole should not be used in conjunction with flucatisone (Medical Economics, 2005).
Adverse effects ofcromofyn. Few adverse effects have been reported with cromolyn inhalers. Throat irritation, bad taste, bronchospasm, cough, wheeze, and nausea are rare adverse effects. Cromolyn has not been evaluated adequately in pregnant or nursing women, or children younger than age 5 (Medical Economics, 2005; Randolph, 2000).
The Challenge of Patient Education in Inhaler Treatment
For some patients, the coordinated technique needed to obtain the full dose of medication from a squeeze-and-breathe pMDI is challenging. Studies show that many patients do not use proper technique, resulting in inadequate delivery of medication (Crompton, 2004; Girard & Roche, 2002; Molimard et al., 2003; Richter, 2004; Rubin & Durotoye, 2004). Poor technique often results in oropharyngeal deposition of medication which can lead to laryngeal irritation, hoarseness, and Candida infection of the throat (Mirza, Kasper Schwartz, & Antin-Ozerkis, 2004). Medication inhalation may be facilitated with the use of a spacer, which is a short tube attached to the inhaler. Spacers can only be used with some pMDIs, not all devices. The spacer acts as a holding chamber that keeps the medication from escaping into the air. Releasing the medication into the spacer chamber allows the patient extra time to inhale more slowly and increases the amount of mist reaching the lungs (Dempsey, Wilson, Coutie, & Lipworth, 1999; Melani et al., 2004). The Aerochamber P/us is a spacer device which can be used with a pMDI. A built-in whistle alerts the patient if inhalation flow is too fast. An optional mask and detailed patient instructions accompany this product (Forest Pharmaceuticals, 2004; Medical Economics, 2005).
Molimard and colleagues (2003) studied 3,811 patients who used different inhaler devices for 1 month. These investigators found that 76% of patients made at least one error with use of pMDIs compared to 49% to 55% with breath-actuated inhalers. Treatment- compromising errors were made by 11% to 12% of patients who used the Aerolizer, Autohaler, or Diskus, compared to 28% and 32% of patients respectively treated with pMDI and Turbuhaler. Another group of researchers evaluated patient use of the Turbuhaler and found that fewer than 50% of patients demonstrated correct technique when using the device (Epstein, Maidenberg, Hallet, Khan, & Chapman, 2001). However, according to Welch and colleagues (2004), the Turbuhaler was easier to use and preferred by patients compared to pMDIs. Investigators found that asthma patients learned proper use of the Pulmicort Turbuhaler more easily than the Flovent, Vanceril, and Aerobid pMDI devices.
In summary, high numbers of patients with asthma and/or COPD do not use inhaler devices correctly resulting in suboptimal therapeutic results.
Also, studies show that many patients fail to hold inhaled medication in their lungs for the full 10 seconds (Epstein et al., 2001; Girard & Roche, 2002; Newman, 2004). This final step in the inhaler technique is required for optimal pulmonary absorption of medication, regardless of type of device used.
DPIs have some advantages over pMDIs. DPIs are environmentally friendly and breath-activated, requiring no coordinated activation by the patient. However, the delivery of medication depends on the strength of patient inspiration. Patients with asthma and COPD, particularly those experiencing bronchospasm, have weak inspiratory strength which limits effectiveness of breath-actuated MDIs or DPIs (van der Palen, 2003).
Patient Education Materials
Lastly, patients may have difficulty keeping track of medication doses remaining in their inhaler. A recent study revealed that a large percentage of patients did not keep track of canister doses and unknowingly continued to use empty pMDIs for up to twice the intended duration (Rubin & Durotoye, 2004). Manufacturers recommend that patients write the date of initial use on the canister and calculate the doses used. To track dose utilization, the patient needs to note the first day of use on the canister and count the number of days of use. The canister's inhalation capacity should be divided by how many inhalations are used per day. For example, an average pMDI holds 200 inhalations. If the current month has 30 days and a patient began using the inhaler on the first day of the month, taking two puffs twice a day, the following calculation method is used:
* 30 days x 2 puffs x 2 times per day =120 inhalations used
* 200 inhalations in canister 120 inhalations used = 80 inhalations remaining
The problem arises when a patient does not keep a record of the days of inhaler use or uses the inhaler various numbers of times per day. This is a common problem for patients using inhaler devices without built-in dose counters. Alternatively, an attachment called The Doser (MEDITRACK Products, 1999), ordered by a pharmacist, can be placed on top of a pMDI which can track doses used.
Research shows there is no one ideal inhaler device currently available. All inhaler devices require detailed patient instruction. Health care providers should provide stepby-step verbal instruction and written patient education materials. A patient demonstration is necessary with professional feedback about technique. With the varied devices available, many nurses and physicians may lack the expertise to teach proper use of specific inhalers. Each device is accompanied by patient instructions. In addition, some pharmaceutical Web sites provide instructional videos or downloadable materials (see Table 2).
Both persistent asthma and COPD are chronic inflammatory conditions with potential for acute bronchospastic episodes.
Patients should be warned not to spray these medications into the eyes because precipitation of glaucoma can occur.
3M Pharmaoeuticals. (2000). General information about Maxair Autohaler (pirbuterol acetate inhalation aerosol). Patient instructions for use. Retrieved January 1, 2005, from http:// www.3M.com/us/health care/pharma/maxair
Allen, D.B. (2004). Systemic effects of inhaled corticosteroids in children. Current Opinions in Pediatrics, 16(4), 440-444.
American Thoracic Societ\y (ATS). (1995). Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Journal of Respiratory Critical Care Medicine, 152, S77-S121.
Asthma Society of Canada. (2004). How to use your Diskhaler. Retrieved January 1, 2005, from http://www.asthma. ca/adults/ treatmenfdiskhaler
AstraZeneca. (2002). Pulmicort turbuhaler (budesonide inhalation powder). Patient instructions for use. Retrieved January 1, 2005, from http://www.astrazeneca-us.com
Bacharier, L.B., Raissy, H.H., Wilson, L, McWilliams, B., Strunk, R.C., & Kelly, H.W. (2004). Long term effect of budesonide on hypothalamic-pituitary-adrenal axis function in children with mild to moderate asthma. Pediatrics, 113(6), 1693-1699.
Boehringer Ingelheim Pharmaceuticals. (2004). Spiriva HandiHaler ( tiotropium bromide inhalation powder). Retrieved January 1, 2005, from http://www.spiriva.com
Calverly, P.M., & Barnes, P.J. (2000). Are inhaled steroids beneficial in COPD? A pro/con debate. American Journal of Respiratory Critical Care Medicine, 161, 341-344.
Chetta, A., Foresi, A., Del Donno, M., Bertorelli, G., Pesci, A. & Olivieri, D. (1997). Airway remodeling is a distinctive feature of asthma and is related to severity of disease. Chest, 111, 852-857.
Chrischilles, L., Gilden, D., Kubisiak, J., Rubenstein, L., & Shah, H. (2002). Delivery of ipratropium and albuterol combination therapy for chronic obstructive pulmonary disease: Effectiveness of a two-in-one inhaler versus separate inhalers. American Journal of Managed Care, 8(10), 902-911.
Clark, D.J., & Lipworth, B.J. (1997). Adrenal suppression with chronic dosing of flucatisone propionate compared with budesonide in adult asthmatic patients. Thorax, 52(1), 55-58.
Clark, D.J., Clark, R.A., & Lipworth, B.J. (1996). Adrenal suppression with inhaled budesonide and flucatisone propionate given by large volume spacer to asthmatic children. Thorax, 51(9), 941- 943.
Crompton, G.K. (2004). How to achieve good compliance with inhaled asthma therapy. Respiratory Medicine, 98(Suppl. B), S35- S40.
Dempsey, O.J., Wilson, A.M., Coutie, W.J., & Lipworth, B.J. (1999). Evaluation of the effect of a large volume spacer on the systemic bioactivity of flucatisone propionate metered-dose inhaler. Chest, 116(4), 935-940.
Doherty, D.E. (2004). The pathophysiology of airway dysfunction. American Journal of Medicine, 117(Suppl. 12A), 11S-23S.
Elias, J.A., Zhu, Z., Chupp, G., & Homer, R.J. (1999). Airway remodeling in asthma. Journal of Clinical Investigation, 104, 1001- 1006.
Epstein, S., Maidenberg, ?., Hallet, D., Khan, K., & Chapman, K.R. (2001). Patient handling of a dry-powder inhaler in clinical practice. Chest, 120(5), 1480-1484.
Food and Drug Administration (FDA). U.S. Department of Health and Human Services. (1997). FDA talk paper. FDA seek public comment regarding meter dose inhalers containing ozone- depleting propellants. Retrieved December 27, 2004, from http://www.fda.gov/ bbs/ topics/ANSWERS/ANS00789.html
Forest Pharmaceuticals, Inc. (2004). The Aerochamber-plus valved holding chamber. Retrieved February 16, 2004, from http:// www.aerochambervhc.com
Girard, V., & Roche, N. ( 2002). Misuse of corticosteroid metered- dose inhaler is associated with decreased asthma stability. European Respiratory Journal, 19(2), 246-251.
GlaxoSmithKline. (2004a). How to use Serevent Diskus (salmeterol xinofoate inhalation powder). Retrieved January 1, 2005, from at http://serevent.com/usage_ instructions.html
GlaxoSmithKline. (2004b). Advair Diskus instructions (flucatisone propionate 100 meg and salmeterol 50 meg inhalation powder). Retrieved January 1, 2005, from http://advair.com//printables/ asthma_inhaler
Goldberg, S., Einot, T., Algur, N., Schwartz, S., Greenberg, A.C., Picard, E., et al. (2002). Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: Comparison between dry powder inhaler and pressurized metered-dose inhaler attached to spacer. Annals of Allergy, Asthma, & Immunology, 89(6), 566-571.
Guhan, A.R., Cooper, S., Oborne, J., Lewis, S., Bennett, J., STattersfield, A.E. (2000). Systemic effects of formoterol and salmeterol: A dose-response comparison in healthy subjects. Thorax, 55(8), 650-656.
Highland, K.B., Strange, C., & Heffner, J.E. (2003). Long term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Annals of Internal Medicine, 138, 969- 973.
Lippincott, Williams, & Wilkins. (2004). News capsules: Flovent Rotadisk discontinued. Retrieved January 1, 2005, from http:// www.edruginfo.com/nc_ floventrotadiskdiscontinued
McPhee, S.J., Lingappa, VR., Ganong, W.F, & Lange, J.D. (2000). Pathophysiology of disease: An introduction to clinical medicine (3rd ed.). New York: Lange Medical Books/McGraw Hill.
Medical Economics. (2005). Physician's desk reference. Montvale, NJ: Medical Economics.
MEDITRACK Products. (1999). The doser. Retrieved on February 16, 2004, from http://www.doser.com
Melani, A.S., Zanchetta, D., Barbato, N., Sestini, P., Cinti, C., Canessa, P.A., et al. (2004). Inhalation technique and variables associated with misuse of conventional metered-dose inhalers and newer dry powder inhalers in experienced adults. Annals of Allergy, Asthma & Immunology, 93(5), 439-446.
Mirza, N., Kasper Schwartz, S., & Antin-Ozerkis, D. (2004). Laryngeal findings in users of combination corticosteroid and bronchodilator therapy. Laryngoscope, 114(9), 1566-1569.
Molimard, M., Raherison, C., Lignot, S., Depont, R, Abouelfath, A., & Moore, N. (2003). Assessment of handling of inhaler devices in real life: An observational study in 3811 patients in primary care. Journal of Aerosol Medicine, 16(3), 249-254.
Murray, J., Rosenthal, R., Somerville, L., Blake, K., House, K., Baitinger, L., et al. (2004). Flucatisone propionate and salmeterol administered via Diskus compared with salmeterol or flucatisone propionate alone in patients suboptimally controlled with short- acting beta2-agonists. Annals of Allergy, Asthma, & Immunology, 93(4), 351-359.
National Asthma Education and Prevention Program (NAEPP). (2003). Expert panel report: Guidelines for the diagnosis and management of asthma update on selected topics-2002. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health/ National Heart, Lung, & Blood Institute (NIH/NHBLI). Bethesda, MD: National Institutes of Health.
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National Institutes of Health /National Heart, Lung, & Blood Institute (NIH/NHBLI)/ World Health Organization (WHO) Workshop Report. (2003). Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Retrieved January 1, 2005, from http://www.goldcopd.com
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Randolph, C. (2000). Exercise-induced asthma: Pathophysiology, diagnosis, and management for the primary care provider. American Journal of Sports Medicine, 2, 383-394, 399.
Richter, K. (2004). Successful use of DPI systems in asthmatic patients-key parameters. Respiratory Medicine, 98(Suppl. B), S22- S27.
Rodrigo, G.J., & Rodrigo, C. (2000). First-line therapy for adult patients with acute asthma receiving a multiple dose protocol of ipratropium bromide plus albuterol in the emergency department. American Journal of Respiratory Critical Care Medicine, 161(16), 1862-1868.
Rossinen, J., Partanen, J., Stenius-Aarniala, B., & Nieminen, M.S. (1998). Salbutamol inhalation has no effect on myocardial ischaemia, arrhythmias, and heart-rate variability in patients with coronary artery disease plus asthma or chronic obstructive pulmonary disease. Journal of Internal Medicine, 243(5), 361-366.
Rubin, B.K., & Durotoye, L. (2004). How do patients determine that their metered dose inhaler is empty? Chest, 726(4), 1134-1137.
Skrepnek, G.H., & Skrepnek, S.V. (2004). An assessment of therapeutic regimens in the treatment of acute exacerbations in chronic obstructive pulmonary disease and asthma. American Journal of Managed Care, 10(5 Suppl.), S139-S152.
van der Palen, J. (2003). Peak inspiratory flow through diskus and turbuhaler, measured by means of a peak inspiratory flow meter (InCheck DIAL). Respiratory Medicine, 97(3), 285-289.
Wardlaw, A., Larivee, P., Eller, J., Cockcroft, D.W., Ghaly, L., & Harris, A.G. (2004). Efficacy and safety of mometasone furcate dry powder inhaler vs. flucatisone propionate metered-dose inhaler in asthma subjects previously using flucatisone propionate. Annals of Allergy, Asthma, & Immunology, 93(1), 49-55.
Welch, M.J., Nelson, H.S., Shapiro, G., Bensch, G.W., Sokol, W.N., Smith, J.A., et al. (2004). Comparison of patient preference and ease of teaching inhaler technique for Pulmicort Turbuhaler versus pressurized metered-dose inhalers. Journal of Aerosol Medicine, 17(2), 129-139.
Wilson, A.M., Clark, D.J., Devlin, M.M., McFarlane, L.C., & Lipworth, BJ. (1998). Adrenocortical activity with repeated administration of once daily inhaled flucatisone propionate and budesonide in asthmatic adults. European Journal of Clinical Pharmacology, 53(5), 317-320.
Ten Capriotti, DO, MSN, CRNP, RN, is a Clinical Associate Professor, Villanova University, College of Nursing, Villanova, PA.
Copyright Anthony J. Jannetti, Inc. Jun 2005