Module 6 Respiratory Module Content PDF

Unit A: Allergic Rhinitis, Cough, and Upper Respiratory Infection (URI) Upper Respiratory Infection/Illness Antihistamines/Histamine-1 Receptor Antagonists The H1 receptor antagonists are broken down to 1st generation antihistamines and 2nd generation antihistamines. Antihistamines will not...

Unit A: Allergic Rhinitis, Cough, and Upper Respiratory Infection (URI) Upper Respiratory Infection/Illness Antihistamines/Histamine-1 Receptor Antagonists The H1 receptor antagonists are broken down to 1st generation antihistamines and 2nd generation antihistamines. Antihistamines will not treat the cause of rhinorrhea and sneezing with a cold, as symptoms are not related to an allergen. Their secondary effect (the anticholinergic side effect of antihistamines) may provide relief by drying the mucous membranes and nasal secretions. H1RAs bind selectively to H1 -histaminic receptors, thereby blocking the actions of histamine at these sites. H1-antagonists do not block H2 receptors or the release of histamine from mast cells or basophils. They don't prevent histamine release, but instead, they act by competitively inhibiting its binding. Antihistamines target the following symptoms of a cold: itching, sneezing, ocular symptoms, and nasal discharge, but remember, it's their anticholinergic effects versus their antihistamine effects. If the concentration of the antihistamine drugs at the receptor site exceeds the concentration of histamine, then the effects of histamine are blocked. Why do antihistamines have anticholinergic effects? The H1-antihistamines have been available for more than 60 years and were synthesized based on a chemical structure similar to that used to develop cholinergic muscarinic antagonists, tranquilizers, and antihypertensive agents. These antihistamines have low receptor specificity and interact with both peripheral and central histamine receptors and readily cross the blood-brain barrier. This leads to significant central nervous system side effects, including sedation, drowsiness, somnolence, fatigue, cognitive decline, psychomotor effects, and loss of coordination. These antihistamines are potent muscarinic receptor antagonists too. This can lead to serious anticholinergic side effects, such as sinus tachycardia, dry skin, dry mucous membranes, dilated pupils, constipation, ileus, urinary retention, and agitated delirium. The mnemonic "blind as a bat, dry as a bone, red as a beet, mad as a hatter, and hot as a hare" often is used to help describe and identify patients suffering from anticholinergic effects. 1st generation antihistamines: 1st generation antihistamines have a relatively quick onset of action of about 15 minutes to 30 minutes. With regular use, tolerance or drug failure occurs after several weeks to months. This is because antihistamines can induce the production of hepatic enzymes that actually break them down (they help with their own destruction). Use caution in narrow-angle glaucoma: antihistamines can increase intraocular pressure. These medications have the potential to narrow the drainage angle of the eye, preventing eye fluid from exiting properly and resulting in high eye pressure. Also, be cautious in patients with benign prostatic hypertrophy/hyperplasia, as antihistamines can decrease urine flow. The elderly are particularly susceptible to anticholinergic effects. The older or 1st generation crosses the blood- brain barrier, hence the sedative effects. As these drugs block the histamine receptors (remember, they are located in the central nervous system), they also end up slowing down neuronal firing and the production of neurotransmitters, resulting in sedative effects. The sedation can lead to impaired learning and memory; use sparingly if at all.  2nd generation antihistamines act peripherally, so these H1 receptor blockers are less sedating. Why don't the 2nd generation of antihistamines exert sedative effects? These drugs are large molecules, have low lipid solubility, and can't cross the blood-brain barrier. They have a low affinity for the histamine receptors in the brain. If they do cross the blood-brain barrier, it is in negligible amounts. The only exception is cetirizine/Zyrtec, as it's the one 2nd generation with a long half-life and sedative effects. Be cautious recommending in those for whom sedation could impair their functioning (e.g., pilots). As a class, the onset is about 1-2.5 hours. To reach a steady-state, it takes 1-3 days, but food can impair their absorption. The 2nd generation H1 receptor antagonists are generally well-tolerated, but a headache, dry mouth, dyspepsia, nausea, and fatigue may occur. Fexofenadine (Allegra) may interact with antifungals, causing concentrations of this antihistamine to become increased. Fexofenadine (Allegra) can also prolong QT intervals if combined with other drugs that prolong the QT interval. More on Antihistamines: Oral antihistamines reduce rhinitis, sneezing, and itching but have minimal effect on nasal congestion. They provide relief of urticaria and angioedema in about 70% of patients and are more effective for prevention rather than the reversal of histamine effects. One common effect of this first-generation antihistamine in children is a paradoxical reaction where instead of somnolence, the child exhibits hyperactivity. Remember, first-generation antihistamines should be avoided in the elderly due to potential side effects. The second-generation antihistamines are more selective for peripheral H1 receptors and cause less sedation, as they do not cross the blood-brain barrier. However, use caution with cetirizine (Zyrtec), as it does cause some sedation, as compared to the other second-generation agents. Avoid in pilots or those requesting non-sedating options. Cough and Cold Medications These are often combination products, typically with acetaminophen or ibuprofen, a decongestant, an antihistamine, a cough suppressant and/or a cough expectorant. They can also contain alcohol. Caution patients and provide the necessary education. This would include the risks of too much acetaminophen (Tylenol) on the liver, oral decongestants and hypertension, antihistamines and sedation, and possibly alcohol and its risk of causing sedation and/or cognitive concerns. Be sure to check labels and educate your patients to check labels to make sure they are getting only what product they need. Provide education on the safety concerns with driving or operating heavy machinery. Parents with young children should be advised to use only single rather than combination products. This is also true during pregnancy and lactation. The rationale for this is four-fold: choosing single agent products helps to lessen the risk of overdosing, each ingredient can be dosed separately based on age and weight, it avoids giving an unnecessary medication, and if a reaction to medication were to occur, it'd be much easier to determine the offending agent. Recent studies have demonstrated that cough and cold medicines (CCMs) are often unsafe in the pediatric population. Many have been removed from the market. Check the labeling. It is recommended by the FDA that OTC products not be used in those under the age of 2. Nasal Decongestants: There is little evidence supporting their efficacy. These drugs are vasoconstrictors and relieve nasal congestion by constricting the blood vessels of the nasal mucosa that has been dilated by histamine. They are sympathomimetic amines, chemically similar to norepinephrine. Formulations are oral or topical (aka nasal formulation). Nasal decongestants are available over-the-counter, but often they are combined with other agents such as antihistamines, pain relievers, or caffeine--just to name a few. They can also help the nasal congestion associated with allergic rhinitis by acting on adrenergic receptors, which cause vasoconstriction in the nasal mucosa, decreasing inflammation. The adverse effects can include sneezing, nasal dryness, and rebound nasal congestion (aka rhinitis medicamentosa). They are not recommended for more than three days because patients may develop rhinitis medicamentosa or may have a rebound or recurring congestion. Oral Decongestants: These activate alpha1-adrenergic receptors, leading to vasoconstriction of the nasal blood vessels, which may help relieve congestion. These medications' side effects can be a little more significant. There are numerous side effects, including elevated blood pressure and heart rate, insomnia, and palpitations. Avoid in hypertension, arrhythmias, and in patients with sleeping problems. If you are unsure of how the client will respond to oral decongestants, it is best to use the over-the-counter formulations, as these have shorter-duration products. Antitussives: For example, codeine, dextromethorphan, and diphenhydramine are agents that prevent or relieve a nonproductive cough. However, evidence still does not indicate their effectiveness in suppressing cough associated with the common cold. Cough suppression should be used only when the client has a nonproductive cough or for rest at night (and only if needed). Opioids should be avoided in patients with chronic obstructive pulmonary disease or a history of substance abuse. Opioids may provide optimal cough suppression. Relief from dextromethorphan (Robitussin), the principal ingredient in most over-the-counter cough medication, can be found as a single agent (but it requires time to look for it, as it is often combined with other products). Benzonatate (Tessalon Perles) may be helpful for minor nonproductive coughs for individuals for whom dextromethorphan does not work or for whom opioids may not be prescribed. Expectorants: Expectorants are meant to thin secretions and make them more fluidic to increase the effectiveness of cough (e.g., guaifenesin). Encourage increased consumption of fluids for increased effectiveness. These can be helpful for a productive cough, especially in the first few days. Allergic Rhinitis Now, regarding the medications used to treat the symptoms associated with allergic rhinitis, think of them as two ma jor groups of medications, the controllers and the relievers. The controllers are prescribed to help keep the symptoms at bay, "to control them." The relievers will relieve the more acute symptoms. Of course, allergen avoidance is always recommended. Immunotherapy is an option as well. Allergic Rhinitis Issue Intervention Comment Allergen avoidance/environmental Education on ways to lessen Educate 1st control exposure. e.g., fluticasone propionate (Flonase) e.g., montelukast (Singulair) - There Controller therapy (prevent Intranasal corticosteroids (high is some concern with the use of symptoms by decreasing efficacy). Singulair to manage Allergic Rhinitis inflammatory mediators Leukotriene modifiers because of neuropsychiatric effects (risk vs benefits) 2 nd generation oral antihistamines Reliever therapy relieves acute Intranasal antihistamines (great for e.g., loratadine (Claritin) symptoms by blocking the action of nasal symptom relief) e.g., azelastine (Astelin) histamine (a potent inflammatory Ocular antihistamines (work great for e.g., Olopatadine (Patanol) mediator). allergic conjunctivitis) Immunotherapy- restores tolerance For patients with allergic rhinitis who Usually requires a consult with a to an allergen by reducing its have an inadequate response to specialist, delivered via SQ or SL tendency to induce IgE production. symptoms with standard therapies routes. Anti-Histamines Intranasal Antihistamines These have a rapid onset of action and may aid in reducing nasal congestion. Offer intranasal antihistamines (in patients > 5 years old) as an alternative or additional first-line therapy for allergic rhinitis. Consider a combination of intranasal corticosteroids and intranasal antihistamines for moderate to severe nasal symptoms of seasonal allergic rhinitis. There is evidence that higher nasal tissue levels achieved by intranasal administration lead to anti-inflammatory effects as well. Intranasal antihistamines compete with histamine for H1-receptor sites and inhibit the release of histamine and other mediators involved in the body's allergic response. When used intranasally, they reduce hyper- reactivity of the airways too. They can cause the adverse effects of sedation and bitter taste. The sedative effects are less than with oral antihistamines. Leukotriene modifiers This class inhibits the action of leukotrienes, some of the other inflammatory mediators that are released by eosinophils and mast cells. Leukotrienes act primarily to cause nasal congestion, airway constriction (a narrowing of the airways), increased mucus production, swelling and inflammation in the lungs. So, the leukotriene modifiers work by decreasing smooth muscle constriction of the vessels, decreasing blood vessel permeability, and decreasing the inflammatory response. This class is the most effective when taken at bedtime. It may take several days to see a benefit with this class of medications. These agents are great add-ons after second-generation antihistamines and intranasal steroid sprays. They are less effective than intranasal steroids, and there is only modest improvement when taking this class of medication as a monotherapy agent. By blocking these leukotrienes, the symptoms of nasal congestion are relieved. You will usually see more improvement in symptom control when used as add-on therapy. There are two agents that are approved for the treatment of allergies: Montelukast (Singulair) and zafirlukast (Accolate). We will focus on montelukast (Singulair). Montelukast (Singulair) has a Black Box Warning about the potential risk of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking, and behavior (including suicide), and tremor. While the precaution was extended to all agents in this class, particular concern has been raised about montelukast due to its widespread use in both adult and pediatric patients for multiple indications. Montelukast is approved for the chronic treatment of asthma, acute prevention of exercise-induced bronchial constriction, and relief of both perennial and seasonal allergic rhinitis symptoms. Singulair is approved for adults and children six months of age and older. This is different than the age of approval for Singulair in asthma. For asthma, the approval of Singulair is for 12 months and older (this can also vary by the resource used). Educate patients about these risks and document their understanding. Singulair can be very effective, but we must educate our patients accordingly. Nasal Corticosteroids These medications interrupt inflammation by suppressing the synthesis of histamine as well as other inflammatory mediators. The inflammatory mediator blockage is very important. These medications must be used daily in order to build up the barrier to block the allergic cascade. Offer intranasal corticosteroids, as they are the most effective treatment for allergic rhinitis. Intranasal corticosteroids are most effective when given continuously but can be used on an as-needed basis. They are very effective in preventing allergy symptoms. Because it takes approximately five days for intranasal steroids to develop an effective barrier in the nares to prevent allergy symptoms, recommend an oral antihistamine for the first five days of use. If the patient has intermittent symptoms, then use antihistamines as a barrier that cannot be built up successfully. If, however, the patient has seasonal or perennial allergic rhinitis, then the daily use of a nasal steroid should prevent allergy symptoms. The most common cause of the lack of efficacy of intranasal steroids is improper usage. A recent study identified four factors that prevent efficacy: not using it on a daily basis, inserting the tip of the spray bottle deep into the nares (the tip should be at the entrance of the nares), not following the angle of the nose with the tip of the spray bottle, and not depressing the plunger completely so that the patient is not receiving a full dose. Some providers may give the patient a five-day course of prednisone, called a prednisone burst (the same dose once a day for five days) for immediate relief if the patient has tried multiple antihistamines without success and is miserable. This provides symptom relief for five days while the nasal steroid builds up the invisible barrier. Unless essential, oral prednisone should not be given if the patient is diabetic due to steroids elevating blood sugar. Intranasal Cromolyn Intranasal Cromolyn is less effective than intranasal corticosteroids. They inhibit histamine release and suppress inflammation. These are good alternatives for patients who are not candidates for corticosteroids. Most effective when regularly used prior to the onset of allergic symptoms. However, it requires frequent dosing, 3-4 times/day, limiting its use. Allergic Conjunctivitis Ocular allergy is underdiagnosed and has a significant impact on the life of the patient. The combination of allergic conjunctivitis and allergic rhinitis is termed rhinoconjunctivitis. The symptoms can be seasonal or perennial. Eyes are itchy (75% of patients report itching), and the inner canthus may be red and itchy, tearing, swollen eyelids, redness, and conjunctival inflammation. Ocular administration of mast cell stabilizers, antihistamines, or dual-action medications are considered first-line therapies. Consider referral to an ophthalmologist in patients with significant comorbidities, if corticosteroids are needed, or if new ocular symptoms develop. Naphazoline/pheniramine (Naphcon-A, Opcon-A) Naphazoline is a decongestant and pheniramine is an anti-histamine. This is available over the counter and is quite effective. It is not indicated for children under age 6. Olopatadine (Patanol/Pataday) is an ocular antihistamine. It is available only by prescription and can be quite expensive. Patanol is approved for children three years of age and older. Pataday is approved for children two years of age and older. Pregnancy and Lactation During pregnancy, patients are more prone to colds, infections, and allergies due to hormonal and immunological changes. First, recommend non-pharmacologic treatments such as rest, hydration, a diet high in fruits and vegetables, and saline nasal spray or washes. Remind pregnant patients that colds are usually short-lived and that it is safest to avoid medications in the first trimester if possible. When more relief is needed than what can be obtained from non-pharmacologic methods, treat the specific complaint and prescribe a single medication to target that symptom. Avoid drugs that are combination, long-acting, extended-release, or contain alcohol. Most over-the-counter medications have several drug components—especially cough, cold, and allergy products, which frequently contain a combination of decongestants, antihistamines, expectorants, corticosteroids, analgesics, and other active ingredients. Also, note that many sore throat sprays and lozenges contain soothing agents, antiseptics, and anesthetics—some of which are contraindicated in both pregnancy and lactation. When recommending pharmacologic treatment for the common cold or URI, treat specific symptoms and, again, avoid combination treatments. Intranasal Corticosteroids  Nasal corticosteroids are likely the most effective agent for allergic rhinitis and are often considered first-line during pregnancy. Budesonide [Rhinocort] is the only corticosteroid that is in pregnancy category B. Data is available on use in the first trimester only; however, given Rhinocort's safety profile in the gestational period of greatest concern, this is reassuring. In addition, nasal corticosteroids overall are considered safe in pregnancy due to their high first-pass hepatic uptake and low maternal systemic absorption—amounts absorbed into the bloodstream are probably too small to affect a fetus. Beclomethasone (Beconase AQ) and intranasal cromolyn sodium (NasalCrom) also have good evidence for effectiveness and safety with use during pregnancy. The use of these medications during lactation is also probably safe. As with adult dosing, systemic availability after maternal inhalation is low. Beclomethasone, Flonase, and Nasonex are all category C, and safety in lactation is unknown. As with Rhinocort, characteristics such as poor oral bioavailability and rapid first-pass hepatic uptake will likely result in low to insignificant amounts of infant exposure. Oxymetazoline (Afrin and an active ingredient in common OTC nasal preparations), xylometazoline (Novorin, Sinutab nasal spray), and naphazoline are pregnancy category C, possibly unsafe in lactation, and should be avoided. Oxymetazoline may reduce milk supply. Antihistamines Many pregnant patients experience worsening allergies during pregnancy. Unless sedation is an issue, start with the older, sedating, first-generation antihistamines since they have been the most widely studied in pregnancy. Studies show Chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl), and doxylamine (Unisom SleepTabs) do not have teratogenic effects and can relieve symptoms of both watery eyes and rhinorrhea. Begin with chlorpheniramine. This drug has a high safety profile and has been on the market the longest of any antihistamine. If used in small, occasional doses, small amounts of diphenhydramine or chlorpheniramine are considered safe for breastfeeding. However, large doses or prolonged use may cause infant sedation and a reduction in milk supply, especially if combined with a sympathomimetic (such as Sudafed). It is preferable to start with the 2nd generation, non-sedating antihistamines with breastfeeding, especially with a newborn or premature infant. When appropriate, instruct the mother to take a single dose at bedtime after the last breastfeeding session of the day or, if during the day, before the infant's longest sleep period. Cetirizine (Zyrtec) Cetirizine (Zyrtec) a 2nd generation antihistamine has not been associated with teratogenicity in any trimester and small, occasional doses are likely harmless with breastfeeding. Similar to loratadine, cetirizine may decrease milk supply, especially if combined with a sympathomimetic (such as pseudoephedrine). Prescribe at the lowest dose, after a feeding, and before the infant's longest sleep period. The British Society for Allergy and Clinical Immunology recommends cetirizine at the lowest dose for the shortest period of time as the first-line antihistamine with lactation. Doxylamine  Doxylamine is a tried and true medication known for its safety in pregnancy. However, use with breastfeeding is possibly unsafe. With a similar structure to Benadryl, doxylamine likely passes into breast milk and may cause sedation and paradoxical CNS stimulation. Levels have not been measured, and no human studies are available. It is preferable to choose a safer, non-sedating antihistamine for use with lactation, such as the 2nd generation antihistamines mentioned above. Use with caution, especially for infants with respiratory disorders. Antitussives You will find mixed information on the fetal effects associated with codeine (category C). Some sources claim safe to use during pregnancy, while others report that first-trimester use is associated with fetal malformations. Remember that all opioids pass through the placental barrier. This is a classic example of a prescribing challenge: you must learn the reasons why codeine is a category C medication and be able to relay this in a manner that the patient can understand. She can then make an informed choice. A pregnant patient may decide to try a cold and cough preparation that contains codeine if the cough is having a significant impact on her well-being (such as sleep deprivation). During breastfeeding, the use of any narcotic can cause infant drowsiness and sedation. Newborns are especially sensitive to even small amounts of narcotic analgesics, and their behavior must be monitored closely. Recall the section in pharmacogenomics featuring the mother with ultrarapid CYP2D6 metabolism and infant overdose with maternal codeine use. If other analgesics have failed, prescribe the smallest dose possible and for the shortest amount of time – preferably for no more than four days. Time dosages and feedings for the least exposure possible. Instruct the mother to monitor weight gain and warning signs of sedation such as drowsiness, breathing difficulties, and decreased interest in feeding. The AAP considers codeine to be compatible with breastfeeding. Both guaifenesin and dextromethorphan are pregnancy category C. Guaifenesin in the first trimester may be associated with birth defects. For non-pregnant and pregnant patients alike, antitussives are known to be ineffective; therefore, it is best to avoid use in pregnancy due to unknown side effects and potential risks. Neither the excretion of guaifenesin in milk nor its effect on breastfed infants has been studied. This medication is used in infants as young as two months; therefore, infant exposure from maternal intake is likely much smaller than when given directly. Even so, since effectiveness is questionable, it is best to completely avoid the medication and any possible risks. Similarly, studies are not available on dextromethorphan's presence in milk or its effect on infants. However, it is given to infants at one month. As with guaifenesin, infant exposure from the maternal intake is likely much smaller than when given directly. Overall, recommended against medications known to be ineffective. Decongestants Decongestants are not considered first-line for rhinitis in pregnancy. However, if non-pharmacologic and other methods are ineffective, decongestants may be used for acute congestive episodes. To relieve the acute onset of symptoms, use for short periods only, preferably less than three days. Start with nasal routes of administration instead of oral. Oxymetazoline nasal spray (Afrin®), category C, is a good first-line but should be used for no more than three days consecutively due to the potential of rebound congestion. While data is limited, adverse effects have been noted in case reports only. Normal amounts for short-term use appear to be safe in pregnancy. Pseudoephedrine (Sudafed®) is also category C. Although not confirmed, Sudafed is associated with an increased risk of gastroschisis with first-trimester use but is considered safe in the 2nd and 3rd trimesters; avoid use in the first trimester. Pseudoephedrine likely reaches the breastmilk in small amounts but may cause occasional irritability. Pseudoephedrine has decreased milk production with as little as one dose. Pregnant women who use Sudafed during pregnancy should be cautioned about this potential risk and counseled on strategies to help maintain their milk supply. The American Academy of Pediatrics (AAP) cautions against the use of pseudoephedrine because of the potential to interfere with lactation. Data is mixed on Phenylephrine (Neo-Synephrine, Sudafed PE, AH-CHEW D, Rhinall): some sources consider this class safe, while others claim these meds may cause fetal hypoxia. In healthy pregnancies, in which uteroplacental sufficiency is not an issue, short-term use is likely safe. The safety of oxymetazoline (Afrin®) and pseudoephedrine use during lactation is unknown. Information on oxymetazoline during breastfeeding is unavailable; however, very little should reach the infant through breastmilk with nasal administration and limited absorption into the maternal bloodstream. Consider the use of nasal oxymetazoline before oral- systemic decongestants (such as Sudafed). BBW: Review the drugs in this module that have a BBW - for example Singular Don't Forget the QT Review the drugs in this section that may affect the QT - for example, Benadryl, Afrin, & Sudafed (crediblemeds.org) Unit B: Asthma and COPD Asthma Guidelines to Follow There are 2 main bodies that provide treatment recommendations for asthma. These include 1) the Global Initiative for Asthma (GINA) and 2) the Guidelines for the Diagnosis and Management of Asthma (EPR-4), which comes from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. In recent years, the GINA guideline broke away from the EPR and recommended some of the biggest changes in asthma management in over 50 years. However, GINA states that they are not guidelines, but rather, are integrated evidence-based strategies focusing on translating the evidence into clinical practice. The National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 4 (EPR-4) Guidelines for the Diagnosis and Management of Asthma is the preferred guideline for the care of individuals with asthma.Educate about the use of Inhalers - Assess - Have your patients bring in their medications to review the proper techniques. The 2-Pronged Approach Think of treating asthma as using a two-pronged approach. First and foremost, you must bronchodilate the lungs (and it must be accomplished rather quickly). This can be done with a short-acting beta-agonist (quick onset) or the one long-acting beta-agonist Formoterol (as this long-acting beta-agonist has a rapid onset too, but then the benefit of longer duration). And to a lesser extent, short-acting muscarinic agents. The second part of the prong is decreasing inflammation. This is crucial and is typically done with inhaled corticosteroids. Asthma is classified based on symptoms. The classes include mild intermittent, mild persistent, moderate persistent, and severe persistent. Asthma Medications Relievers These medications are provided to all patients with asthma for “as-needed relief” from the acute, breakthrough symptoms of asthma or from the symptoms of an asthma exacerbation. These agents include short-acting beta-2 agonists (SABAs), short-acting muscarinic agents (SAMAs), and oral corticosteroids. Controllers/Maintenance These medicines prevent and control symptoms by decreasing airway inflammation, controlling symptoms, and reducing future risks. The controllers include the inhaled corticosteroids, leukotriene modifiers, and or the inhaled corticosteroids combined with the long-acting beta-2-agonists. Beta-2 agonists Beta-2 agonists: These promote smooth airway muscle relaxation. The inhaled beta-agonists include the rescue drug, a short-acting beta-agonist (SABAs) called albuterol (ProAir HFA), and long-acting beta-agonists (LABAs) such as salmeterol (Serevent) or formoterol (Perforomist). The long-acting beta-agonists are used to achieve sustained bronchodilation and are classified as maintenance drugs; but in asthma use the long-acting beta2 agonists only in combination with an inhaled corticosteroid, not as monotherapy. The short-acting beta2 agonists are the “quick” reliever medications. However, they speed things up quickly; the side effects are nervousness, shakiness, tremors, and palpitations. In patients with cardiovascular disease, beta2-agonists may increase the risk of arrhythmias. Albuterol has been determined to be an agent that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction. Beta-2 agonists may also produce changes in ECG, hence prolonging the QT interval. Use with caution in patients with diabetes mellitus as beta2-agonists may increase serum glucose levels and aggravate preexisting diabetes and ketoacidosis. In patients with glaucoma, these drugs may elevate intraocular pressure. Oral corticosteroids Oral corticosteroids: Short-term therapy with oral prednisone may be necessary for asthma treatment depending on the severity of the symptoms. Steroids are typically given in short “bursts” in asthma exacerbations. This may be done in conjunction with starting an inhaled glucocorticoid; to give coverage until the inhaled corticosteroid can kick-in. Once doses are much higher (typically >40 mg--although doses as low as 20 mg in smaller more frail patients), a taper may be required if taken longer than 10-14 days. A dose of 40 mg for five days in an adult is a great burst and does not typically require a taper. Headaches, dizziness, trouble sleeping, inappropriate happiness, severe mood swings, hyperglycemia, and bone loss are all potential side effects of the corticosteroids. Adrenal suppression is seen with oral corticosteroid use, typically at high doses for extended amounts of time. This risk is an increased occurrence in young children. Ultimately, the suppression of the hypothalamic-pituitary axis may lead to an adrenal crisis. To help lessen the risk, the withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Adult patients receiving doses as low as 20 mg per day of prednisone (or equivalent) may be susceptible, especially if taken for more than 14 days. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids. Aerosol steroids do not provide the amount of systemic steroids needed to treat patients having trauma, surgery, or infections. Select surgical patients on long-term, high-dose, inhaled corticosteroids should be given stress doses of hydrocortisone IV during the surgical period and the dose reduced rapidly within 24 hours after surgery. Immunosuppression. Prolonged use of corticosteroids may increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to killed or inactivated vaccines. Exposure to chickenpox or measles should be avoided. Corticosteroids should not be used to treat viral hepatitis or cerebral malaria. Close observation is required in patients with latent tuberculosis (TB) and/or TB reactivity; restrict use in active TB (only fulminating or disseminated TB in conjunction with antituberculosis treatment). Kaposi sarcoma. Prolonged treatment with corticosteroids has been associated with the development of Kaposi sarcoma; if noted, discontinuation of therapy should be considered. Myopathy. An acute myopathy has been reported with high-dose corticosteroids, usually in patients with neuromuscular transmission disorders; may involve ocular and/or respiratory muscles. Psychiatric disturbances. Corticosteroid use may cause psychiatric disturbances, including euphoria, insomnia, mood swings, personality changes, severe depression or frank psychotic manifestations. Preexisting psychiatric conditions may be exacerbated by corticosteroid use.  Cardiovascular disease. Use with caution in patients with heart failure and/or hypertension; long-term use has been associated with electrolyte disturbances, fluid retention, and hypertension. Use with caution in patients with a recent history of myocardial infarction. Diabetes. Use corticosteroids with caution in patients with diabetes mellitus; they may alter glucose production/regulation leading to hyperglycemia. Gastrointestinal disease. Use with caution in patients with GI diseases (diverticulitis, peptic ulcer disease, ulcerative colitis) due to perforation risk. FYI: Dosing. Short-term therapy with oral prednisone may be necessary for asthma treatment depending on the severity of the symptoms. Steroids are typically given in short “bursts” in asthma exacerbations. This may be done in conjunction with starting an inhaled glucocorticoid; to give coverage until the inhaled corticosteroid can kick in. Once doses are much higher (typically >40 mg--although doses as low as 20 mg in smaller more frail patients), a taper may be required if taken longer than 10-14 days. A dose of 40 mg for 5 days in an adult is a great burst and does not typically require a taper. Headaches, dizziness, trouble sleeping, inappropriate happiness, severe mood swings, hyperglycemia, and bone loss are all potential side effects of the corticosteroids. Taking NSAIDs while on systemic corticosteroids greatly increases the risk of GI bleed. Inhaled Corticosteroids: Inhaled corticosteroids pose the same side effects as oral steroids, but often at a much lower rate. These drugs are the mainstay of maintenance therapy. Asthma is a process of inflammation in addition to bronchoconstriction and addressing both facets is crucial. Because inhaled glucocorticoids do not provide immediate relief of bronchoconstriction, they should not be used alone for someone experiencing acute asthma symptoms. Steroids may be given by inhaler, nebulizer, or systemically (oral or IV). There are many different glucocorticoid inhalers available. Advair is used quite commonly in asthma because it combines a long-acting B2-agonist Salmeterol with the steroid fluticasone and is an inhaled powder. Many people find Advair’s Diskus system of inhaled medication simpler to use correctly than the aerosol MDIs. However, the individual must be able to inhale deeply in order to achieve the desired benefit. Concerns with inhaled corticosteroids. Growth tra jectories and the use of steroid inhalers in the pediatric population can be a concern for parents. There have been mixed reports on the long-term effect of inhaled steroids on the height of children with asthma. Research demonstrates that there is a reduction in growth velocity in the first year of using ICS. The good news is that the growth velocity returns to normal and this delay in the first year of usage does not impact height as an adult. Additionally, bone loss is a risk with prolonged high-dose inhaled steroids, so teach your patients other ways to help fight the potential loss (calcium and vitamin D supplementation, weight-bearing exercise, and not smoking). Use with caution in patients with cataracts and/or glaucoma. The increased intraocular pressure can significantly worsen or increase the patient’s risk for these conditions. Please consider routine eye exams in chronic users.  Discontinuation of therapy. A gradual tapering of the inhaled steroid dose may be required prior to discontinuing therapy, especially for patients on high-dose inhaled corticosteroids. There have been reports of systemic corticosteroid withdrawal symptoms when withdrawing oral inhalation therapy. Local oropharyngeal Candida infections have been reported; if this occurs, treat appropriately while continuing the inhaled corticosteroid therapy. Patients should be instructed to rinse the mouth with water without swallowing after each use. Prolonged use of inhaled and oral corticosteroids may increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit the response to vaccines. Mast cell stabilizers Mast cell stabilizer comes in an intranasal formulation, optical, and oral formulations. Cromolyn sodium (Intal, Nasalcrom) are examples. Mast cell stabilizers are anti-inflammatory agents that prevent bronchoconstriction. They block the release of histamine and SRS-A (the slow-reacting substance of anaphylaxis) from sensitized mast cells. This class takes several weeks for full effect but can be used for both allergies and asthma. This class helps by preventing the mast cell from releasing histamine, leukotrienes, and the slow-reacting substance of anaphylaxis. Mast cell stabilizers prevent bronchoconstriction that manifests early or late in response to the inhaled antigen. It comes in several formulations including nasal, oral, and inhalation. Cromolyn suppresses inflammation and it should not be used for acute symptoms, but rather for prophylaxis in asthma. It requires dosing three to four times a day and there are more effective agents. Side effects can include headaches, nasal irritation, cough, and bronchospasms. Antileukotrienes Leukotriene Receptor Antagonists (LTRAs) and Leukotriene Synthesis Inhibitors. The antileukotrienes are used as controller medications (they do not help with acute symptoms). They can be used for the prevention of exercise- induced bronchospasm, an alternative to ICS in asthma management, in asthma-exacerbated respiratory disease, and in allergic rhinitis management. Zafirlukast (Accolate) and montelukast (Singulair) are the LTRAs and zileuton (Zyflo) is a leukotriene synthesis inhibitor. The LTRAs bind to cysteinyl leukotrienes (CysLT) type-1 receptors found in the human airway (smooth muscle cells and macrophages), which prevents airway edema, smooth muscle contraction, and other respiratory inflammation. The leukotrienes are also released from the nasal mucosa after allergen exposure. Montelukast sodium may inhibit symptoms of allergic rhinitis. So, if you block or antagonize the receptors, you are blocking the inflammatory cascade (well, at least one of the many pathways). The leukotriene inhibitor zileuton is a selective inhibitor of 5-lipoxygenase, which is the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits the formation of leukotrienes; inflammatory mediators. With Zileuton, monitor liver function tests at baseline, monthly for 3 months, every 2-3 months for the first year, then periodically. Contraindications include active liver disease or serum aminotransferase concentrations ≥ 3 times the upper limit of normal. Life-threatening drug interactions may occur with propranolol, theophylline, or warfarin.  Zafirlukast (Accolate) may be used in children 5 years of age and older while montelukast (Singulair), may be used in children as young as 12 months. (This is different from the age of approval for Singulair in allergies. For asthma, the approval of Singulair is for 12 months and older. This can also vary by resource used). Singulair has a boxed warning, as you learned in the allergy section, but it is worth mentioning again. The boxed warning of psychiatric disturbances including agitation, aggressive behavior or hostility, anxiousness, depression, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behaviors, and tremor can occur. Please educate and then document the patient’s understanding of education. The leukotriene receptor antagonists (LTRAs) montelukast and zafirlukast are alternatives to a low-dose ICS for patients who are unable or unwilling to use an ICS. Leukotriene modifiers are less effective than ICSs for asthma control (ICS are much more effective). LTRAs are also generally less effective than inhaled LABAs as add-on therapy in patients whose asthma is not well controlled on an ICS alone. The 5-lipoxygenase inhibitor zileuton causes more adverse effects than LTRAs and is generally reserved for use as add-on therapy in severe asthma. Short and long-acting muscarinic antagonists (SAMAs and LAMAs) Acetylcholine binds to muscarinic receptors to play a key role in the pathophysiology of asthma, leading to bronchoconstriction, increased mucus secretion, inflammation and airway remodeling. Anticholinergics (the SAMAs and the LAMAs) are muscarinic receptor antagonists that are used in the treatment of chronic obstructive pulmonary disease and asthma. The SAMAs/LAMAs, by blocking the binding of acetylcholine to the muscarinic receptors, cause bronchodilation, decreased mucus, and less airway inflammation. The inhaled LAMA, tiotropium bromide, is FDA-approved for the maintenance treatment of asthma in patients ≥6 years old. In patients with moderate to severe asthma, adding tiotropium to an ICS improves lung function and modestly decreases symptoms and the risk of exacerbations. Other inhaled LAMAs are also effective for the treatment of asthma. The three-drug inhaler containing the ICS fluticasone furoate, the LAMA umeclidinium, and the LABA vilanterol (Trelegy Ellipta), previously approved for use in COPD, is now also FDA-approved for maintenance treatment of asthma in adults.* Methylxanthines The methylxanthines theophylline (Theodur) has been used in the past for the treatment of asthma but is less commonly used now because of better alternatives and the many side effects associated with theophylline therapy. Toxicity can be a concern (often toxic levels are reached before methylxanthines is effective). The monitoring lessens its usage, as it checks blood levels of 12-15 mg/dl is expected. The multiple drug interactions macrolides, quinolones, cimetidine, and anticonvulsants. The side effects are stomach upset, heartburn, trouble sleeping, headache, nervousness or irritability, rapid heart rate, and rapid breathing. In terms of treating chronic obstructive pulmonary disease, the use of theophylline is controversial and lacks data. Theophylline may favorably impact functional impairment, but the exact effects are unclear. Theophylline is not a preferred agent for COPD exacerbations due to its potential for toxicity. The availability of safer alternatives has significantly reduced the use of theophylline for persistent asthma. It is occasionally used in patients whose asthma is not controlled with an ICS and a LABA. Monitoring serum theophylline concentrations is recommended to maintain peak levels between 10 and 15 mcg/mL Long-acting beta2-agonists Salmeterol (Serevent) is a long-acting beta-2 agonist that is often added to an inhaled corticosteroid fluticasone and together, this is the drug Advair. As mentioned above, this comes in a purple diskus for long-acting control of bronchoconstriction as well as the anti-inflammatory effects of the inhaled steroid. The long-acting beta-2 agonists are often used as monotherapy agents in the treatment of chronic obstructive pulmonary disease, but not for patients with asthma as monotherapy agents. Black Box Warning: Do not use it as a monotherapy agent in asthma. This leads to a greater risk of asthma-related deaths. The use of long-acting beta-2 agonists for the treatment of asthma as monotherapy without a concomitant inhaled corticosteroid is contraindicated. A second boxed warning with the long- acting beta-2 agonists as monotherapy agents is the increased risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require the addition of a long-acting beta-2 agonist to an inhaled corticosteroid, a fixed-dose combination product containing both should be used to ensure adherence with both drugs. The side effects include rapid heartbeat or palpitations, headache, dizziness, nausea, vomiting, diarrhea, anxiety, and tremor. Additionally, salmeterol has been shown to prolong the QT interval. Monoclonal Antibodies The concern with monoclonal antibodies is the risk for immune-type reactions (whenever you see something that deals with the immune system, think of the possibility of immune reactions). These reactions can include vasculitis, eosinophilia, and hypersensitivity reactions such as urticaria, and conjunctivitis. Examples of Monoclonal antibodies: Anti-IgE Antibody, omalizumab (Xolair); IL-5 Receptor Antagonists; reslizumab (Cinqair); and IL-4 Receptor Alpha Antagonists, dupilumab (Dupixent). Anti-IgE Antibody, omalizumab (Xolair) works by limiting the ability of allergens to trigger the release of histamine, leukotrienes, and other inflammatory mediators. It is FDA-approved for severe asthma and chronic idiopathic urticaria. Omalizumab inhibits IgE binding to the high-affinity IgE receptors on mast cells and basophils. By decreasing bound IgE, the activation and release of mediators in the allergic response is lessened. Serum-free IgE levels and the number of high-affinity IgE receptors are decreased. Long-term treatment in patients with allergic asthma showed a decrease in asthma exacerbations and corticosteroid usage. Dosing for asthma is based on body weight and pretreatment total IgE serum levels. Omalizumab has a Black Box Warning regarding anaphylaxis and bronchospasm. Anaphylaxis has occurred as early as after the first dose of omalizumab but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, observe patients closely for an appropriate period after omalizumab administration; observe patients for 2 hours after the first 3 injections and 30 minutes after subsequent injections. Healthcare providers administering omalizumab should be prepared to manage anaphylaxis which can be life- threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if such symptoms occur. Instruct patients to get emergency medical treatment right away if any symptoms of anaphylaxis develop and that symptoms can occur 24 hours or longer after drug administration. Advise the patient that this drug is not indicated for acute asthma attacks, acute bronchospasm, or status asthmaticus. ** Special Alert: FYI only Xolair (omalizumab) is not indicated for home administration. Interleukin-5 Receptor Antagonists. Reslizumab (Cinqair) is an interleukin-5 (IL-5) receptor antagonist used for asthma. IL-5 is a selective cytokine that is responsible for the differentiation and maturation of eosinophils in the bone marrow. By inhibiting IL-5, these drugs work by decreasing the production of eosinophils. These are used in asthma, but only when the asthma is severe and due to eosinophilia (eosinophilia asthma). They are not first-line but are add-on agents. In terms of negative effects, this class is typically well-tolerated. Headaches, however, are the most reported side effects. This class may cause transient rises in the CPK. Additionally, this class can lead to immunogenicity and anaphylaxis. Malignancies were observed during clinical trials with the ma jority being diagnosed within less than 6 months of drug exposure; neoplasms observed were diverse with no predominant histologic type. Reslizumab (Cinquair) has a Black Box Warning related to anaphylaxis. Interleukin-4 Receptor Alpha Antagonists. Dupilumab (Dupixent) is used for moderate to severe asthma. Interleukin-4 is an inflammatory cytokine. This drug inhibits IL4 cytokine-induced inflammatory responses; while also reducing other inflammatory mediators, such as IL-13. There are no contraindications. The side effects include primarily, injection site reactions. However, since it is a monoclonal IgG antibody and since IgG molecules are known to cross the placenta, exposure to the fetus during pregnancy may occur. However, as we know, uncontrolled asthma is associated with adverse events during pregnancy as well (increased risk of preeclampsia, preterm birth, low birth weight infants). Ongoing data collection to monitor pregnancy and infant outcomes following exposure to dupilumab. Hypersensitivity reactions, including urticaria and rash, can occur. If the signs/symptoms of a serious hypersensitivity reaction develop discontinue immediately. In rare cases, patients may present with serious systemic eosinophilia. Conjunctivitis and keratitis have been reported; educate patients to report new-onset or worsening eye symptoms to the health care provider. This class is also approved for atopic dermatitis and chronic sinusitis with nasal polyps. Asthma and Pregnancy During pregnancy, the patient is the primary source of oxygen and gas exchange for the fetus and optimal functioning during this cascade of events is essential. Up to 8% of pregnant patients suffer from asthma. Symptoms may improve during pregnancy, remain constant, or worsen. No matter the presentation or degree of disease--mild and chronic, or acute exacerbations--pharmacologic treatment for asthma in pregnancy is safer than untreated asthma. Uncontrolled asthma is associated with an increased rate of preeclampsia, preterm birth, fetal growth restriction, and perinatal mortality; however, healthy pregnancy and fetuses are attainable with adequate and consistent control.  Poorly controlled asthma or asthma exacerbations may have a greater fetal and pregnancy risk than what is associated with appropriately used asthma medications. Albuterol is the preferred short-acting beta-agonist when asthma treatment is needed during pregnancy. In 2019 the 2008 ACOG guidelines on the management of Asthma in Pregnancy were reaffirmed. Unlike the management in the non-pregnant patient, the guidelines did not include the addition of an inhaled steroid for mild, intermittent asthma (step 1). What is the appropriate rescue therapy for asthma during pregnancy? Inhaled short-acting β2-agonists are the rescue therapy of choice for asthma during pregnancy. Inhaled albuterol is the first-choice, short-acting β2-agonist for pregnant women, although other agents also may be appropriate. In general, patients should use up to two treatments of inhaled albuterol or nebulized albuterol for most symptoms; higher doses can be used for severe symptom exacerbation. To avoid maternal and fetal hypoxia, patients should be counseled to start rescue therapy. What controller therapy is used for asthma during pregnancy? For those with mild, intermittent asthma, no controller therapy is indicated. The use of inhaled corticosteroids is to decrease airway inflammation. Budesonide is the preferred inhaled corticosteroid for use during pregnancy. However, no data indicate that the other inhaled corticosteroid preparations are unsafe during pregnancy. Therefore, the use of any inhaled corticosteroids may be continued in patients whose asthma was well controlled by these agents before pregnancy. Asthma and Lactation Most asthma medications are considered safe during lactation. However, there is limited research overall and the provider must consult the most recent published data on a case-by-case basis. Albuterol and budesonide are considered safe due to low bioavailability and maternal serum levels. With these medications, passage to the breastmilk is minimal. Other asthma medications have known neonatal side effects. For example, Theophylline may cause hyperstimulation and disrupted sleep. Even so, breastfeeding is still indicated due to its overwhelming benefits. To decrease exposure, the client may breastfeed before medication administration, and abstain for 2-4 hours after. However, you will rarely, if ever see a client of childbearing age on theophylline due to its side effects and the benefits of the inhaled corticosteroids. Chronic Obstructive Pulmonary Disease The term chronic obstructive pulmonary disease includes the two conditions that involve airway obstruction chronic bronchitis and emphysema. Pharmacologic therapy is used to reduce symptoms, reduce the frequency and severity of exacerbations, improve exercise tolerance, and improve health status. There is no conclusive clinical trial evidence that any existing medications modify the long-term decline in lung function. Influenza and pneumococcal vaccinations decrease the incidence of lower respiratory tract infections. Pulmonary rehabilitation improves symptoms, quality of life, and physical and emotional participation in everyday activities. Vaccines Ensure that patients with COPD are informed of all indicated immunizations (influenza, pneumococcal pneumonia, Tdap, Zoster, and others) to reduce exacerbations and other poor outcomes. Bronchodilators for Chronic Obstructive Pulmonary Disease Bronchodilators are often given regularly to prevent or reduce symptoms. Toxicity is dose-related. The use of short-acting bronchodilators regularly is generally not recommended; unless you are treating occasional dyspnea. Most patients who experience more than occasional dyspnea should be prescribed long-acting bronchodilator therapy. Choose a long-acting beta-agonist, a long-acting muscarinic antagonist, or both. If patients have persistent symptoms while taking one long-acting bronchodilator, prescribe them both (or a combination agent containing these two long-acting bronchodilators). Anticholinergics are used for bronchodilation and to decrease secretions. Long-acting bronchodilators are used to keep the airways open long-term. Short-acting bronchodilators SABAs & SAMAs should not be used regularly but rather to relieve acute symptoms. Combining a SABA (albuterol) and a SAMA (ipratropium) is more effective than taking either agent alone. The only SAMA agent available is ipratropium bromide (Atrovent). It’s available both as an inhaler and as a nebulizer solution. When using ipratropium, it is important to emphasize the need for increased fluid intake. The main side effect is dryness of the mouth. Long-acting bronchodilators LABAs & LAMAs. Regular treatment with a long-acting bronchodilator (either a LABA and LAMA) is recommended in those with moderate to severe symptoms. LAMAs, such as tiotropium bromide (Spiriva) are typically taken daily to keep the airways open long-term and are more effective than the LABAs in preventing exacerbations. The adverse effects seen with LABAs are tachycardia, palpitations, QT prolongation, hypokalemia, tremors, cramping, headaches, insomnia, and an increase in serum glucose levels. There are also increased occurrences of angina and myocardial infarctions reported. LAMA's adverse effects include dry mouth, increases in intraocular pressure (use cautiously in glaucoma), urinary retention, and pharyngeal irritation. There may be a possible link between cardiovascular events and LAMAs (evidence is not clear). *Educate about the use of Inhalers - Assess - Have your patients bring in their medications to review the proper techniques.* Methylxanthines-theophylline (Theodur) This is a pill taken daily that is also a good bronchodilator. At low concentrations, it has anti-inflammatory properties too. That being said, it does appear to reduce exacerbations and is generally not recommended. It’s usually reserved as a last resort and mainly due to side effects as it is metabolized by cytochrome P450. The clearance of the drug declines with age which further increases the risk of toxicity. Dose-related adverse effects can include nausea, nervousness, headache, and insomnia. At the above therapeutic serum concentrations, vomiting, hypokalemia, hyperglycemia, tachycardia, cardiac arrhythmias, tremors, and seizures can occur. Combination Inhalers To make this convenient for patients (and sometimes less costly), many of these medicines have been combined in the following inhalers. Short-acting beta-2-agonist plus short-acting muscarinic antagonist. This combination is usually prescribed for use on an as-needed basis to open airways, e.g., albuterol/ ipratropium bromide (e.g., DuoNeb) Long-acting beta-2 agonist plus inhaled corticosteroid. As with asthma, these may also be prescribed for chronic obstructive pulmonary disease. Long-acting beta-2 agonist plus long-acting muscarinic antagonist. Combining these two long-acting bronchodilators seems to work well for some people with chronic obstructive pulmonary disease. These are all inhalers taken once or twice daily. Long-acting beta-2 agonist plus a muscarinic antagonist plus an inhaled corticosteroid. Some people may benefit from a combination of these three medicines. Anti-inflammatory Therapy in Chronic Obstructive Pulmonary Disease Inhaled corticosteroids (ICS) The inhaled corticosteroids may be used in patients with chronic obstructive pulmonary disease to decrease the inflammation; especially in those with high eosinophilia counts or in those that have an asthma component. Although commonly used as monotherapy for asthma control, inhaled corticosteroids (ICS) are not approved worldwide for use as monotherapy in COPD patients of any severity. Long-term ICS use is associated with safety concerns such as an increased risk of pneumonia, active tuberculosis, and osteoporosis (Yawn, Mintz, & Doherty, 2021). Combination agents containing inhaled corticosteroids along with long-acting beta-agonists are considered appropriate step-up therapy for patients experiencing chronic obstructive pulmonary disease exacerbations while taking long-acting bronchodilators. Oral Corticosteroids Oral Corticosteroids are used for treating acute exacerbations in hospitalized patients or during emergent situations, as they have been shown to reduce treatment failure, and the rate of relapse, and they can improve lung function and breathlessness. Remember, steroids have numerous side effects and in patients with severe chronic obstructive pulmonary disease, steroids can contribute to muscle weakness, decreased functionality, and even respiratory failure. Therefore, although they have a role in the management of acute exacerbations, they have no role in chronic daily treatment. If taken acutely (for less than 5-10 days) adverse effects are not as significant. If oral steroids are taken chronically and the patient experiences extreme physical stress (e.g., MVA and surgery), then they are at risk for death from the increased steroid demand to help the body cope. Phosphodiesterase-4 (PDE4) enzyme inhibitor Roflumilast (Daliresp) can be added in patients with chronic bronchitis who continue to have or maximal inhaled therapy. The primary action is to reduce inflammation by inhibiting the breakdown of intracellular cyclic AMP. This class ends up increasing the cAMP in the lungs and thus, decreases lung inflammation; which helps to slow the progression of COPD. It is not a bronchodilator and therefore, it is not to be used for the treatment of acute bronchospasms. This drug class’s anti-inflammatory effects include suppression of cytokine release and inhibition of lung infiltration by neutrophils and other leukocytes. Pulmonary remodeling and mucociliary malfunction are also attenuated, making the cough and excessive mucus production reduced and mucociliary clearance improved. These agents have many adverse effects including diarrhea, nausea, reduced appetite, weight loss, abdominal pain, sleep disturbances, and headaches. These seem to lessen over time. Monitor liver enzymes, as hepatotoxicity can occur. Neuropsychiatric effects (e.g., anxiety, depression, insomnia) have been reported with use; rarely, suicidal behavior/ideation and completed suicide were reported. Assess risk versus benefits before prescribing in patients with a history of depression with suicidal behavior/ideations and instruct patients/caregivers to report psychiatric symptoms ASAP. Other Drugs for COPD Antibiotics In older studies, the continuous use of antibiotics had no effect on the frequency of exacerbations. However, more recent studies have shown that regular use may reduce exacerbation rates (likely because some antibiotics act as anti- inflammatory agents as well). Azithromycin (Zithromax) can be used in non-smokers who continue to have exacerbations on maximally inhaled therapy. Mucolytics and the antioxidant agent Mucolytics and the antioxidant agent, n-acetyl-cysteine: In patients not receiving inhaled corticosteroids, regular treatment with mucolytics and N-acetyl-cysteine may reduce exacerbations and improve health status. Delivery of inhaled medications Inhalation has three advantages. The therapeutic effects are enhanced by delivering drugs directly to their site of action. Systemic effects with inhalers are minimized and there is a rapid relief of acute attacks. There are three types of inhalation devices: Metered-dose inhalers (MDIs), Dry Powdered Inhalers (DPIs), and Nebulizers. MDIs: Small, hand-held devices that delivered a measured dose of the drug with each actuation. This method requires hand-breath coordination. Even with optimal use, only ~10% of the drug reaches the lungs. Spacers should be encouraged with the MDI. These can increase the delivery of the aerosolized drug to the lungs while minimizing oral thrush that can occur from steroids (don't forget to have patients brush and clean out their mouth after inhaled steroid use). When using metered-dose inhalers, when two inhalations are needed, an interval of at least 1 minute should separate the first inhalation from the second. DPIs: These are used to deliver drugs in the form of a dry, micronized powder, directly to the lungs. DPIs do not require hand-breath coordination. DPIs deliver more drug to the lungs ~20%. Spacers aren’t needed. Nebulizers: A small machine is used to convert a drug solution into a mist that is much finer than those produced by inhalers, resulting in less drug deposition on the oropharynx and increased delivery to the lungs. Either through a face mask or through a mouthpiece, the nebulized mist can be absorbed. Hand-breath coordination is not a concern. BBW/Boxed Warning Review the drugs in this module that have a BBW. for example: LABAs Don't Forget the QT Review the drugs in this section that may affect the QT - for example, Salmeterol (crediblemeds.org). Unit C: Medications for Smoking Cessation Smoking Cessation Tobacco use is the leading cause of preventable disease and death in the United States. Cigarette smoking is a ma jor modifiable health risk factor. We should be asking our patients about nicotine use at every healthcare visit. Educate about the benefits of not smoking (prevention) and/or the benefits of quitting. Quitting is difficult. The average smoker attempts to quit about five times before succeeding. Offer pharmacotherapy for smoking cessation, when appropriate, as this increases the chance of success by 50 %. Pharmacology for Smoking Cessation Nicotine replacement therapy (NRTs) Nicotine replacement therapy is an effective aid in smoking cessation. The goal of nicotine replacement therapy is to relieve both the cravings and the urges for nicotine, as well as to reduce the withdrawal symptoms. There appears to be little difference overall in the effectiveness of different types of NRT on cessation. These drugs bind to nicotine receptors. NRTs are available as gum, transdermal patch, nasal spray, and lozenge. Precautions. In those with a history of cardiovascular disease, nicotine can increase heart rate and blood pressure or recent myocardial infarction. Despite this increased risk, NRT appears to be safe when given to smokers with cardiovascular disease; but please still be cautious. Discontinue use if irregular heartbeat or palpitations occur. Generally, avoid use during the immediate post-myocardial infarction period, in patients with serious arrhythmias, or with severe or worsening angina. GI disease: Use with caution in patients with esophagitis or active gastric or peptic ulcer disease, healing may be delayed. Caution: Renal and Hepatic impairment nicotine clearance is decreased in moderate to severe renal impairment and moderate to severe hepatic impairment; consider dose reduction. Formulations: Gum is an over-the-counter agent. Its adverse effects include hypersalivation, hiccups, dyspepsia, and mouth and jaw soreness (much like chewing gum). This might serve as an oral substitute for tobacco, it can delay/lessen weight gain, it has easy titration, and it can be used with other agents. The disadvantages are that it needs to be dosed frequently, it might be problematic for patients with significant dental work or jaw issues, and it might not be acceptable or desirable for some patients to chew gum in social situations. The lozenge is also an over-the-counter medicine. Adverse effects can include nausea, hiccups, cough, and insomnia. The advantages are similar to the gum and include that it can serve as an oral substitute for tobacco, it can delay/lessen weight gain, it has easy titration, and it can be used with other agents. The disadvantage is the need for frequent dosing which can compromise its adherence. It can lead to stomach upset, nausea, and loose stools. Transdermal Patch is another over-the-counter medicine. Its adverse effects include local skin reactions (erythema, pruritus, burning), headaches, and sleep disturbances (if the patch remains on at night). This is due to any nighttime nicotine absorption (unless the patient smokes at night); however, most should remove the patch at night. The advantages include its once-daily dosing, it can be used in combination with other agents as it delivers consistent nicotine levels over 24 hours. The disadvantage is that when used as monotherapy, it cannot be titrated to acutely manage withdrawal symptoms. It is not recommended for use by patients with dermatologic conditions (e.g., psoriasis, eczema, or atopic dermatitis). It works well with bupropion (Zyban). Nasal Spray requires a prescription. Adverse effects include nasal and/or throat irritation (hot, peppery, or burning sensation), rhinitis, tearing, sneezing, cough, and headache. Advantages include that it can be titrated to rapidly manage withdrawal symptoms and it can be used in combination with other agents. Disadvantages are the need for frequent dosing can compromise adherence, nasal administration might not be acceptable or desirable for some patients, it can cause nasal irritation, and it is not recommended for use by patients with chronic nasal disorders or severe reactive airway disease. Partial Nicotinic Agonist Varenicline: You may see the brand name Chantix however, the FDA recently placed the Brand name Chantix on the "Discontinued Drug Product List. The FDA published information about carcinogens in the Pfizer product Chantix. You may see the name Chantix in your resources - replace it with Varenicline the generic name. The generic name Varenicline is used. Varenicline is a partial neuronal nicotinic receptor agonist. It prevents nicotine stimulation of the dopaminergic system associated with nicotine addiction. Additionally, it binds to the 5-HT3 receptor (significance not determined) with moderate affinity. The stimulation to the dopamine activity is to a much smaller degree than nicotine does, but there is still a decrease in craving and withdrawal symptoms. Varenicline may enhance the adverse or even toxic effects of alcohol. Specifically, alcohol tolerance may be decreased, and the risk for neuropsychiatric adverse effects may be increased. These neuropsychiatric effects may include hostility, agitation, anger, depression, and suicidal feelings. Histamine receptor antagonists may increase the serum concentration of varenicline. Varenicline may enhance the adverse and toxic effects of nicotine. Varenicline may cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness; such as operating machinery and driving. There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking varenicline (Lexidrug). may also occur, as well as depression and an increased potential for suicide (discuss risks and plan with the patient). This drug may also lower the seizure threshold for patients with or without a history of seizures placing them at risk of having seizures. Caution in patients with renal impairment A 2011 meta-analysis suggested a potential increased risk of cardiovascular events (MI) with varenicline. It is hypothesized to be due to effects on nicotinic acetylcholine receptors which may impact cardiovascular function. Pregnancy: The efficacy of varenicline as an aid to smoking cessation in pregnancy has not been established. Lactation: Infants exposed via breast milk should be monitored for seizures or excessive vomiting. Antidepressant, Dopamine/Norepinephrine Re-uptake inhibitor Bupropion SR (Zyban): Bupropion has been licensed for the treatment of tobacco dependence. While originally developed as an antidepressant in the US, its efficacy in smoking cessation appears to be independent of its antidepressant effect. Bupropion comes in sustained-release tablets. Bupropion is an effective aid to smoking cessation. It has antidepressant effects and the primary mechanism of action is thought to be dopaminergic and/or noradrenergic. It is contraindicated with a history of a seizure disorder, history of anorexia or bulimia, and patients undergoing abrupt discontinuation of ethanol or sedatives, including benzodiazepines, barbiturates, or antiepileptic drugs. It should not be used with the MAO inhibitors (concurrently or within 14 days of discontinuing either bupropion or the MAO inhibitor). The adverse effects include suicidal thoughts, mood changes, hallucinations, panic, and depression. There is a Black Box Warning related to suicidal thoughts and behavior in children, adolescents, and young adults. Monitor closely for the emergence of suicidal thoughts. It can also cause restlessness, insomnia, anxiety, anorexia, and cognitive impairment. Combining the nicotine patch with bupropion (Zyban) has been shown to be quite effective. Combination treatment showed a trend toward higher abstinence rates at 6 years, which suggests the possibility of long-term benefits. But tell patients on this combination not to smoke at all. The patch will be slowly titrated down. Pregnancy: Bupropion and its metabolites cross the placenta. Data specific to cardiovascular malformations is inconsistent. Additional information is needed to show that bupropion is effective for the treatment of smoking cessation in pregnant patients. Weigh Risk vs Benefits. Lactation: Bupropion and its active metabolites are present in breast milk. Seizures and sleep disturbances have been reported in breastfeeding infants. Monitor daily for changes in sleep, feeding patterns and behavior, as well as growth and neurodevelopment (Lexidrug) BBW: Review the drugs in this module that have a BBW - for example, Antidepressants.