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.** Antihistamine...

**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 major 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 | **Intervention** | **Comment** | | Issue** | | | +=======================+=======================+=======================+ | Allergen | Educate 1st | Education on ways to | | avoidance/environment | | lessen exposure. | | al | | | | control | | | +-----------------------+-----------------------+-----------------------+ | Controller therapy | Intranasal | e.g., fluticasone | | (prevent symptoms by | corticosteroids (high | propionate (Flonase) | | decreasing | efficacy). | | | inflammatory | | e.g., montelukast | | mediators | Leukotriene modifiers | (Singulair) - There | | | | is some concern with | | | | the use of Singulair | | | | to manage Allergic | | | | Rhinitis because of  | | | | neuropsychiatric | | | | effects (risk vs | | | | benefits)  | +-----------------------+-----------------------+-----------------------+ | Reliever therapy | 2 nd generation oral | e.g., loratadine | | relieves acute | antihistamines  | (Claritin) | | symptoms by blocking | | | | the action of | Intranasal | e.g., azelastine | | histamine (a potent | antihistamines (great | (Astelin) | | inflammatory | for nasal symptom | | | mediator). | relief) | e.g., Olopatadine | | | | (Patanol) | | | Ocular antihistamines | | | | (work great for | | | | allergic | | | | conjunctivitis) | | +-----------------------+-----------------------+-----------------------+ | Immunotherapy- | For patients with | Usually requires a | | restores tolerance to | allergic rhinitis who | consult with a | | an allergen by | have an inadequate | specialist, delivered | | reducing its tendency | response to symptoms | via SQ or SL routes. | | to induce IgE | with standard | | | production. | therapies | | +-----------------------+-----------------------+-----------------------+   **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)